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EP3220954A2 - Procédé de préparation de formulation parentérale d'anidulafungine - Google Patents

Procédé de préparation de formulation parentérale d'anidulafungine

Info

Publication number
EP3220954A2
EP3220954A2 EP15861353.9A EP15861353A EP3220954A2 EP 3220954 A2 EP3220954 A2 EP 3220954A2 EP 15861353 A EP15861353 A EP 15861353A EP 3220954 A2 EP3220954 A2 EP 3220954A2
Authority
EP
European Patent Office
Prior art keywords
anidulafungin
acid
hydroxypropylbetadex
pharmaceutically acceptable
active
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP15861353.9A
Other languages
German (de)
English (en)
Other versions
EP3220954A4 (fr
Inventor
Mitesh Natavarlal Patel
Mafatlal Tribhovandas DAVE
Pranavkumar Jayesh Choksi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gufic Biosciences Ltd
Original Assignee
Gufic Biosciences Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Gufic Biosciences Ltd filed Critical Gufic Biosciences Ltd
Publication of EP3220954A2 publication Critical patent/EP3220954A2/fr
Publication of EP3220954A4 publication Critical patent/EP3220954A4/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • the present invention relates to freeze dried, micelle-forming surfactant free pharmaceutical formulation of Anidulafungin along with a suitable solubilizing agent and acidifying agent for parenteral administration.
  • the pharmaceutical formulation provides sufficient solubilisation and stabilization of Anidulafungin thus improving the shelf life and reduces the likelihood of precipitation during storage.
  • the invention further relates to a process of preparation thereof.
  • Invasive fungal infections are a major and growing cause of morbidity and mortality in immune compromised patients such as patients with HIV/AIDS infection, those with hematologic malignancies (eg, leukemia, lymphoma), those with solid tumors, or among patients undergoing solid-organ, bone marrow, or hematopoietic stem cell transplantation, or who have been exposed to high-dose corticosteroids.
  • hematologic malignancies eg, leukemia, lymphoma
  • solid tumors or among patients undergoing solid-organ, bone marrow, or hematopoietic stem cell transplantation, or who have been exposed to high-dose corticosteroids.
  • corticosteroids hematopoietic stem cell transplantation
  • Anidulafungin is a semi synthetic lipopetide in the echinocandin class of antifungal drugs, which is administered intravenously to treat mucosal and invasive fungal infections. (Jose A. Vazquez, MD, Clinical Therapeutics/Volume 27, Number 6, 2005).
  • Anidulafungin is N-[(3S,6S,9S,l lR,15S,18S,20R,21R,24S,25S,26S)-6-[(lS,2R)-l,2- dihydroxy-2-(4-hydroxyphenyl)ethyl]-l l,20,21,25-tetrahydroxy-3,15-bis[(lR)-l- hydroxyethyl]-26-methyl-2,5,8, 14, 17,23-hexaoxo- 1 ,4,7, 13,16,22-hexaaza tricycle [22.3.0.09,13]heptacosan-18-yl]- 4- ⁇ 4-[4-(-(pentyloxy)phenyl]phenyl ⁇ benzamide)(Fig l)is insoluble in water with a pKa of 9.46. The solubility of Anidulafungin decreases further strongly when the pH is below 4.
  • Anidulafungin is marketed as lyophilized product for intravenous infusion by Pfizer under the trade name Eraxis. Anidulafungin is indicated for the treatment of oesophageal candidiasis, candidemia, and other invasive Candida infections including intra-abdominal abscess and peritonitis.
  • Currently available formulations in lyophilized vial contain micelle-forming surfactant which does not provide a freeze-dried product with desirable characteristics due to the sensitivity of surfactant against freeze drying. The presence of the surfactant causes the freeze-dried cake to "collapse" resulting in a residue at the bottom of the vial instead of a well-formed cake.
  • US6960564 discloses a freeze-dried formulation comprising anidulafungin, or a pharmaceutically acceptable salt thereof; a micelle-forming surfactant in an amount greater than 5% by weight which is selected from a polysorbate, a polyoxyethylene castor oil derivative, a polyoxyethylene stearate or combinations thereof; a bulking agent selected from mannitol, sucrose, trehalose, lactose, or mixtures thereof; and stabilizing agent comprising sucrose, fructose, trehalose or mixtures thereof.
  • a freeze-dried formulation comprising anidulafungin, or a pharmaceutically acceptable salt thereof; a micelle-forming surfactant in an amount greater than 5% by weight which is selected from a polysorbate, a polyoxyethylene castor oil derivative, a polyoxyethylene stearate or combinations thereof; a bulking agent selected from mannitol, sucrose, trehalose, lactose, or mixtures thereof; and stabilizing agent comprising sucrose
  • Cyclodexrtin and their derivatives are known generally to improve the dissolution rate of drugs and find applications in pharmaceutical delivery systems.
  • the complexes show increased aqueous solubility for pharmaceuticals with intrinsically low aqueous solubility resulting in the improved bioavailability of the drug.
  • the use of cyclodextrin for increasing the solubility of azole antifungals are known, however, the prior art is silent on use of cyclodextrin for increasing the solubility of Anidulafungin.
  • the present invention provides freeze dried, micelle-forming surfactant free pharmaceutical formulation of anidulafungin or pharmaceutically acceptable salt thereof along with a suitable solubilizing agent and acidifying agent for parenteral administration.
  • the solubility of Anidulafungin is increased by adding solubilizing agents selected from modified cyclodextrin derivatives such as hydroxypropylbetadex, sulfobutyl ether betacyclodextrin sodium or Tris buffer Hydrochloride salt.
  • the solubilizing agent is present in an amount in the ratio of 1 :20 to 1 :100, preferably 1 :62, more preferably 1 :44 by weight of the active.
