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WO2018219804A1 - Self-microemulsifying drug delivery systems - Google Patents

Self-microemulsifying drug delivery systems Download PDF

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Publication number
WO2018219804A1
WO2018219804A1 PCT/EP2018/063778 EP2018063778W WO2018219804A1 WO 2018219804 A1 WO2018219804 A1 WO 2018219804A1 EP 2018063778 W EP2018063778 W EP 2018063778W WO 2018219804 A1 WO2018219804 A1 WO 2018219804A1
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Prior art keywords
glycerides
alkyl
composition
salts
surfactant
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Application number
PCT/EP2018/063778
Other languages
French (fr)
Inventor
Ildiko Terebesi
Peter Serno
Steffen SANDMANN
Original Assignee
Bayer Pharma Aktiengesellschaft
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Publication of WO2018219804A1 publication Critical patent/WO2018219804A1/en

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    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin

Definitions

  • the present invention relates to self-microemulsifying drug delivery systems ("SMEDDS”) of selective partial adenosine A1 receptor agonists, with enhanced bioavailability, and a process of preparing said SMEDDS.
  • SMEDDS self-microemulsifying drug delivery systems
  • SMEDDS Self-microemulsifying drug delivery systems
  • a SMEDDS is a mixture of a drug, an oil or lipid, a surfactant, and optionally a co-solvent or co-surfactant, that rapidly forms a transparent (or at least translucent), stable microemulsion upon dilution with water (see Eur. J. Pharm Sci. 2009, 38, 479-488).
  • SMEDDS offer numerous advantages: spontaneous formation, ease of manufacture, thermodynamic stability, and improved solubilization of bioactive materials ⁇ see Adv. Colloid Interface Sci. 2006, 128-130, 47-64).
  • the invention thus provides a composition comprising
  • Selective partial adenosine A1 receptor agonists are compounds of the formula (X)
  • R 1 represents (Ci-C 4 )-alkyl
  • R 2 represents (Ci-C 4 )-alkyl
  • (Ci-C 4 )-alkyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, trifluoromethoxy, (Ci-C 4 )- alkoxy, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkoxy and (Ci-C 4 )-alkylsulphonyl,
  • R 1 and R 2 each represent hydrogen
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a 4- to 7-membered het- erocycle which may contain a further heteroatom from the group consisting of N, O and S, where the 4- to 7-membered heterocycle may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, (Ci- C4)-alkyl, trifluoromethyl and (Ci-C4)-alkoxy,
  • the compounds according to the invention may exist in stereoisomeric forms (enantiomers, diastereomers).
  • the invention therefore encompasses the enantiomers or dia- stereomers and the respective mixtures thereof. It is possible to isolate the stereoisomerically homogeneous constituents from such mixtures of enantiomers and/or diastereomers in a known manner.
  • the present invention encompasses all the tautomeric forms.
  • Preferred salts in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also encompassed are salts which are not themselves suitable for pharmaceutical applications but can be used, for example, for isolation or purification of the compounds of the invention.
  • Physiologically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulphonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, trifluoro- acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • hydrochloric acid hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, trifluoro- acetic acid, propionic acid, lactic acid, tart
  • Physiologically acceptable salts of the compounds of the invention also include salts of conventional bases, by way of example and with preference alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, by way of example and with preference ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzyla- mine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
  • alkali metal salts e.g. sodium and potassium salts
  • alkaline earth metal salts e.g. calcium and magnesium salts
  • ammonium salts derived from ammonia or organic amines
  • solvates in the context of the invention are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a specific form of the solvates in which the coordination is with water. Solvates preferred in the context of the present invention are hydrates. In the context of the present invention, unless specified otherwise, the substituents are defined as follows:
  • Alkyl in the context of the invention is a linear or branched alkyl radical having 1 to 4 carbon atoms. Preferred examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
  • Cvcloalkyl in the context of the invention is a monocyclic saturated carbocycle having 3 to 7 ring carbon atoms.
  • Preferred examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Alkoxy in the context of the invention is a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms.
  • Preferred examples include: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy.
  • Cycloalkoxy in the context of the invention is a monocyclic saturated carbocycle which has 3 to 7 carbon atoms and is bonded via an oxygen atom.
  • Preferred examples include: cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy.
  • Alkylsulphonyl in the context of the invention is a straight-chain or branched alkyl radical which has 1 to 4 carbon atoms and is attached via a sulphonyl group.
  • Preferred examples include: me- thylsulphonyl, ethylsulphonyl, n-propylsulphonyl, isopropylsulphonyl, n-butylsulphonyl and tert- butylsulphonyl.
  • Heterocycle in the context of the invention is a saturated heterocycle which has a total of 4 to 7 ring atoms, contains one or two ring heteroatoms from the group consisting of N, O and S and is attached via a ring carbon atom or optionally a ring nitrogen atom.
  • Examples include: azetidinyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpho- linyl, thiomorpholinyl and azepanyl. Preference is given to azetidinyl, pyrrolidinyl, piperidinyl and morpholinyl.
  • the selective partial adenosine A1 receptor agonists are compounds of the formula (X), in which
  • R 1 represents (Ci-C3)-alkyl
  • R 2 represents (Ci-C3)-alkyl
  • (Ci-C3)-alkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, methoxy, ethoxy, cyclopropyl and cyclobutyl,
  • R 1 and R 2 each represent hydrogen
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycle which may contain a further heteroatom from the group consisting of N, O and S, where the 4- to 6-membered heterocycle may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, trifluoromethoxyl, (Ci-C4)-alkyl, trifluoromethoxy, methoxy and ethoxy,
  • the selective partial adenosine A1 receptor agonists are compounds of the formula (X), in which
  • R 1 represents ethyl
  • R 2 represents ethyl
  • R 1 and R 2 each represent hydrogen
  • R 1 and R 2 together with the nitrogen atom to which they are attached form an azetidinyl, pyrroli- dinyl or piperidinyl ring,
  • azetidinyl ring may be substituted by a methoxy substituent
  • the selective partial adenosine A1 receptor agonists are selected from the group consisting of
  • compositions according to the present invention are in particular selected from the following list:
  • the selective partial adenosine A1 receptor agonists are present in the compositions according to the invention in a concentration range of 1 to 5 mg/mL, preferably in the range of 1.5 to 3.5 mg/mL, further preferred in the range of 2.25 to 3 mg/mL.
  • cardi- ovascular disorders like e.g. coronary heart disease, ischemic injury during acute coronary syndrome, angina pectoris, heart failure, worsening chronic heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), myocardial infarction and atrial fibrillation
  • Suitable oils or lipids are medium- or long-chain glycerides, which contain fatty acids of varying chain lengths and degrees of unsaturation.
