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WO2022101269A1 - Formulations and dosage regimen for oral delivery of adsorbents in the gut - Google Patents

Formulations and dosage regimen for oral delivery of adsorbents in the gut Download PDF

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Publication number
WO2022101269A1
WO2022101269A1 PCT/EP2021/081246 EP2021081246W WO2022101269A1 WO 2022101269 A1 WO2022101269 A1 WO 2022101269A1 EP 2021081246 W EP2021081246 W EP 2021081246W WO 2022101269 A1 WO2022101269 A1 WO 2022101269A1
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WO
WIPO (PCT)
Prior art keywords
formulation
adsorbent
administered
use according
methacrylic acid
Prior art date
Application number
PCT/EP2021/081246
Other languages
French (fr)
Inventor
Florence SEJOURNE
Sakina Sayah-Jeanne
Original Assignee
Da Volterra
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Filing date
Publication date
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Publication of WO2022101269A1 publication Critical patent/WO2022101269A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/44—Elemental carbon, e.g. charcoal, carbon black
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system

Definitions

  • the invention relates to a dosage regimen for administering a formulation for the delayed and controlled delivery of an adsorbent into the lower intestine of mammals.
  • the invention further relates to uses of this formulation, in particular to pharmaceutical uses.
  • antibiotics When antibiotics are administered, either orally or parenterally, a significant fraction is not absorbed and reaches the gastro-intestinal tract. When those antibiotic residues reach the colon, they provoke a serious disruption of the intestinal microbiota: several bacterial populations are decimated whereas others (sometimes pathogenic and resistant to antibiotics) proliferate; this new transient state of the microbiota is called dysbiosis. The intestinal microbiota balance is hence disturbed and may take weeks to months to fully recover, i.e. return to its original equilibrium. Other drugs are also known to disrupt the microbiota such as some anti-cancer chemotherapies.
  • a disrupted microbiota can no longer fulfil its physiological functions, leading to many adverse consequences such as altered immunity and immune response, colonization of the intestine by pathogenic bacteria such as Clostridioides difficile (formerly Clostridium difficile), altered metabolism with increased risk of inflammation, metabolic syndrome or obesity, and emergence and dissemination of antibiotic resistance.
  • pathogenic bacteria such as Clostridioides difficile (formerly Clostridium difficile)
  • the medical community has well acknowledged today that preserving the microbiota balance and diversity during antibiotic treatments could prevent serious medical conditions such as C. difficile infections and graft-versus-host-disease in patients undergoing a hematopoietic stem cell transplant. Maintaining a healthy microbiota could also prevent the selection and colonization of multi -resistant bacteria, and therefore limit the emergence and spread of antimicrobial resistance and prevent subsequent life-threatening infections. Finally, it is anticipated that maintaining the microbiota equilibrium is a driver for long-term health, and could favor better outcomes (such as increased survival) for cancer patients treated with anti-cancer therapies, and in particular those involving the immune system such as immune checkpoint inhibitors.
  • Formulations and methods were previously developed by the present Applicant to eliminate from the lower part of the gut pharmaceutical agents that can induce dysbiosis, and to thus protect the intestinal microbiota.
  • One approach to achieve this goal is to administer an adsorbent to eliminate such pharmaceutical agents, more specifically antibiotics, in the lower part of the intestine. More particularly, the adsorbent is released between the part of the intestine where such pharmaceutical agents are absorbed (e.g. duodenum and jejunum) and where their deleterious effect on the commensal bacteria occur (caecum and colon).
  • Such formulations are also advantageous in reducing or eliminating the side effects of other pharmaceutical agents or metabolites thereof in the late ileum, caecum and colon.
  • Such formulations are also advantageous in the treatment of disease states characterized by the accumulation of substances in the lower part of the gastrointestinal tract. More generally, such formulations can be used in the treatment of a condition, either pathological or not, which is caused, maintained and/or enhanced by the presence, or the presence in excess quantities, of certain substances in the lower part of the gastrointestinal tract, specifically in the late ileum, the caecum, or the colon.
  • the initial dosage regimen consisted in an administration of 5.1 g of the adsorbent, three times a day, which corresponded to 7.5 g of formulation.
  • a therapeutic agent for example, an antibiotic
  • the present invention provides such advantageous dosage regimen.
  • An advantageous dosage regimen of a formulation useful for treating a side effect of an intestinal microbiota dysbiosis-inducing pharmaceutical agent is provided.
  • a formulation comprising:
  • adsorbent is released from the formulation in a desired part of the intestine, preferably in the lower part of the intestine; for use in a method for treating a side effect of an intestinal microbiota dysbiosis-inducing pharmaceutical agent; wherein the formulation is administered to the subject at a dose from about 6.8 g to about 8.9 g of adsorbent three times per day.
  • the formulation is administered to the subject according to a dosage regimen comprising the following sequential steps:
  • the formulation is administered at a dose of about 8.2 g of absorbent three times per day over the first period of time, in step (1). In another particular embodiment, the formulation is administered at a dose of about 8.2 g of absorbent twice per day over the second period of time, in step (2). In another embodiment, the formulation is administered to the subject simultaneously to the treatment with said intestinal microbiota dysbiosis-inducing pharmaceutical agent.
  • the first period of time is a period of at least 1 day, in particular a period of at least 3 consecutive days, preferably a period of 3 or 4 consecutive days.
  • the second period of time begins the day following the last day of the first period.
  • the second period terminates at least at the end of the treatment with said pharmaceutical agent inducing an intestinal microbiota dysbiosis.
  • the second period terminates 1, 2, 3, 4 or 5 days, in particular 2 days after the end of the treatment with said pharmaceutical agent inducing an intestinal microbiota dysbiosis.
  • the adsorbent is activated charcoal.
  • the amount of adsorbent is comprised between 60% and 80%, preferably between 62% and 75%, preferably between 63% and 70% by weight of the total formulation.
  • the amount of adsorbent is about 68% by weight of the formulation.
  • the carrageenan is a kappa-carrageenan.
  • the amount of carrageenan is about 1% to about 20%, preferably from about 5% to about 20%, preferably from about 10% to about 17.5% by weight of the total formulation.
  • the amount of carrageenan is about 12% by weight of the formulation.
  • the external coating formed around the core is a pH-dependent enterosoluble polymer.
  • the pH-dependent enterosoluble polymer is selected in the group consisting of cellulose acetate trimellitate (CAT), cellulose acetate phthalate (CAP), anionic copolymers based on methylacrylate, methylmethacrylate and methacrylic acid, anionic copolymers based on methylacrylate, methylmethacrylate and methacrylic acid 7:3: 1, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), methacrylic acid and ethyl acrylate copolymers, methacrylic acid and ethyl acrylate copolymer, methacrylic acid and methyl methacrylate copolymers 1 : 1, methacrylic acid and methyl methacrylate copolymers (1 :2 ratio), polyvinyl acetate phthalate (PV
  • the external coating is a mixture of methyl methacrylate and methacrylic acid, and methacrylic acid and ethyl acrylate copolymer, in a ratio comprised between 99:1 and 80:20.
  • a further coating is provided between the core and the external pH-dependent layer, said further coating being in particular selected in the group consisting of:
  • - pH-dependent polymers in particular shellac type polymers, anionic copolymers based on methylacrylate, methylmethacrylate and methacrylic acid, Methacrylic acid and ethyl acrylate copolymer, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS),
  • - pH-independent water-soluble polymers such as PVP or high molecular weight cellulose polymers such as hydroxypropylmethylcellulose (HPMC) or hydroxypropylcellulose (HPC),
  • - pH-independent insoluble polymers such as ethylcellulose polymers or ethyl acrylate methyl methacrylate copolymer
  • the polymer layer that dissolves in a pH-independent manner comprises at least one cellulose-derivative selected from the group consisting of hydroxypropylcellulose or ethylcellulose.
  • the polymer layer that dissolves in a pH-independent manner is made of a 1 :9 to 9: 1, preferably 2:8 to 3:7, mixture of methacrylic acid and ethyl acrylate copolymer and ethyl acrylate methyl methacrylate copolymer.
  • the formulation is used in a method for treating a side effect of an intestinal microbiota dysbiosisinducing pharmaceutical agent.
  • the formulation is used in a method for eliminating or reducing the antibiotic-associated adverse effects of antibiotic agents, in particular for eliminating or reducing the emergence of antibiotic resistance or for eliminating or reducing diarrhea.
  • the antibiotic and the formulation are administered simultaneously by oral route.
  • the pharmaceutical agent is selected in the group consisting of antineoplastic agents, for example topoisomerase I inhibitors such as Irinotecan, anti-inflammatory compounds or inhibitor of interleukin- 1 such as diacerhein, pancrelipase, selective phosphodiesterase 4 inhibitor used for the treatment of Chronic obstructive Pulmonary Disease (COPD) such as roflumilast or cilomilast and compounds having anti-inflammatory and antimitotic activities such as colchicines, Irinotecan or a metabolite thereof, in particular SN-38.
  • COPD Chronic obstructive Pulmonary Disease
  • the invention relates to a formulation including a core comprising an adsorbent and carrageenan, layered with a coating such that the absorbent is released from the formulation in a desired part of the intestine, for use in the treatment of conditions in a subject in need thereof.
  • the formulation is administered to the subject with a dose of adsorbent of about 8.2 g three times per day.
  • the dosage regimen of the invention comprises, in this order:
  • a first step comprising the administration of a daily loading dose, over a first period of time;
  • the “daily loading dose” of the invention corresponds to the total dose of adsorbent administered in one day, in step (1).
  • the daily loading dose corresponds to a dose of adsorbent from about 6.8 g to about 8.9 g, administered three times per day.
  • the “daily maintenance dose” of the invention corresponds to the total dose of adsorbent administered in one day, in step (2).
  • the daily maintenance dose corresponds to a dose of adsorbent from about 6.8 g to about 8.9 g, administered twice per day.
  • the “daily loading dose” is higher than the “daily maintenance dose”.
  • the daily loading dose administered over the first period of time e.g. from about 20.4 g to about 26.7 g per day of adsorbent
  • the daily maintenance dose administered over the second period of time e.g. from about 13.6 g to about 17.8 g per day of adsorbent.
  • the formulation is administered according to a dosage regimen comprising the following sequential steps:
  • administering at least one dose of the formulation per day over a second period of time; wherein administration during the first period of time comprises at least one more dose administration per day than during the second period of time.
  • the formulation is administered according to a dosage regimen comprising the following sequential steps: (1) administering at least three doses of the formulation per day over a first period of time; and
  • administering at least two doses of the formulation per day over a second period of time; wherein administration during the first period of time comprises at least one more dose administered per day than during the second period of time.
  • the dosage regimen of the invention comprises the following sequential steps:
  • the formulation is administered at a dose of adsorbent of about 8.2 g three times per day in step (1). In another particular embodiment, the formulation is administered at a dose of adsorbent of about 8.2 g twice per day in step (2).
  • the formulation is administered to the subject according to a dosage regimen comprising the following sequential steps:
  • the present inventors have found that administering a daily loading dose as high as 6.8 to 8.9 g of adsorbent, three times per day for a prolonged period of time, increases the efficiency of the formulation, when compared to the administration of a dose of 5.1 g of adsorbent three times per day (see Example 5). Unexpectedly, the administration of such a high loading dose was shown to be safe and well tolerated. See Example 1 demonstrating that a strong increase in the dose of adsorbent (from 5.1 g three times a day to 8.2 g three times a day) did not increases the number of adverse events.
  • the present inventors surprisingly showed that such a high loading dose did not increase interference with the pharmacokinetics of concomitantly-given drugs such as antibiotics (see Example 2).
  • the present inventors provide a two-step dosage regimen comprising after step (1) of administering the daily loading dose as described above, a step (2) of administering a daily maintenance dose.
  • Patient compliance is improved since step (2) requires two administrations of a single dose of about 6.8 g to about 8.9 g of adsorbent, instead of step (1) which comprises three administrations of a single dose of about 6.8 g to about 8.9 g of adsorbent.
  • the number of administrations or intakes is reduced in step (2), thus reducing the total daily dose administered to the subject.
  • such dosage regimen comprising (1) the administration of a daily loading dose (with three intakes per day) as described above followed by (2) the administration of a daily maintenance dose (with two intakes per day) as described above does not drastically reduce the amount of adsorbent present and active in the lower intestinal tract, when compared to a dosage regimen comprising only the administration of the formulation with three intakes per day.
  • Such dosage regimen comprising (1) the administration of a daily loading dose (unit dose administered three times a day) followed by (2) the administration of a daily maintenance dose (unit dose administered twice a day) can be considered as bioequivalent to a dosage regimen using the same unit dose three times a day, as observed on pharmacokinetic parameters (see Example 3).
  • a dosing regimen comprising the administration of a loading dose (e.g. 8.2 g of adsorbent three times a day) during 4 days followed by the administration of a maintenance dose (e.g. 8.2 g of adsorbent twice a day) during 5 days, results in a higher exposure of the lower gastrointestinal tract to activated charcoal than with a dosing regimen comprising the administration of 5.1 g of adsorbent three times a day during 9 days (see Example 4).
  • a loading dose e.g. 8.2 g of adsorbent three times a day
  • a maintenance dose e.g. 8.2 g of adsorbent twice a day
  • step (1) is prior to step (2).
  • step (1) and step (2) do not overlap.
  • the first period of time and the second period of time each have a duration of at least 1 day. In a particular embodiment, the first period of time and the second period of time each have a duration of more than 1 day. In addition, the first period of time and the second period of time do not overlap. In the context of the present invention, the formulation is administered every day over the first period of time, and is administered every day over the second period of time.
  • the first period of time is immediately followed by the second period of time.
  • the second period of time begins the day following the last day of the first period.
  • the first period of time of step (1) ends on Day 4 (i.e. the daily loading dose is administered on Day 1, Day 2, Day 3 and Day 4)
  • the second period of time of step (2) starts on Day 5 (i.e. the daily maintenance dose is administered on Day 5, and the following days).
  • the duration of the second period of time, during which the daily maintenance dose is administered, is as long as needed, and may be adapted by the skilled person.
  • the first period of time is a period of at least 1 day such as a period of 1, 2, 3 or 4 consecutive days.
  • the first period of time is a period of at least 3 consecutive days such as a period of 3 or 4 consecutive days.
  • the first period of time is a period of at most 4 consecutive days.
  • the first period of time is a period of 3 or 4 consecutive days.
  • the daily loading dose of the formulation is administered on Day 1, on Day 2, on Day 3 and optionally on Day 4.
  • the formulation is administered at a dose from about 6.8 g to about 8.9 g of adsorbent, in particular of about 8.2 g of adsorbent, 3 times per day on Day 1, 3 times per day on Day 2, 3 times per day on Day 3 and optionally 3 times per day on Day 4.
  • the formulation is administered according to the dosage regimen of the invention, which comprises the following sequential steps:
  • the formulation is used for treating a side effect of an intestinal microbiota dysbiosis-inducing pharmaceutical agent.
  • the formulation according to the invention is administered to the subject simultaneously or concomitantly to the treatment with said pharmaceutical agent.
  • the maintenance dose is administered at least until the end of the treatment with the pharmaceutical agent inducing an intestinal microbiota dysbiosis (i.e. the second period of time in step (2) terminates at least at the end of the treatment of said pharmaceutical agent inducing an intestinal microbiota dysbiosis).
  • the maintenance dose is administered until 1, 2, 3, 4 or 5 days, in particular 2 days after the end of the treatment with said pharmaceutical agent inducing an intestinal microbiota dysbiosis (i.e. the second period of time in step (2) terminates 1, 2, 3, 4 or 5 days, in particular 2 days after the end of the treatment with said pharmaceutical agent inducing an intestinal microbiota dysbiosis).
  • the formulation is administered according to the dosage regimen of the invention, which comprises the following sequential steps:
  • the formulation administered in accordance with the dosage regimen of the invention is described, as follows. Methods of preparing the formulation, and methods of treatment using the formulation, are also disclosed below.
  • the formulation is suitable for oral administration of an adsorbent and delivery of said adsorbent in the lower part of the intestine, i.e. in the late ileum, the caecum and/or the colon.
  • the carrageenan and adsorbent are present as a mixture, which mixture being compressed or aggregated to form a core (the core being further herein referred to as a particle or pellet or core pellet).
  • the core is coated with one or more coating layers.
  • the coated pellets can be further inserted in capsules or pills.
  • the coated pellets can also be presented in sachets, sticks, bottles, drinking straws or any other convenient containers.
  • the formulations of the invention are solid dosage forms useful for delivering an adsorbent to a desired part of the intestine, advantageously in the late ileum, the caecum or the colon.
  • the external and/or intermediate coatings are in particular provided to minimize (preferably to totally prevent) the impact of the adsorbent on the normal absorption process of a therapeutic agent (for example, an antibiotic) by the host organism when said therapeutic agent is administered along with the formulation according to the invention.
  • a therapeutic agent for example, an antibiotic
  • the adsorbent thus formulated is prevented from non-specifically adsorbing material and compounds present in the gastrointestinal tract all the way to the terminal part of the small intestine. This results in the release of a non-saturated adsorbent, fully or almost fully efficient adsorbent in the specific part of the intestine where its action is needed.
  • Suitable adsorbents include activated charcoal, clays, including bentonite, kaolin, montmorrillonite, attapulgite, halloysite, laponite, and the like, silica, including colloidal silica, mesoporous silica, fumed silica, zeolites and the like, talc, cholesteramine and the like, polystyrene sulfonates and the like, mono and poly sulfonated resins, and any other resins of interest such as those used for bacteriologic testing.
  • activated charcoal clays, including bentonite, kaolin, montmorrillonite, attapulgite, halloysite, laponite, and the like
  • silica including colloidal silica, mesoporous silica, fumed silica, zeolites and the like, talc, cholesteramine and the like, polystyrene sulfonates and the like,
  • adsorbents such as activated charcoal USP (Merck, France or other sources), kaolin (VWR, France or other sources), attapulgite (Lavollee, France or other sources), bentonite (Acros Organics, France or other sources), Talc USP (VWR, France or other sources).
  • activated charcoal USP Merck, France or other sources
  • kaolin VWR, France or other sources
  • attapulgite Lavollee, France or other sources
  • bentonite Acros Organics, France or other sources
  • Talc USP VWR, France or other sources
  • the amount of adsorbent to produce a single dosage form may vary depending upon the host being treated and the overall capacity and selectivity of the adsorbent towards the antibiotic(s).
  • the amount of adsorbent to produce a single dosage form will generally be that amount of the compound which produces a desired effect.
  • the desired effect may be a therapeutic effect, for example a therapeutically significant decrease in the amount of the antibiotic, metabolite thereof, bacterial toxin, or other compound which causes adverse effects in the terminal parts of the gut, in particular in the colon, as compared to when the formulation is not administered.
  • the amount of the adsorbent will range from about 1 % to about 99 % by weight of the core, preferably from about 50 % to about 95 %, most preferably from about 65 % to about 95%, in particular from about 80 % to about 95 % by weight of the core.
  • the formulation comprises an absorbent from about 1% to about 85% by weight of the total formulation, preferably from about 50% to about 80%, most preferably from about 60% to about 80%, in particular from about 62% to about 75% by weight of the total formulation, even preferably from about 63% to 70% by weight of the total formulation.
  • the amount of absorbent represents about 68% in weight of the weight of the total formulation.
  • activated charcoal is used.
  • activated charcoal preferentially has a specific area above 1500 m 2 /g, preferentially above 1600 m 2 /g and best above 1800 m 2 /g.
  • Carrageenan is a naturally-occurring family of linear sulphated polysaccharides which are extracted from red seaweeds. It is a high molecular weight polysaccharide made up of repeating galactose and 3, 6-anhydrogalactose (3, 6- AG) units, both sulfated and non-sulfated. The units are joined by alternating alpha 1-3 and beta 1-4 glycosidic linkages.
  • Three basic types of carrageenan are available commercially, i.e. kappa, iota, and lambda carrageenan, which differ by the number and position of the ester sulfate groups on the galactose units.
  • the carrageenan can be selected from kappa, iota and lamba carrageenan, and mixtures thereof.
  • the adsorbent is mixed with kappa- carrageenan.
  • the mixture comprises activated charcoal and kappa- carrageenan.
  • the amount of carrageenan is between about 5% and about 25%, more preferably between about 10% and about 23%, by weight of the core (which comprises the mixture of the adsorbent with the carrageenan).
  • the amount of carrageenan is about 15% by weight of the core (mixture of the adsorbent with the carrageenan).
  • the core may contain 85% of an adsorbent and 15% of carrageenan, by weight of the core.
  • the formulation comprises carrageenan from about 1% to about 20% by weight of the total formulation, preferably from about 5% to about 20%, most preferably from about 10% to about 17.5% by weight of the total formulation.
  • the amount of carrageenan represents about 12% of the weight of the total formulation.
  • a mixture of activated charcoal and carrageenan is provided with the weight ratio indicated above.
  • the core (preferably in the form of a pellet) may be produced by any suitable means known to the skilled artisan.
  • granulation techniques are adapted to produce said core.
  • the core may be obtained by mixing the adsorbent and the carrageenan in the ratio indicated above, adding a solvent such as water to proceed to wet granulation, followed by extrusion spheronization or one-pot pelletization. Any remaining water can be removed, for example, by drying using conventional techniques the resulting pellets.
  • Other techniques known by those skilled in the art can be direct compression or fluid-bed wet granulation.
  • the core, or core pellet, of the invention has an average weight particle size in the range from 250 to 3000 pm, in particular 500 to 3000 pm.
  • the core size can be comprised between 500 and 1000 pm, or between 800 and 1600 pm.
  • the weight average particle size is determined by sieving different fractions in size, weighting the fractions and calculating the average particle size from the weights. The method is well known to a skilled person in the field of the invention.
  • the mixture of an adsorbent, in particular activated charcoal, and carrageenan has unexpectedly good formulation properties, including:
  • composition comprising a mixture of an adsorbent, preferably activated charcoal, with carrageenan (in particular kappa-carrageenan).
  • Said mixture may be the form of a particle (a compact mixture obtainable, for example, by an extrusion spheronization process), also termed a pellet, or core pellet, in the present application.
  • the core can further include conventional excipients such as antiadherents, binders, fillers, diluents, flavours, colours, lubricants, glidants, preservatives, sorbents and sweeteners.
  • excipients such as antiadherents, binders, fillers, diluents, flavours, colours, lubricants, glidants, preservatives, sorbents and sweeteners.
  • the amounts of such excipients can vary, but will typically be in the range of 0.1 to 10% by weight of the core. Of course, the person skilled in the art will adapt these amounts so that the added excipient does not negatively impact on the advantageous properties of the mixture of carrageenan with the adsorbent.
  • the core of the formulation (preferably in the form of a pellet) is covered with a coating such that the adsorbent is released from the formulation in a desired part of the intestine.
  • a coating such that the adsorbent is released from the formulation in a desired part of the intestine.
  • the core of the formulation can be covered or coated with a coating such that the adsorbent is released from the formulation in the lower part of the intestine, i.e. in the late ileum, caecum and/or colon.
  • a coating can be used which ensures that the formulation will not release the adsorbent until it is in the desired part of the intestine, namely in the late ileum, the caecum or the colon.
  • the coating may be selected from coatings which are pH-sensitive, redox-sensitive or sensitive to particular enzymes or bacteria.
  • Enteric coatings are well known to those skilled in the art (for example, reference is made to Chourasia MK and Jain SK, "Pharmaceutical approaches to colon targeted drug delivery systems", J Pharm PharmaceutSci 6(1): 33-66, 2003).
  • Preferred coating materials are those which are pH sensitive, i.e. pH-dependent enterosoluble polymers.
  • pH-dependent enterosoluble polymers As will be apparent in the following parts of the application, the choice of the pH- dependent enterosoluble polymer can be made by taking into account the pH profile of the gastro intestinal tract of the mammal who will be the recipient of the treatment (also herein referred to as the "host being treated").
  • the term "enterosoluble polymer” denotes a polymer that is stable and does not dissolve in the stomach and the upper parts of the gastrointestinal tract, but readily dissolves when it arrives at the desired part of the gut to release the active material contained therein.
  • the solubility of a pH- dependent enterosoluble polymer depends on the conditions of acidity or alkalinity found all along the gut.
  • the pH-dependent enterosoluble polymer can be selected among cellulose acetate trimellitate (CAT), cellulose acetate phthalate (CAP) such as Aquateric®, anionic copolymers based on methylacrylate, methylmethacrylate and methacrylic acid, anionic copolymers based on methylacrylate, methylmethacrylate and methacrylic acid 7:3: 1 such as Eudragit® FS30D, Hydroxypropyl methylcellulose phthalate (HPMCP), Hydroxypropylmethylcellulose acetate succinate (HPMCAS) LF, LG, MF, MG or HF Grades such as Aqoat®, methacrylic acid and ethyl acrylate copolymers such as Eudragit® L100-55, methacrylic acid and ethyl acrylate copolymer such as Eudragit® L30D-55, methacrylic acid and methyl methacrylate copolymers 1 : 1 such as Eudragit® a
  • the pH-dependent enterosoluble polymer used in the external layer dissolves at a pH equal to 6.0 and above. Even more preferably, it dissolves at a pH equal to 7.0 and above.
