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WO2007147873A1 - Composition pharmaceutique à administration par voie orale contenant un principe actif peu soluble dans l'eau - Google Patents

Composition pharmaceutique à administration par voie orale contenant un principe actif peu soluble dans l'eau Download PDF

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Publication number
WO2007147873A1
WO2007147873A1 PCT/EP2007/056207 EP2007056207W WO2007147873A1 WO 2007147873 A1 WO2007147873 A1 WO 2007147873A1 EP 2007056207 W EP2007056207 W EP 2007056207W WO 2007147873 A1 WO2007147873 A1 WO 2007147873A1
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WIPO (PCT)
Prior art keywords
composition according
pharmaceutically acceptable
composition
alkyl
active agent
Prior art date
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PCT/EP2007/056207
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English (en)
Inventor
Rajesh Jain
Kour C. Jindal
Amarjit Singh
Munish Talwar
Henricus R. M. Gorissen
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.)
Panacea Biotec Ltd
Abbott Healthcare Products BV
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Panacea Biotec Ltd
Solvay Pharmaceuticals BV
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Priority to BRPI0713709-5A priority Critical patent/BRPI0713709A2/pt
Priority to AU2007263016A priority patent/AU2007263016A1/en
Priority to EP07730293A priority patent/EP2037890A1/fr
Priority to MX2008016418A priority patent/MX2008016418A/es
Priority to JP2009515884A priority patent/JP2009541267A/ja
Priority to EA200970045A priority patent/EA200970045A1/ru
Application filed by Panacea Biotec Ltd, Solvay Pharmaceuticals BV filed Critical Panacea Biotec Ltd
Priority to CA002654243A priority patent/CA2654243A1/fr
Publication of WO2007147873A1 publication Critical patent/WO2007147873A1/fr
Priority to IL195653A priority patent/IL195653A0/en
Anticipated expiration legal-status Critical
Priority to NO20090265A priority patent/NO20090265L/no
Ceased legal-status Critical Current

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    • 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
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • 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
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/485—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to an improved oral pharmaceutical compositions
  • at least one poorly water soluble active substance also referred to as active agent
  • active agent preferably an endothelin conversion enzyme (ECE) inhibitor and/or a neutral endopeptidase (NEP) inhibitor
  • ECE endothelin conversion enzyme
  • NEP neutral endopeptidase
  • an alkali system in an amount greater than 10% w/w of the composition preferably comprising a mixture of at least two alkaline compounds and optionally one or more pharmaceutically acceptable excipients.
  • the active agent is a compound of the alkali system comprising a mixture of at least two alkaline compounds in the ratio 1:20 to 20:1, the active agent is a compound of the
  • Ri is selected from the group consisting of (Ci-C 6 )alkoxy(Ci-C 6 )alkyl which may be substituted by a (Ci-C6)alkoxy, phenyl-(Ci-C 6 )-alkyl and phenyloxy- (Ci-C6)-alkyl wherein the phenylgroup may be substituted with (Ci-Ce)alkyl,
  • R_ 2 and R 3 are both independently hydrogen or halogen
  • R 4 is a biolabile ester forming group
  • M is a hydrogen or a metal ion, preferably a bivalent metal ion.
  • n is 1, 2 or 3; or its pharmaceutically acceptable hydrates and solvates.
  • the active agent is lH-l-Benzazepine-1- acetic acid, 3-[[[ 1 -[2-(ethoxycarbonyl)-4-phenylbutyl]cyclopentyl]carbonyl]amino]- 2,3,4,5-tetrahydro-2-oxo- (SLV 306).
  • SLV 306 An even more preferred compound is said compound in its 3S,2'R form. The most preferred compound is SLV-306 as its Ca2+ salt or its pharmaceutically acceptable hydrates and solvates.
  • suitable groups R 4 forming bio labile esters include lower alkyl groups, phenyl or phenyl-lower-alkyl groups which are optionally substituted in the phenyl ring by lower alkyl or by a lower alkylene chain bonded to two adjacent carbon atoms, dioxolanylmethyl groups which are optionally substituted in the dioxolane ring by lower alkyl, or C2 -C6 -alkanoyloxymethyl groups which are optionally substituted on the oxymethyl group by lower alkyl.