  • lipid ingredients include synthetic lipids and lipids of natural sources:
  • Caprol 3GO i.e. C8:C10 triglyceride
  • Labrafac® Lipophile WL 1349 ⁇ medium chain triglycerides [caprylic (C8) 50-80%, capric (C10) 20-50%] ⁇
  • Labrafac® PG propylene glycol dicaprylocarate
  • Labrafil® M 2130 CS laauroyl polyoxyl-6 glycerides
  • oils from apricot kernel, canola, castor, coconut, corn, olive, palm, palm kernel, peanut, safflower, sesame, soybean, sunflower.
  • the fatty acid composition of the natural product oils is as follows (see Drug Dev. Ind. Pharm. 2013, 39, 1-19):
  • the lipid is preferably selected from Labrafil® M 1944 CS, MaisineTM 35-1 , Capmul® MCM and soybean oil.
  • Suitable surfactant should have a hydrophilic-lipophilic balance (HLB) value of 12 or higher, preferably in the range of 12 to 15.
  • HLB hydrophilic-lipophilic balance
  • Labrasol® ⁇ caprylocaproyl macrogol-8-glycerides [caprylic (C8) 50-80%, capric (C10) 20-50%] ⁇ , Cremophor® EL or ELP (polyoxy-35-castor oil), Cremophor® RH40 (polyoxy-40-hydrogenated castor oil), Cremophor® A25 ⁇ Macrogol 25 cetostearyl ether [stearic (C18) and cetyl (C16)] ⁇ , Vitamin E® TPGS (Vit E d-a-tocopheryl polyethylene glycol 1000 succinate), Gelucire® 44/14 ⁇ lau- royl polyoxylglycerides [C12 (40-50%); C14 (14-24%); C8 (4-10%), C10 (3-9%), C16 (4-14%), C18 (5-5%)] ⁇ , Gelucire® 50/13 ⁇ stearoyl polyoxyl-32 glycerides [C16 (40-50%); C18 (48-58%); C16
  • Preferred surfactants are Labrasol®, Cremophor® RH40, Cremophor® EL, Cremophor® ELP and Tween® 80.
  • Co-solvents or co-surfactant are selected from medium chain length alcohols (C2-C8), propylene glycol, PEG 300 or PEG 400.
  • composition according to the invention comprises the following:
  • composition according to the invention comprises 10 to 50 % (v/v) of the oil or lipid, more preferably 10 to 30%.
  • composition according to the invention comprises 35 to 85 % (v/v) of the surfactant.
  • composition according to the invention comprises 0 to 40 % (v/v) of the co-solvent or co- surfactant, preferably 10 to 40%.
  • Contents of the excipients is given in % (v/v) based on the content of lipid, surfactant and co- solvent or co-surfactant.
  • compositions according to the invention comprise the following li- pid/surfactant/co-solvent or co-surfactant:
  • compositions according to the invention comprising one of the following lipid/surfactant co-solvent or co-surfactant combinations:
  • composition containing as active ingredient the compound of formula (II), 30% Labrafil® M 1944 CS, 70% Labrasol (where the percentages given relate to the content of lipid and surfactant only).
  • the invention thus provides a composition comprising
  • R 1 represents (Ci-C4)-alkyl
  • R 2 represents (Ci-C4)-alkyl
  • (Ci-C4)-alkyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, trifluorometh- oxy, (Ci-C4)-alkoxy, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkoxy and (Ci-C4)-alkylsulphonyl, or
  • R 1 and R 2 each represent hydrogen
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a 4- to 7- membered heterocycle which may contain a further heteroatom from the group consisting of N, O and S,
  • 4- to 7-membered heterocycle may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of fluorine, trifluorome- thyl, (Ci-C4)-alkyl, trifluoromethyl and (Ci-C4)-alkoxy,
  • an oil or lipid selected from Caprol 3GO (i.e. C8:C10 triglyceride), Labrafac® Lipophile WL 1349 ⁇ medium chain triglycerides [caprylic (C8) 50-80%, capric (C10) 20-50%] ⁇ , Labrafac® PG (propylene glycol dicaprylocarate), Labrafil® M 1944 CS ⁇ oleoyl polyoxyl-6 glycerides [oleic (C18:1 ) 58-68%, linoleic (C18:2) 22-32%] ⁇ , Labrafil® M 2125 CS ⁇ linoleoyl polyoxyl-6 glycerides [oleic (C18:1 ) 24-34%, linoleic (C18:2) 53-63%] ⁇ , Labrafil® M 2130 CS (lauroyl polyoxyl-6 glycerides), Labrafac® CM 10 ⁇ C8-C10 polygly
  • a surfactant having a hydrophilic-lipophilic balance (HLB) value of 12 or higher, and
  • a co-solvent or co-surfactant selected from medium chain length alcohols (C2- C8), propylene glycol, PEG 300 or PEG 400, or both.
  • compositions according to the invention Another subject of the invention is a method for preparing the compositions according to the invention. Thereby, the excipients are mixed until a clear solution is obtained. In the second step the active ingredient is dissolved in the excipients mixture under stirring. If necessary, slight warming an sonication by ultrasound is applied to facilitate the dissolution of the active ingredient.
  • the composition according to the invention can be packaged in any pharmaceutical composition for oral administration.
  • Suitable oral compositions that comprise the composition according to the invention are generally capsules, including hard gelatin capsules or soft gelatin capsules.
  • soft gelatin capsules are made with a gelatin shell, optionally in association with plasticizers such as glycerine and/or sorbitol. Encapsulation is achieved by techniques known in the art. If hard capsules are used, this may be prepared of gelatin or HPMC.
  • the composition according to the invention may be packaged into a solid dosage form, e.g. by absorption to absorbing carriers, such as Neusilin® or Fujicalin®.
  • the received dry granules can further be processed, e.g. by compression to tablets.
  • the final solid for- mulation still maintains its property to be readily converted to a microemulsion in vivo, which thereby enhances the dissolution of the drug.
  • Tween® 80 (83.3 %) and soybean oil (16.7%) are mixed until a homogeneous liquid is obtained. Therein the active ingredient is dissolved under stirring at a concentration of 2.89 mg/ml.
  • Cremophor ® ELP 75%) and Capmul ® MCM (25%) are mixed until a homogeneous liquid is obtained. Therein the active ingredient is dissolved under stirring at a concentration of 2.4mg/ml.
  • the emulsification property in aqueous media is summarized in table 1.
  • Labrafil M1944CS (30%) and Labrasol (70%) are mixed until a homogeneous liquid is obtained. Therein the active ingredient is dissolved under stirring at a concentration of 2.9mg/ml.
  • Propylene glycol (10%), ethanol (14%), Maisine 35-1 (36%) and Cremophor® RH40 (40%) are mixed until a homogeneous liquid is obtained. Therein the active ingredient is dissolved under stir- ring at a concentration of 2.33mg/ml.