  • the polymer may in particular be selected in the group consisting of shellac such as SSB® Aquagold, anionic copolymers based on methyl acrylate, methyl methacrylate and methacrylic acid 7:3: 1 such as Eudragit® FS30D, methacrylic acid and methyl methacrylate copolymers 1 :2 such as Eudragit®S-100 and Eudragit® S12,5, HPMCAS such as Aqoat® AS-MF, MG or HF grades or hydroxypropyl methylcellulose phthalate (HPMCP) such as HP- 55 grade.
  • shellac such as SSB® Aquagold
  • anionic copolymers based on methyl acrylate, methyl methacrylate and methacrylic acid 7:3: 1 such as Eudragit® FS
  • Eudragit® copolymers are commercialized by Evonik. Their composition is known to the skilled artisan and may be found, in particular, in US 2008/0206350 (USSN 12/034,943).
  • the pH dependent enterosoluble polymer is selected first for its ability to resist acidic pH found into the upper part of the gastro-intestinal tract (GIT) of most mammals and second to fulfill requirement of delivering the active agent into the lower part of the intestine, i.e. preferentially the late ileum, the caecum or the colon.
  • the coating thickness can be adapted to finely tune the release of the adsorbent into the desired part of the intestine.
  • the enterosoluble polymer layer can represent from 10% to 40% of the weight of the total formulation. In a preferred embodiment, the amount of enterosoluble layer is at least 12% of the total weight of the formulation. In a preferred embodiment, the enterosoluble polymer layer represents from about 13% to about 35% by weight of the total formulation, even more preferably, from about 14% to about 20%. In a particular embodiment, the enterosoluble polymer layer is present in the formulation in an amount of about 16% by weight of the total formulation.
  • the type and/or amount of enterosoluble polymer which can be used to coat the core of the invention may be selected by using a Biodis dissolution tester (USP III release apparatus).
  • the pH-dependent enterosoluble coating can also include various combinations of different pH- dependent enterosoluble polymers. Those skilled in the art are able to select such mixtures of pH- dependent polymers taking into account their general knowledge in this field. For example, as mentioned in the above cited article of Chourasia and Jain, a combination of two methacrylic acid polymers such as Eudragit® LI 00-55 and Eudragit® SI 00 can be provided around the core of the invention.
  • the external coating contains Eudragit FS30D, or a mixture of Eudragit FS30D and Eudragit L30D-55 in a weight ratio comprised in particular between 99: 1 to 80:20 (FS30D:L30D-55).
  • the pH-dependent enterosoluble polymer is selected from
  • the formulation according the invention comprises:
  • a layer comprising an anionic copolymer based on methyl acrylate, methyl methacrylate and methacrylic acid 7:3: 1 , such as Eudragit® FS30D.
  • the formulation according the invention comprises:
  • the formulation according the invention comprises:
  • the external enterosoluble layer may be applied onto the core by any suitable means known to a person skilled in the art.
  • it can be applied using classical fluid bed technology where a water-based or solvent-based solution of coating is applied by spray-drying onto the core.
  • the formulation can be dried and a further coating can be applied. Multiple coatings can thus be applied successively using spray drying technology.
  • the colonic region has a high presence of microbial anaerobic organisms providing reducing conditions.
  • the external coating may suitably comprise a material which is redoxsensitive.
  • Such coatings may comprise azopolymers which can for example consist of a random copolymer of styrene and hydroxyethyl methacrylate, cross-linked with divinylazobenzene synthesized by free radical polymerization, the azopolymer being broken down enzymatically and specifically in the colon, or disulphide polymers (see PCT/BE91/00006).
  • amylose for example a coating mixture can be prepared by mixing amylose-butan-l-ol complex (glassy amylose) with Ethocel aqueous dispersion (Milojevic et awl., Proc. Int. Symp. Contr. Rel. Bioact. Mater. 20, 288, 1993), or a coating formulation comprising an inner coating of glassy amylose and an outer coating of cellulose or acrylic polymer material (Allwood et al GB 9025373.3), pectin, a polysaccharide which is degraded by colonic bacterial enzymes (Ashford et al., Br Pharm.
  • a coating mixture can be prepared by mixing amylose-butan-l-ol complex (glassy amylose) with Ethocel aqueous dispersion (Milojevic et awl., Proc. Int. Symp. Contr. Rel. Bioact. Mater. 20, 288, 1993), or a coating
  • modified guar gum such as borax modified guar gum (Rubenstein and Gliko-Kabir, S.T.P. Pharma Sciences 5, 41-46, 1995), P-cyclodextrin (Siekeer al., Eu. J. Pharm. Biopharm.
  • saccharide containing polymers by which a polymeric construct is included comprising a synthetic oligosaccharide-containing biopolymer including methacrylic polymers covalently coupled to oligosaccharides such as cellobiose, lactulose, raffinose, and stachyose, or saccharide-containing natural polymers including modified mucopolysaccharides such as cross-linked chondroitin sulfate; methacrylate-galactomannan (Lehmann and Dreher, Proc. Int. Symp. Control. Rel. Bioact. Mater.18, 331, 1991) and pHsensitive hydrogels (Kopecek et al., J. Control.Rel. 19, 121, 1992).
  • Resistant starches e.g. glassy amylose, are starches that are not broken down by the enzymes in the upper gastrointestinal tract but are degraded by enzymes in the colon.
  • the formulation according to the invention comprises:
  • an absorbent preferably activated charcoal
  • carrageenan preferably kappa carrageenan
  • adsorbent is released from the formulation in a desired part of the intestine, preferably in the lower part of the intestine, in particular a layer of a pH-dependent enterosoluble polymer;
  • the absorbent is present in an amount from about 60% to about 80% by weight of the total formulation, preferably from about 62% to about 75% by weight of the total formulation, preferably from about 63% to 70% by weight of the total formulation, preferably about 68% by weight of the total formulation;
  • carrageenan is present in an amount from about 1% to about 20%, preferably from about 5% to about 20%, preferably from about 10% to about 17.5% by weight of the total formulation, preferably about 12% by weight of the total formulation;
  • enterosoluble polymer is present in an amount from about 10% to about 20% by weight of the total formulation, preferably from about 12% to about 18% by weight of the total formulation, preferably about 16% by weight of the total formulation.
  • the formulation described above comprises at least one further coating provided between the core and the external enteric coating.
  • This further layer(s) also referred to as “intermediate coating” is provided to further delay the release of the adsorbent when necessary.
  • the intermediate coating is in particular provided to minimize (preferably to totally prevent) the impact of the adsorbent on the normal absorption process of a therapeutic agent (for example, an antibiotic) by the host organism when said therapeutic agent is administered, for example orally, along with the formulation according to the invention.
  • a therapeutic agent for example, an antibiotic
  • the intermediate coating is provided onto the core of the invention, and a further coating is applied with a pH-dependent enterosoluble polymer, such as EudragitTM FS30D (as explained above) or a mixture Eudragit® FS30D and Eudragit® L30D-55, in a weight ratio comprised between 99: 1 and 80:20.
  • a pH-dependent enterosoluble polymer such as EudragitTM FS30D (as explained above) or a mixture Eudragit® FS30D and Eudragit® L30D-55, in a weight ratio comprised between 99: 1 and 80:20.
  • the pH-dependent enterosoluble polymer protects the core from the acidic environment found in the upper part of the gastro-intestinal tract. Once the pH-dependent polymer is dissolved, further delayed release of the adsorbent can be obtained due to the intermediate coating.
  • the intermediate coating can contain pH-dependent or pH-independent polymers.
  • examples include those described above in "external enterosoluble layer” part, and in particular shellac type polymers such as SSB® Aquagold, anionic copolymers based on methyl acrylate, methyl methacrylate and methacrylic acid 7:3: 1 such as Eudragit® FS30D, methacrylic acid and ethyl acrylate copolymer such as Eudragit® L30D-55, HPMCAS such as Aqoat AS-MF, MG or HF grades or hydroxypropyl methylcellulose phthalate (HPMCP) such as HP-55 grade.
  • shellac type polymers such as SSB® Aquagold, anionic copolymers based on methyl acrylate, methyl methacrylate and methacrylic acid 7:3: 1 such as Eudragit® FS30D, methacrylic acid and ethyl acrylate copolymer such as Eudragit® L30D-55, HPMCAS such as Aqoat AS-MF,
  • the intermediate coating can be a mixture of pH-dependent polymers such as Eudragit® FS30D and Eudragit® L30D-55, in a ratio comprised between 99: 1 and 80:20 pH-independent polymers can be selected among slowly water-soluble polymers and water insoluble polymers.
  • pH-independent water-soluble polymers include polyvinylpyrolidone (PVP) and high molecular weight cellulose polymers such as hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose (HPC).
  • pH-independent insoluble polymers include ethylcellulose polymers and ethyl acrylate methyl methacrylate copolymer (such as Eudragit® NE30D).
  • the intermediate coating contains a mixture of polymers.
  • the mixture of polymers comprises polymers of the same type.
  • the mixture can comprise a pH-dependent polymer with another pH-dependent polymer, a pH-independent soluble polymer with another pH-independent soluble polymer, or a pH- independent insoluble polymer with another pH-independent insoluble polymer.
  • the mixture of polymers comprises polymers of different types.
  • the mixture can comprise a pH-dependent polymer with a pH-independent polymer (either water soluble or insoluble), a pH-independent soluble polymer with a pH-independent insoluble polymer, or a pH- dependent polymer with a pH-independent soluble polymer and a pH-independent insoluble polymer.
  • the intermediate coating can comprise the mixture of a pH-dependent polymer with a pH-independent polymer, such as a mixture of Eudragit® L30D55 with Eudragit® NE30D (for example, in a weight ratio between about 1 :9 and about 9:1, in particular between about 2:8 and about 3:7).
  • the core according to the invention can be coated with a single pH-dependent polymer, such as an anionic copolymer based on methylacrylate, methylmethacrylate and methacrylic acid (such as a tercopolymer of methylacrylate, methylmethacrylate and methacrylic acid 7:3: 1, for example Eudragit® FS30D).
  • a single pH-dependent polymer such as an anionic copolymer based on methylacrylate, methylmethacrylate and methacrylic acid (such as a tercopolymer of methylacrylate, methylmethacrylate and methacrylic acid 7:3: 1, for example Eudragit® FS30D).
  • the same type of formulations can be administered after parenteral administration of the antibiotic, where residual antibiotic is found in the gastrointestinal tract after bile or intestinal membrane excretion. In this case, there is no risk of interaction of the adsorbent with the normal absorption of the antibiotic.
  • the intermediate coating is selected in order to achieve a delay of about 20 minutes to about 2 hours in the release of the adsorbent, as measured by in vitro testing such as with a BioDis dissolution tester (USP III release apparatus).
  • USP III release apparatus a BioDis dissolution tester
  • the dosage form is successively placed into glass tubes filled with approximately 200mL of dissolution media with a composition yielding pH, buffer capacity and osmolarity corresponding to the different sections of the gastrointestinal tract, such as described by Jantratid et al. in Pharm.Res. 25 (2008), 1663-1676.
  • This allows a good simulation of in vivo release before testing into mammals. pH, fed vs fasted state, and various other physiological conditions can be tested.
  • BioDis system it is possible for those skilled in the art to finely tune the formulation to achieve a desired pre-determined delayed release.
  • a particular embodiment of the invention relates to a formulation comprising:
  • the invention relates to a formulation comprising:
  • carrageenan preferably kappa-carrageenan
  • an intermediate coating selected in the group consisting of HPMC, ethylcellulose and a mixture of methacrylic acid and ethyl acrylate copolymer such as Eudragit® L30D-55 and ethyl acrylate methyl methacrylate copolymer such as Eudragit® NE30D (for example in a mixture weight ratio of 1 :9 to 9:1, preferably of 2:8 to 3:7), and
  • the formulation of the invention comprises: - a core containing a composition comprising activated charcoal mixed with carrageenan (preferably kappa-carrageenan),
  • ethylcellulose intermediate coating preferably a 1.5-2.5% ethylcellulose coating, most preferably a 2% ethylcellulose intermediate coating (w/w of the total formulation), and
  • the formulation of the invention comprises:
  • intermediate coating made of a 2:8 to 3:7 mixture of methacrylic acid and ethyl acrylate copolymer (such as Eudragit® L30D-55) and ethyl acrylate methyl methacrylate copolymer (such as Eudragit® NE30D), and
  • the formulation of the invention comprises:
  • ethylcellulose intermediate coating preferably a 1.5-2.5% ethylcellulose coating, most preferably a 2% ethylcellulose intermediate coating (w/w of the total formulation), and
  • the formulation of the invention comprises:
  • the formulation can further include conventional excipients such as anti adherents, binders, plasticizers, emulsifiers, fillers, diluents, flavours, colours, lubricants, glidants, preservatives, sorbents and sweeteners.
  • excipients such as anti adherents, binders, plasticizers, emulsifiers, fillers, diluents, flavours, colours, lubricants, glidants, preservatives, sorbents and sweeteners.
  • the amounts of such excipients can vary, but will typically be in the range of 0.1 to 10% by weight of the formulation. In a particular embodiment, the amounts of such excipients will range from about 3% to about 5% by weight of the formulation.
  • the present invention provides pharmaceutically acceptable dosage forms which comprise a therapeutically-effective amount of one or more of the adsorbents described above, formulated together with carrageenan and one or more pharmaceutically acceptable additives or excipients.
  • the dosage forms of the invention are specially formulated for administration in solid form.
  • therapeutically-effective amount means that amount of one or more of the compounds described above, material, or formulation comprising one or more of the compounds described above which is effective for producing some desired therapeutic effect.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, formulations, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically-acceptable additive or excipient means a pharmaceutically-acceptable material, formulation or vehicle, such as a solid filler, diluent, excipient involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • a pharmaceutically-acceptable material, formulation or vehicle such as a solid filler, diluent, excipient involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • Each additive must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • Dosage forms that contain multiple units can be preferred in order to improve the in vivo dispersion of the adsorbent, such as activated charcoal.
  • Such core pellets present more practical flexibility, because coating can be directly achieved on their surface, for example, using a fluid bed system.
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, plasticizers, emulsifier, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the dosage form.
  • Dosage forms of the present invention are suitable for oral administration.
  • the formulations can conveniently be presented in unit dosage form and can be prepared by any methods well known in the art of pharmacy.
  • Dosage forms of the invention suitable for oral administration can be in the form of capsules, tablets, sachets, sticks, drinking straws each containing a predetermined amount of the adsorbent formulation.
  • a tablet can be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets can be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose or polysaccharide), surface- activated or dispersing agent.
  • Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent such as water.
  • the solid dosage forms described above can be combined in a final dosage form comprising single or multiple units.
  • multiple units include multilayer tablets, capsules containing tablets, pellets, granules, etc.
  • the core of the invention is coated with a layer of an external coating, and optionally an intermediate coating as provided above.
  • the coated formulation (coated with an external enteric coating, and comprising or not an intermediate coating) can further be combined in a unit drug dosage form, such as a tablet, capsule, and the like, which can be further coated with a coating material for effective delayed-release which include, but are not limited to, cellulosic polymers such as hydroxypropyl cellulose, hydroxy ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, methylcellulose, carboxymethylcellulose sodium, copolymers such as polyvinyl pyrrolidone; hydroxypropyl methyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate and acrylic acid polymers and copolymers, preferably formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate, and other methacrylic resins that are commercially
  • the preferred coating weights for particular coating materials can be readily determined by those skilled in the art by evaluating individual release profiles for tablets, pellets and granules prepared with different quantities of various coating materials.
  • the coating formulation can include conventional additives, such as plasticizers, emulsifiers, pigments, colorants, stabilizing agents, glidants, etc.
  • a plasticizer is normally present to reduce the fragility of the coating, and will generally represent about 5 wt. % to 50 wt. % relative to the dry weight of the polymer.
  • typical plasticizers include polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, triethyl acetyl citrate, castor oil and acetylated monoglycerides.
  • a stabilizing agent is preferably used to stabilize particles in the dispersion.
  • Typical stabilizing agents are nonionic emulsifiers such as sorbitan esters, polysorbates and polyvinylpyrrolidone. Glidants are recommended to reduce sticking effects during film formation and drying, and will generally represent approximately 0 wt. % to 100 wt. % of the polymer weight in the coating solution.
  • One effective glidant is talc.
  • Other glidants such as magnesium stearate and glycerol monostearates can also be used.
  • Pigments such as titanium dioxide can also be used.
  • Small quantities of an anti-foaming agent such as a silicone (e.g., simethicone), can also be added to the coating formulation.
  • These dosage forms can be administered to humans and animals for therapy by any suitable route of administration.
  • the formulation is presented in a unit dosage form comprising from about 6.8 g to about 8.9 g of adsorbent.
  • the formulation is presented in a unit dosage form comprising about 8.2 g of adsorbent.
  • the formulation is presented in a unit dosage form comprising:
  • an absorbent as described above in an amount from about 60% to about 80% by weight of the total formulation, preferably from about 62% to 75% by weight of the total formulation, preferably from about 63% to 70% by weight of the total formulation, preferably about 68% by weight of the total formulation;
  • an enterosoluble polymer as described above in an amount from about 10% to about 20% by weight of the total formulation, preferably about 12% to about 18% by weight of the total formulation, preferably about 16% by weight of the total formulation.
  • the effective daily dose of the adsorbent is administered as two or three sub-doses administered separately at appropriate intervals throughout the day, preferably in unit dosage forms.
  • the effective daily dose of the formulation is administered as two or three sub- doses of about 6.8 g to about 8.9 g of adsorbent, preferably about 8.2 g of adsorbent, administered separately at appropriate intervals throughout the day, preferably in unit dosage forms.
  • the effective daily dose of the adsorbent is administered as two or three sub-doses administered separately before each meal throughout the day, preferably in unit dosage forms.
  • the effective daily dose of the formulation is administered as two or three sub-doses of about 6.8 g to about 8.9 g of adsorbent, preferably about 8.2 g of adsorbent, administered separately before breakfast, before lunch and/or before dinner throughout the day, preferably in unit dosage forms.
  • the formulation according to the invention may be used in a method for eliminating the adverse effects of therapeutic agents, in particular, but not only, of antibiotics.
  • the formulation of the invention and the therapeutic agent are administered simultaneously or concomitantly.
  • the amount of adsorbent may be adapted to the amount of therapeutic agent administered to the subject in need thereof.
  • the weight ratio between the adsorbent and the antibiotic agent may be above 1, more preferably above 2, even more preferably above 3, and most preferably above 9.
  • the formulation comprising the adsorbent is administered before the administration of the antibiotics that are prescribed concomitantly or simultaneously to the patient.
  • the administration of the formulation according to the invention to an animal is preferably carried out by including it in the animal's food. This is preferably accomplished by preparing an appropriate feed premix containing the formulations according to the invention in an effective amount and incorporating the premix into the complete ration. Accordingly, the present invention also relates to an animal food premix comprising food and formulations as described above. The invention also relates to an animal food ration comprising the formulations according to the invention.
  • Therapeutic applications The formulation administered according to the dosage regimen of the invention can be used to treat conditions and disorders for which intestinal delivery of adsorbents is suitable.
  • the invention also relates to a formulation administered according to the dosage regimen of the invention, for use as a medicament.
  • treatment denotes any treatment which is designed to cure, alleviate, remove or lessen the symptoms of, or prevent or reduce the possibility of contracting, any disorder or malfunction of the human or animal body induced by a microbiota dysbiosisinducing pharmaceutical agent.
  • the subject receiving this treatment is any animal in need thereof, including primates, in particular humans, and other mammals such as equines, cattle, swine and sheep; poultry and pets in general may also be recipients of such a treatment.
  • the subject receiving the treatment is a human, in particular an adult. In a preferred embodiment, the subject is 16 years old or more.
  • the formulation administered according to the dosage regimen of the invention is for use in a method for the treatment of a side effect of a dysbiosis-inducing pharmaceutical agent.
  • the formulation comprises:
  • the adsorbent is released from the formulation in a desired part of the intestine, preferably in the lower part of the intestine; and is for use in a method for treating a side effect of an intestinal microbiota dysbiosis-inducing pharmaceutical agent; wherein the formulation is administered at a dose from about 6.8 g to about 8.9 g of adsorbent three times per day.
  • the formulation can be administered to adsorb and therefore remove from the intestine any drug, metabolite or prodrug thereof, or toxin. This may be done after oral or parenteral administration of an active drug, in order to prevent the drug, metabolite or prodrug thereof to reach the lower intestine and/or colon, which could be useful for limiting or decreasing adverse effects in the subject being treated.
  • the present invention relates to the formulation administered according to the dosage regimen described above, for use in a method for eliminating drugs in the intestinal tract before they reach the colon or as they reach the colon, preferably before they reach the caecum or as they reach the caecum and proximal colon.
  • the invention further provides a method for eliminating drugs in the intestinal tract before they reach the colon or as they reach the colon, preferably before they reach the caecum or as they reach the caecum and proximal colon, comprising administering to a patient in need thereof a formulation according to the dosage regimen of the invention.
  • the invention provides a formulation administered according to the dosage regimen described above, for use in a method for reducing or eliminating the side effect(s) of a drug in the intestinal tract, wherein the formulation eliminates the drug before it reaches the colon or as it reaches the colon, preferably before it reaches the caecum or as it reaches the caecum and proximal colon.
  • the dysbiosis-inducing pharmaceutical agent may be an antibiotic, and the formulation administered according to the dosage regimen of the invention, being used to treat a side effect of such an antibiotic.
  • side effects include, without limitation, the development of antibiotic resistance, the development of an infection by Clostridioides difficile or other pathogenic bacteria, a decrease in the efficacy of an anticancer agent in a subject in need thereof, a risk of developing or aggravating graft-versus-host disease in a subject or the risk of a decreased overall survival in a subject.
  • the adsorbent will adsorb residual antibiotics, and the formulation is administered according to the dosage regimen of the invention to a patient who has been, is being, or will be administered an antibiotic. Any antibiotic that can be adsorbed into/onto the adsorbent can be partially or totally inactivated and has no antibiotic activity once fully adsorbed.
  • antibiotic designates any compound that kills or inhibits the growth of microorganisms such as bacteria, fungi, or protozoans, in particular bacteria.
  • Antibiotics that may be eliminated thanks to the invention include but are not limited to:
  • - beta-lactams including:
  • penicillins such as penicillin G, penicillin V, ampicillin, amoxicillin, bacampicillin, carbenicillin, carbenicillin indanyl, ticarcillin, azlocillin, mezlocillin, piperacillin, and the like
  • penicillinase-resistant penicillins such as methicillin, oxacillin, cioxacillin, dicloxacillin, nafcillin and the like
  • cephalosporins such as: first generation cephalosporins (such as cefadroxil, cephalexin, cephradine, cephalothin, cephapirin, cefazolin, and the like) ; second generation cephalosporins (such as cefaclor, cefamandole, cefonicid, cefoxitin, cefotetan, cefuroxime, cefuroxime axetil, cefinetazole, cefprozil, loracarbef, ceforanide, and the like) ; third generation cephalosporins (such as cefepime, cefoperazone, cefotaxime, ceftizoxime, ceftriaxone, ceftazidime, cefixime, cefpodoxime, ceftibuten, and the like) ; fourth generation cephalosporins (such as cefclidine, cefepime, cefozopran, cefpirome
  • carbapenems such as imipenem, meropenem, ertapenem, doripenem and the like
  • quinolones such as nalidixic acid
  • fluoroquinolones such as cinoxacin, ciprofloxacin, moxifloxacin, levofloxacin, ofloxacin, gatifloxacin, gelifloxacin, norfloxacin and the like
  • - sulfonamides e.g., sulfanilamide, sulfadiazine, sulfamethoxazole, sulfisoxazole, sulfacetamide, sulfamethoxydiazine and the like
  • - aminoglycosides e.g., streptomycin, gentamicin, tobramycin, amikacin, netilmicin, kanamycin, neomycins B, C and E), spectinomycin, puromycin, gentamicin, and the like
  • tetracyclines such as tetracycline, chlortetracycline, oxytetracycline, methacycline, doxycycline, minocycline, tigecycline, eravacycline and the like
  • - macrolides such as erythromycin, azithromycin, clarithromycin, fidaxomicin, telithromycin, josamycin, oleandomycin, spiramycin, tylosin, roxithromycin, cethromycin, solithromycin, and the like
  • glycopeptides such as vancomycin, oritavancin, telavancin, teicoplanin, dalbavancin, ramoplanin and the like
  • oxazolidinones such as linezolid, posizolid, tedizolid, radezolid, cycloserine and the like
  • phenicols such as chloramphenicol, tiamphenicol and the like
  • polymyxins such as polymyxin A, B, C, D, El(colistin A), or E2, colistin B or C, and the like
  • diaminopyrimidines such as trimethoprim, often used in conjunction with sulfamethoxazole, pyrazinamide, and the like
  • sulfones such as dapsone, sulfoxone sodium, and the like
  • rifamycins such as rifampicin, rifabutin, rifapentine, rifalasil, rimamixin, and the like
  • antibiotic also covers combinations of antibiotics.