  • the pH of the formulation is maintained in the range of 3 to 7, preferably between 4 to 6, more preferably between 4.0 and 5.5 using acidifying agents selected from organic acids such as Succinic acid, acetic acid, citric acid, tartaric acid, lactic acid or inorganic acid such as hydrochloric acid.
  • acidifying agents selected from organic acids such as Succinic acid, acetic acid, citric acid, tartaric acid, lactic acid or inorganic acid such as hydrochloric acid.
  • the pharmaceutical composition of Anidulafungin, solubilizing agent and an acidifying agent is freeze dried and is provided as a drug concentrate.
  • the present invention provides a method for increasing solubility of anidulafungin in an aqueous solution.
  • Anidulafungin is an uncrystalline powder with a pKa of 9.46 and is insoluble in water.
  • the solubility of Anidulafungin decreases further strongly when the pH is below 4.
  • a suitable solubilizer such as modified cyclodextrin derivatives or Tris buffer and maintaining appropriate pH of the formulation.
  • the present invention relates to freeze dried, micelle forming surfactant free pharmaceutical composition for parenteral administration comprising; Anidulafungin or a pharmaceutically acceptable salt thereof,
  • Anidulafungin or a pharmaceutically acceptable salt is present in the composition in an amount from 1 mg to 100 mg/vial; more preferably 50mg/vial and lOOmg/vial.
  • the solubility of Anidulafungin is increased using a suitable solubilizing agent where Anidulafungin can be maintained in a dissolved state in the aqueous solution thereby preventing crystallization or crystalline growth of Anidulafungin.
  • the solubilizing agent is selected from modified cyclodextrin derivatives such as hydroxypropylbetadex, sulfobutyl ether betacyclodextrin sodium or Tris buffer Hydrochloride salt.
  • the solubilizing agent is present in an amount in the ratio of 1 :20 to 1 :100, preferably 1 :62, more preferably 1 :44by weight of the active.
  • the pH of the formulation is maintained in the range of 3 to 7, preferably between 4 to 6, more preferably between 4.0 and 5.5 using acidifying agent selected from organic acid such as succinic acid, acetic acid, citric acid, tartaric acid, lactic acid or inorganic acid such as hydrochloric acid.
  • organic acid such as succinic acid, acetic acid, citric acid, tartaric acid, lactic acid or inorganic acid such as hydrochloric acid.
  • composition after freeze drying is chemically and physically stable over an extended period of time and is suitable for intended pharmaceutical use after reconstitution with water for injection, sodium chloride injection or 5% dextrose injection which is represented in the examples below.
  • the aqueous intravenous composition of the invention may also comprise a physiologically and pharmaceutically acceptable compound effective to render the aqueous intravenous composition isotonic, i.e. to have an osmotic pressure corresponding to that of a 0.9% solution of sodium chloride.
  • a physiologically and pharmaceutically acceptable compound effective to render the aqueous intravenous composition isotonic, i.e. to have an osmotic pressure corresponding to that of a 0.9% solution of sodium chloride.
  • chloride salts such as NaCl
  • saccharide such as sorbitol, mannitol and dextrose/glucose.
  • the preparation of isotonic solutions is well known for one skilled in the art.
  • the diluents suitable for the purpose of present invention include 5% Dextrose, 5% Glucose, Ringers solution, Lactated Ringers solution, saline solution and half normal saline.
  • the present invention provides a method of increasing solubility of Anidulafungin in an aqueous solution comprising the step of combining Anidulafungin aqueous solution with a solubilising agent and an acidifying agent. Alternately, adding solubilizing agent and an acidifying agent to the aqueous solution of Anidulafungin.
  • the solubilizing agent being the pharmaceutically acceptable solubilizing agent selected from modified cyclodextrin derivatives such as hydroxypropylbetadex, sulfobutyl ether betacyclodextrin sodium or Tris buffer Hydrochloride salt; preferably Hydroxypropylbetadex.
  • the acidifying agent is selected from organic acid such as succinic acid, acetic acid, citric acid, tartaric acid, lactic acid or inorganic acid such as hydrochloric acid, preferably tartaric acid or 0. IN hydrochloric acid.
  • organic acid such as succinic acid, acetic acid, citric acid, tartaric acid, lactic acid or inorganic acid such as hydrochloric acid, preferably tartaric acid or 0. IN hydrochloric acid.
  • the pH of aqueous composition is fixed such that the drug is sufficiently solubilized to achieve the desired concentration before reconstitution with suitable vehicle/solvent.
  • the present invention provides a method of increasing solubility of Anidulafungin in an aqueous solution comprising, adding 22% solution of Hydroxypropylbetadex as solubilizing agent and 0.1 N solution of hydrochloric acid as acidifying agent to the aqueous solution of Anidulafungin.
  • the invention provides a process for preparation of pharmaceutical composition, in particular for intravenous infusion, comprising Anidulafungin or a pharmaceutically acceptable salt thereof as the active ingredient, a pharmaceutically acceptable solubilizing agent, acceptable acidifying agent.
  • Anidulafungin or pharmaceutically acceptable salt thereof initially is solubilized in an aqueous solution containing solubilizing agent, preferably in the ratio 1 :44 followed by addition of acidifying agent, preferably 0.1 N Hydrochloric acid to adjust pH of solution to an acceptable level of range between 4.0- 5.5 followed by filtration from 0.22 micron filter paper.
  • the filtrate is then freeze dried to render it sterile and filling 10 ml quantity of filter solution in sterile glass container of 20 ml vial size.