  • the in-vivo plasma pharmacokinetics of the compound of formula (II) were investigated in fasted male Wistar rats after single peroral administration of four SMEDDS (selected from above examples based on the following main formulation component: Labrafil, Cremophor RH40, Cremophor ELP and Tween80) compared to a solution of a prodrug of the compound of formula (II).
  • the four SMEDDS were ready-to-use formulations for directly dosing of the animals with an administration volume of 5 mL/kg. Since the compound of formula (II) has a very low solubility in water for the purpose of comparison with the formulations according to the invention the hydrochloride salt of the prodrug (i.e. 2- ⁇ 4-[2-( ⁇ [2-(4-chlorophenyl)-1 ,3-thiazol-4-yl]methyl ⁇ sulfanyl)-3,5- dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl]phenoxy ⁇ ethyl L-alanyl-L-alaninate hydrochloride) is used to obtain a solution.
  • This prodrug of the compound of formula (II) was dissolved in a PEG-400/EtOH- based formulation and dosed in 5 mL/kg to the animals.
  • the administered doses are related to the compound of formula (II). Plasma samples were collected at predefined time points up to 30 h post dosing for the SMEDDS and up to 96 h post dosing for the solution.
  • the calculated pharmacokinetic parameters refer to the compound of formula (II) (analyte) and are summarized in the table below.
  • the relative bioavailability (F re i, prodrug solution set to 100 %) was 147% for Labrafil, thus clearly higher then solution, and ranged between 70 % - 76 % for Cremophor RH40, Cremophor ELP and Tween80. Since the compound of formula (II) has a very low solubility in water it is thus surprising that such a high relative bioavailability can be reached using the SMEDDS formulations according to the invention, in one case even much higher when compared with the prodrug solution.
  • the maximum concentration of the compound of formula (II) in rat plasma was reached 3 h after administration of the prodrug in solution, whereas t ma x of the four SMEDDS was between 5 h - 7 h, thus somewhat later.
  • the dose-normalized C ma x of the compound of formula (II) was 0.0716 kg/L after dosing as prodrug in solution.
  • Cmax of the four SMEDDS was lower compared to solution ranging between 0.033 kg/L and 0.052 kg/L.
  • the elimination half-life of the compound of formula (II) was about 6 h determined in the interval up to 32 h when administered as prodrug in solution.
  • the elimination half-life of the compound of formula (II) was slightly longer in Labrafil with approx.

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Abstract

The present invention relates to self-microemulsifying drug delivery systems ("SMEDDS") of se- lective partial adenosine A1 receptor agonists, with enhanced bioavailability, and a process of preparing said SMEDDS.

Description

Self-microemulsifyinq drug delivery systems
The present invention relates to self-microemulsifying drug delivery systems ("SMEDDS") of selective partial adenosine A1 receptor agonists, with enhanced bioavailability, and a process of preparing said SMEDDS.
Poor soluble drugs in their crystalline form often show poor bioavailability. This might be managed by transforming the crystalline into a dissolved / solubilized form, e.g. by using SMEDDS.
Self-microemulsifying drug delivery systems ("SMEDDS") are known as formulations useful for the oral administration of drugs (see Eur. J. Pharm Sci. 2000, 11 Suppl. 2, S93-S98). A SMEDDS is a mixture of a drug, an oil or lipid, a surfactant, and optionally a co-solvent or co-surfactant, that rapidly forms a transparent (or at least translucent), stable microemulsion upon dilution with water (see Eur. J. Pharm Sci. 2009, 38, 479-488). SMEDDS offer numerous advantages: spontaneous formation, ease of manufacture, thermodynamic stability, and improved solubilization of bioactive materials {see Adv. Colloid Interface Sci. 2006, 128-130, 47-64).
The invention thus provides a composition comprising
(a) a selective partial adenosine A1 receptor agonist,
(b) an oil or lipid,
(c) a surfactant, and
(d) optionally a co-solvent or co-surfactant, or both.
Selective partial adenosine A1 receptor agonists according to this invention are compounds of the formula (X)
Figure imgf000002_0001
in which
R1 represents (Ci-C4)-alkyl,
R2 represents (Ci-C4)-alkyl,
where (Ci-C4)-alkyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, trifluoromethoxy, (Ci-C4)- alkoxy, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkoxy and (Ci-C4)-alkylsulphonyl,
or R1 and R2 each represent hydrogen
or
R1 and R2 together with the nitrogen atom to which they are attached form a 4- to 7-membered het- erocycle which may contain a further heteroatom from the group consisting of N, O and S, where the 4- to 7-membered heterocycle may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, (Ci- C4)-alkyl, trifluoromethyl and (Ci-C4)-alkoxy,
and the salts, solvates, and solvates of the salts thereof.
Depending on their structure, the compounds according to the invention may exist in stereoisomeric forms (enantiomers, diastereomers). The invention therefore encompasses the enantiomers or dia- stereomers and the respective mixtures thereof. It is possible to isolate the stereoisomerically homogeneous constituents from such mixtures of enantiomers and/or diastereomers in a known manner.
If the compounds according to the invention can occur in tautomeric forms, the present invention encompasses all the tautomeric forms.
Preferred salts in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also encompassed are salts which are not themselves suitable for pharmaceutical applications but can be used, for example, for isolation or purification of the compounds of the invention.
Physiologically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulphonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, trifluoro- acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
Physiologically acceptable salts of the compounds of the invention also include salts of conventional bases, by way of example and with preference alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, by way of example and with preference ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzyla- mine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
Designated as solvates in the context of the invention are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a specific form of the solvates in which the coordination is with water. Solvates preferred in the context of the present invention are hydrates. In the context of the present invention, unless specified otherwise, the substituents are defined as follows:
Alkyl in the context of the invention is a linear or branched alkyl radical having 1 to 4 carbon atoms. Preferred examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
Cvcloalkyl in the context of the invention is a monocyclic saturated carbocycle having 3 to 7 ring carbon atoms. Preferred examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
Alkoxy in the context of the invention is a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms. Preferred examples include: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy.
Cycloalkoxy in the context of the invention is a monocyclic saturated carbocycle which has 3 to 7 carbon atoms and is bonded via an oxygen atom. Preferred examples include: cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy.
Alkylsulphonyl in the context of the invention is a straight-chain or branched alkyl radical which has 1 to 4 carbon atoms and is attached via a sulphonyl group. Preferred examples include: me- thylsulphonyl, ethylsulphonyl, n-propylsulphonyl, isopropylsulphonyl, n-butylsulphonyl and tert- butylsulphonyl.