  • the invention thus also relates to the formulation administered according to the dosage regimen of the invention as described above, for use in a method for eliminating residual antibiotics in the intestinal tract, preferably before they reach the colon or as they reach the colon. More preferably, the formulation is used in a method for eliminating residual antibiotics in the intestinal tract, preferably before they reach the caecum or as they reach the caecum and proximal colon.
  • the adsorbent is preferably delivered between the part of the intestine where the antibiotics are absorbed (duodenum and jejunum) and where their deleterious effect on the commensal bacteria (composing the gut microbiota) occur (caecum and colon).
  • the invention further relates to a method for eliminating residual antibiotics in the intestinal tract, preferably before they reach the colon or as they reach the colon, most preferably before they reach the caecum or as they reach the caecum and proximal colon comprising administering the formulation to a subject in need thereof according to the dosage regimen of the invention.
  • the invention further relates to the formulation administered according to the dosage described above, for use in a method for eliminating the adverse effects of antibiotic agents in the intestinal tract, in particular for eliminating the development of antibiotic resistance, antibiotic treatment- associated development of C. difficile (or other pathogenic bacteria), antibiotic treatment- associated fungal infections or antibiotic treatment-associated diarrhea.
  • the invention further relates to a method for eliminating the adverse effects of antibiotic agents in the intestinal tract, comprising administering the formulation to a subject in need thereof according to the dosage regimen of the invention.
  • the present invention provides a kit, comprising an antibiotic, and a formulation as described above.
  • the kit may be a kit-of-parts, for simultaneous, separate or sequential use in the treatment of an infection against which the antibiotic is suitable.
  • the present invention relates to a formulation administered according to the dosage regimen of the invention, for use in a method for improving the therapeutic efficacy of an anticancer agent, such as an immuno-oncology agent.
  • the invention also relates to a formulation administered according to the dosage regimen of the invention, for use in a method for treating or preventing cancer, in combination with an anticancer agent, such as an immuno-oncology agent.
  • the invention further relates to a formulation administered according to the dosage regimen of the invention, for use in a method for treating or preventing cancer, in combination with an anticancer agent, such as an immuno-oncology agent, thereby improving the efficacy of said anticancer agent.
  • the invention also relates to a formulation administered according to the dosage regimen of the invention, for use in a method for treating or preventing cancer, in combination with an anticancer agent, such as an immuno-oncology agent, thereby preserving the efficacy of said anticancer agent.
  • the invention further relates to a formulation administered according to the dosage regimen of the invention, for use in a method for treating or preventing cancer, in combination with an anticancer agent, such as an immuno-oncology agent, thereby potentiating the efficacy of said anticancer agent.
  • the formulation may be administered at any point in the therapy, e.g. before, during and/or after the anticancer agent, such as an immuno-oncology agent.
  • the formulation may be administered as soon as the patient is diagnosed with a malignancy, even if the intent to administer an anticancer agent only constitutes a remote possibility.
  • Anticancer agents also sometimes referred to as antineoplastic agents, are substances that act against cancer in a mammal, such as a human being.
  • the term “anticancer agent” includes, without limitation, chemicals and biological agents that affect directly a cancer cell, or indirectly such as by affecting the vascularisation of the cancer cell.
  • anticancer agents include, without limitation, chemotherapeutic molecules such as cytostatic agents, cytotoxic agents and anti-angiogenesis agents, anticancer antibodies targeting cancer cells, anticancer peptides and anticancer viruses.
  • chemotherapeutic molecules such as cytostatic agents, cytotoxic agents and anti-angiogenesis agents
  • anticancer antibodies targeting cancer cells include, without limitation:
  • - tubulin poisons e.g. docetaxel, paclitaxel
  • platinum compounds e.g. cisplatin, carboplatin, oxaliplatin,
  • DNA intercalating agents for example anthracyclines
  • topoisomerase inhibitors such as etoposide
  • - antimetabolites e.g. methotrexate, cytarabine (ara-C), gemcitabine, 5-Fluorouracil,
  • - alkylators e.g. mechlorethamine, melphalan, carmustine, ifosfamide, or cyclophosphamide
  • - targeted agents such as enzyme inhibitor, in particular kinase inhibitors, e.g. erlotinib, sorafenib, imatinib, or proteasome inhibitors such as bortezomib, Carfizomib, Ixazomib,
  • a growth factor receptor such as trastuzumab, bevacizumab and cetuximab
  • Anthracyclines include, without limitation, doxorubicin and daunorubicin.
  • Topoisomerase inhibitors further include, without limitation, camptothecin, irinotecan, topotecan, and derivatives thereof.
  • Antimetabolites further include, without limitation, capecitabine and pemetrexed.
  • the anticancer agent is an immuno-oncology agent.
  • Immuno-oncology agents also known as immuno-targeted agents
  • An immuno-oncology may more particularly act by modulating the action of immune cells.
  • immuno-oncology agents comprise agents that modulate or inhibit immune checkpoints such as 2B4, 4-1BB (CD137), AaR, B7-H3, B7-H4, BAFFR, BTLA, CD2, CD7, CD27, CD28, CD30, CD38, CD40, CD80, CD83 ligand, CD86, CD160, CD200, CDS, CEACAM, CTLA-4, GITR, HVEM, ICAM-1, KIR, LAG-3, LAIR1, LFA-1 (CD 11 a/CD 18), LIGHT, NKG2A, NKG2C, NKp80, 0X40, PD-1, PD-L1, PD-L2, SLAMF7, TGFRp, TIGIT, Tim3 and VISTA.
  • immune checkpoints such as 2B4, 4-1BB (CD137), AaR, B7-H3, B7-H4, BAFFR, BTLA, CD2, CD7, CD27, CD28, CD30, CD38, CD40, CD80
  • Immuno-oncology agents may be in the form of antibodies, peptides, small molecules or viruses.
  • the immuno-oncology agent is an antibody against PD-1, PD-L1 or PD-L2.
  • the immuno-oncology agent is an inhibitor of arginase, CTLA-4, indoleamine 2,3-dioxygenase, and/or PD-1/PD-L1.
  • the immuno- oncology agent is abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab, ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED 14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofat
  • an immuno-oncology agent may be any agent that may be used in the treatment of malignant diseases and that acts, at least in part, by involving the immune system, or has an immune system-related mode of action.
  • the immuno-oncology agent may be selected from, without limitation: - an immune checkpoint inhibitor such as a PD-1 inhibitor, e.g. nivolumab or pembrolizumab;
  • an immune checkpoint inhibitor such as a PDL-1 inhibitor, e.g. atezolizumab, avelumab, or durvalumab; or a CTLA-4 inhibitor, e.g. ipilimumab,
  • a cancer vaccine e.g. sipuleucel-T
  • an immunomodulator such as thalidomide, lenalidomide, pomalidomide,
  • non-specific immunotherapy e.g. interferons, or interleukins
  • CAR chimeric antigen receptor
  • the anticancer agent is an anti -PD-1 antibody.
  • the anti-PD-1 antibody is selected from nivolumab and pembrolizumab.
  • the anticancer agent is selected from Afatinib, Aflibercept, Alemtuzumab, Alitretinoin, Altretamine, Anagrelide, Arsenic trioxide, Asparaginase, Atezolizumab, Avelumab, Axitinib, Azacitidine, Bendamustine, Bevacizumab, Bexarotene, Bleomycin, Bortezomib, Bosutinib, Busulfan, Cabazitaxel, Capecitabine, Carboplatin, Carmofur, Carmustine, Cetuximab, Chlorambucil, Chlormethine, Cisplatin, Cladribine, Clofarabine, Crizotinib, Cyclophosphamide, Cytarabine, dacarbazine, Dactinomycin, Dasatinib, Daunorubicin, Decitabine, Denileukin diftitox
  • the formulation administered according to the dosage regimen of the invention and the anticancer agent may be used to treat or prevent a cancer or multiple cancers in a subject.
  • the cancer may be one or a variant of a cancer selected from Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Adrenocortical Carcinoma, Anal Cancer, Appendix Cancer, Atypical Teratoid/Rhabdoid Tumor, Basal Cell Carcinoma, Bile Duct Cancer, Bladder Cancer, Bone Cancer, Brain Tumor, Astrocytoma, Brain and Spinal Cord Tumor, Brain Stem Glioma, Central Nervous System Atypical Teratoid/Rhabdoid Tumor, Central Nervous System Embryonal Tumors, Breast Cancer, Bronchial Tumors, Burkitt Lymphoma, Carcinoid Tumor, Carcinoma of Unknown Primary, Central Nervous System Cancer, Cervical Cancer, Childhood Cancers, Chordoma, Chronic Lymp
  • the cancer may be selected from:
  • tumours of epithelial origin affecting organs such as breast (breast adenocarcinoma), skin (melanoma), lung (non-small cell lung cancer and small cell lung cancer), kidney (renal cell carcinoma), pancreas (pancreatic carcinoma), bladder,
  • lymphoma multiple myeloma
  • lymphoma lymphoma
  • NHL acute lymphoblastic leukemia
  • CLL chronic lymphocytic leukemia
  • myologenous leukemia such as acute myolegenous leukemia (AML), and crhonic myelogenous leukemia (CML)
  • hairy cell leukemia T-cell prolymphocytic leukemia, large granular lymphocytic leukemia, adut T-cell leukemia, adult T-cell lymphoma/leukemia.
  • the cancer is selected from a cancer of the lung, a melanoma, a cancer of the pancreas, a cancer of the kidneys, refractory leukemia and lymphoma.
  • the method of the invention may further comprise administering one or more additional therapeutic agents conjointly with the anticancer agent.
  • therapeutic agents that may be conjointly administered with the anticancer agent include, without limitation: aminoglutethimide, amsacrine, anastrozole, asparaginase, AZD5363, Bacillus Calmette-Guerin vaccine (beg), bicalutamide, bleomycin, bortezomib, buserelin, busulfan, campothecin, capecitabine, carboplatin, carfilzomib, carmustine, chlorambucil, chloroquine, cisplatin, cladribine, clodronate, cobimetinib, colchicine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, demethoxyviridin, dexamethasone, di chloroa
  • anticancer therapy is a combination therapy with an immuno-oncology agent and at least one other anticancer agent.
  • the patient may be administered with an immuno-oncology agent and at least one other anticancer agent selected from platinum salts (such as cisplatin, carboplatin and the like), pemetrexed and etoposide.
  • the at least one other anticancer agent may be:
  • the present invention provides a kit, comprising an anticancer agent, and a formulation as described above.
  • the kit may be for use in treating a condition or disease as described herein.
  • the present invention provides a method of treating or preventing cancer, comprising conjointly administering a formulation according to the dosage regimen of the invention and an anticancer agent. Thanks to the invention, administering the anticancer agent and the formulation according to the invention provides improved efficacy relative to individual administration of the anticancer agent.
  • the anticancer agent is administered within about 5 minutes to within about 7 hours after the formulation according to the invention.
  • the a solid dosage form according to the invention is administered multiple times before the anticancer agent is administered in order to ensure that the anticancer immunosurveillance system of the patient is improved.
  • the formulation according to the invention may be administered at least 2, at least 3, at least 4, at least 5, at least 6 or at least 7 days before administration of the anticancer agent.
  • the formulation administered according to the dosage regimen of the invention is for use in a subject who has a cancer and who is administered, will be administered or has been administered with a substance, besides the anticancer agent, that may disturb the gut microbiota of said patient. Thanks to the invention, the deleterious impact of such substances may be prevented and thus the efficacy of the anticancer agent may be improved. Therefore, the invention relates to a method for mitigating the deleterious effects a substance may have on the gut microbiota of a subject suffering from cancer, said subject being the recipient of an anticancer agent therapy, comprising administering to said subject an effective amount of a solid dosage form according to the invention.
  • the substance is a pharmaceutical substance administered to treat a pathological condition in the patient.
  • certain pharmaceutical substances may be administered in order to treat a disease, but may have a deleterious effect on the gut microbiota when they reach the lower part of the intestine.
  • the subject is still to receive the pharmaceutical substance for benefiting its desired effects but, on the other hand, solutions to avoid its secondary effects should be provided.
  • Illustrative substances having this behaviour include antibiotics.
  • Antibiotics may be administered to a subject in order to treat a bacterial infection. However, since antibiotics are, by design, able to affect bacterial growth or survival, they threaten the gut microbiota balance and may induce dysbiosis when they reach the lower part of the intestine.
  • dysbiosis-inducing pharmaceutical substances include, without limitation: chemotherapy agents, such as taxanes (e.g. docetaxel, paclitaxel), anthracyclines (e.g. doxorubicin), topoisomerase inhibitors (e.g. etoposide, irinotecan), antimetabolites (e.g. methotrexate, cytarabine, 5-fluorouracil, gemcitabine, pemetrexed), alkylating agents (e.g.
  • chemotherapy agents such as taxanes (e.g. docetaxel, paclitaxel), anthracyclines (e.g. doxorubicin), topoisomerase inhibitors (e.g. etoposide, irinotecan), antimetabolites (e.g. methotrexate, cytarabine, 5-fluorouracil, gemcitabine, pemetrexed), alkylating agents (e.g.
  • melphalan kinase inhibitors
  • antifungal agents such as voroconazole, ambisome, posoconazole
  • antiviral agents such as acyclovir, methisazone
  • anti-inflammatory agents such as aspirin, ibuprofen
  • - proton pump inhibitors such as omeprazole, pantoprazole, esomeprazole.
  • the formulation is administered according to the dosage regimen of the invention to a subject who has a cancer and who is treated, will be treated or has been administered with a dysbiosis-inducing pharmaceutical substance, such as an antibiotic.
  • the formulation as provided herein may be administered to the subject even long before initial administration of the anticancer agent.
  • the subject may have been diagnosed with a malignancy but the treatment could not begin before several days, weeks, months or years.
  • a dysbiosis-inducing pharmaceutical agent such as an antibiotic
  • the formulation may be administered according to the dosage regimen of the invention to the subject even long before the start or after the end of administration of the anticancer agent. Firstly, it may unfortunately be that the subject’s cancer could relapse.
  • the formulation as described herein is preferably administered during the whole course of the anticancer agent therapy, when the subject is to receive a therapy with a dysbiosis-inducing pharmaceutical substance, such as an antibiotic.
  • the invention relates to a formulation administered according to the dosage regimen of the invention for improving the efficacy of an anticancer agent in a subject in need of such an anticancer agent, wherein the subject is also administered with a dysbiosisinducing pharmaceutical substance, such as an antibiotic.
  • the invention also relates to a formulation administered according to the dosage regimen of the invention, for use in the prevention of the decrease of efficacy of an anticancer agent in a subject when said subject is administered with a dysbiosis-inducing pharmaceutical substance, such as an antibiotic.
  • the invention also relates to a formulation administered according to the dosage regimen of the invention for use to maintain the efficacy of an anticancer agent in a subject when said subject is administered with a dysbiosis-inducing pharmaceutical substance, such as an antibiotic.
  • the invention further relates to a formulation administered according to the dosage regimen of the invention for use along with a dysbiosis-inducing pharmaceutical substance, such as an antibiotic, in a subject in need of an anticancer agent therapy.
  • a dysbiosis-inducing pharmaceutical substance such as an antibiotic
  • the invention further relates to a formulation administered according to the dosage regimen of the invention, for use in combination with a dysbiosis-inducing pharmaceutical substance, such as an antibiotic, in a method for the treatment or prevention of a disease that may be treated or prevented with said dysbiosis-inducing pharmaceutical substance, wherein the subject in need of said treatment is also in need of an anticancer therapy.
  • a dysbiosis-inducing pharmaceutical substance such as an antibiotic
  • the invention further relates to a formulation administered according to the dosage regimen of the invention, for use in a subject in need of an anticancer agent, for preventing the impact of a dysbiosis-inducing pharmaceutical substance, such as an antibiotic, on the efficacy of said anticancer agent.
  • a dysbiosis-inducing pharmaceutical substance such as an antibiotic
  • the invention further relates to a formulation administered according to the dosage regimen of the invention for use in a subject in need of an anticancer agent, for preventing the decrease in efficacy of said anticancer agent potentially induced by a dysbiosis-inducing pharmaceutical substance, such as an antibiotic, administered to said subject to treat or prevent another pathological condition that may be treated or prevented with said dysbiosis-inducing pharmaceutical substance.
  • a dysbiosis-inducing pharmaceutical substance such as an antibiotic
  • the formulation is administered according to the dosage regimen of the invention, to the subject almost simultaneously with a dysbiosis-inducing pharmaceutical substance, for example an antibiotic.
  • a dysbiosis-inducing pharmaceutical substance for example an antibiotic.
  • the formulation of the invention is administered shortly before, simultaneously, and/or shortly after administration of the dysbiosis-inducing pharmaceutical substance, in particular an antibiotic, preferably shortly before.
  • the formulation of the invention is administered less than 30 minutes before or after the dysbiosis-inducing pharmaceutical substance, in particular an antibiotic, has been administered, in particular less than 20 minutes, less than 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 minutes, or less than one minute before or after the dysbiosisinducing pharmaceutical substance, in particular an antibiotic, has been administered.
  • the formulation is administered at least once a day, in particular at least twice a day, more particularly three times a day or four times a day.
  • the formulation is administered during the whole course of the treatment with the dysbiosis-inducing pharmaceutical substance, in particular with an antibiotic.
  • the formulation of the invention may be administered a longer time than the dysbiosis-inducing pharmaceutical substance, in particular than an antibiotic, in order to ensure that any residual dysbiosis-inducing pharmaceutical substance, in particular any residual antibiotic, is eliminated.
  • the formulation of the invention may still be administered at least one day after, such as two days after interruption of the administration of the dysbiosisinducing pharmaceutical substance, in particular after the administration of an antibiotic.
  • the invention relates to a formulation administered according to the dosage regimen of the invention, for use in combination with an antibiotic, in particular almost simultaneously, to a subject who is in need of an anticancer agent.
  • the formulation prevents the adverse effects the antibiotic could have on the intestinal microbiota of the subject, and therefore may improve the therapeutic efficacy of the anticancer agent.
  • the disclosure also relates to a kit comprising a formulation as described above and a dysbiosis-inducing pharmaceutical substance, such as an antibiotic.
  • the kit may be for use in the treatment or prevention of a pathological condition that may be treated or prevented with the dysbiosis-inducing pharmaceutical substance, such as an antibiotic.
  • the dysbiosis-inducing pharmaceutical substance is an antibiotic.
  • the kit may further comprise instructions to implement the methods of the present invention, aiming at preventing the decrease in the efficacy of an anticancer agent.
  • the components of the kit may be administered simultaneously, separately or sequentially.
  • the formulation of the invention may, in particular, be administered before, during, or after the administration of the dysbiosisinducing pharmaceutical agent, such as an antibiotic, in particular shortly before or shortly after, more particularly shortly before.
  • GVHD graft versus host disease
  • the present invention also to the treatment, prevention or delaying GVHD or reduction of the severity of GVHD based on the administration of a formulation according to the dosage regimen of the invention.
  • the present invention can be used to prevent disruption of the microbiota in patients receiving an allogeneic hematopoietic stem cell transplant and prevent or delay the occurrence of or reduce the severity of GVHD.
  • the present invention may also prevent a decreased overall survival for these patients.
  • the formulation administered according to the dosage regimen of the invention is for use in a subject who is administered, will be administered or has been administered with an agent that may disturb the gut microbiota of said subject. Thanks to the invention, the deleterious impact of such agents may be prevented. Therefore, the invention relates to a method for mitigating the deleterious effects a pharmaceutical agent may have on the gut microbiota of a subject who is or could be a recipient of an immuno-competent transplant, comprising administering the formulation to said subject according to the dosage regimen of the invention, for inactivating a dysbiosis-inducing pharmaceutical agent.
  • the dysbiosis-inducing pharmaceutical agent may be a pharmaceutical agent administered to treat a pathological condition in the subject as described above.
  • the formulation as described above may be administered according to the dosage regimen of the invention even long before transplantation.
  • the subject may have been selected as a transplant recipient but the treatment could not begin before several days, weeks, months or years.
  • a dysbiosis-inducing pharmaceutical agent such as an antibiotic
  • the formulation as provided herein may be administered to the subject even long after the day of transplantation.
  • halting the systematic administration of a solid dosage form of the invention when the subject receives a dysbiosis-inducing pharmaceutical substance, such as an antibiotic could severely impair the efficacy of a future transplantation.
  • the formulation as provided herein is administered to the subject almost simultaneously with a dysbiosis-inducing pharmaceutical agent, for example an antibiotic, as defined above in the section relating to cancer treatment.
  • a dysbiosis-inducing pharmaceutical agent for example an antibiotic, as defined above in the section relating to cancer treatment.
  • the invention relates to a formulation administered according to the dosage regimen provided herein for use in combination with an antibiotic, in particular almost simultaneously, to a subject who is in need of a transplant.
  • the formulation prevents the adverse effects the antibiotic could have on the intestinal microbiota of the subject, and therefore may treat or prevent GVHD.
  • the invention can be used appropriately in patients at risk of GVHD such as patients taking antibiotics waiting for a hematopoietic stem cell transplant (HSCT) procedure, to prevent GVHD occurrence or reduce the severity of a GVHD episode should one episode occur despite the initial treatment with the invention.
  • HSCT hematopoietic stem cell transplant
  • the invention can be used in patients in wait of, or during the course of a HSCT procedure when they receive antibiotics, in particular during the neutropenia phase.
  • the invention can also be used in these patients when they receive antibiotics before the neutropenia phase in order to maintain an optimal microbiota equilibrium.
  • the invention can also be used in patients diagnosed with a cancer of the blood or bone-marrow when they receive antibiotics in order to maintain the microbiota in the best possible state for the longest possible time and improve the outcome of a HSCT if this procedure is deemed necessary to cure the patient.
  • the invention can also be used in patients having received a HSCT procedure when they receive antibiotics in order to prevent the occurrence of the GVHD syndrome or avoid the worsening of acute or chronic GVHD if the patient already suffers from the disease.
  • the invention can be used every time the subject takes antibiotics.
  • the invention may also be used after the subject has received a fecal microbial transplant or a treatment with probiotics to restore his or her microbiota diversity and is at risk of GVHD.
  • the subject was administered with an immunosuppressive agent, such as methotrexate, tacrolimus, everolimus, sirolimus, mycophenolate mofetil or cyclosporine A.
  • an immunosuppressive agent such as methotrexate, tacrolimus, everolimus, sirolimus, mycophenolate mofetil or cyclosporine A.
  • the subject was administered with an anti-inflammatory drug such as with a corticosteroid.
  • the subject has fever.
  • the antibiotic to be eliminated from the intestine of the subject has been prescribed because of said fever.
  • the formulation administered according to the dosage regimen of the invention is for use in a method for preventing the alteration of the microbiota in a subject who has received, receives or will received an allogeneic hematopoietic stem cell transplant.
  • the invention can further be used in subjects at high risk of GVHD such as subjects who had a previous episode of GVHD in the years prior to a novel antibiotic cure, a novel hospitalization or a novel immune-suppressive cure.
  • the disclosure also relates to a kit comprising a formulation as described above and a dysbiosis-inducing pharmaceutical agent, such as an antibiotic, or to a kit comprising a formulation as described above and an antibiotic.
  • the kit may be for use in the treatment or prevention of a pathological condition that may be treated or prevented with the dysbiosis-inducing pharmaceutical agent, such as an antibiotic.
  • the dysbiosisinducing pharmaceutical agent is an antibiotic.
  • the kit may further comprise instructions to implement the methods of the present invention, aiming at treating or preventing GVHD.
  • the components of the kit may be administered simultaneously, separately or sequentially.
  • the formulation provided herein may, in particular, be administered before, during, or after the administration of the dysbiosis-inducing pharmaceutical agent, such as an antibiotic, in particular shortly before or shortly after, more particularly shortly before.
  • the formulation administered according to the dosage regimen according to the invention can be used to adsorb and therefore remove from the intestine any toxin.
  • the formulation may also be administered according to the dosage regimen of the invention, to a patient who suffers from the effects of bacterial or fungal toxins on the colon.
  • bacterial or fungal toxins include mycotoxins, endotoxins or enterotoxins, such as those produced by Clostridioides difficile (believed to be a major cause of post-antibiotic diarrhea throughout the world).
  • the invention thus also relates to a formulation administered according to the dosage regimen as described above, for use in a method for eliminating the effects of bacterial or fungal toxins in the colon.
  • the invention further relates to a method for eliminating the effects of bacterial or fungal toxins on the colon, comprising administering the formulation to a subject in need thereof according to the dosage regimen of the invention.
  • the invention also relates to a formulation administered according to the dosage regimen as described above, for use in a method for the treatment of disease states characterized by the accumulation of substances in the lower part of the gastrointestinal tract, this accumulation being responsible for the development of a number of pathological conditions.
  • the formulation can be useful for the treatment of conditions such as, but not limited to, hepatic encephalopathy, irritable bowel syndrome, chronic renal disease, C. difficile associated diarrhea or antibiotic associated diarrhea.
  • Representative substances which can be adsorbed by the formulation disclosed herein include, but are not limited to, ammonia, indoles, advanced glycation end products (AGEs) and certain bacterial toxins.
  • the formulation administered according to the dosage regimen of the invention can be administered to a patient who suffers from Chronic Kidney Disease (CKD).