  • the formulation of the current invention is meant for administration via the IV route, the selection of the above ingredients is done keeping in mind their compatibilities and stability during the rigorous process for lyophilization and also in terms of safety for use in patients as an intravenous injectable which is isotonic with blood tonicity.
  • the active ingredient of the composition needs to be dissolved sufficiently in the composition i.e. be free from visible particles.
  • freeze dried/lyophilized powder is used to obtain clear colourless solution, free from visible particles.
  • Freeze drying process involves cooling of product at suitable temperature not less than - 50°C, raising temperature to 0°C at suitable pressure of 200 mtorr to 100 mtorr in 45 hours, then at 75 mtorr, further raising temperature to +15°C in 22 hrs.
  • the freeze dried Anidulafungin when reconstituted with 15 ml of suitable vehicle contains final drug concentrate of 3.33 mg/ml.
  • the pharmaceutical composition of the invention described herein is freeze dried composition, which may also be prepared by dissolving Anidulafungin first in aqueous vehicle containing solubilizing agent then adjusting pH to desired range using acidifying agent.
  • freeze drying process for such a low soluble active ingredient needs special care and it is an art in its own way because of low concentration of solute (about 0.5%) and maximum amount of aqueous vehicle e.g. water for injection.
  • the freeze dried drug may be diluted with suitable diluent before administration as IV injection.
  • the final concentration of solution may be reduced to further desired level using 5% Dextrose infusion prior to administration to a patient.
  • the invention provides a method of treating or preventing an infection caused by a fungus or a parasite in an animal in need thereof which comprises administering to said animal an effective amount of the pharmaceutical composition of the instant invention.
  • the present invention relates to the use of anidulaiungin parenteral formulation for treating or preventing an infection caused by a fungus or a parasite in an animal in need thereof.
  • compositions of the present invention are administered to a patient according to a dosing regimen.
  • a dosing regimen for any particular patient will depend on a variety of factors, including age, body weight, general health, sex, diet, time of administration, specific disease being treated, and the severity of the condition among other factors and the judgment of the treating physician.
  • Other features and embodiments of the invention will become apparent by the following examples which are given for illustration of the invention rather than limiting its intended scope. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art.
  • Anidulaiungin (active) or pharmaceutically acceptable salt was added to an aqueous solution containing pre-decided quantity of Kollidon PF 12 and stirred for some time. Solution was further sonicated. The solution was divided in to 4 equal parts.
  • citric acid solution was added but Anidulafungin did not dissolve in it and remained as undissolved particles.
  • Anidulafungin (active) or pharmaceutically acceptable salt was added to an aqueous solution containing pre-decided quantity of Kollidon PF 12 and stirred for some time. Solution was further sonicated. To this solution 1% sodium hydroxide solution was added drop wise but the resulting clear solution changed color and assay of active went down and out of specifications when measured by spectrophotometer.
  • Trisodium citrate solution was added drop wise but the active remained insoluble.
  • Suitable trial was done using micelle forming surfactant like Polysorbate 80 to dissolve active product Anidulafungin in aqueous base along with suitable acidifying agent like tartaric acid and isotonic agent like mannitol, to check and compare solubility and stability of liquid preparation. Accordingly following process was followed:
  • Example 18 For process validation further two trials were taken on similar line of Example 17 and results are summarized in tabular form as follow as Example 18 & Example. 19.
  • freeze dried product so obtained dissolved easily in 15ml water for injection, to form clear colourless solution.
  • the present invention provides water soluble Anidulafungin as freeze dried stable formulation, stable for 6 months, when stored at 25°C.
  • the pharmaceutical composition comprising anidulafungin as active is free from micelle forming surfactants such as polysorbates, lecithin, bilesalts, polyoxyethylene, castor oils and mixtures thereof without compromising solubility of drug and whose solution before Lyophilization has a pH between 4.0 to 5.5.
  • surfactants such as polysorbates, lecithin, bilesalts, polyoxyethylene, castor oils and mixtures thereof without compromising solubility of drug and whose solution before Lyophilization has a pH between 4.0 to 5.5.
  • the formulation is stable for the entire period of the shelf life.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Inorganic Chemistry (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne une formulation pharmaceutique lyophilisée d'anidulafungine sans tensioactif et formant des micelles, conjointement avec un agent de solubilisation approprié et un agent acidifiant pour une administration parentérale. La formulation pharmaceutique confère une solubilisation et stabilisation suffisantes de l'anidulafungine, permet d'améliorer la durée de conservation et réduit la probabilité de précipitation pendant le stockage. L'invention concerne également un procédé de préparation de ladite formulation.
EP15861353.9A 2014-11-19 2015-09-07 Procédé de préparation de formulation parentérale d'anidulafungine Withdrawn EP3220954A4 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN3668MU2014 2014-11-19
PCT/IN2015/000349 WO2016079749A2 (fr) 2014-11-19 2015-09-07 Procédé de préparation de formulation parentérale d'anidulafungine