Heterocycle in the context of the invention is a saturated heterocycle which has a total of 4 to 7 ring atoms, contains one or two ring heteroatoms from the group consisting of N, O and S and is attached via a ring carbon atom or optionally a ring nitrogen atom. Examples include: azetidinyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpho- linyl, thiomorpholinyl and azepanyl. Preference is given to azetidinyl, pyrrolidinyl, piperidinyl and morpholinyl.
In one embodiment of the invention the selective partial adenosine A1 receptor agonists are compounds of the formula (X), in which
R1 represents (Ci-C3)-alkyl,
R2 represents (Ci-C3)-alkyl,
where (Ci-C3)-alkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, methoxy, ethoxy, cyclopropyl and cyclobutyl,
or
R1 and R2 each represent hydrogen
or
R1 and R2 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycle which may contain a further heteroatom from the group consisting of N, O and S, where the 4- to 6-membered heterocycle may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, trifluoromethoxyl, (Ci-C4)-alkyl, trifluoromethoxy, methoxy and ethoxy,
and the salts, solvates, and solvates of the salts thereof.
In one embodiment of the invention the selective partial adenosine A1 receptor agonists are compounds of the formula (X), in which
R1 represents ethyl,
R2 represents ethyl,
or
R1 and R2 each represent hydrogen
or
R1 and R2 together with the nitrogen atom to which they are attached form an azetidinyl, pyrroli- dinyl or piperidinyl ring,
where the azetidinyl ring may be substituted by a methoxy substituent,
and the salts, solvates, and solvates of the salts thereof.
In one embodiment of the invention the selective partial adenosine A1 receptor agonists are selected from the group consisting of
2-amino-6-({[2-(4-chlorophenyl)-1 ,3-thiazol-4-yl]methyl}sulphanyl)-4-[4-(2-hydroxyethoxy)phenyl]- pyridine-3,5-dicarbonitrile (known from WO 03/053441 ),
2-({[2-(4-chlorophenyl)-1 ,3-thiazol-4-yl]methyl}sulphanyl)-6-(diethylamino)-4-[4-(2-hydroxyethoxy)- phenyl]pyridine-3,5-dicarbonitrile (known from WO 2010/086101 ),
2-({[2-(4-chlorophenyl)-1 ,3-thiazol-4-yl]methyl}sulphanyl)-4-[4-(2-hydroxyethoxy)phenyl]-6-(3- methoxyazetidin-1 -yl)pyridine-3,5-dicarbonitrile (known from WO 2010/086101 ),
2-({[2-(4-chlorophenyl)-1 ,3-thiazol-4-yl]methyl}sulphanyl)-4-[4-(2-hydroxyethoxy)phenyl]-6-(pyrroli- din-1 -yl)pyridine-3,5-dicarbonitrile(known from WO 2010/086101 ),
2-({[2-(4-chlorophenyl)-1 ,3-thiazol-4-yl]methyl}sulphanyl)-4-[4-(2-hydroxyethoxy)phenyl]-6-(piperi- din-1 -yl)pyridine-3,5-dicarbonitrile (known from WO 2010/086101 ),
and the salts, solvates, and solvates of the salts thereof.
Selective partial adenosine A1 receptor agonists which may be converted into the compositions according to the present invention are in particular selected from the following list:
2-Amino-6-({[2-(4-chlorophenyl)-1 ,3-thiazol-4-yl]methyl}sulfanyl)-4-[4-(2-hydroxyethoxy)phenyl]- pyridine-3,5-dicarbonitrile (known from WO 03/053441 and also known as Capadenoson)
Figure imgf000006_0001
2-({[2-(4-Chlorophenyl)-1 ,3-thiazol-4-yl]methyl}sulfanyl)-4-[4-(2-hydroxyethoxy
1-yl)pyridine-3,5-dicarbonitrile (known from WO 2010/086101 and also known as Neladenoson)
Figure imgf000006_0002
The selective partial adenosine A1 receptor agonists are present in the compositions according to the invention in a concentration range of 1 to 5 mg/mL, preferably in the range of 1.5 to 3.5 mg/mL, further preferred in the range of 2.25 to 3 mg/mL.
The compounds according to formula (X), in particular according to formula (I) and (II), act as partial adenosine A1 receptor agonists and may be used for the prevention and/or treatment of cardi- ovascular disorders like e.g. coronary heart disease, ischemic injury during acute coronary syndrome, angina pectoris, heart failure, worsening chronic heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), myocardial infarction and atrial fibrillation
Suitable oils or lipids are medium- or long-chain glycerides, which contain fatty acids of varying chain lengths and degrees of unsaturation. Examples of lipid ingredients include synthetic lipids and lipids of natural sources:
Caprol 3GO (i.e. C8:C10 triglyceride), Labrafac® Lipophile WL 1349 {medium chain triglycerides [caprylic (C8) 50-80%, capric (C10) 20-50%]}, Labrafac® PG (propylene glycol dicaprylocarate), Labrafil® M 1944 CS {oleoyl polyoxyl-6 glycerides [oleic (C18:1 ) 58-68%, linoleic (C18:2) 22-32%]}, Labrafil® M 2125 CS {linoleoyl polyoxyl-6 glycerides [oleic (C18:1 ) 24-34%, linoleic (C18:2) 53- 63%]}, Labrafil® M 2130 CS (lauroyl polyoxyl-6 glycerides), Labrafac® CM 10 {C8-C10 polygly- colized glycerides [caprylic (C8) 50%, capric (C10) 50%]}, Labrafil® WL 2609 BS {linoleoyl macrogol glycerides [oleic (C18:1 ) 24-34%, linoleic (C18:2) 53-63%]}, Lauroglycol™ 90 {propylene glycol monolaurate Type II [monoesters > 90%, C12 (lauric acid) > 95%]}, Lauroglycol™ FCC {propylene glycol laurate Type I [monoesters 45-70%, 30-55% diester >95% C12], Maisine™ 35-1 {glyceryl monolinoleate [C18:2 >50% max; C18:1 10-35%; C18:0 <6%; C16 4-20%]}, Capryol™ 90 {propylene glycol monocaprylate [>90% monoester of C8 (caprylic acid)]}, Capryol™ PGMC 90 (propylene glycol monocaprylate; >60% Monoester >90% C8), Peceol™ {glyceryl mono-oleate [C18:1 > 60%; C18:2 < 35%; C18:0 < 6%; C16 < 12% 0-5%]}, Plurol oleique® CC497 (polyglyceryl-3 dioleate), Plurol® (diisostearate triglycerol diisostearate), Transcutol® HP [diethylene glycol monoethyl ether (>99.9%)], Transcutol® P (diethylene glycol monoethyl ether), Captex® 355 (caprylic/capric triglyceride), Captex® 200 (propylene glycol dicaprylate/dicaprate), Migliol® 810 {medium chain fatty acids [C8 (65-80%); C10 (20-35%)]}, Migliol® 812 {medium chain fatty acids [C8 (50-65%); C10 (30- 45%)]}, Migliol® 840 (medium chain diesters of propylene glycols), Miglyol® 818 {medium chain fatty acids [C8 (45-65%); C10 (30-45%); C18:2 (2-5%)]}, Capmul® MCM {glyceryl monocaprylate [(58% monoglyceride, 36% diglyceride, 5% triglyceride; 80% C8, 20% C10)]}, Capmul® MCM C8 {glyceryl monocaprylate [(68% monoglyceride, 27% diglyceride, 3% triglyceride; >95% C8, 3% C10)]}, Capmul® MCM C10 {glyceryl monocaprylate [(>45% monoglyceride; >45% C10)], Imwitor® 742 [monoglyceride/diglyceride/triglyceride of C8 and C10 fatty acid (45-55% monoglyceride)], Imwitor® 928 [monoglyceride/diglyceride/triglyceride of saturated fatty acids of coconut oil (40% MG)], Myrj® 45 {PEG 400 monostearate polyoxy 8 stearate [Stearic (C18) acid]};
or natural product oils from apricot kernel, canola, castor, coconut, corn, olive, palm, palm kernel, peanut, safflower, sesame, soybean, sunflower.