  • CKD Chronic Kidney Disease
  • Advanced glycation end products (AGEs), phenols (for example p-cresyl sulphate) and indoles (for example, indoxyl sulfate) are representative toxins generated or introduced in the body via the intestine which can be involved in CKD.
  • the invention relates to the formulation administered according to the dosage regimen as defined above for use in a method for the treatment of CKD.
  • the invention more specifically relates to a formulation administered according to the dosage regimen as described above, for use in a method for eliminating toxins involved in the generation of uremic retention solutes.
  • the invention further relates to a method for eliminating the effects of toxins involved in the generation of uremic retention solutes, comprising administering the formulation to a subject in need thereof, according to the dosage regimen of the invention. More specifically, the invention relates to the elimination or reduction of the amount of AGEs, phenols (for example p-cresylsulphate) and/or indoles (for example, indoxyl sulfate) in the lower part of the intestine (i.e., the late ileum, the caecum or the colon). uses
  • the formulation administered according to the dosage regimen of the invention can further be administered to a patient who suffers from Inflammatory Bowel Disease (IBD), in particular from ulcerative colitis or Crohn's disease. Thanks to the formulation of the invention, it is possible to induce or re-establish immunological tolerance by recomposing the commensal microflora in the intestine by adsorbing excess non-specific mucosal bacteria or aggressive metabolites, mediators and products that accumulate in the intestinal mucosa such as nitric oxide, oxygen radicals, prostaglandins, leukotrienes, histamine, proteases, and matrix metallo-proteinases.
  • IBD Inflammatory Bowel Disease
  • the invention thus relates to the formulation administered according to the dosage regimen as described above, for use in a method for inducing or re-establishing immunological tolerance in a patient who suffers from an IBD, in particular from ulcerative colitis or Crohn's disease.
  • the invention therefore also relates to a method for the treatment of an IBD, in particular of ulcerative colitis or Crohn's disease, comprising administering the formulation to a patient in need thereof, according to the dosage regimen of the invention.
  • the invention further relates to a formulation administered according to the dosage regimen as described above for use in a method for eliminating or reducing the amount of excess non-specific mucosal bacteria or aggressive metabolites, mediators and products that accumulate in the intestinal mucosa such as nitric oxide, oxygen radicals, prostaglandins, leukotrienes, histamine, proteases or matrix metallo-proteinases.
  • the formulation administered according to the dosage regimen of the invention can further be administered to a patient who receive chemotherapies in order to capture and inactivate the chemotherapeutic molecules which can also disrupt the gut microbiota.
  • the formulation administered according to the dosage regimen of the invention can also be used to treat Hepatic Encephalopathy (HE).
  • HE Hepatic Encephalopathy
  • the formulation administered according to the dosage regimen according to invention can for example be used to adsorb ammonia produced by bacteria in the gut of a patient in need thereof.
  • the invention relates to a formulation administered according to the dosage regimen as described above, for the elimination or reduction of nitrogenous compounds, notably ammonia, in the gut of a subject in need thereof.
  • the invention also relates to a method for eliminating or reducing the amount of nitrogenous compounds, notably ammonia, in the gut of a subject in need thereof, comprising administering the formulation to said patient, according to the dosage regimen as described above.
  • the formulation according to the invention may be incorporated in food.
  • the formulation administered according to the dosage regimen according to the invention may be incorporated in a medical food (or drug food) either without or with an antibiotic, if the food is intended to be used as a therapeutic formulation.
  • the formulation according to the invention may be in the form of a food premix, which will serve as a food additive.
  • Adsorbents besides being useful in a therapeutic context, are able to eliminate a wide range of molecules. Accordingly, the formulations administered according to the dosage regimen of the invention may be implemented in methods in which the release of an adsorbent in the lower parts of the intestine would be advantageous.
  • the formulation administered according to the dosage regimen of the invention may be used for reducing flatulencies (for example via H2S adsorption), stool smell (for example via ammonium adsorption), halitosis, food intolerance, etc.
  • D AVI 32 a colon targeted adsorbent
  • D AVI 32 comprises : (i) a core comprising activated charcoal (between 63% and 70% by weight of the total formulation) mixed with carrageenan (between 10% and 17.5% by weight of the total formulation) in the form of a pellet, and (ii) a layer of an external coating that dissolves above pH 7.0 of an anionic methacrylic copolymer comprising methylmethacrylate and methacrylic acid.
  • colon-targeted adsorbent used in the experimental part refers to the same formulation, which is described in the above paragraph.
  • This colon-targeted adsorbent is in the form of a multiparticulate formulation, wherein each particulate is a pellet comprising activated charcoal layered with an external coating as described above.
  • the colon-targeted adsorbent “D AVI 32” was previously tested in humans at the dose of 7.5 g of formulation three times a day (i.e. 5.1 g of activated charcoal three times a day). No data was available to support the use of a colon-targeted adsorbent at the dose of 8.2 g of adsorbent three times a day for a prolonged period of time.
  • a pharmaceutical agent for example an antibiotic
  • the skilled person could predict that an increase in the amount of activated charcoal would interfere with such pharmaceutical agents by adsorbing the same before it could reach its location of absorption into the organism (generally the small intestine).
  • the subjects aged 18-60 years were randomized into 12 parallel study groups (1 : 1 randomization) and each study group was allocated to receive:
  • beta-lactam antibiotics intravenously, from DI to D5 morning: ceftriaxone (1 g oad), or piperacillin/tazobactam (4 g /0.5 g q8h), or ceftazidime/avibactam (2 g /0.5 g q8h), or no beta-lactam; and
  • Colon-targeted Colon-targeted adsorbent (5.1 g adsorbent (8.2 g No colon-targeted of activated of activated adsorbent charcoal) charcoal)
  • n (%) number of subjects experiencing an adverse event (percentage of the tested group)
  • nae number of adverse events
  • beta-lactam antibiotics intravenously, from DI to D5 morning: ceftriaxone (1 g oad), or piperacillin/tazobactam (4 g /0.5 g q8h), or ceftazidime/avibactam (2 g /0.5 g q8h), or no beta-lactam; and
  • the plasma pharmacokinetics for each P-lactam antibiotic were evaluated on the 5 th day of treatment (D5) by measuring the area under the time curve of the plasmatic antibiotic concentration from the beginning of infusion, to T, i.e. the time of the next antibiotic infusion (24h for ceftriaxone, 8h for piperacillin and ceftazidime). AUCO-T values for each antibiotic were compared between groups using an analysis of variance (ANOVA).
  • Example 3 A dosing regimen consisting of a loading dose of 8.2 g of activated charcoal three times a day during at least 3 days followed by a maintenance dose of 8.2 g of activated charcoal twice a day, allows to reach 80% and more of the exposure of activated charcoal of a dosing regimen consisting of a dose of 8.2 g of activated charcoal three times a day.
  • the exposure of the lower intestinal tract to the adsorbent (activated charcoal) depending on the dosing regimen was modeled using a transit compartment model with a linear elimination from the lower gastrointestinal tract.
  • the antibiotic treatment was assumed to be of 7 days, and the total duration of the colon targeted adsorbent treatment was assumed to be of 9 days (duration of the antibiotic treatment + 2 additional days).
  • Table 4 summarizes the parameters for the 4 dosing regimens.
  • Table 5 summarizes the ratio of AUC and Cmax between regimens of different loading dose durations, and a 8.2 g TID regimen. Table 5:
  • the regimen consisting of a loading dose of 8.2 g of activated charcoal TID during 3 or 4 days followed by a maintenance dose of 8.2 g of activated charcoal BID, meets the classical criteria for bioequivalence in that it falls within the bioequivalence limits of 80%-125% of the pharmacokinetic parameters of a 8.2 g TID regimen.
  • Example 4 A dosing regimen consisting of a loading dose of 8.2 g of activated charcoal three times a day during 4 days followed by a maintenance dose of 8.2 g of activated charcoal twice a day during 5 days, results in a higher exposure of the lower gastrointestinal tract to activated charcoal than with a dosing regimen of 5.1 g of activated charcoal three times a day during 9 days.
  • the exposure of the lower intestinal tract to the adsorbent (activated charcoal) depending on the dosing regimen was modeled using a transit compartment model with a linear elimination from the lower gastrointestinal tract.
  • the antibiotic treatment was assumed to be of 7 days, and the total duration of the colon targeted adsorbent treatment was assumed to be of 9 days (duration of the antibiotic treatment + 2 additional days).
  • the exposure of the lower gastrointestinal tract to adsorbent (activated charcoal) was evaluated for two types of DAV132 dosing regimens:
  • a dosing regimen consisting in a loading dose of 8.2 g of activated charcoal three times a day (TID) during 4 days, followed by a maintenance dose of 8.2 g of activated charcoal twice a day (BID) during 5 days (called COM4, as in example 3)
  • Table 6 summarizes the parameters for the 2 dosing regimens, and their ratio.
  • Example 5 clinical trial to evaluate different adsorbent dose regimens

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Abstract

The invention relates to a dosage regimen for administering a formulation for the delayed and controlled delivery of an adsorbent into the lower intestine of mammals. The formulation includes a carrageenan and an adsorbent, such as activated charcoal. The invention further relates to uses of this formulation, in particular to pharmaceutical uses. In one embodiment, the formulation is used to eliminate or reduce the side effects in the intestine, in particular in the colon, of pharmaceutical agents that are administered as a treatment for a disorder, but that have side effects when they reach the late ileum, the caecum or the colon.

Description

FORMULATIONS AND DOSAGE REGIMEN FOR ORAL DELIVERY OF ADSORBENTS IN THE GUT
The invention relates to a dosage regimen for administering a formulation for the delayed and controlled delivery of an adsorbent into the lower intestine of mammals. The invention further relates to uses of this formulation, in particular to pharmaceutical uses.
BACKGROUND OF THE INVENTION
When antibiotics are administered, either orally or parenterally, a significant fraction is not absorbed and reaches the gastro-intestinal tract. When those antibiotic residues reach the colon, they provoke a serious disruption of the intestinal microbiota: several bacterial populations are decimated whereas others (sometimes pathogenic and resistant to antibiotics) proliferate; this new transient state of the microbiota is called dysbiosis. The intestinal microbiota balance is hence disturbed and may take weeks to months to fully recover, i.e. return to its original equilibrium. Other drugs are also known to disrupt the microbiota such as some anti-cancer chemotherapies.
Similarly to a damaged organ, a disrupted microbiota can no longer fulfil its physiological functions, leading to many adverse consequences such as altered immunity and immune response, colonization of the intestine by pathogenic bacteria such as Clostridioides difficile (formerly Clostridium difficile), altered metabolism with increased risk of inflammation, metabolic syndrome or obesity, and emergence and dissemination of antibiotic resistance.
The medical community has well acknowledged today that preserving the microbiota balance and diversity during antibiotic treatments could prevent serious medical conditions such as C. difficile infections and graft-versus-host-disease in patients undergoing a hematopoietic stem cell transplant. Maintaining a healthy microbiota could also prevent the selection and colonization of multi -resistant bacteria, and therefore limit the emergence and spread of antimicrobial resistance and prevent subsequent life-threatening infections. Finally, it is anticipated that maintaining the microbiota equilibrium is a driver for long-term health, and could favor better outcomes (such as increased survival) for cancer patients treated with anti-cancer therapies, and in particular those involving the immune system such as immune checkpoint inhibitors. Formulations and methods were previously developed by the present Applicant to eliminate from the lower part of the gut pharmaceutical agents that can induce dysbiosis, and to thus protect the intestinal microbiota. One approach to achieve this goal is to administer an adsorbent to eliminate such pharmaceutical agents, more specifically antibiotics, in the lower part of the intestine. More particularly, the adsorbent is released between the part of the intestine where such pharmaceutical agents are absorbed (e.g. duodenum and jejunum) and where their deleterious effect on the commensal bacteria occur (caecum and colon). These strategies were reported in WO2006122835, W02007132022 and WO2011104275. Such formulations are also advantageous in reducing or eliminating the side effects of other pharmaceutical agents or metabolites thereof in the late ileum, caecum and colon. Such formulations are also advantageous in the treatment of disease states characterized by the accumulation of substances in the lower part of the gastrointestinal tract. More generally, such formulations can be used in the treatment of a condition, either pathological or not, which is caused, maintained and/or enhanced by the presence, or the presence in excess quantities, of certain substances in the lower part of the gastrointestinal tract, specifically in the late ileum, the caecum, or the colon.
Multiple clinical trials have already been performed successfully in healthy volunteers and patients, demonstrating the clinical benefits of such a formulation (De Gunzburg et al. “Protection of the Human Gut Microbiome From Antibiotics.” The Journal of infectious diseases (2018) ; vol. 217,4: 628-636 ; De Gunzburg et al. “Targeted adsorption of molecules in the colon with the novel adsorbent-based medicinal product, DAV132: A proof of concept study in healthy subjects.” J Clin Pharmacol. (2015) ; 55(1): 10-16, Ducher et al. “DAV132 protects intestinal microbiota of patients treated with quinolones. A European phase II randomized controlled trial” ECCMID 2020).
The initial dosage regimen consisted in an administration of 5.1 g of the adsorbent, three times a day, which corresponded to 7.5 g of formulation. However, it would be advantageous to improve the dosage regimen of such administration. In particular, it would be advantageous to provide a dosage regimen that improves the efficiency and clinical benefits of the formulation, without increasing the number of adverse events and without increasing interference with the pharmacokinetics of concomitantly-administered drug(s), or without reducing the efficacy of the concomitantly-administered drug(s). In particular, it would be advantageous to provide a dosage regimen according to which the formulation does not impact the normal absorption process of a therapeutic agent (for example, an antibiotic) when said therapeutic agent is administered orally along with the formulation. It would also be advantageous to provide a dosage regimen improving patient compliance with respect to such formulation. It is further advantageous to limit the costs associated to the administration of such formulation.
The present invention provides such advantageous dosage regimen.
SUMMARY OF THE INVENTION
An advantageous dosage regimen of a formulation useful for treating a side effect of an intestinal microbiota dysbiosis-inducing pharmaceutical agent is provided. In particular, it is herein provided a formulation comprising:
- a core containing a composition comprising an adsorbent mixed with carrageenan, preferably in the form of a pellet, and
- a layer of an external coating formed around the core such that the adsorbent is released from the formulation in a desired part of the intestine, preferably in the lower part of the intestine; for use in a method for treating a side effect of an intestinal microbiota dysbiosis-inducing pharmaceutical agent; wherein the formulation is administered to the subject at a dose from about 6.8 g to about 8.9 g of adsorbent three times per day.
In a particular embodiment, the formulation is administered to the subject according to a dosage regimen comprising the following sequential steps:
(1) administering a dose from about 6.8 g to about 8.9 g of absorbent three times per day, over a first period of time; and
(2) administering a dose from about 6.8 g to about 8.9 g of absorbent twice per day, over a second period of time.
In a particular embodiment, the formulation is administered at a dose of about 8.2 g of absorbent three times per day over the first period of time, in step (1). In another particular embodiment, the formulation is administered at a dose of about 8.2 g of absorbent twice per day over the second period of time, in step (2). In another embodiment, the formulation is administered to the subject simultaneously to the treatment with said intestinal microbiota dysbiosis-inducing pharmaceutical agent.
In a particular embodiment, the first period of time is a period of at least 1 day, in particular a period of at least 3 consecutive days, preferably a period of 3 or 4 consecutive days. In another particular embodiment, the second period of time begins the day following the last day of the first period.
In a particular embodiment, the second period terminates at least at the end of the treatment with said pharmaceutical agent inducing an intestinal microbiota dysbiosis. Preferably, the second period terminates 1, 2, 3, 4 or 5 days, in particular 2 days after the end of the treatment with said pharmaceutical agent inducing an intestinal microbiota dysbiosis.
In a particular embodiment, the adsorbent is activated charcoal. In a particular embodiment, the amount of adsorbent is comprised between 60% and 80%, preferably between 62% and 75%, preferably between 63% and 70% by weight of the total formulation. Preferably, the amount of adsorbent is about 68% by weight of the formulation.
In another particular embodiment, the carrageenan is a kappa-carrageenan. In a particular embodiment, the amount of carrageenan is about 1% to about 20%, preferably from about 5% to about 20%, preferably from about 10% to about 17.5% by weight of the total formulation. Preferably, the amount of carrageenan is about 12% by weight of the formulation.
In a particular embodiment, the external coating formed around the core, is a pH-dependent enterosoluble polymer. In a particular embodiment, the pH-dependent enterosoluble polymer is selected in the group consisting of cellulose acetate trimellitate (CAT), cellulose acetate phthalate (CAP), anionic copolymers based on methylacrylate, methylmethacrylate and methacrylic acid, anionic copolymers based on methylacrylate, methylmethacrylate and methacrylic acid 7:3: 1, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), methacrylic acid and ethyl acrylate copolymers, methacrylic acid and ethyl acrylate copolymer, methacrylic acid and methyl methacrylate copolymers 1 : 1, methacrylic acid and methyl methacrylate copolymers (1 :2 ratio), polyvinyl acetate phthalate (PVAP) and Shellac resins. In a particular embodiment, the polymer dissolves at a pH equal to 6.0 and above. In another particular embodiment, the pH-dependent polymer is selected in the group consisting of:
- shellac,
- hydroxypropylmethylcellulose acetate succinate
- hydroxypropylmethylcellulose phthalate
- anionic copolymers based on methyl acrylate, methyl methacrylate and methacrylic acid, and
- methacrylic acid and methyl methacrylate copolymers (1 :2 ratio).
In a particular embodiment, the external coating is a mixture of methyl methacrylate and methacrylic acid, and methacrylic acid and ethyl acrylate copolymer, in a ratio comprised between 99:1 and 80:20.
In a further particular embodiment, a further coating is provided between the core and the external pH-dependent layer, said further coating being in particular selected in the group consisting of:
- pH-dependent polymers, in particular shellac type polymers, anionic copolymers based on methylacrylate, methylmethacrylate and methacrylic acid, Methacrylic acid and ethyl acrylate copolymer, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS),
- pH-independent water-soluble polymers such as PVP or high molecular weight cellulose polymers such as hydroxypropylmethylcellulose (HPMC) or hydroxypropylcellulose (HPC),
- pH-independent insoluble polymers such as ethylcellulose polymers or ethyl acrylate methyl methacrylate copolymer, and
- mixtures of pH-dependent polymer and a water insoluble, pH-independent polymer such as ethylcellulose or ethyl acrylate methyl methacrylate copolymer (NE30D).
In a particular embodiment, the polymer layer that dissolves in a pH-independent manner comprises at least one cellulose-derivative selected from the group consisting of hydroxypropylcellulose or ethylcellulose. In another particular embodiment, the polymer layer that dissolves in a pH-independent manner is made of a 1 :9 to 9: 1, preferably 2:8 to 3:7, mixture of methacrylic acid and ethyl acrylate copolymer and ethyl acrylate methyl methacrylate copolymer. The formulation is used in a method for treating a side effect of an intestinal microbiota dysbiosisinducing pharmaceutical agent. In a particular embodiment, the formulation is used in a method for eliminating or reducing the antibiotic-associated adverse effects of antibiotic agents, in particular for eliminating or reducing the emergence of antibiotic resistance or for eliminating or reducing diarrhea. In a further particular embodiment, the antibiotic and the formulation are administered simultaneously by oral route.
In another particular embodiment, the pharmaceutical agent is selected in the group consisting of antineoplastic agents, for example topoisomerase I inhibitors such as Irinotecan, anti-inflammatory compounds or inhibitor of interleukin- 1 such as diacerhein, pancrelipase, selective phosphodiesterase 4 inhibitor used for the treatment of Chronic obstructive Pulmonary Disease (COPD) such as roflumilast or cilomilast and compounds having anti-inflammatory and antimitotic activities such as colchicines, Irinotecan or a metabolite thereof, in particular SN-38.
Methods of preparing the formulations are also disclosed. Further objects and applications will become apparent in the following detailed description of the invention.
DETAILED DESCRIPTION
The invention relates to a formulation including a core comprising an adsorbent and carrageenan, layered with a coating such that the absorbent is released from the formulation in a desired part of the intestine, for use in the treatment of conditions in a subject in need thereof.
All the doses expressed below in grams correspond to doses of active principle (namely the adsorbent of the formulation as described below). In a particular embodiment, the formulation is administered to the subject with a dose of adsorbent of about 8.2 g three times per day.
As used herein with respect to any disclosed values or ranges, the term "about" indicates that the stated numerical value allows for slight imprecision, e.g., reasonably close to the value or nearly, such as plus or minus 10%, of the stated values or ranges. Dosage regimen
In a particular embodiment, the dosage regimen of the invention comprises, in this order:
(1) a first step comprising the administration of a daily loading dose, over a first period of time; and optionally
(2) a second step comprising the administration of a daily maintenance dose, over a second period of time.
The “daily loading dose” of the invention corresponds to the total dose of adsorbent administered in one day, in step (1). In a particular embodiment of the invention, the daily loading dose corresponds to a dose of adsorbent from about 6.8 g to about 8.9 g, administered three times per day.
The “daily maintenance dose” of the invention corresponds to the total dose of adsorbent administered in one day, in step (2). In a particular embodiment of the invention, the daily maintenance dose corresponds to a dose of adsorbent from about 6.8 g to about 8.9 g, administered twice per day.
In the context of the present invention, the “daily loading dose” is higher than the “daily maintenance dose”. For example, the daily loading dose administered over the first period of time (e.g. from about 20.4 g to about 26.7 g per day of adsorbent) is higher than the daily maintenance dose administered over the second period of time (e.g. from about 13.6 g to about 17.8 g per day of adsorbent).
According to a particular embodiment, the formulation is administered according to a dosage regimen comprising the following sequential steps:
(1) administering at least two doses of the formulation per day over a first period of time; and
(2) administering at least one dose of the formulation per day over a second period of time; wherein administration during the first period of time comprises at least one more dose administration per day than during the second period of time.
According to a particular embodiment, the formulation is administered according to a dosage regimen comprising the following sequential steps: (1) administering at least three doses of the formulation per day over a first period of time; and
(2) administering at least two doses of the formulation per day over a second period of time; wherein administration during the first period of time comprises at least one more dose administered per day than during the second period of time.
According to a particular embodiment, the dosage regimen of the invention comprises the following sequential steps:
(1) administering a dose from about 6.8 g to about 8.9 g of adsorbent, three times per day, over a first period of time; and
(2) administering a dose from about 6.8 g to about 8.9 g of adsorbent, twice per day, over a second period of time.
In a particular embodiment, the formulation is administered at a dose of adsorbent of about 8.2 g three times per day in step (1). In another particular embodiment, the formulation is administered at a dose of adsorbent of about 8.2 g twice per day in step (2).
In a preferred embodiment, the formulation is administered to the subject according to a dosage regimen comprising the following sequential steps:
(1) administering a dose of adsorbent of about 8.2 g, three times per day, over a first period of time; and
(2) administering a dose of adsorbent of about 8.2 g, twice per day, over a second period of time.
The present inventors have found that administering a daily loading dose as high as 6.8 to 8.9 g of adsorbent, three times per day for a prolonged period of time, increases the efficiency of the formulation, when compared to the administration of a dose of 5.1 g of adsorbent three times per day (see Example 5). Unexpectedly, the administration of such a high loading dose was shown to be safe and well tolerated. See Example 1 demonstrating that a strong increase in the dose of adsorbent (from 5.1 g three times a day to 8.2 g three times a day) did not increases the number of adverse events. In addition, the present inventors surprisingly showed that such a high loading dose did not increase interference with the pharmacokinetics of concomitantly-given drugs such as antibiotics (see Example 2). In order to improve compliance, the present inventors provide a two-step dosage regimen comprising after step (1) of administering the daily loading dose as described above, a step (2) of administering a daily maintenance dose. Patient compliance is improved since step (2) requires two administrations of a single dose of about 6.8 g to about 8.9 g of adsorbent, instead of step (1) which comprises three administrations of a single dose of about 6.8 g to about 8.9 g of adsorbent. The number of administrations or intakes is reduced in step (2), thus reducing the total daily dose administered to the subject. Unexpectedly, such dosage regimen comprising (1) the administration of a daily loading dose (with three intakes per day) as described above followed by (2) the administration of a daily maintenance dose (with two intakes per day) as described above does not drastically reduce the amount of adsorbent present and active in the lower intestinal tract, when compared to a dosage regimen comprising only the administration of the formulation with three intakes per day. Such dosage regimen comprising (1) the administration of a daily loading dose (unit dose administered three times a day) followed by (2) the administration of a daily maintenance dose (unit dose administered twice a day) can be considered as bioequivalent to a dosage regimen using the same unit dose three times a day, as observed on pharmacokinetic parameters (see Example 3). In addition, the present inventors have shown that a dosing regimen comprising the administration of a loading dose (e.g. 8.2 g of adsorbent three times a day) during 4 days followed by the administration of a maintenance dose (e.g. 8.2 g of adsorbent twice a day) during 5 days, results in a higher exposure of the lower gastrointestinal tract to activated charcoal than with a dosing regimen comprising the administration of 5.1 g of adsorbent three times a day during 9 days (see Example 4).
In the context of the present invention, step (1) is prior to step (2). In addition, step (1) and step (2) do not overlap.