  • R 4 forming a bio labile ester is lower alkyl
  • this can be a preferably unbranched alkyl group with 1 to 4, preferably 2, carbon atoms.
  • the group forming a biolabile ester is an optionally substituted phenyl-lower-alkyl group
  • its alkylene chain can contain 1 to 3, preferably 1 carbon atoms.
  • the phenyl ring is substituted by a lower alkylene chain, this can contain 3 to 4, in particular 3, carbon atoms.
  • Particularly suitable phenyl-containing substituents R 4 are phenyl, benzyl or indanyl.
  • R 4 is an optionally substituted alkanoyloxymethyl group
  • its alkanoyloxy group can contain 2 to 6, preferably 3 to 5, carbon atoms and is preferably branched and can be, for example, a pivaloyloxymethyl radical (tert-butylcarbonyloxymethyl radical).
  • compositions of the present invention are easy to formulate and possess improved solubility and stability.
  • the present invention also describes process for preparation of such improved compositions and method of using such compositions.
  • Endothelins are potent vasoconstrictors, promitogens, and inflammatory mediators. They have been implicated in the pathogenesis of various cardiovascular, renal, pulmonary, and central nervous system diseases. Since the final step of the biosynthesis of ETs is catalyzed by a family of endothelin- converting enzymes (ECEs), inhibitors of these enzymes may represent novel therapeutic agents. Currently, seven iso forms of these metallopro teases have been identified; they all share a significant amino acid sequence identity with neutral endopeptidase (NEP), another metallopro tease. Therefore the majority of ECE inhibitors also possess potent NEP inhibitory activity.
  • NEP neutral endopeptidase
  • ECE inhibitors three classes of ECE inhibitors have been synthesized: dual ECE/NEP inhibitors, triple ECE/NEP/ACE inhibitors, and selective ECE inhibitors.
  • An agent which suppresses endothelin production such as an ECE inhibitor, or which inhibits the binding of endothelin to an endothelin receptor, such as an endothelin receptor antagonist, antagonizes various physiological effects of endothelin and produces beneficial effects in a variety of therapeutic areas.
  • Endothelin receptor antagonists and ECE inhibitors are therefore useful in treating a variety of diseases affected by endothelin.
  • a non-exhaustive list of such diseases includes chronic heart failure, myocardial infarction, cardiogenic shock, systemic and pulmonary hypertension, ischemia-repurfusion injury, atherosclerosis, coronary and systemic vasospastic disorders, cerebral vasospasm, and subarachnoid hemorrhage and the like.
  • SLV-306 (daglutril) is an orally active inhibitor of neutral endopeptidase (NEP) and endothelin conversion enzyme (ECE). It belongs to the class of benzazepine, benzoxazepine and benzothiazepine-N-acetic acid derivatives which contains an oxo group in the alpha position relative to the nitrogen atom and are substituted in position 3 by a l-(carboxyalkyl) cyclopentyl-carbonylamino radical.
  • EP 0830863, WO00/48601 and WO01/03699 are related to the use of the above compounds in the improvement of gastrointestinal blood flow, in the treatment of hypertension and in the treatment and prophylaxis of cardiac damages induced by adriamycin and comparable anti-cancer drugs, respectively.
  • WO 03/068266 describes an oral solid solution formulation of compounds of formula (I) having enhanced bio-availability compared with said active substance in a traditionally formulated form.
  • this formulation has superior bioavailability properties, it has the draw-back that it is formed via a melt mixture leading to some restrictions: it has to be formulated either into a capsule, or into a tablet via melt- extrusion technique. Further the size of the formulation will be too large for higher dosages.
  • WO 06/067150 (not pre-published) describes an oral immediate release formulation of compounds of formula (I) comprising the active substance in an amount up to 60% of the total weight of the formulation, at least 10 % w/w of an alkaline compound or a mixture of alkaline compounds, between 0.1 and 10% w/w of one ore more surfactants and optionally auxiliary materials in an amount of between 1% and 45% of the total weight of the formulation.