The fatty acid composition of the natural product oils is as follows (see Drug Dev. Ind. Pharm. 2013, 39, 1-19):
Oil C8 C10 C12 C14 C16 C18 C18:1 C18:1-OH C18:2 C18:3
Apricot kernel - - - - - 1.0 64.2 - 28.3 0.2
Canola - - - - 4.7 2.0 60.0 - 21.7 9.1
Castor - - - - 2.0 1.0 7.0 87 3.0 -
Coconut 2.4 2.7 44.4 16.6 9.6 2.8 17.8 - 3.1 0
Corn - - - - 10.7 1.6 24.5 - 10.7 1.1
Olive - - - - 12.9 71.2 71.2 - 10.0 0.9
Palm - - - 1.0 45.0 40.0 40.0 - 2.0 -
Palm kernel - 4.0 48.0 16.0 8.0 15.0 15.0 - 36.0 -
Peanut - - - - 12.0 48.0 48.0 - 36.0 0
Safflower - - - - 5.5 11.1 1 1.1 - 81.4 0.4
Sesame - - - - 9.0 41.0 41.0 - 45.0 -
Soybean - - - - 10.4 21.5 21.5 - 51.5 7.8
Sunflower - - - - 6.2 20.7 20.7 - 67.9 0.2 The lipid is preferably selected from Labrafil® M 1944 CS, Maisine™ 35-1 , Capmul® MCM and soybean oil.
To form efficient SMEDDS the selected surfactant should have a hydrophilic-lipophilic balance (HLB) value of 12 or higher, preferably in the range of 12 to 15. Suitable surfactant may thus be selected from:
Labrasol® {caprylocaproyl macrogol-8-glycerides [caprylic (C8) 50-80%, capric (C10) 20-50%]}, Cremophor® EL or ELP (polyoxy-35-castor oil), Cremophor® RH40 (polyoxy-40-hydrogenated castor oil), Cremophor® A25 {Macrogol 25 cetostearyl ether [stearic (C18) and cetyl (C16)]}, Vitamin E® TPGS (Vit E d-a-tocopheryl polyethylene glycol 1000 succinate), Gelucire® 44/14 {lau- royl polyoxylglycerides [C12 (40-50%); C14 (14-24%); C8 (4-10%), C10 (3-9%), C16 (4-14%), C18 (5-5%)]}, Gelucire® 50/13 {stearoyl polyoxyl-32 glycerides [C16 (40-50%); C18 (48-58%); C16+18 > 90%]}, Acconon® CC-6 (PEG-6 caprylic/capric glycerides), Brij® 97 {polyoxyl 10 oleyl ether Oleth 10 PEG monooleyl ether [Oleyl (C18:1 )]}, or Tween® 80 (polysorbate 80).
Preferred surfactants are Labrasol®, Cremophor® RH40, Cremophor® EL, Cremophor® ELP and Tween® 80.
Co-solvents or co-surfactant are selected from medium chain length alcohols (C2-C8), propylene glycol, PEG 300 or PEG 400.
In addition to the selective partial adenosine A1 receptor agonists the composition according to the invention comprises the following:
The composition according to the invention comprises 10 to 50 % (v/v) of the oil or lipid, more preferably 10 to 30%.
The composition according to the invention comprises 35 to 85 % (v/v) of the surfactant.
The composition according to the invention comprises 0 to 40 % (v/v) of the co-solvent or co- surfactant, preferably 10 to 40%.
Contents of the excipients is given in % (v/v) based on the content of lipid, surfactant and co- solvent or co-surfactant.
Particularly preferred compositions according to the invention comprise the following li- pid/surfactant/co-solvent or co-surfactant:
(A) Labrafil® M 1944 CS, Labrasol;
(B) Maisine™ 35-1 or Maisine CC, propylene glycol, Cremophor® RH40 and ethanol;
(C) Capmul® MCM, Cremophor® ELP;
(D) soybean oil, Tween® 80. In particular preferred are compositions according to the invention comprising one of the following lipid/surfactant co-solvent or co-surfactant combinations:
(E) 30% Labrafil® M 1944 CS, 70% Labrasol;
(F) 36% Maisine™ 35-1 or Maisine CC, 10% propylene glycol, 40% Cremophore® RH40 and 14% ethanol;
(G) 25% Capmul® MCM, 75% Cremophor® ELP;
(H) 16.7% soybean oil, 83.3% Tween® 80.
Further preferred are compositions (A) to (D) containing as active ingredient the compound of formula (I).
Further preferred are compositions (A) to (D) containing as active ingredient the compound of formula (II).
Very particularly preferred are compositions (E) to (H) containing as active ingredient the compound of formula (I).
Very particularly preferred are compositions (E) to (H) containing as active ingredient the compound of formula (II).
Very particularly preferred is the composition containing as active ingredient the compound of formula (II), 30% Labrafil® M 1944 CS, 70% Labrasol (where the percentages given relate to the content of lipid and surfactant only).