Publications (2)

Publication Number Publication Date
EP3220954A2 true EP3220954A2 (fr) 2017-09-27
EP3220954A4 EP3220954A4 (fr) 2018-06-27

Family

ID=56014644

Family Applications (1)

Application Number Title Priority Date Filing Date
EP15861353.9A Withdrawn EP3220954A4 (fr) 2014-11-19 2015-09-07 Procédé de préparation de formulation parentérale d'anidulafungine

Country Status (4)

Country Link
EP (1) EP3220954A4 (fr)
EA (1) EA201791100A1 (fr)
WO (1) WO2016079749A2 (fr)
ZA (1) ZA201703330B (fr)

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000051564A1 (fr) * 1999-03-03 2000-09-08 Eli Lilly And Company Formulations pharmaceutiques d'echinocandine contenant des tensioactifs formant des micelles
US6991800B2 (en) * 2002-06-13 2006-01-31 Vicuron Pharmaceuticals Inc. Antifungal parenteral products
US20090238867A1 (en) * 2007-12-13 2009-09-24 Scott Jenkins Nanoparticulate Anidulafungin Compositions and Methods for Making the Same
EP3960185A1 (fr) * 2010-06-29 2022-03-02 Merck Sharp & Dohme Corp. Formulations de solution intraveineuse de posaconazole stabilisées par bêta-cyclodextrine substituée

Also Published As

Publication number Publication date
ZA201703330B (en) 2019-07-31
EP3220954A4 (fr) 2018-06-27
WO2016079749A3 (fr) 2016-07-21
EA201791100A1 (ru) 2017-11-30
WO2016079749A2 (fr) 2016-05-26

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