  • docusate sodium is used as the surfactant a good bioavailability of the active substance is obtained.
  • an improved oral pharmaceutical composition comprising at least one poorly soluble active agent, preferably an endothelin conversion enzyme (ECE) inhibitor and/or a neutral endopeptidase (NEP) inhibitor other than a compound of the above general Formula (I) in an amount greater than 10% w/w of the composition, a alkali system in an amount greater than 20% w/w of the composition and optionally one or more pharmaceutically acceptable excipients.
  • ECE endothelin conversion enzyme
  • NEP neutral endopeptidase
  • an improved oral pharmaceutical composition comprising at least one poorly soluble active agent, preferably endothelin conversion enzyme (ECE) inhibitor and/or neutral endopeptidase (NEP) inhibitor, other than a compound of the above general Formula (I), in an amount greater than 10% w/w of the composition, an alkali system in an amount greater than 20% w/w of the composition comprising a mixture of at least two alkaline compounds, and optionally one or more pharmaceutically acceptable excipients.
  • ECE endothelin conversion enzyme
  • NEP neutral endopeptidase
  • an improved oral pharmaceutical composition comprising at least one poorly soluble active agent, preferably endothelin conversion enzyme (ECE) inhibitor and/or neutral endopeptidase
  • ECE endothelin conversion enzyme
  • NEP N-(N-(N-(N-(2-aminoethyl)-2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-(2-aminoethyl)-2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2
  • composition comprising a mixture of at least two alkaline compounds in the ratio 1:20 to 20:1 and optionally one or more pharmaceutically acceptable excipients.
  • It is a further objective of the present invention to provide an improved oral pharmaceutical composition comprising SLV-306 or its pharmaceutically acceptable salts, esters, hydrates, solvates, isomers or derivatives as active agent in an amount greater than 10% w/w of the composition, a alkali system in an amount greater than 20% w/w of the composition comprising a mixture of at least two alkaline compounds in the ratio 1:20 to 20:1 and optionally one or more pharmaceutically acceptable excipients.
  • compositions of the present invention are easier to formulate and possess improved solubility and stability.
  • the present invention provides improved oral pharmaceutical compositions comprising at least one, in acid, poorly soluble active agent, preferably endothelin conversion enzyme (ECE) inhibitor and/or neutral endopeptidase (NEP) inhibitor, other than a compound of the above general Formula (I), in an amount greater than 10% w/w of the composition, an alkali system in an amount greater than 10% w/w of the composition and optionally one or more pharmaceutically acceptable excipients.
  • ECE endothelin conversion enzyme
  • NEP neutral endopeptidase
  • the alkaline system comprises a mixture of at least two alkaline compounds.
  • surfactants are defined as molecules with well defined polar and non-polar regions that allow them to aggregate in solutions to form micelles.
  • surfactants can be non- ionic, anionic, cationic and zwitterionic.
  • non- ionic hydrophilic surfactants are polyoxyethylene sorbitan esters, cremophores and poloxamers.
  • anionic surfactants are sodium lauryl sarcosinate, docusate and pharmaceutically acceptable docusate salts such as docusate calcium, docusate sodium and docusate potassium.
  • Inhibitors of neutral endopeptidase (NEP) and/or endothelin conversion enzyme (ECE) within the scope of this invention include but are not limited to CGS 26303, phosphoramidon, FR901533, TMC-66, SM-19712, SLV-306, KC-12615, KC-90095-1- AC, CGS-26303, CGS-30440, CGS-31447, CGS-26670, Sch-54470, and the pharmaceutically acceptable salts, esters, isomers, derivatives and prodrugs thereof.
  • the alkali system comprises an alkaline compound or a mixture of at least two alkaline compounds selected from but not limited to the group consisting of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, magnesium carbonate, calcium carbonate, tris buffer, triethanolamine; alkaline hydroxides such as sodium hydroxide, potassium hydroxide or magnesium hydroxide; alkaline phosphates such as disodium hydrogen phosphate, dipotassium hydrogen phosphate, dicalcium phosphate; and meglumine or mixtures thereof.