The invention thus provides a composition comprising
(a) a partial adenosine A1 receptor agonist of the formula (X)
Figure imgf000009_0001
in which
R1 represents (Ci-C4)-alkyl,
R2 represents (Ci-C4)-alkyl,
where (Ci-C4)-alkyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, trifluorometh- oxy, (Ci-C4)-alkoxy, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkoxy and (Ci-C4)-alkylsulphonyl, or
R1 and R2 each represent hydrogen
or
R1 and R2 together with the nitrogen atom to which they are attached form a 4- to 7- membered heterocycle which may contain a further heteroatom from the group consisting of N, O and S,
where the 4- to 7-membered heterocycle may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of fluorine, trifluorome- thyl, (Ci-C4)-alkyl, trifluoromethyl and (Ci-C4)-alkoxy,
and the salts, solvates, and solvates of the salts thereof,
an oil or lipid selected from Caprol 3GO (i.e. C8:C10 triglyceride), Labrafac® Lipophile WL 1349 {medium chain triglycerides [caprylic (C8) 50-80%, capric (C10) 20-50%]}, Labrafac® PG (propylene glycol dicaprylocarate), Labrafil® M 1944 CS {oleoyl polyoxyl-6 glycerides [oleic (C18:1 ) 58-68%, linoleic (C18:2) 22-32%]}, Labrafil® M 2125 CS {linoleoyl polyoxyl-6 glycerides [oleic (C18:1 ) 24-34%, linoleic (C18:2) 53-63%]}, Labrafil® M 2130 CS (lauroyl polyoxyl-6 glycerides), Labrafac® CM 10 {C8-C10 polyglycolized glycerides [caprylic (C8) 50%, capric (C10) 50%]}, Labrafil® WL 2609 BS {linoleoyl macrogol glycerides [oleic (C18:1 ) 24-34%, linoleic (C18:2) 53-63%]}, Lauroglycol™ 90 {propylene glycol monolaurate Type II [monoesters > 90%, C12 (lauric acid) > 95%]}, Lauroglycol™ FCC {propylene glycol laurate Type I [monoesters 45-70%, 30-55% diester >95% C12], Maisine™ 35-1 {glyceryl monolinoleate [C18:2 >50% max; C18:1 10-35%; C18:0 <6%; C16 4-20%]}, Capryol™ 90 {propylene glycol monocaprylate [>90% monoester of C8 (caprylic acid)]}, Capryol™ PGMC 90 (propylene glycol monocaprylate; >60% Monoester >90% C8), Peceol™ {glyceryl mono- oleate [C18:1 > 60%; C18:2 < 35%; C18:0 < 6%; C16 < 12% 0-5%]}, Plurol oleique® CC497 (polyglyceryl-3 dioleate), Plurol® (diisostearate triglycerol diisostearate), Trans- cutol® HP [diethylene glycol monoethyl ether (>99.9%)], Transcutol® P (diethylene glycol monoethyl ether), Captex® 355 (caprylic/capric triglyceride), Captex® 200 (propylene glycol dicaprylate/dicaprate), Migliol® 810 {medium chain fatty acids [C8 (65-80%); C10 (20- 35%)]}, Migliol® 812 {medium chain fatty acids [C8 (50-65%); C10 (30-45%)]}, Migliol® 840 (medium chain diesters of propylene glycols), Miglyol® 818 {medium chain fatty acids [C8 (45-65%); C10 (30-45%); C18:2 (2-5%)]}, Capmul® MCM {glyceryl monocaprylate [(58% monoglyceride, 36% diglyceride, 5% triglyceride; 80% C8, 20% C10)]}, Capmul® MCM C8 {glyceryl monocaprylate [(68% monoglyceride, 27% diglyceride, 3% triglyceride; >95% C8, 3% C10)]}, Capmul® MCM C10 {glyceryl monocaprylate [(>45% monoglyceride; >45% C10)], Imwitor® 742 [monoglyceride/diglyceride/triglyceride of C8 and C10 fatty acid (45- 55% monoglyceride)], Imwitor® 928 [monoglyceride/diglyceride/triglyceride of saturated fatty acids of coconut oil (40% MG)], Myrj® 45 {PEG 400 monostearate polyoxy 8 stearate [Stearic (C18) acid]}; or selected from natural product oils from apricot kernel, canola, castor, coconut, corn, olive, palm, palm kernel, peanut, safflower, sesame, soybean, sunflower,
(c) a surfactant having a hydrophilic-lipophilic balance (HLB) value of 12 or higher, and
(d) optionally a co-solvent or co-surfactant selected from medium chain length alcohols (C2- C8), propylene glycol, PEG 300 or PEG 400, or both.
Another subject of the invention is a method for preparing the compositions according to the invention. Thereby, the excipients are mixed until a clear solution is obtained. In the second step the active ingredient is dissolved in the excipients mixture under stirring. If necessary, slight warming an sonication by ultrasound is applied to facilitate the dissolution of the active ingredient. The composition according to the invention can be packaged in any pharmaceutical composition for oral administration.
Suitable oral compositions that comprise the composition according to the invention are generally capsules, including hard gelatin capsules or soft gelatin capsules. For instance, soft gelatin capsules are made with a gelatin shell, optionally in association with plasticizers such as glycerine and/or sorbitol. Encapsulation is achieved by techniques known in the art. If hard capsules are used, this may be prepared of gelatin or HPMC.
In a further embodiment, the composition according to the invention may be packaged into a solid dosage form, e.g. by absorption to absorbing carriers, such as Neusilin® or Fujicalin®. The received dry granules can further be processed, e.g. by compression to tablets. The final solid for- mulation still maintains its property to be readily converted to a microemulsion in vivo, which thereby enhances the dissolution of the drug.
The invention is explained further by means of the following examples.
Examples
After preparation the SMEDDS were characterized with respect to their emulsification properties. Therefore, 0.1 ml of the API-containing SMEDDS-solution is dissolved in 20ml of water for injection and sonicated for 5 min. The thereby formed specimen were visually assessed for their appearance and measured via photon correlation spectroscopy (PCS) for droplet size and polydispersity index (PDI).
Example 1
Tween® 80 (83.3 %) and soybean oil (16.7%) are mixed until a homogeneous liquid is obtained. Therein the active ingredient is dissolved under stirring at a concentration of 2.89 mg/ml.
The emulsification property in aqueous media is summarized in table 1. Example 2
Analogous to example 1 but the mixture is formulated as granulate by adding the SMEDDS to an absorbant.
Example 3
Analogous to example 2 but the mixture is packed into sachets.
Example 4
Analogous to example 2 but the mixture is packed into sticks.
Example 5
Analogous to example 2 but the mixture is processed into immediate-release tablets.
Example 6
Analogous to example 2 but the mixture is processed into orally-dispersible tablets.
Example 7
Analogous to example 2 but the mixture is processed into chewable tablets.
Example 8
Cremophor ® ELP (75%) and Capmul ® MCM (25%) are mixed until a homogeneous liquid is obtained. Therein the active ingredient is dissolved under stirring at a concentration of 2.4mg/ml. The emulsification property in aqueous media is summarized in table 1.
Example 9
Labrafil M1944CS (30%) and Labrasol (70%) are mixed until a homogeneous liquid is obtained. Therein the active ingredient is dissolved under stirring at a concentration of 2.9mg/ml.