The first period of time and the second period of time each have a duration of at least 1 day. In a particular embodiment, the first period of time and the second period of time each have a duration of more than 1 day. In addition, the first period of time and the second period of time do not overlap. In the context of the present invention, the formulation is administered every day over the first period of time, and is administered every day over the second period of time.
In a particular embodiment, the first period of time is immediately followed by the second period of time. According to this embodiment, the second period of time begins the day following the last day of the first period. For the sake of clarity, if the first period of time of step (1) ends on Day 4 (i.e. the daily loading dose is administered on Day 1, Day 2, Day 3 and Day 4), then the second period of time of step (2) starts on Day 5 (i.e. the daily maintenance dose is administered on Day 5, and the following days). The duration of the second period of time, during which the daily maintenance dose is administered, is as long as needed, and may be adapted by the skilled person.
In a particular embodiment, the first period of time is a period of at least 1 day such as a period of 1, 2, 3 or 4 consecutive days. Preferably, the first period of time is a period of at least 3 consecutive days such as a period of 3 or 4 consecutive days. In a particular embodiment, the first period of time is a period of at most 4 consecutive days. Preferably, the first period of time is a period of 3 or 4 consecutive days. According to this preferred embodiment, the daily loading dose of the formulation is administered on Day 1, on Day 2, on Day 3 and optionally on Day 4. Therefore, for example, the formulation is administered at a dose from about 6.8 g to about 8.9 g of adsorbent, in particular of about 8.2 g of adsorbent, 3 times per day on Day 1, 3 times per day on Day 2, 3 times per day on Day 3 and optionally 3 times per day on Day 4.
In a particular embodiment, the formulation is administered according to the dosage regimen of the invention, which comprises the following sequential steps:
(1) administering a dose from about 6.8 g to about 8.9 g of adsorbent, preferably around 8.2 g of adsorbent, three times per day, for 3 or 4 days; and
(2) administering a dose from about 6.8 g to about 8.9 g of adsorbent, preferably around 8.2 g of adsorbent, twice per day, for the following days.
The formulation is used for treating a side effect of an intestinal microbiota dysbiosis-inducing pharmaceutical agent. In a more specific embodiment, the formulation according to the invention is administered to the subject simultaneously or concomitantly to the treatment with said pharmaceutical agent. In a particular embodiment, the maintenance dose is administered at least until the end of the treatment with the pharmaceutical agent inducing an intestinal microbiota dysbiosis (i.e. the second period of time in step (2) terminates at least at the end of the treatment of said pharmaceutical agent inducing an intestinal microbiota dysbiosis). In another particular embodiment, the maintenance dose is administered until 1, 2, 3, 4 or 5 days, in particular 2 days after the end of the treatment with said pharmaceutical agent inducing an intestinal microbiota dysbiosis (i.e. the second period of time in step (2) terminates 1, 2, 3, 4 or 5 days, in particular 2 days after the end of the treatment with said pharmaceutical agent inducing an intestinal microbiota dysbiosis).
In a particular embodiment, the formulation is administered according to the dosage regimen of the invention, which comprises the following sequential steps:
(1) administering a dose from about 6.8 g to about 8.9 g of adsorbent, preferably around 8.2 g of adsorbent, three times per day, for 3 or 4 days; and
(2) administering a dose from about 6.8 g to about 8.9 g of adsorbent, preferably around 8.2 g of adsorbent, twice per day, for the following days and at least until the end of the treatment with said pharmaceutical agent inducing an intestinal microbiota dysbiosis, preferably until 1, 2, 3, 4 or 5 days, in particular until 2 days after the end of the treatment with said pharmaceutical agent inducing an intestinal microbiota dysbiosis.
The formulation administered in accordance with the dosage regimen of the invention is described, as follows. Methods of preparing the formulation, and methods of treatment using the formulation, are also disclosed below.
Formulation
The formulation is suitable for oral administration of an adsorbent and delivery of said adsorbent in the lower part of the intestine, i.e. in the late ileum, the caecum and/or the colon. The carrageenan and adsorbent are present as a mixture, which mixture being compressed or aggregated to form a core (the core being further herein referred to as a particle or pellet or core pellet). The core is coated with one or more coating layers. The coated pellets can be further inserted in capsules or pills. The coated pellets can also be presented in sachets, sticks, bottles, drinking straws or any other convenient containers.
The formulations of the invention are solid dosage forms useful for delivering an adsorbent to a desired part of the intestine, advantageously in the late ileum, the caecum or the colon. The external and/or intermediate coatings are in particular provided to minimize (preferably to totally prevent) the impact of the adsorbent on the normal absorption process of a therapeutic agent (for example, an antibiotic) by the host organism when said therapeutic agent is administered along with the formulation according to the invention. In addition, or alternatively, the adsorbent thus formulated is prevented from non-specifically adsorbing material and compounds present in the gastrointestinal tract all the way to the terminal part of the small intestine. This results in the release of a non-saturated adsorbent, fully or almost fully efficient adsorbent in the specific part of the intestine where its action is needed.
The individual components of the formulations are described in detail below.
Adsorbents
Examples of suitable adsorbents include activated charcoal, clays, including bentonite, kaolin, montmorrillonite, attapulgite, halloysite, laponite, and the like, silica, including colloidal silica, mesoporous silica, fumed silica, zeolites and the like, talc, cholesteramine and the like, polystyrene sulfonates and the like, mono and poly sulfonated resins, and any other resins of interest such as those used for bacteriologic testing. Among these adsorbents, it can be preferred to use those of pharmaceutical grade, such as activated charcoal USP (Merck, France or other sources), kaolin (VWR, France or other sources), attapulgite (Lavollee, France or other sources), bentonite (Acros Organics, France or other sources), Talc USP (VWR, France or other sources).
The amount of adsorbent to produce a single dosage form may vary depending upon the host being treated and the overall capacity and selectivity of the adsorbent towards the antibiotic(s). The amount of adsorbent to produce a single dosage form will generally be that amount of the compound which produces a desired effect. The desired effect may be a therapeutic effect, for example a therapeutically significant decrease in the amount of the antibiotic, metabolite thereof, bacterial toxin, or other compound which causes adverse effects in the terminal parts of the gut, in particular in the colon, as compared to when the formulation is not administered.
The amount of the adsorbent will range from about 1 % to about 99 % by weight of the core, preferably from about 50 % to about 95 %, most preferably from about 65 % to about 95%, in particular from about 80 % to about 95 % by weight of the core.
In a particular embodiment, the formulation comprises an absorbent from about 1% to about 85% by weight of the total formulation, preferably from about 50% to about 80%, most preferably from about 60% to about 80%, in particular from about 62% to about 75% by weight of the total formulation, even preferably from about 63% to 70% by weight of the total formulation. According to a specific embodiment of the invention, the amount of absorbent represents about 68% in weight of the weight of the total formulation.
In a particular embodiment, activated charcoal is used. In one aspect of this embodiment, activated charcoal preferentially has a specific area above 1500 m2/g, preferentially above 1600 m2/g and best above 1800 m2/g.
Carrageenan
Carrageenan is a naturally-occurring family of linear sulphated polysaccharides which are extracted from red seaweeds. It is a high molecular weight polysaccharide made up of repeating galactose and 3, 6-anhydrogalactose (3, 6- AG) units, both sulfated and non-sulfated. The units are joined by alternating alpha 1-3 and beta 1-4 glycosidic linkages. Three basic types of carrageenan are available commercially, i.e. kappa, iota, and lambda carrageenan, which differ by the number and position of the ester sulfate groups on the galactose units.
In one embodiment, the carrageenan can be selected from kappa, iota and lamba carrageenan, and mixtures thereof. In one aspect of this embodiment, the adsorbent is mixed with kappa- carrageenan. In a particular embodiment, the mixture comprises activated charcoal and kappa- carrageenan.
Preferably, the amount of carrageenan is between about 5% and about 25%, more preferably between about 10% and about 23%, by weight of the core (which comprises the mixture of the adsorbent with the carrageenan). According to a specific embodiment of the invention, the amount of carrageenan is about 15% by weight of the core (mixture of the adsorbent with the carrageenan). For example, the core may contain 85% of an adsorbent and 15% of carrageenan, by weight of the core.
In a particular embodiment, the formulation comprises carrageenan from about 1% to about 20% by weight of the total formulation, preferably from about 5% to about 20%, most preferably from about 10% to about 17.5% by weight of the total formulation. According to a specific embodiment of the invention, the amount of carrageenan represents about 12% of the weight of the total formulation.
According to a particular embodiment of the invention, a mixture of activated charcoal and carrageenan is provided with the weight ratio indicated above.
The core (preferably in the form of a pellet) may be produced by any suitable means known to the skilled artisan. In particular, granulation techniques are adapted to produce said core. For example, the core may be obtained by mixing the adsorbent and the carrageenan in the ratio indicated above, adding a solvent such as water to proceed to wet granulation, followed by extrusion spheronization or one-pot pelletization. Any remaining water can be removed, for example, by drying using conventional techniques the resulting pellets. Other techniques known by those skilled in the art can be direct compression or fluid-bed wet granulation.
In one embodiment, the core, or core pellet, of the invention has an average weight particle size in the range from 250 to 3000 pm, in particular 500 to 3000 pm. Several representative size ranges can be preferred. For example, the core size can be comprised between 500 and 1000 pm, or between 800 and 1600 pm. In the context of the present invention, the weight average particle size is determined by sieving different fractions in size, weighting the fractions and calculating the average particle size from the weights. The method is well known to a skilled person in the field of the invention.
The mixture of an adsorbent, in particular activated charcoal, and carrageenan has unexpectedly good formulation properties, including:
- suitable flow characteristics which allows mass transport during extrusion process,
- self-lubricating properties with limited sticking to material,
- sufficient rigidity to keep the shape of the extrudate,
- firmness of the extrudate and enough brittleness which allows smooth cutting of the extrudate, and
- minimum plasticity, which allows good spheronization.
It is also described a composition comprising a mixture of an adsorbent, preferably activated charcoal, with carrageenan (in particular kappa-carrageenan). Said mixture may be the form of a particle (a compact mixture obtainable, for example, by an extrusion spheronization process), also termed a pellet, or core pellet, in the present application.
Those skilled in the art will recognize that the core can further include conventional excipients such as antiadherents, binders, fillers, diluents, flavours, colours, lubricants, glidants, preservatives, sorbents and sweeteners. The amounts of such excipients can vary, but will typically be in the range of 0.1 to 10% by weight of the core. Of course, the person skilled in the art will adapt these amounts so that the added excipient does not negatively impact on the advantageous properties of the mixture of carrageenan with the adsorbent.
External enteric coating
The core of the formulation (preferably in the form of a pellet) is covered with a coating such that the adsorbent is released from the formulation in a desired part of the intestine. Several systems are known to those skilled in the art for delivery of an agent to the different parts of the intestine. A comprehensive review of the different systems that can be implemented is provided in Pinto et al., Int J Pharm. 2010 Aug 16;395(l-2):44-52.
In a particular embodiment of the invention, the core of the formulation can be covered or coated with a coating such that the adsorbent is released from the formulation in the lower part of the intestine, i.e. in the late ileum, caecum and/or colon. Any coating can be used which ensures that the formulation will not release the adsorbent until it is in the desired part of the intestine, namely in the late ileum, the caecum or the colon. The coating may be selected from coatings which are pH-sensitive, redox-sensitive or sensitive to particular enzymes or bacteria. Enteric coatings are well known to those skilled in the art (for example, reference is made to Chourasia MK and Jain SK, "Pharmaceutical approaches to colon targeted drug delivery systems", J Pharm PharmaceutSci 6(1): 33-66, 2003).
Preferred coating materials are those which are pH sensitive, i.e. pH-dependent enterosoluble polymers. As will be apparent in the following parts of the application, the choice of the pH- dependent enterosoluble polymer can be made by taking into account the pH profile of the gastro intestinal tract of the mammal who will be the recipient of the treatment (also herein referred to as the "host being treated"). The term "enterosoluble polymer" denotes a polymer that is stable and does not dissolve in the stomach and the upper parts of the gastrointestinal tract, but readily dissolves when it arrives at the desired part of the gut to release the active material contained therein. The solubility of a pH- dependent enterosoluble polymer depends on the conditions of acidity or alkalinity found all along the gut.
In a particular embodiment, the pH-dependent enterosoluble polymer can be selected among cellulose acetate trimellitate (CAT), cellulose acetate phthalate (CAP) such as Aquateric®, anionic copolymers based on methylacrylate, methylmethacrylate and methacrylic acid, anionic copolymers based on methylacrylate, methylmethacrylate and methacrylic acid 7:3: 1 such as Eudragit® FS30D, Hydroxypropyl methylcellulose phthalate (HPMCP), Hydroxypropylmethylcellulose acetate succinate (HPMCAS) LF, LG, MF, MG or HF Grades such as Aqoat®, methacrylic acid and ethyl acrylate copolymers such as Eudragit® L100-55, methacrylic acid and ethyl acrylate copolymer such as Eudragit® L30D-55, methacrylic acid and methyl methacrylate copolymers 1 : 1 such as Eudragit® L-100 and Eudragit® L12,5, methacrylic acid and methyl methacrylate copolymers 1 :2 such as Eudragit®S-100 and Eudragit® S12,5, Polyvinyl acetate phthalate (PVAP) such as Sureteric® and Opadry ® and Shellac resins such as SSB® Aquagold.
In a preferred embodiment, the pH-dependent enterosoluble polymer used in the external layer dissolves at a pH equal to 6.0 and above. Even more preferably, it dissolves at a pH equal to 7.0 and above. In this context, the polymer may in particular be selected in the group consisting of shellac such as SSB® Aquagold, anionic copolymers based on methyl acrylate, methyl methacrylate and methacrylic acid 7:3: 1 such as Eudragit® FS30D, methacrylic acid and methyl methacrylate copolymers 1 :2 such as Eudragit®S-100 and Eudragit® S12,5, HPMCAS such as Aqoat® AS-MF, MG or HF grades or hydroxypropyl methylcellulose phthalate (HPMCP) such as HP- 55 grade.
The above referred to Eudragit® copolymers are commercialized by Evonik. Their composition is known to the skilled artisan and may be found, in particular, in US 2008/0206350 (USSN 12/034,943). The pH dependent enterosoluble polymer is selected first for its ability to resist acidic pH found into the upper part of the gastro-intestinal tract (GIT) of most mammals and second to fulfill requirement of delivering the active agent into the lower part of the intestine, i.e. preferentially the late ileum, the caecum or the colon.
The person skilled in the art knows that in many mammals, the physiology of the GIT can vary both in terms of pH, length, and transit time. Table 1 below represents the various physiological characteristics of some mammals.
Table 1 : Various intestinal pH found in the gut of different mammals
Figure imgf000018_0001
From KararliTT., Biopharm Drug Dispos. 1995 Jul; 16(5):351-80. Comparison of the gastrointestinal anatomy, physiology, and biochemistry of humans and commonly used laboratory animals. Stevens C. E., and Hume, I. D. 1995. Comparative Physiology of the Vertebrate Digestive System. 2nd ed. New York: Cambridge University Press.
It can be seen from table 1 that most of the enterosoluble polymers will begin to dissolve in the upper part of the small intestine and, thanks to the thickness of the external coating, the adsorbent will be released into the lower part of the intestine by the time dissolution is achieved.
The coating thickness can be adapted to finely tune the release of the adsorbent into the desired part of the intestine. For example, the enterosoluble polymer layer can represent from 10% to 40% of the weight of the total formulation. In a preferred embodiment, the amount of enterosoluble layer is at least 12% of the total weight of the formulation. In a preferred embodiment, the enterosoluble polymer layer represents from about 13% to about 35% by weight of the total formulation, even more preferably, from about 14% to about 20%. In a particular embodiment, the enterosoluble polymer layer is present in the formulation in an amount of about 16% by weight of the total formulation. The type and/or amount of enterosoluble polymer which can be used to coat the core of the invention may be selected by using a Biodis dissolution tester (USP III release apparatus).
The pH-dependent enterosoluble coating can also include various combinations of different pH- dependent enterosoluble polymers. Those skilled in the art are able to select such mixtures of pH- dependent polymers taking into account their general knowledge in this field. For example, as mentioned in the above cited article of Chourasia and Jain, a combination of two methacrylic acid polymers such as Eudragit® LI 00-55 and Eudragit® SI 00 can be provided around the core of the invention.
In a particular embodiment of the invention, the external coating contains Eudragit FS30D, or a mixture of Eudragit FS30D and Eudragit L30D-55 in a weight ratio comprised in particular between 99: 1 to 80:20 (FS30D:L30D-55).
In a particular embodiment, the pH-dependent enterosoluble polymer is selected from
- shellac,
- anionic copolymers based on methyl acrylate, methyl methacrylate and methacrylic acid,
- mixtures of methyl acrylate, methyl methacrylate and methacrylic acid such as Eudragit® FS30D and methacrylic acid and ethyl acrylate copolymer such as Eudragit® L30D-55, in a weight ratio comprised between 99: 1 and 80:20, and
- methacrylic acid and methyl methacrylate 1 :2 copolymers .
In a further particular embodiment, the formulation according the invention comprises:
- a core containing a mixture of activated charcoal with carrageenan (preferably kappa carrageenan), and
- a layer comprising an anionic copolymer based on methyl acrylate, methyl methacrylate and methacrylic acid 7:3: 1 , such as Eudragit® FS30D.
In a further particular embodiment, the formulation according the invention comprises:
- a core containing a mixture of activated charcoal with carrageenan (preferably kappa carrageenan), and - a layer of a mixture of methyl acrylate, methyl methacrylate and methacrylic acid 7:3: 1 copolymer such as Eudragit® FS30D and methacrylic acid and ethyl acrylate copolymer such as Eudragit® L30D-55, in a weight ratio comprised between 99: 1 and 80:20.
In another particular embodiment, the formulation according the invention comprises:
- a core containing a mixture of activated charcoal with carrageenan (preferably kappa carrageenan), and
- a layer of shellac.
The external enterosoluble layer may be applied onto the core by any suitable means known to a person skilled in the art. For example, it can be applied using classical fluid bed technology where a water-based or solvent-based solution of coating is applied by spray-drying onto the core. When the weight gain is reached, the formulation can be dried and a further coating can be applied. Multiple coatings can thus be applied successively using spray drying technology.
Furthermore, the colonic region has a high presence of microbial anaerobic organisms providing reducing conditions. Thus, the external coating may suitably comprise a material which is redoxsensitive. Such coatings may comprise azopolymers which can for example consist of a random copolymer of styrene and hydroxyethyl methacrylate, cross-linked with divinylazobenzene synthesized by free radical polymerization, the azopolymer being broken down enzymatically and specifically in the colon, or disulphide polymers (see PCT/BE91/00006).
Other materials providing release in the colon are amylose, for example a coating mixture can be prepared by mixing amylose-butan-l-ol complex (glassy amylose) with Ethocel aqueous dispersion (Milojevic et awl., Proc. Int. Symp. Contr. Rel. Bioact. Mater. 20, 288, 1993), or a coating formulation comprising an inner coating of glassy amylose and an outer coating of cellulose or acrylic polymer material (Allwood et al GB 9025373.3), pectin, a polysaccharide which is degraded by colonic bacterial enzymes (Ashford et al., Br Pharm. Conference, 1992, Abstract 13), reticulated into a gel by divalent cations such as calcium (Rubenstein et al., Pharm. Res., 10, 258, 1993) or zinc (El-Gibaly, Int. J. Pharmaceutics, 232, 199, 2002), chondroitin sulphate (Rubenstein er awl., Pharm. Res. 9, 276, 1992) and resistant starches (Allwood et nl., PCT WO 89/11269, 1989), dextran hydrogels (Hovgaard and Brondsted, 3rd Eur. Symp. Control. Drug Del., Abstract Book, 1994, 87) modified guar gum such as borax modified guar gum (Rubenstein and Gliko-Kabir, S.T.P. Pharma Sciences 5, 41-46, 1995), P-cyclodextrin (Siekeer al., Eu. J. Pharm. Biopharm. 40 (suppl), 335, 1994), saccharide containing polymers by which a polymeric construct is included comprising a synthetic oligosaccharide-containing biopolymer including methacrylic polymers covalently coupled to oligosaccharides such as cellobiose, lactulose, raffinose, and stachyose, or saccharide-containing natural polymers including modified mucopolysaccharides such as cross-linked chondroitin sulfate; methacrylate-galactomannan (Lehmann and Dreher, Proc. Int. Symp. Control. Rel. Bioact. Mater.18, 331, 1991) and pHsensitive hydrogels (Kopecek et al., J. Control.Rel. 19, 121, 1992). Resistant starches, e.g. glassy amylose, are starches that are not broken down by the enzymes in the upper gastrointestinal tract but are degraded by enzymes in the colon.
In a particular embodiment, the formulation according to the invention comprises:
- a core containing a mixture of an absorbent (preferably activated charcoal), with carrageenan (preferably kappa carrageenan), and
- a layer of an external coating formed around the core such that the adsorbent is released from the formulation in a desired part of the intestine, preferably in the lower part of the intestine, in particular a layer of a pH-dependent enterosoluble polymer;
- wherein the absorbent is present in an amount from about 60% to about 80% by weight of the total formulation, preferably from about 62% to about 75% by weight of the total formulation, preferably from about 63% to 70% by weight of the total formulation, preferably about 68% by weight of the total formulation;
- wherein the carrageenan is present in an amount from about 1% to about 20%, preferably from about 5% to about 20%, preferably from about 10% to about 17.5% by weight of the total formulation, preferably about 12% by weight of the total formulation; and
- wherein the enterosoluble polymer is present in an amount from about 10% to about 20% by weight of the total formulation, preferably from about 12% to about 18% by weight of the total formulation, preferably about 16% by weight of the total formulation.
Intermediate coating
According to a particular embodiment of the invention, the formulation described above comprises at least one further coating provided between the core and the external enteric coating. This further layer(s) (also referred to as "intermediate coating") is provided to further delay the release of the adsorbent when necessary. The intermediate coating is in particular provided to minimize (preferably to totally prevent) the impact of the adsorbent on the normal absorption process of a therapeutic agent (for example, an antibiotic) by the host organism when said therapeutic agent is administered, for example orally, along with the formulation according to the invention. This embodiment is particularly suited to the case where the administered therapeutic agent has a delayed absorption profile, as a consequence of the time necessary to achieve maximum concentration of the agent into the blood (Tmax).
According to a particular embodiment, the intermediate coating is provided onto the core of the invention, and a further coating is applied with a pH-dependent enterosoluble polymer, such as Eudragit™ FS30D (as explained above) or a mixture Eudragit® FS30D and Eudragit® L30D-55, in a weight ratio comprised between 99: 1 and 80:20. The pH-dependent enterosoluble polymer protects the core from the acidic environment found in the upper part of the gastro-intestinal tract. Once the pH-dependent polymer is dissolved, further delayed release of the adsorbent can be obtained due to the intermediate coating.
The intermediate coating can contain pH-dependent or pH-independent polymers.
Among the pH-dependent polymers that can be used as intermediate coating, examples include those described above in "external enterosoluble layer" part, and in particular shellac type polymers such as SSB® Aquagold, anionic copolymers based on methyl acrylate, methyl methacrylate and methacrylic acid 7:3: 1 such as Eudragit® FS30D, methacrylic acid and ethyl acrylate copolymer such as Eudragit® L30D-55, HPMCAS such as Aqoat AS-MF, MG or HF grades or hydroxypropyl methylcellulose phthalate (HPMCP) such as HP-55 grade. In a particular embodiment, the intermediate coating can be a mixture of pH-dependent polymers such as Eudragit® FS30D and Eudragit® L30D-55, in a ratio comprised between 99: 1 and 80:20 pH-independent polymers can be selected among slowly water-soluble polymers and water insoluble polymers. Non limiting examples of pH-independent water-soluble polymers include polyvinylpyrolidone (PVP) and high molecular weight cellulose polymers such as hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose (HPC). Further non limiting examples of pH-independent insoluble polymers include ethylcellulose polymers and ethyl acrylate methyl methacrylate copolymer (such as Eudragit® NE30D). In a particular embodiment of the invention, the intermediate coating contains a mixture of polymers. In a first alternative, the mixture of polymers comprises polymers of the same type. For example, the mixture can comprise a pH-dependent polymer with another pH-dependent polymer, a pH-independent soluble polymer with another pH-independent soluble polymer, or a pH- independent insoluble polymer with another pH-independent insoluble polymer. In another alternative, the mixture of polymers comprises polymers of different types. The mixture can comprise a pH-dependent polymer with a pH-independent polymer (either water soluble or insoluble), a pH-independent soluble polymer with a pH-independent insoluble polymer, or a pH- dependent polymer with a pH-independent soluble polymer and a pH-independent insoluble polymer. For example, the intermediate coating can comprise the mixture of a pH-dependent polymer with a pH-independent polymer, such as a mixture of Eudragit® L30D55 with Eudragit® NE30D (for example, in a weight ratio between about 1 :9 and about 9:1, in particular between about 2:8 and about 3:7).