  • the alkali system is present in an amount greater than 10% w/w of the composition, more preferably greater than 20% w/w, or is present in an amount greater than 30% w/w, 40% w/w, 50% w/w, 55% w/w or 60% w/w of the composition.
  • the alkali system of the composition comprises a mixture of at least two alkaline compounds in the ratio 1 :20 to 20:1 w/w.
  • the endothelin conversion enzyme (ECE) inhibitor or neutral endopeptidase (NEP) inhibitor has the general formula (Formula- 1)
  • Ri is a selected from the group consisting Of (Ci-C 6 ) alkoxy(Ci-Ce) alkyl which may be substituted by a (Ci-C 6 ) alkoxy, phenyl-(Ci-C6)-alkyl and phenyloxy-
  • R 2 and R 3 are both independently hydrogen or halogen
  • R 4 is a biolabile ester forming group
  • M is a hydrogen or a metal ion, preferably a bivalent metal ion n is 1, 2 or 3;
  • the active agent is the endothelin conversion enzyme (ECE) inhibitor and neutral endopeptidase (NEP) inhibitor, SLV-306, of chemical formula 3-(l-(2'-(Ethoxycarbonyl)-4'-phenyl-butyl)- cyclopentan- 1 - carbonylamino)-2,3 ,4,5-tetrahydro-2-oxo- IH-I -benzazepin- 1 -acetic acid or at least one pharmaceutically acceptable salt, esters hydrate, solvate, isomer or derivative thereof.
  • EAE endothelin conversion enzyme
  • NEP neutral endopeptidase
  • the active agent is SLV- 306 in its calcium salt form .
  • the most preferred compound, with the alkali system comprising a mixture of at least two alkaline compounds in the ratio 1:20 to 20:1 w/w, is the SLV-306 calcium salt in its 3S, 2'R form.
  • This compound is referred to as Compound S-Ca
  • the corresponding acid (1 H- 1-Benzazepine-l -acetic acid, 3[[[l-[2-(ethoxycarbonyl)-4- phenylbutyl]-cyclopentyl]carbonyl]amino]-2,3,4,5-tetrahydro-2-oxo-)
  • Compound S-H the corresponding sodium salt
  • Compound S-Na the corresponding sodium salt
  • the active agent of Formula- 1 is present in the composition in an amount between about 10% and 80% by weight of the composition, preferably in an amount between about 15 and 75% by weight of the composition.
  • the active agent is or may optionally be used in a micronized form.
  • the alkali system comprises a mixture of sodium bicarbonate and sodium carbonate (Effer-SodaTM-12) marketed by SPI Pharma.
  • Effer-SodaTM-12 is a highly stable, surface modified sodium bicarbonate powder. It is produced by converting the surface of sodium bicarbonate particles to sodium carbonate.
  • Effer-SodaTM-12 contains 83-90% w/w sodium bicarbonate and 10-17% w/w sodium carbonate.
  • the outer layer of sodium carbonate absorbs moisture (from the atmosphere or composition) and forms sodium sesquicarbonate, which is stable up to 70 0 C temperature. This protection mechanism provided by the heat stable sodium sesquicarbonate prevents early effervescent reaction at ambient and elevated temperature storage conditions.
  • solid alkaline compounds like the bicarbonates and carbonates as indicated above are often used in combination with solid acidic compounds (e.g. citric acid, tartaric acid, adipic acid, fumaric acid, succinic acid, ascorbic acid, nicotinic acid, saccharin, aspirin, malic acid, sodium dihydrogen phosphate, disodium dihydrogen pyrophosphate, sodium dihydrogen citrate and disodium hydrogen citrate) in effervescent compositions.
  • solid acidic compounds e.g. citric acid, tartaric acid, adipic acid, fumaric acid, succinic acid, ascorbic acid, nicotinic acid, saccharin, aspirin, malic acid, sodium dihydrogen phosphate, disodium dihydrogen pyrophosphate, sodium dihydrogen citrate and disodium hydrogen citrate
  • the composition preferably does not contain an acidic compound.