The emulsification property in aqueous media is summarized in table 1.
Example 10
Propylene glycol (10%), ethanol (14%), Maisine 35-1 (36%) and Cremophor® RH40 (40%) are mixed until a homogeneous liquid is obtained. Therein the active ingredient is dissolved under stir- ring at a concentration of 2.33mg/ml.
The emulsification property in aqueous media is summarized in table 1 using the compound of formula (II) as active ingredient.
Table 1 : Overview of visual assessment and PCS-results
Figure imgf000012_0001
API cone, largest peak PDI
Ex. SMEDDS formulation Appearance Z-Average
[mg/ml] (nm) (<0.5)
Propylenglycol / Ethanol /
10 Maisine 35-1 / Cremophor RH40 2.33 opalescent 97.8 64.56 0.408 (10/14/36/40) (v/v/v/v)
Example 1 1
The in-vivo plasma pharmacokinetics of the compound of formula (II) were investigated in fasted male Wistar rats after single peroral administration of four SMEDDS (selected from above examples based on the following main formulation component: Labrafil, Cremophor RH40, Cremophor ELP and Tween80) compared to a solution of a prodrug of the compound of formula (II).
The four SMEDDS were ready-to-use formulations for directly dosing of the animals with an administration volume of 5 mL/kg. Since the compound of formula (II) has a very low solubility in water for the purpose of comparison with the formulations according to the invention the hydrochloride salt of the prodrug (i.e. 2-{4-[2-({[2-(4-chlorophenyl)-1 ,3-thiazol-4-yl]methyl}sulfanyl)-3,5- dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl]phenoxy}ethyl L-alanyl-L-alaninate hydrochloride) is used to obtain a solution. This prodrug of the compound of formula (II) was dissolved in a PEG-400/EtOH- based formulation and dosed in 5 mL/kg to the animals.
The administered doses are related to the compound of formula (II). Plasma samples were collected at predefined time points up to 30 h post dosing for the SMEDDS and up to 96 h post dosing for the solution. The calculated pharmacokinetic parameters refer to the compound of formula (II) (analyte) and are summarized in the table below.
Example 9 10 8 1
Dose [mg/kg] 2.41 14.5 11.65 12.0 14.45
40% Cremo¬
10% EtOH phor RH40, 75% Cremo¬
30% Labrafil 83.3% 40% PEG400 36% Maisine, phor ELP,
Formulation M1944CS. Tween80,
50% demin. 14% Ethanol, 25% Campul
70% Labrasol 16.7% Sojaol water 10% PropylMCM
ene glycol
Appl. Vol. [mL/kg] 5 5 5 5 5
Animals
o
per time point
AUC Mg · h/L 1910 16900 6800 6650 8670
AUCnorm kg · h/L 0.794 1.17 0.584 0.554 0.600 tlast h 96.0 30.0 30.0 30.0 30.0
Cmax M9/L 172 741 604 401 480
Cmax,norm kg/L 0.0716 0.051 1 0.0519 0.0334 0.0333 tmax h 3.00 5.00 5.00 5.00 7.00 t½ h 22.9 16.4 5.98 10.3 8.95
Rpoints 3 3-4 3-3 3-3 3-3
RRange h 32.0-96.0 5.00-30.0 7.00-30.0 7.00-30.0 7.00-30.0 t½ apparent h 5.94
Rpoints 5
RRange h 5.00-32.0
Frel % 100 147 73.5 69.8 75.6 The exposure of the compound of formula (II) in terms of AUCnorm was 0.794 kg · h/L when administered as prodrug in solution. The exposures of the four SMEDDS were as follows: 1.17 kg · h/L for Labrafil, 0.584 kg-h/L for Cremophor RH40, 0.554 kg-h/L for Cremophor ELP and 0.60 kg · h/L for Tween80. The relative bioavailability (Frei, prodrug solution set to 100 %) was 147% for Labrafil, thus clearly higher then solution, and ranged between 70 % - 76 % for Cremophor RH40, Cremophor ELP and Tween80. Since the compound of formula (II) has a very low solubility in water it is thus surprising that such a high relative bioavailability can be reached using the SMEDDS formulations according to the invention, in one case even much higher when compared with the prodrug solution.
The maximum concentration of the compound of formula (II) in rat plasma was reached 3 h after administration of the prodrug in solution, whereas tmax of the four SMEDDS was between 5 h - 7 h, thus somewhat later. The dose-normalized Cmax of the compound of formula (II) was 0.0716 kg/L after dosing as prodrug in solution. Cmax of the four SMEDDS was lower compared to solution ranging between 0.033 kg/L and 0.052 kg/L. The elimination half-life of the compound of formula (II) was about 6 h determined in the interval up to 32 h when administered as prodrug in solution. The elimination half-life of the compound of formula (II) was slightly longer in Labrafil with approx. 16 h (interval up to 30 h), 10 h in Cremophor ELP (interval up to 30 h) and 9 h in Tween80 (interval up to 30 h) and was similar to solution with approx. 6 h in Cremophor RH40 (interval up to 30 h). Additionally, a long terminal elimination half-life of the compound of formula (II) was calculated for solution with about 23 h in the interval up to 96 h. However, no plasma sam- pies were collected later 30 h post dosing after SMEDDS administration.

Claims

Claims
1 . Composition comprising
(a) a selective partial adenosine A1 receptor agonist of the formula (X)
Figure imgf000015_0001
in which
R1 represents (Ci-C4)-alkyl,
R2 represents (Ci-C4)-alkyl,
where (Ci-C4)-alkyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, tri- fluoromethoxy, (Ci-C4)-alkoxy, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkoxy and (Ci- C4)-alkylsulphonyl,
or
R1 and R2 each represent hydrogen
or
R1 and R2 together with the nitrogen atom to which they are attached form a 4- to 7- membered heterocycle which may contain a further heteroatom from the group consisting of N, O and S,
where the 4- to 7-membered heterocycle may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, (Ci-C4)-alkyl, trifluoromethyl and (Ci-C4)-alkoxy, and the salts, solvates, and solvates of the salts thereof,
(b) an oil or lipid,
(c) a surfactant, and
(d) optionally a co-solvent or co-surfactant, or both.
2. The composition as claimed in claim 1 , comprising a selective partial adenosine A1 agonist of the formula (X), in which
R1 represents (Ci-C3)-alkyl,
R2 represents (Ci-C3)-alkyl, where (Ci-C3)-alkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, methoxy, eth- oxy, cyclopropyl and cyclobutyl,
or
R1 and R2 each represent hydrogen
or
R1 and R2 together with the nitrogen atom to which they are attached form a 4- to 6- membered heterocycle which may contain a further heteroatom from the group consisting of N, O and S,
where the 4- to 6-membered heterocycle may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, trifluoro- methoxyl, (Ci-C4)-alkyl, trifluoromethoxy, methoxy and ethoxy,
and the salts, solvates, and solvates of the salts thereof.