For a pharmaceutical agent given by oral route, for example an antibiotic, which has a Tmax between about 1 and about 2 hours (such as ciprofloxacin), the core according to the invention can be coated with a single pH-dependent polymer, such as an anionic copolymer based on methylacrylate, methylmethacrylate and methacrylic acid (such as a tercopolymer of methylacrylate, methylmethacrylate and methacrylic acid 7:3: 1, for example Eudragit® FS30D). Release of the adsorbent is achieved in vitro and in vivo (in particular in a human subject) after about 4-6 hours, which limits the interaction of the adsorbent with the normal absorption process of the antibiotic, or another pharmaceutical agent. The same type of formulations can be administered after parenteral administration of the antibiotic, where residual antibiotic is found in the gastrointestinal tract after bile or intestinal membrane excretion. In this case, there is no risk of interaction of the adsorbent with the normal absorption of the antibiotic.
In the case where pharmaceutical agents with delayed absorption (Tmax above 2 hours), and in particular antibiotics such as third generation cephalosporins, are given by oral route concomitantly with the adsorbent material formulated in a delayed delivery system such as those described above, it may be preferable to further delay the release of the adsorbent. This can be achieved, for example, by primarily coating the core with between about 1 and about 3% ethylcellulose (w/w of the total formulation), preferably 1.5-2.5% (w/w of the total formulation), more preferably with 2% ethylcellulose or a mixture of Eudragit® L30D-55 with Eudragit® NE30D (between 10-40%, preferably between 15-35% w/w of the total formulation) further coated with at least 15% (w/w of the total formulation) of Eudragit® FS30D.
In a particular embodiment, the intermediate coating is selected in order to achieve a delay of about 20 minutes to about 2 hours in the release of the adsorbent, as measured by in vitro testing such as with a BioDis dissolution tester (USP III release apparatus). In this system, the dosage form is successively placed into glass tubes filled with approximately 200mL of dissolution media with a composition yielding pH, buffer capacity and osmolarity corresponding to the different sections of the gastrointestinal tract, such as described by Jantratid et al. in Pharm.Res. 25 (2008), 1663-1676. This allows a good simulation of in vivo release before testing into mammals. pH, fed vs fasted state, and various other physiological conditions can be tested. Using the BioDis system, it is possible for those skilled in the art to finely tune the formulation to achieve a desired pre-determined delayed release.
According to the above, a particular embodiment of the invention relates to a formulation comprising:
- a core containing a composition comprising an adsorbent mixed with carrageenan,
- an layer of an external coating which is a pH-dependent enterosoluble polymer, and
- an intermediate coating provided between the core and the external layer.
In a particular embodiment, the invention relates to a formulation comprising:
- a core containing a composition comprising activated charcoal mixed with carrageenan (preferably kappa-carrageenan), preferably in the form of a pellet,
- an intermediate coating selected in the group consisting of HPMC, ethylcellulose and a mixture of methacrylic acid and ethyl acrylate copolymer such as Eudragit® L30D-55 and ethyl acrylate methyl methacrylate copolymer such as Eudragit® NE30D (for example in a mixture weight ratio of 1 :9 to 9:1, preferably of 2:8 to 3:7), and
- an external layer of an anionic copolymer based on methyl acrylate, methyl methacrylate and methacrylic acid 7:3: 1, such as Eudragit® FS30D.
In another particular embodiment, the formulation of the invention comprises: - a core containing a composition comprising activated charcoal mixed with carrageenan (preferably kappa-carrageenan),
- a 1-3 % ethylcellulose intermediate coating, preferably a 1.5-2.5% ethylcellulose coating, most preferably a 2% ethylcellulose intermediate coating (w/w of the total formulation), and
- a 15% (w/w of the total formulation) external layer of an anionic copolymer based on methyl acrylate, methyl methacrylate and methacrylic acid 7:3: 1, such as Eudragit® FS30D.
In a further particular embodiment, the formulation of the invention comprises:
- a core containing a composition comprising activated charcoal mixed with carrageenan (preferably kappa-carrageenan),
- a 15-35% (w/w of the total formulation) intermediate coating made of a 2:8 to 3:7 mixture of methacrylic acid and ethyl acrylate copolymer (such as Eudragit® L30D-55) and ethyl acrylate methyl methacrylate copolymer (such as Eudragit® NE30D), and
- a 15% (w/w of the total formulation) external layer of an anionic copolymer based on methyl acrylate, methyl methacrylate and methacrylic acid, such as Eudragit® FS30D.
In another particular embodiment, the formulation of the invention comprises:
- a core containing a composition comprising activated charcoal mixed with carrageenan (preferably kappa-carrageenan),
- a 1-3 % ethylcellulose intermediate coating, preferably a 1.5-2.5% ethylcellulose coating, most preferably a 2% ethylcellulose intermediate coating (w/w of the total formulation), and
- a 15% to 35% (w/w of the total formulation) external layer of a mixture of methyl methacrylate and methacrylic acid such as Eudragit® FS30D and methacrylic acid and ethyl acrylate copolymer such as Eudragit® L30D-55, in a weight ratio comprised between 99:1 and 80:20.
In a further particular embodiment, the formulation of the invention comprises:
- a core containing a composition comprising activated charcoal mixed with carrageenan (preferably kappa-carrageenan),
- a 15-35% (w/w of the total formulation) intermediate coating made of a 2:8 to 3:7 mixture of methacrylic acid and ethyl acrylate copolymer (such as Eudragit® L30D-55) and ethyl acrylate methyl methacrylate copolymer (such as Eudragit® NE30D), and - a 15% to 35% (w/w of the total formulation) external layer of a mixture of methyl methacrylate and methacrylic acid such as Eudragit® FS30D and methacrylic acid and ethyl acrylate copolymer such as Eudragit® L30D-55, in a weight ratio comprised between 99:1 and 80:20.
Other excipients
Those skilled in the art will recognize that the formulation can further include conventional excipients such as anti adherents, binders, plasticizers, emulsifiers, fillers, diluents, flavours, colours, lubricants, glidants, preservatives, sorbents and sweeteners. The amounts of such excipients can vary, but will typically be in the range of 0.1 to 10% by weight of the formulation. In a particular embodiment, the amounts of such excipients will range from about 3% to about 5% by weight of the formulation.
Dosage forms
In another aspect, the present invention provides pharmaceutically acceptable dosage forms which comprise a therapeutically-effective amount of one or more of the adsorbents described above, formulated together with carrageenan and one or more pharmaceutically acceptable additives or excipients. As described in detail below, the dosage forms of the invention are specially formulated for administration in solid form.
The phrase "therapeutically-effective amount" as used herein means that amount of one or more of the compounds described above, material, or formulation comprising one or more of the compounds described above which is effective for producing some desired therapeutic effect.
The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, formulations, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The phrase "pharmaceutically-acceptable additive or excipient" as used herein means a pharmaceutically-acceptable material, formulation or vehicle, such as a solid filler, diluent, excipient involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each additive must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
Dosage forms that contain multiple units, such as core pellets individually coated with enterosoluble polymers such as the one described above, can be preferred in order to improve the in vivo dispersion of the adsorbent, such as activated charcoal. Such core pellets present more practical flexibility, because coating can be directly achieved on their surface, for example, using a fluid bed system.
Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, plasticizers, emulsifier, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the dosage form.
Dosage forms of the present invention are suitable for oral administration. The formulations can conveniently be presented in unit dosage form and can be prepared by any methods well known in the art of pharmacy.
Dosage forms of the invention suitable for oral administration can be in the form of capsules, tablets, sachets, sticks, drinking straws each containing a predetermined amount of the adsorbent formulation.
A tablet can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose or polysaccharide), surface- activated or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent such as water.
The solid dosage forms described above can be combined in a final dosage form comprising single or multiple units. Examples of multiple units include multilayer tablets, capsules containing tablets, pellets, granules, etc. The core of the invention is coated with a layer of an external coating, and optionally an intermediate coating as provided above. The coated formulation (coated with an external enteric coating, and comprising or not an intermediate coating) can further be combined in a unit drug dosage form, such as a tablet, capsule, and the like, which can be further coated with a coating material for effective delayed-release which include, but are not limited to, cellulosic polymers such as hydroxypropyl cellulose, hydroxy ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, methylcellulose, carboxymethylcellulose sodium, copolymers such as polyvinyl pyrrolidone; hydroxypropyl methyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate and acrylic acid polymers and copolymers, preferably formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate, and other methacrylic resins that are commercially available under the tradename Eudragit® (Rohm Pharma or Evonik, Westerstadt, Germany), including Eudragit® L30D-55 and LI 00-55 (soluble at pH 5.5 and above), Eudragit® L-100 (soluble at pH 6.0 and above), Eudragit® S (soluble at pH 7.0 and above, as a result of a higher degree of esterification), and Eudragit FS30D an anionic copolymer of methacrylic acid, methyl acrylate and methylmethacrylate 7:3: 1; ethyl cellulose, cellulose acetate; Eudragit® NE, RL and RS (water-insoluble polymers having different degrees of permeability and expandability) vinyl acetate, vinylacetate phthalate, vinylacetatecrotonic acid copolymer, and ethylene- vinyl acetate copolymer; vinyl polymers and; Enzymatically degradable polymers such as azo polymers, pectin, chitosan, amylose and guar gum; zein and shellac.
The preferred coating weights for particular coating materials can be readily determined by those skilled in the art by evaluating individual release profiles for tablets, pellets and granules prepared with different quantities of various coating materials.
It is the combination of materials, method and form of application that produce the desired release characteristics.
The coating formulation can include conventional additives, such as plasticizers, emulsifiers, pigments, colorants, stabilizing agents, glidants, etc. A plasticizer is normally present to reduce the fragility of the coating, and will generally represent about 5 wt. % to 50 wt. % relative to the dry weight of the polymer. Examples of typical plasticizers include polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, triethyl acetyl citrate, castor oil and acetylated monoglycerides. A stabilizing agent is preferably used to stabilize particles in the dispersion. Typical stabilizing agents are nonionic emulsifiers such as sorbitan esters, polysorbates and polyvinylpyrrolidone. Glidants are recommended to reduce sticking effects during film formation and drying, and will generally represent approximately 0 wt. % to 100 wt. % of the polymer weight in the coating solution. One effective glidant is talc. Other glidants such as magnesium stearate and glycerol monostearates can also be used. Pigments such as titanium dioxide can also be used. Small quantities of an anti-foaming agent, such as a silicone (e.g., simethicone), can also be added to the coating formulation.
These dosage forms can be administered to humans and animals for therapy by any suitable route of administration.
In a particular embodiment, the formulation is presented in a unit dosage form comprising from about 6.8 g to about 8.9 g of adsorbent. Preferably, the formulation is presented in a unit dosage form comprising about 8.2 g of adsorbent.
In a particular embodiment, the formulation is presented in a unit dosage form comprising:
- an absorbent as described above, in an amount from about 60% to about 80% by weight of the total formulation, preferably from about 62% to 75% by weight of the total formulation, preferably from about 63% to 70% by weight of the total formulation, preferably about 68% by weight of the total formulation;
- carrageenan as described above, in an amount from about 1% to about 20%, preferably from about 5% to about 20%, preferably from about 10% to about 17.5% by weight of the total formulation, preferably about 12% by weight of the total formulation; and
- an enterosoluble polymer as described above, in an amount from about 10% to about 20% by weight of the total formulation, preferably about 12% to about 18% by weight of the total formulation, preferably about 16% by weight of the total formulation.
In particular, the effective daily dose of the adsorbent is administered as two or three sub-doses administered separately at appropriate intervals throughout the day, preferably in unit dosage forms. In particular, the effective daily dose of the formulation is administered as two or three sub- doses of about 6.8 g to about 8.9 g of adsorbent, preferably about 8.2 g of adsorbent, administered separately at appropriate intervals throughout the day, preferably in unit dosage forms.
In particular, the effective daily dose of the adsorbent is administered as two or three sub-doses administered separately before each meal throughout the day, preferably in unit dosage forms. In particular, the effective daily dose of the formulation is administered as two or three sub-doses of about 6.8 g to about 8.9 g of adsorbent, preferably about 8.2 g of adsorbent, administered separately before breakfast, before lunch and/or before dinner throughout the day, preferably in unit dosage forms.
As already mentioned, the formulation according to the invention may be used in a method for eliminating the adverse effects of therapeutic agents, in particular, but not only, of antibiotics. According to a particular embodiment of this method, the formulation of the invention and the therapeutic agent are administered simultaneously or concomitantly. As such the amount of adsorbent may be adapted to the amount of therapeutic agent administered to the subject in need thereof. In this case, the weight ratio between the adsorbent and the antibiotic agent may be above 1, more preferably above 2, even more preferably above 3, and most preferably above 9.
In a preferred embodiment, the formulation comprising the adsorbent is administered before the administration of the antibiotics that are prescribed concomitantly or simultaneously to the patient.
The administration of the formulation according to the invention to an animal is preferably carried out by including it in the animal's food. This is preferably accomplished by preparing an appropriate feed premix containing the formulations according to the invention in an effective amount and incorporating the premix into the complete ration. Accordingly, the present invention also relates to an animal food premix comprising food and formulations as described above. The invention also relates to an animal food ration comprising the formulations according to the invention.
Applications
Therapeutic applications: The formulation administered according to the dosage regimen of the invention can be used to treat conditions and disorders for which intestinal delivery of adsorbents is suitable.
Accordingly, the invention also relates to a formulation administered according to the dosage regimen of the invention, for use as a medicament.
The term "treatment" or declinations thereof denotes any treatment which is designed to cure, alleviate, remove or lessen the symptoms of, or prevent or reduce the possibility of contracting, any disorder or malfunction of the human or animal body induced by a microbiota dysbiosisinducing pharmaceutical agent.
The subject receiving this treatment is any animal in need thereof, including primates, in particular humans, and other mammals such as equines, cattle, swine and sheep; poultry and pets in general may also be recipients of such a treatment.
In a particular embodiment, the subject receiving the treatment is a human, in particular an adult. In a preferred embodiment, the subject is 16 years old or more.
In a particular embodiment, the formulation administered according to the dosage regimen of the invention is for use in a method for the treatment of a side effect of a dysbiosis-inducing pharmaceutical agent.
In a particular embodiment, the formulation comprises:
- a core containing a composition comprising an adsorbent mixed with carrageenan, preferably in the form of a pellet, and
- a layer of an external coating formed around the core such that the adsorbent is released from the formulation in a desired part of the intestine, preferably in the lower part of the intestine; and is for use in a method for treating a side effect of an intestinal microbiota dysbiosis-inducing pharmaceutical agent; wherein the formulation is administered at a dose from about 6.8 g to about 8.9 g of adsorbent three times per day. The formulation can be administered to adsorb and therefore remove from the intestine any drug, metabolite or prodrug thereof, or toxin. This may be done after oral or parenteral administration of an active drug, in order to prevent the drug, metabolite or prodrug thereof to reach the lower intestine and/or colon, which could be useful for limiting or decreasing adverse effects in the subject being treated.
As such, the present invention relates to the formulation administered according to the dosage regimen described above, for use in a method for eliminating drugs in the intestinal tract before they reach the colon or as they reach the colon, preferably before they reach the caecum or as they reach the caecum and proximal colon.
The invention further provides a method for eliminating drugs in the intestinal tract before they reach the colon or as they reach the colon, preferably before they reach the caecum or as they reach the caecum and proximal colon, comprising administering to a patient in need thereof a formulation according to the dosage regimen of the invention.
Furthermore, the invention provides a formulation administered according to the dosage regimen described above, for use in a method for reducing or eliminating the side effect(s) of a drug in the intestinal tract, wherein the formulation eliminates the drug before it reaches the colon or as it reaches the colon, preferably before it reaches the caecum or as it reaches the caecum and proximal colon.
The terms "substance", "drug", "therapeutic agent" and "pharmaceutical agent", and terms derived therefrom, are herein used interchangeably and refer to a compound that provides a desired biological or pharmacological effect when administered to a human or animal.
Treatment or prevention of conditions related to antibiotic administration
The dysbiosis-inducing pharmaceutical agent may be an antibiotic, and the formulation administered according to the dosage regimen of the invention, being used to treat a side effect of such an antibiotic. Such side effects include, without limitation, the development of antibiotic resistance, the development of an infection by Clostridioides difficile or other pathogenic bacteria, a decrease in the efficacy of an anticancer agent in a subject in need thereof, a risk of developing or aggravating graft-versus-host disease in a subject or the risk of a decreased overall survival in a subject.
The adsorbent will adsorb residual antibiotics, and the formulation is administered according to the dosage regimen of the invention to a patient who has been, is being, or will be administered an antibiotic. Any antibiotic that can be adsorbed into/onto the adsorbent can be partially or totally inactivated and has no antibiotic activity once fully adsorbed.
The term “antibiotic” designates any compound that kills or inhibits the growth of microorganisms such as bacteria, fungi, or protozoans, in particular bacteria. Antibiotics that may be eliminated thanks to the invention include but are not limited to:
- beta-lactams including:
- penicillins (such as penicillin G, penicillin V, ampicillin, amoxicillin, bacampicillin, carbenicillin, carbenicillin indanyl, ticarcillin, azlocillin, mezlocillin, piperacillin, and the like),
- penicillinase-resistant penicillins (such as methicillin, oxacillin, cioxacillin, dicloxacillin, nafcillin and the like),
- cephalosporins, such as: first generation cephalosporins (such as cefadroxil, cephalexin, cephradine, cephalothin, cephapirin, cefazolin, and the like) ; second generation cephalosporins (such as cefaclor, cefamandole, cefonicid, cefoxitin, cefotetan, cefuroxime, cefuroxime axetil, cefinetazole, cefprozil, loracarbef, ceforanide, and the like) ; third generation cephalosporins (such as cefepime, cefoperazone, cefotaxime, ceftizoxime, ceftriaxone, ceftazidime, cefixime, cefpodoxime, ceftibuten, and the like) ; fourth generation cephalosporins (such as cefclidine, cefepime, cefozopran, cefpirome, cefquionome and the like) ; fifth and further generation cephalosporins (such as ceftobiprole, ceftaroline, ceftolozane and the like),
- carbapenems (such as imipenem, meropenem, ertapenem, doripenem and the like)
- monobactams (such as aztreonam, and the like),
- quinolones (such as nalidixic acid) and fluoroquinolones (such as cinoxacin, ciprofloxacin, moxifloxacin, levofloxacin, ofloxacin, gatifloxacin, gelifloxacin, norfloxacin and the like),
- sulfonamides (e.g., sulfanilamide, sulfadiazine, sulfamethoxazole, sulfisoxazole, sulfacetamide, sulfamethoxydiazine and the like), - aminoglycosides (e.g., streptomycin, gentamicin, tobramycin, amikacin, netilmicin, kanamycin, neomycins B, C and E), spectinomycin, puromycin, gentamicin, and the like),
- tetracyclines (such as tetracycline, chlortetracycline, oxytetracycline, methacycline, doxycycline, minocycline, tigecycline, eravacycline and the like),
- macrolides (such as erythromycin, azithromycin, clarithromycin, fidaxomicin, telithromycin, josamycin, oleandomycin, spiramycin, tylosin, roxithromycin, cethromycin, solithromycin, and the like),
- glycopeptides (such as vancomycin, oritavancin, telavancin, teicoplanin, dalbavancin, ramoplanin and the like),
- oxazolidinones (such as linezolid, posizolid, tedizolid, radezolid, cycloserine and the like),
- phenicols (such a chloramphenicol, tiamphenicol and the like),
- lincosamides (such as clindamycin, lincomycin and the like),
- Streptogramins (such as pristinamycin, quinupristin/dalfopristin, virginiamycin and the like)
- polymyxins (such as polymyxin A, B, C, D, El(colistin A), or E2, colistin B or C, and the like),
- diaminopyrimidines (such as trimethoprim, often used in conjunction with sulfamethoxazole, pyrazinamide, and the like),
- sulfones (such as dapsone, sulfoxone sodium, and the like),
- para-aminobenzoic acid,
- bacitracin,
- isoniazid,
- rifamycins (such as rifampicin, rifabutin, rifapentine, rifalasil, rimamixin, and the like)
- ethambutol,
- ethionamide,
- capreomycin,
- clofazimine, and
- any other antibacterial agent.
The term “antibiotic” also covers combinations of antibiotics.
The invention thus also relates to the formulation administered according to the dosage regimen of the invention as described above, for use in a method for eliminating residual antibiotics in the intestinal tract, preferably before they reach the colon or as they reach the colon. More preferably, the formulation is used in a method for eliminating residual antibiotics in the intestinal tract, preferably before they reach the caecum or as they reach the caecum and proximal colon. According to the invention, the adsorbent is preferably delivered between the part of the intestine where the antibiotics are absorbed (duodenum and jejunum) and where their deleterious effect on the commensal bacteria (composing the gut microbiota) occur (caecum and colon). The invention further relates to a method for eliminating residual antibiotics in the intestinal tract, preferably before they reach the colon or as they reach the colon, most preferably before they reach the caecum or as they reach the caecum and proximal colon comprising administering the formulation to a subject in need thereof according to the dosage regimen of the invention.
The invention further relates to the formulation administered according to the dosage described above, for use in a method for eliminating the adverse effects of antibiotic agents in the intestinal tract, in particular for eliminating the development of antibiotic resistance, antibiotic treatment- associated development of C. difficile (or other pathogenic bacteria), antibiotic treatment- associated fungal infections or antibiotic treatment-associated diarrhea. The invention further relates to a method for eliminating the adverse effects of antibiotic agents in the intestinal tract, comprising administering the formulation to a subject in need thereof according to the dosage regimen of the invention.
In another embodiment, the present invention provides a kit, comprising an antibiotic, and a formulation as described above. The kit may be a kit-of-parts, for simultaneous, separate or sequential use in the treatment of an infection against which the antibiotic is suitable.
Cancer treatment
The present invention relates to a formulation administered according to the dosage regimen of the invention, for use in a method for improving the therapeutic efficacy of an anticancer agent, such as an immuno-oncology agent. The invention also relates to a formulation administered according to the dosage regimen of the invention, for use in a method for treating or preventing cancer, in combination with an anticancer agent, such as an immuno-oncology agent. The invention further relates to a formulation administered according to the dosage regimen of the invention, for use in a method for treating or preventing cancer, in combination with an anticancer agent, such as an immuno-oncology agent, thereby improving the efficacy of said anticancer agent. The invention also relates to a formulation administered according to the dosage regimen of the invention, for use in a method for treating or preventing cancer, in combination with an anticancer agent, such as an immuno-oncology agent, thereby preserving the efficacy of said anticancer agent. The invention further relates to a formulation administered according to the dosage regimen of the invention, for use in a method for treating or preventing cancer, in combination with an anticancer agent, such as an immuno-oncology agent, thereby potentiating the efficacy of said anticancer agent.
The formulation may be administered at any point in the therapy, e.g. before, during and/or after the anticancer agent, such as an immuno-oncology agent. In particular, the formulation may be administered as soon as the patient is diagnosed with a malignancy, even if the intent to administer an anticancer agent only constitutes a remote possibility. Anticancer agents, also sometimes referred to as antineoplastic agents, are substances that act against cancer in a mammal, such as a human being. The term “anticancer agent” includes, without limitation, chemicals and biological agents that affect directly a cancer cell, or indirectly such as by affecting the vascularisation of the cancer cell. For example, anticancer agents include, without limitation, chemotherapeutic molecules such as cytostatic agents, cytotoxic agents and anti-angiogenesis agents, anticancer antibodies targeting cancer cells, anticancer peptides and anticancer viruses. Illustrative anticancer agents include, without limitation:
- tubulin poisons, taxanes, e.g. docetaxel, paclitaxel,
- platinum compounds, e.g. cisplatin, carboplatin, oxaliplatin,
- agents interfering with DNA replication such as DNA intercalating agents, for example anthracyclines,
- topoisomerase inhibitors such as etoposide,
- antimetabolites, e.g. methotrexate, cytarabine (ara-C), gemcitabine, 5-Fluorouracil,
- alkylators, e.g. mechlorethamine, melphalan, carmustine, ifosfamide, or cyclophosphamide,
- targeted agents, such as enzyme inhibitor, in particular kinase inhibitors, e.g. erlotinib, sorafenib, imatinib, or proteasome inhibitors such as bortezomib, Carfizomib, Ixazomib,
- monoclonal antibodies targeting the extracellular region of a growth factor receptor, such as trastuzumab, bevacizumab and cetuximab,
- immuno-oncology agents, and
- combinations thereof. Anthracyclines include, without limitation, doxorubicin and daunorubicin. Topoisomerase inhibitors further include, without limitation, camptothecin, irinotecan, topotecan, and derivatives thereof. Antimetabolites further include, without limitation, capecitabine and pemetrexed.
In a particular embodiment, the anticancer agent is an immuno-oncology agent. Immuno-oncology agents (also known as immuno-targeted agents) act against tumors, at least in part, by involving the immune system, or by an immune system-related mode of action. An immuno-oncology may more particularly act by modulating the action of immune cells.
Examples of immuno-oncology agents comprise agents that modulate or inhibit immune checkpoints such as 2B4, 4-1BB (CD137), AaR, B7-H3, B7-H4, BAFFR, BTLA, CD2, CD7, CD27, CD28, CD30, CD38, CD40, CD80, CD83 ligand, CD86, CD160, CD200, CDS, CEACAM, CTLA-4, GITR, HVEM, ICAM-1, KIR, LAG-3, LAIR1, LFA-1 (CD 11 a/CD 18), LIGHT, NKG2A, NKG2C, NKp80, 0X40, PD-1, PD-L1, PD-L2, SLAMF7, TGFRp, TIGIT, Tim3 and VISTA.