  • the pharmaceutical compositions of present invention optionally comprise one or more pharmaceutically acceptable excipients selected from but not limited to a group comprising diluents, disintegrants, binders, polymers, solubilizers, fillers, bulking agents, anti-adherants, anti-oxidants, buffering agents, colorants, flavoring agents, coating agents, plasticizers, surfactants, organic solvents, stabilizers, preservatives, lubricants, glidants, chelating agents, and the like known to the art used either alone or in combination thereof.
  • a pharmaceutically acceptable excipients selected from but not limited to a group comprising diluents, disintegrants, binders, polymers, solubilizers, fillers, bulking agents, anti-adherants, anti-oxidants, buffering agents, colorants, flavoring agents, coating agents, plasticizers, surfactants, organic solvents, stabilizers, preservatives, lubricants, glidants, chelating agents,
  • Diluents that can be used in the present invention include lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, and the like or mixtures thereof.
  • Binders that can be used in the present invention include acacia, alginic acid and salts thereof, cellulose derivatives, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyethylene glycol, gums, polysaccharide acids, gelatin, polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer, polymethacrylates, hydroxypropyl-methylcellulose, ethylcellulose, starch, pregelatinized starch, tragacanth, dextrin, microcrystalline cellulose, sucrose, or glucose, and the like or mixtures thereof can be used.
  • Disintegrants useful in the present invention are selected from but not limited to starches, pregelatinized starch, celluloses, cross-linked carboxymethylcellulose, crospovidone, crosslinked polyvinylpyrrolidone, a calcium or a sodium alginate complex, clays, alginates, sodium starch glycolate, croscarmellose sodium and the like or mixtures thereof.
  • Lubricants that can be used in the present invention include magnesium stearate, sodium stearyl fumarate, hydrogenated vegetable oil, stearic acid, glyceryl behenate, stearates, waxes and the like or mixtures thereof can be used.
  • Stabilizers such as antioxidants, buffers, or acids, and the like are useful in the present invention.
  • Glidants such as talc, colloidal silicon dioxide or the like.
  • Polymers that can be used in formulating a composition according to the present invention include cellulosic derivatives, polyalkylene oxides, acrylic acid and methacrylic acid polymers, crosslinked polyacrylic acids, polysaccharide gums such as xanthan gum, veegum, agar, guar gum, locust bean gum, gum arabic, okra gum, alginic acid, alginates, bentonite, arabinoglactin, pectin, tragacanth, scleroglucan, dextran, amylose, amylopectin, dextrin, and the like or mixtures thereof can also be additionally used in formulating the compositions of the present invention.
  • polysaccharide gums such as xanthan gum, veegum, agar, guar gum, locust bean gum, gum arabic, okra gum, alginic acid, alginates, bentonite, arabinoglactin, pectin
  • Solubilizers such as polyethylene glycol and their derivatives, for example, Gelucire® such as Gelucire® 50/13 (Gattefosse); polyoxyethylene alkyl ethers such as polyoxyethylene stearyl ether, polyoxyethylene oleyl ether and polyoxyethylene cetyl ether which are available under the Brij® and Cetomacrogol® series trade names; polyvinylpyrrolidone K-30, polyvinylpyrrolidone K-90 or Kollidon® VA 64; polar solvent; and the like used either alone or in combination.
  • Gelucire® such as Gelucire® 50/13 (Gattefosse)
  • polyoxyethylene alkyl ethers such as polyoxyethylene stearyl ether, polyoxyethylene oleyl ether and polyoxyethylene cetyl ether which are available under the Brij® and Cetomacrogol® series trade names
  • the present invention also relates to a process of preparing the formulation as described above.
  • the process for the preparation of such improved compositions comprises of the following steps: i) mixing the active agent and alkali system optionally with one or more pharmaceutically acceptable excipients, and ii) formulating the mixture produced in (i) into a suitable dosage form.
  • this process comprises the following steps: i) mixing the active agent, alkali system, and lubricant, ii) optionally adding one or more other pharmaceutically acceptable excipients, forming a mixture, and iii) formulating the mixture produced in (i) and (ii) into a suitable dosage form.