The composition as claimed in claims 1 or 2, comprising a selective partial adenosine A1 agonist of the formula (X), in which
R1 represents ethyl,
R2 represents ethyl,
or
R1 and R2 each represent hydrogen
or
R1 and R2 together with the nitrogen atom to which they are attached form an azetidinyl, pyr- rolidinyl or piperidinyl ring,
where the azetidinyl ring may be substituted by a methoxy substituent,
and the salts, solvates, and solvates of the salts thereof.
The composition as claimed in any of claims 1 to 3, wherein the selective partial adenosine A1 agonist is selected from Capadenoson of formula (I) or Neladenoson of formula (II).
The composition as claimed in any of claims 1 to 4, wherein the oil or lipid is selected from the group consisting of medium- or long-chain glycerides, which contain fatty acids of varying chain lengths and degrees of unsaturation, of example Caprol 3GO (i.e. C8:C10 triglyceride), Labrafac® Lipophile WL 1349 {medium chain triglycerides [caprylic (C8) 50-80%, capric (C10) 20-50%]}, Labrafac® PG (propylene glycol dicaprylocarate), Labrafil® M 1944 CS {oleoyl polyoxyl-6 glycerides [oleic (C18:1 ) 58-68%, linoleic (C18:2) 22-32%]}, Labrafil® M 2125 CS {linoleoyi polyoxyl-6 glycerides [oleic (C18:1 ) 24-34%, linoleic (C18:2) 53-63%]}, Labrafil® M 2130 CS (lauroyi polyoxyl-6 glycerides), Labrafac® CM 10 {C8-C10 polyglycolized glycerides [caprylic (C8) 50%, capric (C10) 50%]}, Labrafil® WL 2609 BS {linoleoyi macrogol glycerides [oleic (C18:1 ) 24-34%, linoleic (C18:2) 53-63%]}, Lauroglycol™ 90 {propylene glycol mono- laurate Type II [monoesters > 90%, C12 (lauric acid) > 95%]}, Lauroglycol™ FCC {propylene glycol laurate Type I [monoesters 45-70%, 30-55% diester >95% C12], Maisine™ 35-1 {glyceryl monolinoleate [C18:2 >50% max; C18:1 10-35%; C18:0 <6%; C16 4-20%]}, Capryol™ 90 {propylene glycol monocaprylate [>90% monoester of C8 (caprylic acid)]}, Capryol™ PGMC 90 (propylene glycol monocaprylate; >60% Monoester >90% C8), Peceol™ {glyceryl mono- oleate [C18:1 > 60%; C18:2 < 35%; C18:0 < 6%; C16 < 12% 0-5%]}, Plurol oleique® CC497 (polyglyceryl-3 dioleate), Plurol® (diisostearate triglycerol diisostearate), Transcutol® HP [di- ethylene glycol monoethyl ether (>99.9%)], Transcutol® P (diethylene glycol monoethyl ether), Captex® 355 (caprylic/capric triglyceride), Captex® 200 (propylene glycol dicapry- late/dicaprate), Migliol® 810 {medium chain fatty acids [C8 (65-80%); C10 (20-35%)]}, Migliol® 812 {medium chain fatty acids [C8 (50-65%); C10 (30-45%)]}, Migliol® 840 (medium chain diesters of propylene glycols), Miglyol® 818 {medium chain fatty acids [C8 (45-65%); C10 (30-45%); C18:2 (2-5%)]}, Capmul® MCM {glyceryl monocaprylate [(58% monoglyceride, 36% diglyceride, 5% triglyceride; 80% C8, 20% C10)]}, Capmul® MCM C8 {glyceryl monocaprylate [(68% monoglyceride, 27% diglyceride, 3% triglyceride; >95% C8, 3% C10)]}, Capmul® MCM C10 {glyceryl monocaprylate [(>45% monoglyceride; >45% C10)], Imwitor® 742 [monoglyceride/diglyceride/triglyceride of C8 and C10 fatty acid (45-55% monoglyceride)], Imwitor® 928 [monoglyceride/diglyceride/triglyceride of saturated fatty acids of coconut oil (40% MG)], Myrj® 45 {PEG 400 monostearate polyoxy 8 stearate [Stearic (C18) acid]}; or natural product oils from apricot kernel, canola, castor, coconut, corn, olive, palm, palm kernel, peanut, safflower, sesame, soybean, sunflower.
The composition of claim 5, wherein the lipid is selected from Labrafil® M 1944 CS, Maisine™ 35-1 , Capmul® MCM and soybean oil.
The composition as claimed in any of claims 1 to 6, wherein the surfactant has a hydrophilic- lipophilic balance (HLB) value of 12 or higher, for example Labrasol® {caprylocaproyl macro- gol-8-glycerides [caprylic (C8) 50-80%, capric (C10) 20-50%]}, Cremophor® EL or ELP (poly- oxy-35-castor oil), Cremophor® RH40 (polyoxy-40-hydrogenated castor oil), Cremophor® A25 {Macrogol 25 cetostearyl ether [stearic (C18) and cetyl (C16)]}, Vitamin E® TPGS (Vit E d-otocopheryl polyethylene glycol 1000 succinate), Gelucire® 44/14 {lauroyl polyoxylglycer- ides [C12 (40-50%); C14 (14-24%); C8 (4-10%), C10 (3-9%), C16 (4-14%), C18 (5-5%)]}, Gelucire® 50/13 {stearoyl polyoxyl-32 glycerides [C16 (40-50%); C18 (48-58%); C16+18 > 90%]}, Acconon® CC-6 (PEG-6 caprylic/capric glycerides), Brij® 97 {polyoxyl 10 oleyl ether Oleth 10 PEG monooleyl ether [Oleyl (C18:1 )]}, or Tween® 80 (polysorbate 80).
The composition of claim 7, wherein the surfactant is selected from Labrasol®, Cremo- phore® RH40, Cremophore® EL, Cremophor® ELP and Tween® 80. The composition as claimed in any of claims 1 to 8 comprising
(a) a selective partial adenosine A1 receptor agonist,
(b) 10 to 50 % (v/v) of an oil or lipid,
(c) 35 to 85 % (v/v) of a surfactant, and
(d) 0 to 40 % (v/v) of a co-solvent or co-surfactant, or both.
0. A process for preparing the compositions according to claims 1 to 9, characterized in that excipients (b) and (c) and optionally (d) are mixed until a clear solution is obtained, and that in a second step the selective partial adenosine A1 receptor agonist is dissolved in this mixture under stirring.
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