Immuno-oncology agents may be in the form of antibodies, peptides, small molecules or viruses. In a particular embodiment, the immuno-oncology agent is an antibody against PD-1, PD-L1 or PD-L2.
In a particular embodiment, the immuno-oncology agent is an inhibitor of arginase, CTLA-4, indoleamine 2,3-dioxygenase, and/or PD-1/PD-L1. In certain embodiments, the immuno- oncology agent is abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab, ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED 14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab, pidilizumab, rituximab, ticilimumab, samalizumab, or tremelimumab.
More generally, an immuno-oncology agent may be any agent that may be used in the treatment of malignant diseases and that acts, at least in part, by involving the immune system, or has an immune system-related mode of action. For example, the immuno-oncology agent may be selected from, without limitation: - an immune checkpoint inhibitor such as a PD-1 inhibitor, e.g. nivolumab or pembrolizumab;
- an immune checkpoint inhibitor such as a PDL-1 inhibitor, e.g. atezolizumab, avelumab, or durvalumab; or a CTLA-4 inhibitor, e.g. ipilimumab,
- a cancer vaccine, e.g. sipuleucel-T;
- an immunomodulator such as thalidomide, lenalidomide, pomalidomide,
- a non-specific immunotherapy, e.g. interferons, or interleukins; and
- a chimeric antigen receptor (CAR)-T cell therapy, e.g. tisagenlecleucel, or axicabtagene ciloleucel, and
- combinations thereof.
In a particular embodiment, the anticancer agent is an anti -PD-1 antibody. In a further particular embodiment, the anti-PD-1 antibody is selected from nivolumab and pembrolizumab.
In a particular embodiment of the invention, the anticancer agent is selected from Afatinib, Aflibercept, Alemtuzumab, Alitretinoin, Altretamine, Anagrelide, Arsenic trioxide, Asparaginase, Atezolizumab, Avelumab, Axitinib, Azacitidine, Bendamustine, Bevacizumab, Bexarotene, Bleomycin, Bortezomib, Bosutinib, Busulfan, Cabazitaxel, Capecitabine, Carboplatin, Carmofur, Carmustine, Cetuximab, Chlorambucil, Chlormethine, Cisplatin, Cladribine, Clofarabine, Crizotinib, Cyclophosphamide, Cytarabine, Dacarbazine, Dactinomycin, Dasatinib, Daunorubicin, Decitabine, Denileukin diftitox, Denosumab, Docetaxel, Doxorubicin, Durvalumab, Epirubicin, Erlotinib, Estramustine, Etoposide, Everolimus, Floxuridine, Fludarabine, Fluorouracil, Fotemustine, Gefitinib, Gemcitabine, Gemtuzumab ozogamicin, Hydroxycarbamide, Ibritumomab tiuxetan, Idarubicin, Ifosfamide, Imatinib, Ipilimumab, Irinotecan, Isotretinoin, Ixabepilone, Lapatinib, Lenalidomide, Lomustine, Melphalan, Mercaptopurine, Methotrexate, Mitomycin, Mitoxantrone, Nedaplatin, Nelarabine, Nilotinib, Nivolumab, Ofatumumab, Oxaliplatin, Paclitaxel, Panitumumab, Panobinostat, Pazopanib, Pembrolizumab, Pemetrexed, Pentostatin, Pertuzumab, Pomalidomide, Ponatinib, Procarbazine, Raltitrexed, Regorafenib, Rituximab, Romidepsin, Ruxolitinib, Sorafenib, Streptozotocin, Sunitinib, Tamibarotene, Tegafur, Temozolomide, Temsirolimus, Teniposide, Thalidomide, Tioguanine, Topotecan, Tositumomab, Trastuzumab, Tretinoin, Valproate, Valrubicin, Vandetanib, Vemurafenib, Vinblastine, Vincristine, Vindesine, Vinflunine, Vinorelbine and Vorinostat. The formulation administered according to the dosage regimen of the invention and the anticancer agent may be used to treat or prevent a cancer or multiple cancers in a subject. In certain embodiments, the cancer may be one or a variant of a cancer selected from Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Adrenocortical Carcinoma, Anal Cancer, Appendix Cancer, Atypical Teratoid/Rhabdoid Tumor, Basal Cell Carcinoma, Bile Duct Cancer, Bladder Cancer, Bone Cancer, Brain Tumor, Astrocytoma, Brain and Spinal Cord Tumor, Brain Stem Glioma, Central Nervous System Atypical Teratoid/Rhabdoid Tumor, Central Nervous System Embryonal Tumors, Breast Cancer, Bronchial Tumors, Burkitt Lymphoma, Carcinoid Tumor, Carcinoma of Unknown Primary, Central Nervous System Cancer, Cervical Cancer, Childhood Cancers, Chordoma, Chronic Lymphocytic Leukemia (CLL), Chronic Myelogenous Leukemia (CML), Chronic Myeloproliferative Disorders, Colon Cancer, Colorectal Cancer, Craniopharyngioma, Cutaneous T-Cell Lymphoma Ductal Carcinoma In Situ (DCIS), Embryonal Tumors, Endometrial Cancer, Ependymoblastoma, Ependymoma, Epidermoid Carcinoma, Esophageal Cancer, Esthesioneuroblastoma, Ewing Sarcoma, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, Eye Cancer, Fibrous Histiocytoma of Bone, Gallbladder Cancer, Gastric Cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumors (GIST), Germ Cell Tumor, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Ovarian Germ Cell Tumor, Gestational Trophoblastic Tumor, Glioma, Hairy Cell Leukemia, Head and Neck Cancer, Heart Cancer, Hepatocellular Cancer, Histiocytosis, Langerhans Cell Cancer, Hodgkin Lymphoma, Hypopharyngeal Cancer, Intraocular Melanoma, Islet Cell Tumors, Kaposi Sarcoma, Kidney Cancer, Langerhans Cell Histiocytosis, Large Cell Lung Carcinoma, Laryngeal Cancer, Leukemia, Lip and Oral Cavity Cancer, Liver Cancer, Lobular Carcinoma In Situ (LCIS), Lung Cancer, Lymphoma, AIDS-Related Lymphoma, Macroglobulinemia, Male Breast Cancer, Medulloblastoma, Medulloepithelioma, Melanoma, Merkel Cell Carcinoma, Malignant Mesothelioma, Metastatic Squamous Neck Cancer with Occult Primary, Midline Tract Carcinoma Involving NUT Gene, Mouth Cancer, Multiple Endocrine Neoplasia Syndrome, Multiple Myeloma/Plasma Cell Neoplasm, Mycosis Fungoides, Myelodysplastic Syndrome, Myelodysplastic/Myeloproliferative Neoplasm, Chronic Myelogenous Leukemia (CML), Acute Myeloid Leukemia (AML), Myeloma, Multiple Myeloma, Chronic Myeloproliferative Disorder, Nasal Cavity Cancer, Paranasal Sinus Cancer, Nasopharyngeal Cancer, Neuroblastoma, Non-Hodgkin Lymphoma, Non-Small Cell Lung Cancer, Oral Cancer, Oral Cavity Cancer, Lip Cancer, Oropharyngeal Cancer, Osteosarcoma, Ovarian Cancer, Pancreatic Cancer, Papillomatosis, Paraganglioma, Paranasal Sinus Cancer, Nasal Cavity Cancer, Parathyroid Cancer, Penile Cancer, Pharyngeal Cancer, Pheochromocytoma, Pineal Parenchymal Tumors of Intermediate Differentiation, Pineoblastoma, Pituitary Tumor, Plasma Cell Neoplasm, Pleuropulmonary Blastoma, Breast Cancer, Primary Central Nervous System (CNS) Lymphoma, Prostate Cancer, Rectal Cancer, Renal Cell Cancer, Clear cell renal cell carcinoma, Renal Pelvis Cancer, Ureter Cancer, Transitional Cell Cancer, Retinoblastoma, Rhabdomyosarcoma, Salivary Gland Cancer, Sarcoma, Sezary Syndrome, Skin Cancer, Small Cell Lung Cancer, Small Intestine Cancer, Soft Tissue Sarcoma, Squamous Cell Carcinoma, Squamous Neck Cancer with Occult Primary (e.g., Metastatic), Squamous Cell Carcinoma of the Head and Neck (HNSCC), Stomach Cancer, Supratentorial Primitive Neuroectodermal Tumors, T- Cell Lymphoma, Testicular Cancer, Throat Cancer, Thymoma, Thymic Carcinoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter, Triple Negative Breast Cancer (T BC), Gestational Trophoblastic Tumor, Unknown Primary, Unusual Cancer of Childhood, Urethral Cancer, Uterine Cancer, Uterine Sarcoma, Waldenstrom Macroglobulinemia, and Wilms Tumor.
In particular, the cancer may be selected from:
- tumours of epithelial origin affecting organs such as breast (breast adenocarcinoma), skin (melanoma), lung (non-small cell lung cancer and small cell lung cancer), kidney (renal cell carcinoma), pancreas (pancreatic carcinoma), bladder,
- digestive tumours such as gastro-oesohagial adenocarcinomas,
- head and neck cancers (in particular squamous tumors),
- squamous lung tumours,
- malignancies affecting blood of immune cells such as multiple myeloma, lymphoma (Hodgkin’s and non-Hodgkin’s of all types), leukemia among which lymphocytic leukemia (such as acute lymphoblastic leukemia (ALL), or chronic lymphocytic leukemia, (CLL)), myologenous leukemia (such as acute myolegenous leukemia (AML), and crhonic myelogenous leukemia (CML)), hairy cell leukemia, T-cell prolymphocytic leukemia, large granular lymphocytic leukemia, adut T-cell leukemia, adult T-cell lymphoma/leukemia.
In a particular embodiment, the cancer is selected from a cancer of the lung, a melanoma, a cancer of the pancreas, a cancer of the kidneys, refractory leukemia and lymphoma.
In certain embodiments, the method of the invention may further comprise administering one or more additional therapeutic agents conjointly with the anticancer agent. Representative therapeutic agents that may be conjointly administered with the anticancer agent include, without limitation: aminoglutethimide, amsacrine, anastrozole, asparaginase, AZD5363, Bacillus Calmette-Guerin vaccine (beg), bicalutamide, bleomycin, bortezomib, buserelin, busulfan, campothecin, capecitabine, carboplatin, carfilzomib, carmustine, chlorambucil, chloroquine, cisplatin, cladribine, clodronate, cobimetinib, colchicine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, demethoxyviridin, dexamethasone, di chloroacetate, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gemcitabine, genistein, goserelin, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, lenalidomide, letrozole, leucovorin, leuprolide, levamisole, lomustine, lonidamine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, metformin, methotrexate, miltefosine, mitomycin, mitotane, mitoxantrone, MK-2206, nilutamide, nocodazole, octreotide, olaparib, oxaliplatin, paclitaxel, pamidronate, pazopanib, pentostatin, perifosine, plicamycin, pomalidomide, porfimer, procarbazine, raltitrexed, rituximab, rucaparib, selumetinib, sorafenib, streptozocin, sunitinib, suramin, talazoparib, tamoxifen, temozolomide, temsirolimus, teniposide, testosterone, thalidomide, thioguanine, thiotepa, titanocene di chloride, topotecan, trametinib, trastuzumab, tretinoin, veliparib, vinblastine, vincristine, vindesine, and vinorelbine. Other representative therapeutic agents that may be conjointly administered with the anticancer agent include, without limitation, pemetrexed.
In a particular embodiment, anticancer therapy is a combination therapy with an immuno-oncology agent and at least one other anticancer agent. For example, the patient may be administered with an immuno-oncology agent and at least one other anticancer agent selected from platinum salts (such as cisplatin, carboplatin and the like), pemetrexed and etoposide.
For example, the at least one other anticancer agent may be:
- pemetrexed,
- pemetrexed and platinum salts,
- etoposide, or
- etoposide and platinum salts. In another embodiment, the present invention provides a kit, comprising an anticancer agent, and a formulation as described above. In certain embodiments, the kit may be for use in treating a condition or disease as described herein.
The present invention provides a method of treating or preventing cancer, comprising conjointly administering a formulation according to the dosage regimen of the invention and an anticancer agent. Thanks to the invention, administering the anticancer agent and the formulation according to the invention provides improved efficacy relative to individual administration of the anticancer agent.
In certain embodiments, the anticancer agent is administered within about 5 minutes to within about 7 hours after the formulation according to the invention. In a particular embodiment, the a solid dosage form according to the invention is administered multiple times before the anticancer agent is administered in order to ensure that the anticancer immunosurveillance system of the patient is improved. For example, the formulation according to the invention may be administered at least 2, at least 3, at least 4, at least 5, at least 6 or at least 7 days before administration of the anticancer agent.
In certain aspects, the formulation administered according to the dosage regimen of the invention is for use in a subject who has a cancer and who is administered, will be administered or has been administered with a substance, besides the anticancer agent, that may disturb the gut microbiota of said patient. Thanks to the invention, the deleterious impact of such substances may be prevented and thus the efficacy of the anticancer agent may be improved. Therefore, the invention relates to a method for mitigating the deleterious effects a substance may have on the gut microbiota of a subject suffering from cancer, said subject being the recipient of an anticancer agent therapy, comprising administering to said subject an effective amount of a solid dosage form according to the invention.
In certain embodiments, the substance is a pharmaceutical substance administered to treat a pathological condition in the patient. Indeed, certain pharmaceutical substances may be administered in order to treat a disease, but may have a deleterious effect on the gut microbiota when they reach the lower part of the intestine. The subject is still to receive the pharmaceutical substance for benefiting its desired effects but, on the other hand, solutions to avoid its secondary effects should be provided. Illustrative substances having this behaviour include antibiotics. Antibiotics may be administered to a subject in order to treat a bacterial infection. However, since antibiotics are, by design, able to affect bacterial growth or survival, they threaten the gut microbiota balance and may induce dysbiosis when they reach the lower part of the intestine. This induced dysbiosis may in turn result in a decrease in the efficacy of an anticancer drug administered to the subject. Other illustrative pharmaceutical substances that may induce dysbiosis (also referred to as “dysbiosis-inducing pharmaceutical substances”) include, without limitation: chemotherapy agents, such as taxanes (e.g. docetaxel, paclitaxel), anthracyclines (e.g. doxorubicin), topoisomerase inhibitors (e.g. etoposide, irinotecan), antimetabolites (e.g. methotrexate, cytarabine, 5-fluorouracil, gemcitabine, pemetrexed), alkylating agents (e.g. melphalan), kinase inhibitors (e.g. erlotinib), antifungal agents, such as voroconazole, ambisome, posoconazole, antiviral agents, such as acyclovir, methisazone, anti-inflammatory agents, such as aspirin, ibuprofen; and
- proton pump inhibitors such as omeprazole, pantoprazole, esomeprazole.
Accordingly, in another aspect of the invention the formulation is administered according to the dosage regimen of the invention to a subject who has a cancer and who is treated, will be treated or has been administered with a dysbiosis-inducing pharmaceutical substance, such as an antibiotic.
The formulation as provided herein may be administered to the subject even long before initial administration of the anticancer agent. For example, the subject may have been diagnosed with a malignancy but the treatment could not begin before several days, weeks, months or years. In this case, should the subject suffer, between these events, from a disease that would need a treatment with a dysbiosis-inducing pharmaceutical agent, such as an antibiotic, it would be advantageous to prevent gut microbiota dysbiosis by administering a formulation as provided herein. Likewise, the formulation may be administered according to the dosage regimen of the invention to the subject even long before the start or after the end of administration of the anticancer agent. Firstly, it may unfortunately be that the subject’s cancer could relapse. In this case, halting the systematic administration of the formulation as provided herein when the subject receives a dysbiosisinducing pharmaceutical substance, such as an antibiotic, could severely impair the efficacy of a future therapy with the same or another anticancer agent. Secondly, some therapies, such as gene therapies, may be efficient several years after administration, as long as the therapeutic gene is expressed. In that case, the administration of the formulation as described herein would be beneficial for improving this kind of long-lasting anticancer therapies. Of course, the formulation as described above is preferably administered during the whole course of the anticancer agent therapy, when the subject is to receive a therapy with a dysbiosis-inducing pharmaceutical substance, such as an antibiotic.
In a particular embodiment, the invention relates to a formulation administered according to the dosage regimen of the invention for improving the efficacy of an anticancer agent in a subject in need of such an anticancer agent, wherein the subject is also administered with a dysbiosisinducing pharmaceutical substance, such as an antibiotic.
The invention also relates to a formulation administered according to the dosage regimen of the invention, for use in the prevention of the decrease of efficacy of an anticancer agent in a subject when said subject is administered with a dysbiosis-inducing pharmaceutical substance, such as an antibiotic.
The invention also relates to a formulation administered according to the dosage regimen of the invention for use to maintain the efficacy of an anticancer agent in a subject when said subject is administered with a dysbiosis-inducing pharmaceutical substance, such as an antibiotic.
The invention further relates to a formulation administered according to the dosage regimen of the invention for use along with a dysbiosis-inducing pharmaceutical substance, such as an antibiotic, in a subject in need of an anticancer agent therapy.
The invention further relates to a formulation administered according to the dosage regimen of the invention, for use in combination with a dysbiosis-inducing pharmaceutical substance, such as an antibiotic, in a method for the treatment or prevention of a disease that may be treated or prevented with said dysbiosis-inducing pharmaceutical substance, wherein the subject in need of said treatment is also in need of an anticancer therapy.
The invention further relates to a formulation administered according to the dosage regimen of the invention, for use in a subject in need of an anticancer agent, for preventing the impact of a dysbiosis-inducing pharmaceutical substance, such as an antibiotic, on the efficacy of said anticancer agent.
The invention further relates to a formulation administered according to the dosage regimen of the invention for use in a subject in need of an anticancer agent, for preventing the decrease in efficacy of said anticancer agent potentially induced by a dysbiosis-inducing pharmaceutical substance, such as an antibiotic, administered to said subject to treat or prevent another pathological condition that may be treated or prevented with said dysbiosis-inducing pharmaceutical substance.
In a particular embodiment, the formulation is administered according to the dosage regimen of the invention, to the subject almost simultaneously with a dysbiosis-inducing pharmaceutical substance, for example an antibiotic. By “almost simultaneously”, it is meant that the formulation of the invention is administered shortly before, simultaneously, and/or shortly after administration of the dysbiosis-inducing pharmaceutical substance, in particular an antibiotic, preferably shortly before. In a particular embodiment, the formulation of the invention is administered less than 30 minutes before or after the dysbiosis-inducing pharmaceutical substance, in particular an antibiotic, has been administered, in particular less than 20 minutes, less than 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 minutes, or less than one minute before or after the dysbiosisinducing pharmaceutical substance, in particular an antibiotic, has been administered. In a further particular embodiment, the formulation is administered at least once a day, in particular at least twice a day, more particularly three times a day or four times a day. In a further particular embodiment, the formulation is administered during the whole course of the treatment with the dysbiosis-inducing pharmaceutical substance, in particular with an antibiotic. In a variant of this embodiment, the formulation of the invention may be administered a longer time than the dysbiosis-inducing pharmaceutical substance, in particular than an antibiotic, in order to ensure that any residual dysbiosis-inducing pharmaceutical substance, in particular any residual antibiotic, is eliminated. For example, the formulation of the invention may still be administered at least one day after, such as two days after interruption of the administration of the dysbiosisinducing pharmaceutical substance, in particular after the administration of an antibiotic.
In a particular embodiment, the invention relates to a formulation administered according to the dosage regimen of the invention, for use in combination with an antibiotic, in particular almost simultaneously, to a subject who is in need of an anticancer agent. According to this embodiment, the formulation prevents the adverse effects the antibiotic could have on the intestinal microbiota of the subject, and therefore may improve the therapeutic efficacy of the anticancer agent.
Thus, the disclosure also relates to a kit comprising a formulation as described above and a dysbiosis-inducing pharmaceutical substance, such as an antibiotic. The kit may be for use in the treatment or prevention of a pathological condition that may be treated or prevented with the dysbiosis-inducing pharmaceutical substance, such as an antibiotic. In a particular embodiment of the kit, the dysbiosis-inducing pharmaceutical substance is an antibiotic. The kit may further comprise instructions to implement the methods of the present invention, aiming at preventing the decrease in the efficacy of an anticancer agent. The components of the kit may be administered simultaneously, separately or sequentially. As provided above, the formulation of the invention may, in particular, be administered before, during, or after the administration of the dysbiosisinducing pharmaceutical agent, such as an antibiotic, in particular shortly before or shortly after, more particularly shortly before.
Graft versus host disease (GVHD)
The present invention also to the treatment, prevention or delaying GVHD or reduction of the severity of GVHD based on the administration of a formulation according to the dosage regimen of the invention.
In particular, the present invention can be used to prevent disruption of the microbiota in patients receiving an allogeneic hematopoietic stem cell transplant and prevent or delay the occurrence of or reduce the severity of GVHD. The present invention may also prevent a decreased overall survival for these patients.
In certain aspects, the formulation administered according to the dosage regimen of the invention is for use in a subject who is administered, will be administered or has been administered with an agent that may disturb the gut microbiota of said subject. Thanks to the invention, the deleterious impact of such agents may be prevented. Therefore, the invention relates to a method for mitigating the deleterious effects a pharmaceutical agent may have on the gut microbiota of a subject who is or could be a recipient of an immuno-competent transplant, comprising administering the formulation to said subject according to the dosage regimen of the invention, for inactivating a dysbiosis-inducing pharmaceutical agent.
The dysbiosis-inducing pharmaceutical agent may be a pharmaceutical agent administered to treat a pathological condition in the subject as described above.
The formulation as described above may be administered according to the dosage regimen of the invention even long before transplantation. For example, the subject may have been selected as a transplant recipient but the treatment could not begin before several days, weeks, months or years. In this case, should the subject suffer, between these events, from a disease that would need a treatment with a dysbiosis-inducing pharmaceutical agent, such as an antibiotic, it would be advantageous to prevent gut microbiota dysbiosis by administering a formulation as provided herein. Likewise, the formulation as provided herein may be administered to the subject even long after the day of transplantation. In particular, it may unfortunately be that the subject’s transplant be rejected by the host. In this case, halting the systematic administration of a solid dosage form of the invention when the subject receives a dysbiosis-inducing pharmaceutical substance, such as an antibiotic, could severely impair the efficacy of a future transplantation.
In a particular embodiment, the formulation as provided herein is administered to the subject almost simultaneously with a dysbiosis-inducing pharmaceutical agent, for example an antibiotic, as defined above in the section relating to cancer treatment.
In a particular embodiment, the invention relates to a formulation administered according to the dosage regimen provided herein for use in combination with an antibiotic, in particular almost simultaneously, to a subject who is in need of a transplant. According to this embodiment, the formulation prevents the adverse effects the antibiotic could have on the intestinal microbiota of the subject, and therefore may treat or prevent GVHD.
In a specific embodiment, the invention can be used appropriately in patients at risk of GVHD such as patients taking antibiotics waiting for a hematopoietic stem cell transplant (HSCT) procedure, to prevent GVHD occurrence or reduce the severity of a GVHD episode should one episode occur despite the initial treatment with the invention. In particular, the invention can be used in patients in wait of, or during the course of a HSCT procedure when they receive antibiotics, in particular during the neutropenia phase. The invention can also be used in these patients when they receive antibiotics before the neutropenia phase in order to maintain an optimal microbiota equilibrium. The invention can also be used in patients diagnosed with a cancer of the blood or bone-marrow when they receive antibiotics in order to maintain the microbiota in the best possible state for the longest possible time and improve the outcome of a HSCT if this procedure is deemed necessary to cure the patient.
The invention can also be used in patients having received a HSCT procedure when they receive antibiotics in order to prevent the occurrence of the GVHD syndrome or avoid the worsening of acute or chronic GVHD if the patient already suffers from the disease.
In particular embodiments, the invention can be used every time the subject takes antibiotics. The invention may also be used after the subject has received a fecal microbial transplant or a treatment with probiotics to restore his or her microbiota diversity and is at risk of GVHD.
In a particular embodiment, the subject was administered with an immunosuppressive agent, such as methotrexate, tacrolimus, everolimus, sirolimus, mycophenolate mofetil or cyclosporine A. In another particular embodiment, the subject was administered with an anti-inflammatory drug such as with a corticosteroid.
In a further particular embodiment, the subject has fever. In particular, the antibiotic to be eliminated from the intestine of the subject has been prescribed because of said fever.
In a further particular embodiment, the formulation administered according to the dosage regimen of the invention, is for use in a method for preventing the alteration of the microbiota in a subject who has received, receives or will received an allogeneic hematopoietic stem cell transplant.
The invention can further be used in subjects at high risk of GVHD such as subjects who had a previous episode of GVHD in the years prior to a novel antibiotic cure, a novel hospitalization or a novel immune-suppressive cure.