  • the process comprises: i) mixing SLV-306 or at least one pharmaceutically acceptable salt, ester, hydrate, solvate, isomer or derivative thereof; the alkali system, the disintegrant and the lubricant, ii) optionally adding one or more other pharmaceutically acceptable excipients, forming a mixture, and iii) formulating the mixture produced in (i) and (ii) into a suitable dosage form.
  • the composition of the present invention is in the form of a solid dosage form such as tablets, capsules, patches or the like, preferably as tablets.
  • the tablets can be prepared by either direct compression, dry compression (slugging), or by granulation.
  • the oral composition is prepared by compression or compaction.
  • the granulation technique is either aqueous or non-aqueous.
  • the non-aqueous solvent used is selected from a group comprising ethanol, isopropyl alcohol, ethyl acetate, methyl t-butyl ether (MTBE), and methylene chloride.
  • the compositions of the present invention are in the form of compacted tablets, compressed tablets, moulded tablets, and the like.
  • formulations of the present invention are provided in the form of tablets, these tablets have disintegration times of between 5 minutes and 90 minutes. Preferably the disintegration times are below 60 minutes and most preferably they are below 45 minutes. Formulations with short disintegration times can be prepared by using a mixture of sodium bicarbonate and sodium carbonate as available, e.g., in Effer-SodaTM-12.
  • the present invention also provides a method of using such composition which comprises administering to a patient in need thereof an effective amount of the composition.
  • the compositions can be used in the treatment of chronic heart failure, myocardial infarction, cardiogenic shock, systemic and pulmonary hypertension, ischemia-repurfusion injury, atherosclerosis, coronary and systemic vasospastic disorders, cerebral vasospasm, and subarachnoid hemorrhage.
  • the improved compositions of the present invention are easier to formulate and possess improved solubility and stability.
  • S-Ca were prepared according to the prescription given in Examples 2 and 3 of WO03/059939 starting with the acid prepared according to Example 2 of EP 0733642. In all Examples the actual amount of S-Ca is given. 103.75 mg S-Ca corresponds with 100 mg S-H which is the active principle.
  • Sodium bicarbonate can be obtained from Sigma Aldrich or Canton Labs, India.
  • Effer-SodaTM-12 can be obtained from SPI Pharma, Newcastle, Delaware US. All other auxiliary materials are readily commercially available.
  • the bi-phase dissolution was performed with the USP apparatus 2 configuration.
  • the paddle speed was 50 rpm and the temperature of the vessels (and so the dissolution medium) was maintained at 37.0 0 C using Vankel VK7010 equipment.
  • the dissolution of the formulations was started in 500 ml 0.1 M hydrochloric acid (4.2 ml concentrated hydrochloric acid (HCl) in 500 ml water)(phase 1). After 0, 5, 15 and 30 minutes a sample was taken. After 30 minutes 500 ml 1 M phosphate buffer (32.4 gram sodium di-hydrogen phosphate NaH 2 PO 4 and 124.8 gram di-sodium hydrogen phosphate (Na 2 HPO 4 ) in 1000 ml water was added to phase 1. Addition of the phosphate buffer changed the pH of the dissolution medium from pH 1 in phase 1 to pH 6.8 in phase 2. During the dissolution test the pH of both phases remained unchanged. Samples were taken after 35, 45 and 60 minutes.
  • Example 2 Preparation of a traditionally formulated coated tablet of SLV- 306.
  • Example 3 Preparation of tablets of SLV-306 containing Effer-SodaTM-12
  • step (iii) Compact the material of step (ii) and pass the compact through an appropriate sieve, e.g. a #30 mesh sieve, iv) Mix material of step (iii) with the remaining quantity of Magnesium stearate and Sodium starch glycolate.
  • step (iv) Compress the material of step (iv) using a tablet compression machine vi) Coat the tablets of step (v) by spraying an Opadry II Yellow 85F22185 aqueous suspension on the tablets followed by drying the tablets.
  • Example 1 A comparative dissolution study according to the method described in Example 1 was carried out on one batch of a traditionally formulated tablet (Tablet A, prepared as described in Example 2) and two batches of the calcium salt of SLV-306 (S-Ca) (Tablet B, prepared as described in Example 3(1) and Tablet C, prepared as described in Example 3 (II)).