Thus, the disclosure also relates to a kit comprising a formulation as described above and a dysbiosis-inducing pharmaceutical agent, such as an antibiotic, or to a kit comprising a formulation as described above and an antibiotic. The kit may be for use in the treatment or prevention of a pathological condition that may be treated or prevented with the dysbiosis-inducing pharmaceutical agent, such as an antibiotic. In a particular embodiment of the kit, the dysbiosisinducing pharmaceutical agent is an antibiotic. The kit may further comprise instructions to implement the methods of the present invention, aiming at treating or preventing GVHD. The components of the kit may be administered simultaneously, separately or sequentially. As provided above, the formulation provided herein may, in particular, be administered before, during, or after the administration of the dysbiosis-inducing pharmaceutical agent, such as an antibiotic, in particular shortly before or shortly after, more particularly shortly before.
Elimination of toxins
The formulation administered according to the dosage regimen according to the invention can be used to adsorb and therefore remove from the intestine any toxin.
The formulation may also be administered according to the dosage regimen of the invention, to a patient who suffers from the effects of bacterial or fungal toxins on the colon. Examples of such toxins include mycotoxins, endotoxins or enterotoxins, such as those produced by Clostridioides difficile (believed to be a major cause of post-antibiotic diarrhea throughout the world).
The invention thus also relates to a formulation administered according to the dosage regimen as described above, for use in a method for eliminating the effects of bacterial or fungal toxins in the colon. The invention further relates to a method for eliminating the effects of bacterial or fungal toxins on the colon, comprising administering the formulation to a subject in need thereof according to the dosage regimen of the invention.
Furthermore, the invention also relates to a formulation administered according to the dosage regimen as described above, for use in a method for the treatment of disease states characterized by the accumulation of substances in the lower part of the gastrointestinal tract, this accumulation being responsible for the development of a number of pathological conditions. For example, the formulation can be useful for the treatment of conditions such as, but not limited to, hepatic encephalopathy, irritable bowel syndrome, chronic renal disease, C. difficile associated diarrhea or antibiotic associated diarrhea. Representative substances which can be adsorbed by the formulation disclosed herein include, but are not limited to, ammonia, indoles, advanced glycation end products (AGEs) and certain bacterial toxins.
The formulation administered according to the dosage regimen of the invention can be administered to a patient who suffers from Chronic Kidney Disease (CKD). Advanced glycation end products (AGEs), phenols (for example p-cresyl sulphate) and indoles (for example, indoxyl sulfate) are representative toxins generated or introduced in the body via the intestine which can be involved in CKD. Accordingly, in a particular embodiment, the invention relates to the formulation administered according to the dosage regimen as defined above for use in a method for the treatment of CKD. The invention more specifically relates to a formulation administered according to the dosage regimen as described above, for use in a method for eliminating toxins involved in the generation of uremic retention solutes. The invention further relates to a method for eliminating the effects of toxins involved in the generation of uremic retention solutes, comprising administering the formulation to a subject in need thereof, according to the dosage regimen of the invention. More specifically, the invention relates to the elimination or reduction of the amount of AGEs, phenols (for example p-cresylsulphate) and/or indoles (for example, indoxyl sulfate) in the lower part of the intestine (i.e., the late ileum, the caecum or the colon).
Figure imgf000050_0001
uses
The formulation administered according to the dosage regimen of the invention can further be administered to a patient who suffers from Inflammatory Bowel Disease (IBD), in particular from ulcerative colitis or Crohn's disease. Thanks to the formulation of the invention, it is possible to induce or re-establish immunological tolerance by recomposing the commensal microflora in the intestine by adsorbing excess non-specific mucosal bacteria or aggressive metabolites, mediators and products that accumulate in the intestinal mucosa such as nitric oxide, oxygen radicals, prostaglandins, leukotrienes, histamine, proteases, and matrix metallo-proteinases. The invention thus relates to the formulation administered according to the dosage regimen as described above, for use in a method for inducing or re-establishing immunological tolerance in a patient who suffers from an IBD, in particular from ulcerative colitis or Crohn's disease. The invention therefore also relates to a method for the treatment of an IBD, in particular of ulcerative colitis or Crohn's disease, comprising administering the formulation to a patient in need thereof, according to the dosage regimen of the invention. The invention further relates to a formulation administered according to the dosage regimen as described above for use in a method for eliminating or reducing the amount of excess non-specific mucosal bacteria or aggressive metabolites, mediators and products that accumulate in the intestinal mucosa such as nitric oxide, oxygen radicals, prostaglandins, leukotrienes, histamine, proteases or matrix metallo-proteinases.
The formulation administered according to the dosage regimen of the invention can further be administered to a patient who receive chemotherapies in order to capture and inactivate the chemotherapeutic molecules which can also disrupt the gut microbiota.
The formulation administered according to the dosage regimen of the invention can also be used to treat Hepatic Encephalopathy (HE). A key role is thought to be played in this disorder by circulating gut-derived toxins of nitrogenous compounds, notably ammonia. The formulation administered according to the dosage regimen according to invention can for example be used to adsorb ammonia produced by bacteria in the gut of a patient in need thereof. As such, the invention relates to a formulation administered according to the dosage regimen as described above, for the elimination or reduction of nitrogenous compounds, notably ammonia, in the gut of a subject in need thereof. The invention also relates to a method for eliminating or reducing the amount of nitrogenous compounds, notably ammonia, in the gut of a subject in need thereof, comprising administering the formulation to said patient, according to the dosage regimen as described above.
When the subject to be treated is an animal, for example pet or farm animal, the formulation according to the invention may be incorporated in food. For example, the formulation administered according to the dosage regimen according to the invention may be incorporated in a medical food (or drug food) either without or with an antibiotic, if the food is intended to be used as a therapeutic formulation. Alternatively, the formulation according to the invention may be in the form of a food premix, which will serve as a food additive.
Adsorbents, besides being useful in a therapeutic context, are able to eliminate a wide range of molecules. Accordingly, the formulations administered according to the dosage regimen of the invention may be implemented in methods in which the release of an adsorbent in the lower parts of the intestine would be advantageous. For example, the formulation administered according to the dosage regimen of the invention may be used for reducing flatulencies (for example via H2S adsorption), stool smell (for example via ammonium adsorption), halitosis, food intolerance, etc.
The present invention will be further understood with reference to the following non-limiting examples.
EXAMPLES
Example 1: clinical trial to evaluate the safety
The examples are herein related to the clinical evaluation of the dosage regimen of a colon targeted adsorbent (called “D AVI 32”), which comprises : (i) a core comprising activated charcoal (between 63% and 70% by weight of the total formulation) mixed with carrageenan (between 10% and 17.5% by weight of the total formulation) in the form of a pellet, and (ii) a layer of an external coating that dissolves above pH 7.0 of an anionic methacrylic copolymer comprising methylmethacrylate and methacrylic acid.
The term “colon-targeted adsorbent” used in the experimental part refers to the same formulation, which is described in the above paragraph. This colon-targeted adsorbent is in the form of a multiparticulate formulation, wherein each particulate is a pellet comprising activated charcoal layered with an external coating as described above.
For the sake of clarity, the exact same formulation was used in the experiments detailed below. However, the amount of the multiparticulate formulation administered to the subjects was varied in order to test the effect of an increase in the dose of activated charcoal, which is the active ingredient of the formulation.
The colon-targeted adsorbent “D AVI 32” was previously tested in humans at the dose of 7.5 g of formulation three times a day (i.e. 5.1 g of activated charcoal three times a day). No data was available to support the use of a colon-targeted adsorbent at the dose of 8.2 g of adsorbent three times a day for a prolonged period of time. In particular, it was not known or predictable whether an increase of the amount of activated charcoal administered to a patient would have adverse effects, such as a detrimental effect on the bioavailability of a pharmaceutical agent, for example an antibiotic, co-administered to the patient for its beneficial effect in treating infections. Indeed, the skilled person could predict that an increase in the amount of activated charcoal would interfere with such pharmaceutical agents by adsorbing the same before it could reach its location of absorption into the organism (generally the small intestine).
In order to evaluate whether the strong increase in the dose of activated charcoal would lead to an increased number of adverse events, a clinical trial was designed as follows.
A study in adult human healthy volunteers was conducted in Europe as a prospective, monocentric, randomized, comparative (colon-targeted adsorbent vs. colon-targeted adsorbent) study.
The subjects aged 18-60 years were randomized into 12 parallel study groups (1 : 1 randomization) and each study group was allocated to receive:
- either one of the three following beta-lactam antibiotics, intravenously, from DI to D5 morning: ceftriaxone (1 g oad), or piperacillin/tazobactam (4 g /0.5 g q8h), or ceftazidime/avibactam (2 g /0.5 g q8h), or no beta-lactam; and
- either the colon-targeted adsorbent at the dose of 5.1 g of activated charcoal three times a day, or the colon-targeted adsorbent at the dose of 8.2 g of activated charcoal three times a day, or no colon-targeted adsorbent, from DI to D7, orally.
This study was carried out between May 2019 and December 2019 (first subject first visit - last subject last visit).
A total of 148 subjects were enrolled and randomized, in order to replace 3 subjects who withdrew their consents right after the randomization. The safety associated with the use of the colon- targeted adsorbent for a period of 7 consecutive days was evaluated during the course of the clinical study. Safety results are presented in table 2. Table 2: safety events collected in the clinical study
Colon-targeted Colon-targeted adsorbent (5.1 g adsorbent (8.2 g No colon-targeted of activated of activated adsorbent charcoal) charcoal) Overall
(N=48) (N=49) (N=48) (N=145)
System Organ Class Preferred Term n (%) nae n (%) nae n (%) nae n (%) nae
Any Any 33 (68.8) 78 34 (69.4) 91 34 (70.8) 80 101 (69.7) 249
Gastrointestinal Any 26 (54.2) 47 25 (51.0) 51 29 (60.4) 47 80 (55.2) 145 disorders
Abdominal 1 (2.08) 1 6 (12.2) 7 5 (10.4) 6 12 ( 8.3) 14 distension
Abdominal pain 7 (14.6) 9 6 (12.2) 6 6 (12.5) 7 19 (13.1) 22
Constipation 4 ( 8.3) 4 5 (10.2) 6 2 (4.17) 3 11 ( 7.6) 13
Diarrhoea 12 (25.0) 12 4 ( 8.2) 4 6 (12.5) 6 22 (15.2) 22
Faeces hard 0 0 7 (14.3) 7 1 (2.08) 1 8 ( 5.5) 8
Faeces soft 5 (10.4) 5 5 (10.2) 5 5 (10.4) 6 15 (10.3) 16
Flatulence 2 (4.17) 2 9 (18.4) 9 6 (12.5) 6 17 (11.7) 17
Nausea 3 ( 6.3) 4 3 ( 6.1) 3 2 (4.17) 2 8 ( 5.5) 9
Nervous system Any 10 (20.8) 12 11 (22.4) 13 7 (14.6) 10 28 (19.3) 35 disorders n (%) = number of subjects experiencing an adverse event (percentage of the tested group) nae = number of adverse events
Overall, the safety results showed that oral administration of 5.1 g or 8.2 g of activated charcoal three times a day, during 7 days, was safe and well tolerated up to the highest dose tested when compared to no colon-targeted adsorbent treatment, either with or without antibiotic treatment. Co-administrations did not lead to unexpected safety findings. There were no statistically significant changes between the groups although the dose of active principle, the activated charcoal, was increased by 60%. Example 2: clinical trial to evaluate the drug interactions with antibiotics
It is well-known in clinical practice that a non-specific adsorbent should not be taken concomitantly with other medications because of the strong risk of interaction and reduced efficacy of the medication with increased risk of disease or comorbidity treatment failure for the patients. The interaction is obviously increasing when the dose of adsorbent is increasing.
In order to evaluate whether the strong increase in the dose of activated charcoal would increase interreference with the pharmacokinetics of concomitantly-given drugs, a clinical trial was designed as follows.
A study in adult human healthy volunteers was conducted in Europe as a prospective, monocentric, randomized, comparative (colon-targeted adsorbent vs. colon-targeted adsorbent) study. The subjects aged 18-60 years were randomized into 12 parallel study groups (1 :1 randomization) and each study group was allocated to receive:
- either one of the three beta-lactam antibiotics, intravenously, from DI to D5 morning: ceftriaxone (1 g oad), or piperacillin/tazobactam (4 g /0.5 g q8h), or ceftazidime/avibactam (2 g /0.5 g q8h), or no beta-lactam; and
- either the colon-targeted adsorbent at the dose of 5.1 g of activated charcoal three times a day, or the colon-targeted adsorbent at the dose of 8.2 g of activated charcoal three times a day, or no colon-targeted activated charcoal, from DI to D7, orally.
The plasma pharmacokinetics for each P-lactam antibiotic were evaluated on the 5th day of treatment (D5) by measuring the area under the time curve of the plasmatic antibiotic concentration from the beginning of infusion, to T, i.e. the time of the next antibiotic infusion (24h for ceftriaxone, 8h for piperacillin and ceftazidime). AUCO-T values for each antibiotic were compared between groups using an analysis of variance (ANOVA).
This study was carried out between May 2019 and December 2019 (first subject first visit - last subject last visit). A total of 148 subjects were enrolled and randomized, in order to replace 3 subjects who withdrew their consents right after the randomization. The plasma PK parameters for each antibiotic given concomitantly with the colon-targeted adsorbent are described in Table 3.
Table 3:
Figure imgf000056_0001
For each beta-lactam, the AUCO-T at steady-state (D5) were not different across groups. This indicates that no effect of the colon-targeted adsorbent was observed on the plasma exposure at steady-state (AUCO-T at D5) of beta-lactams given concomitantly measured comparatively to subjects receiving the same beta-lactam treatment and not receiving a colon-targeted adsorbent.
The absence of effect was seen at the dose of 5.1 g of activated charcoal three times a day but also, surprisingly in spite of the strong increase in the dose, (+60%) at the dose of 8.2 g of activated charcoal three times a day. This clinical study demonstrates that the colon-targeted adsorbent of the invention can be used at the dose of 8.2 g of activated charcoal, three times a day, never tested before, with no interaction with drugs administered concomitantly. Example 3: A dosing regimen consisting of a loading dose of 8.2 g of activated charcoal three times a day during at least 3 days followed by a maintenance dose of 8.2 g of activated charcoal twice a day, allows to reach 80% and more of the exposure of activated charcoal of a dosing regimen consisting of a dose of 8.2 g of activated charcoal three times a day.
The exposure of the lower intestinal tract to the adsorbent (activated charcoal) depending on the dosing regimen was modeled using a transit compartment model with a linear elimination from the lower gastrointestinal tract. The antibiotic treatment was assumed to be of 7 days, and the total duration of the colon targeted adsorbent treatment was assumed to be of 9 days (duration of the antibiotic treatment + 2 additional days). Several types of dosing regimens were tested:
8.2 g of activated charcoal three times a day (TID) during 9 days
8.2 g of activated charcoal twice a day (BID) during 9 days
- And regimens consisting of a 8.2 g of activated charcoal TID loading dose followed by a
8.2 g of activated charcoal BID maintenance regimen, with different loading dose durations (COM3, COM4: 3 and 4 days of loading dose, respectively) and a total duration of 9 days
The pharmacokinetic parameters tested were the following:
- AUC'. Area Under the Curve to infinity of activated charcoal (mg/g*days) Cmax: maximal concentration of activated charcoal (mg/g)
Table 4 summarizes the parameters for the 4 dosing regimens.
Table 4:
INDEX BID COM3 COM4 TID
Figure imgf000057_0001
Cmax 74.3 100.7 107.2 111.4
Table 5 summarizes the ratio of AUC and Cmax between regimens of different loading dose durations, and a 8.2 g TID regimen. Table 5:
INDEX COM3/TID COM4/TID
Figure imgf000058_0001
Cmax 0.91 0.97
The results show that a regimen consisting of a loading dose of 8.2 g of adsorbent (activated charcoal) TID during 3 or 4 days followed by a maintenance dose of 8.2 g of activated charcoal BID can be considered as bioequivalent to a 8.2 g TID regimen, as it allows to reach almost 80% of the AUC of a 8.2 g TID regimen, and more than 90% of the Cmax of a 8.2 g TID regimen. From the foregoing, the regimen consisting of a loading dose of 8.2 g of activated charcoal TID during 3 or 4 days followed by a maintenance dose of 8.2 g of activated charcoal BID, meets the classical criteria for bioequivalence in that it falls within the bioequivalence limits of 80%-125% of the pharmacokinetic parameters of a 8.2 g TID regimen.
Example 4: A dosing regimen consisting of a loading dose of 8.2 g of activated charcoal three times a day during 4 days followed by a maintenance dose of 8.2 g of activated charcoal twice a day during 5 days, results in a higher exposure of the lower gastrointestinal tract to activated charcoal than with a dosing regimen of 5.1 g of activated charcoal three times a day during 9 days.
The exposure of the lower intestinal tract to the adsorbent (activated charcoal) depending on the dosing regimen was modeled using a transit compartment model with a linear elimination from the lower gastrointestinal tract.
The antibiotic treatment was assumed to be of 7 days, and the total duration of the colon targeted adsorbent treatment was assumed to be of 9 days (duration of the antibiotic treatment + 2 additional days). The exposure of the lower gastrointestinal tract to adsorbent (activated charcoal) was evaluated for two types of DAV132 dosing regimens:
- A dosing regimen consisting in a loading dose of 8.2 g of activated charcoal three times a day (TID) during 4 days, followed by a maintenance dose of 8.2 g of activated charcoal twice a day (BID) during 5 days (called COM4, as in example 3)
- A dosing regimen consisting in 5.1 g of activated charcoal TID during 9 days The pharmacokinetic parameters tested were the following:
- AUC'. Area Under the Curve to infinity of activated charcoal (mg/g*days) Cmax: maximal concentration of activated charcoal (mg/g).
Table 6 summarizes the parameters for the 2 dosing regimens, and their ratio.
Table 6 :
INDEX COM4 5.1 G TID RATIO COM4/5.1 G
TID
AUC 816.7 626.5 1.304
Cmax 107.2 69.6 1.540
The results show that a dosing regimen consisting in a loading dose of 8.2 g of activated charcoal TID during 4 days, followed by a maintenance dose of 8.2 g of activated charcoal BID during 5 days allows to reach a higher exposure of the lower gastrointestinal tract in activated charcoal (with an AUC 30.4% higher) and a higher Cmax than with a dosing regimen of 5.1 g of activated charcoal TID during 9 days.
Example 5: clinical trial to evaluate different adsorbent dose regimens
In the clinical study of example 3, the fecal concentration for piperacillin was measured in subjects’ feces at baseline and every day until day 9. The Area Under the Curve (AUC) for the fecal concentration between baseline and Day 9 is computed to evaluate the exposure of the gut microbiota to antibiotics and is presented in table 7. Table 7:
Figure imgf000060_0001
This study demonstrates the dose of 8.2 g TID of activated charcoal is able to achieve a more powerful capture and inactivation of antibiotics circulating in the colon of healthy volunteers treated with antibiotics.

Claims

1. A formulation comprising:
- a core containing a composition comprising an adsorbent mixed with carrageenan, preferably in the form of a pellet, and
- a layer of an external coating formed around the core such that the adsorbent is released from the formulation in a desired part of the intestine, preferably in the lower part of the intestine; for use in a method for treating a side effect of an intestinal microbiota dysbiosis-inducing pharmaceutical agent; wherein the formulation is administered to a human subject at a dose from 6.8 g to 8.9 g of adsorbent three times per day.
2. The formulation for use according to claim 1, wherein the formulation is administered to the subject according to a dosage regimen comprising the following sequential steps:
(1) administering a dose from 6.8 g to 8.9 g of adsorbent three times per day, over a first period of time; and
(2) administering a dose from 6.8 g to 8.9 g of adsorbent twice per day, over a second period of time.
3. The formulation for use according to claim 2, wherein the formulation is administered at a dose of 8.2 g plus or minus 10% of adsorbent three times per day over the first period of time, in step (1).
4. The formulation for use according to claim 2 or 3, wherein the formulation is administered at a dose of 8.2 g plus or minus 10% of adsorbent twice per day over the second period of time, in step (2).
5. The formulation for use according to any one of the preceding claims, wherein the formulation is administered to the subject simultaneously to the treatment with said pharmaceutical agent.
6. The formulation for use according to any one of claims 2-5, wherein the first period of time is a period of at least 1 day, in particular a period of at least 3 consecutive days, preferably a period of 3 or 4 consecutive days.
7. The formulation for use according to any one of claims 2-6, wherein the second period of time begins the day following the last day of the first period.
8. The formulation for use according to any one of claims 2-7, wherein the second period terminates at least at the end of the treatment with said pharmaceutical agent inducing an intestinal microbiota dysbiosis, preferably terminates 1, 2, 3, 4 or 5 days, in particular 2 days after the end of the treatment with said pharmaceutical agent inducing an intestinal microbiota dysbiosis.
9. The formulation for use according to any one of the preceding claims, wherein the adsorbent is activated charcoal.
10. The formulation for use according to any one of the preceding claims, wherein the amount of adsorbent is comprised between 60% and 80%, preferably between 62% and 75%, preferably between 63% and 70% by weight of the total formulation, wherein the amount of adsorbent is preferably 68% by weight of the formulation.
11. The formulation for use according to any one of the preceding claims, wherein the carrageenan is a kappa-carrageenan.
12. The formulation for use according to any one of the preceding claims, wherein the amount of carrageenan is comprised between 1% and 20%, preferably between 5% and 20%, preferably between 10% and 17.5% by weight of the formulation, wherein the amount of carrageenan is preferably 12% by weight of the formulation.
13. The formulation for use according to any one of the preceding claims, wherein the external coating is a pH-dependent enterosoluble polymer.
14. The formulation for use according to claim 13, wherein the pH-dependent enterosoluble polymer is selected in the group consisting of cellulose acetate trimellitate (CAT), cellulose acetate phthalate (CAP), anionic copolymers based on methylacrylate, methylmethacrylate and methacrylic acid, anionic copolymers based on methylacrylate, methylmethacrylate and methacrylic acid 7:3: 1, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), methacrylic acid and ethyl acrylate copolymers, methacrylic acid and ethyl acrylate copolymer, methacrylic acid and methyl methacrylate copolymers 1 : 1, methacrylic acid and methyl methacrylate copolymers (1 :2 ratio), Polyvinyl acetate phthalate (PVAP) and Shellac resins.
15. The formulation for use according to claim 13 or 14, wherein the polymer dissolves at a pH equal to 6.0 and above.
16. The formulation for use according to claim 15, wherein the pH-dependent polymer is selected in the group consisting of
- shellac,
- hydroxypropylmethylcellulose acetate succinate
- hydroxypropylmethylcellulose phthalate
- anionic copolymers based on methyl acrylate, methyl methacrylate and methacrylic acid, and
- methacrylic acid and methyl methacrylate copolymers (1 :2 ratio).
17. The formulation for use according to any one of the preceding claims, wherein the external coating is a mixture of a methyl acrylate, methyl methacrylate and methacrylic acid copolymer, and a methacrylic acid and ethyl acrylate copolymer, in a ratio comprised between 99: 1 and 80:20.
18. The formulation for use according to any one of claims 1-16, wherein the external coating is an anionic copolymer based on methyl acrylate, methyl methacrylate and methacrylic acid.
19. The formulation for use according to any one of claims 13 to 18, wherein a further coating is provided between the core and the external pH-dependent layer, said further coating being in particular selected in the group consisting of:
- pH-dependent polymers, in particular shellac type polymers, anionic copolymers based on methylacrylate, methylmethacrylate and methacrylic acid, Methacrylic acid and ethyl acrylate copolymer, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS),
- pH-independent water-soluble polymers such as PVP or high molecular weight cellulose polymers such as hydroxypropylmethylcellulose (HPMC) or hydroxypropylcellulose (HPC), - pH-independent insoluble polymers such as ethylcellulose polymers or ethyl acrylate methyl methacrylate copolymer, and
- mixtures of pH-dependent polymer and a water insoluble, pH-independent polymer such as ethylcellulose or ethyl acrylate methyl methacrylate copolymer (NE30D).
20. The formulation for use according to claim 19, wherein the polymer layer that dissolves in a pH-independent manner comprises at least one cellulose-derivative selected from the group consisting of hydroxypropylcellulose or ethylcellulose.
21. The formulation for use according to claim 19, wherein the polymer layer that dissolves in a pH-independent manner is made of a 1 :9 to 9: 1, preferably 2:8 to 3:7, mixture of methacrylic acid and ethyl acrylate copolymer and ethyl acrylate methyl methacrylate copolymer.
22. The formulation for use according to any one of the preceding claims, for use in a method for eliminating or reducing the antibiotic-associated adverse effects of antibiotic agents, in particular for eliminating or reducing the emergence of antibiotic resistance or for eliminating or reducing diarrhea.
23. The formulation for use according to claim 22, wherein said antibiotic and said formulation are administered simultaneously by oral route.
24. The formulation for use according to claim 1, wherein said pharmaceutical agent is selected in the group consisting of antineoplastic agents, for example topoisomerase I inhibitors such as Irinotecan, anti-inflammatory compounds or inhibitor of interleukin- 1 such as diacerhein, pancrelipase, selective phosphodiesterase 4 inhibitor used for the treatment of Chronic obstructive Pulmonary Disease (COPD) such as roflumilast or cilomilast and compounds having antiinflammatory and anti-mitotic activities such as colchicines, Irinotecan or a metabolite thereof, in particular SN-38.
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