  • Example 5 Preparation of film-coated tablets of SLV-306 containing Effer- Soda.
  • Example 6 Preparation of capsules of SLV-306.

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Epidemiology (AREA)
  • Inorganic Chemistry (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des compositions pharmaceutiques améliorées, destinées à une administration par voie orale, comprenant au moins un agent actif peu soluble dans l'eau, de préférence un inhibiteur de l'enzyme de conversion de l'endothéline (ECE) et/ou un inhibiteur de l'endopeptidase neutre (NEP) à hauteur de plus de 10 % poids/poids de la composition, le système alcalin comprenant, mieux encore, un mélange d'au moins deux composés alcalins présents selon un rapport de 1 : 20 à 20 : 1, l'agent actif étant le SLV-306 ou un sel, ester, hydrate, solvate, isomère ou dérivé de celui-ci acceptable sur le plan pharmaceutique ; un système alcalin à hauteur de plus de 10 % poids/poids de la composition comprenant, de préférence, un mélange d'au moins deux composés alcalins et, éventuellement, un ou plusieurs excipients acceptables sur le plan pharmaceutique. L'invention concerne également un procédé de préparation de telles compositions améliorées et un procédé d'utilisation d'une telle composition.
PCT/EP2007/056207 2006-06-22 2007-06-21 Composition pharmaceutique à administration par voie orale contenant un principe actif peu soluble dans l'eau Ceased WO2007147873A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
AU2007263016A AU2007263016A1 (en) 2006-06-22 2007-06-21 Oral pharmaceutical composition of a poorly water-soluble active substance
EP07730293A EP2037890A1 (fr) 2006-06-22 2007-06-21 Composition pharmaceutique à administration par voie orale contenant un principe actif peu soluble dans l'eau
MX2008016418A MX2008016418A (es) 2006-06-22 2007-06-21 Composicion farmaceutica oral de una sustancia activa escasamente soluble en agua.
JP2009515884A JP2009541267A (ja) 2006-06-22 2007-06-21 低い水溶性活性物質の経口製薬学的組成物
EA200970045A EA200970045A1 (ru) 2006-06-22 2007-06-21 Фармацевтическая композиция для перорального введения плохо растворимого в воде активного вещества
BRPI0713709-5A BRPI0713709A2 (pt) 2006-06-22 2007-06-21 composição farmacéutica oral, processo de preparação de uma composição, e, método para usar composição
CA002654243A CA2654243A1 (fr) 2006-06-22 2007-06-21 Composition pharmaceutique a administration par voie orale contenant un principe actif peu soluble dans l'eau
IL195653A IL195653A0 (en) 2006-06-22 2008-12-02 Oral pharmaceutical composition of a poorly water-soluble active substance
NO20090265A NO20090265L (no) 2006-06-22 2009-01-16 Oral farmasoytisk sammensetning av en enkel vannloselig aktiv substans

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US81557906P 2006-06-22 2006-06-22
US60/815,579 2006-06-22
EP06115881.2 2006-06-22
IN1473DE2006 2006-06-22
EP06115881 2006-06-22
IN1473/DEL/2006 2006-06-22

Publications (1)

Publication Number Publication Date
WO2007147873A1 true WO2007147873A1 (fr) 2007-12-27

Family

ID=38475974

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2007/056207 Ceased WO2007147873A1 (fr) 2006-06-22 2007-06-21 Composition pharmaceutique à administration par voie orale contenant un principe actif peu soluble dans l'eau

Country Status (9)

Country Link
EP (1) EP2037890A1 (fr)
JP (1) JP2009541267A (fr)
KR (1) KR20090033246A (fr)
AU (1) AU2007263016A1 (fr)
CA (1) CA2654243A1 (fr)
EA (1) EA200970045A1 (fr)
IL (1) IL195653A0 (fr)
NO (1) NO20090265L (fr)
WO (1) WO2007147873A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002087621A1 (fr) * 2001-04-30 2002-11-07 Shire Laboratories Inc. Preparation pharmaceutique comprenant des inhibiteurs de l'ace/nep et des renforcateurs de biodisponibilite
WO2003068266A1 (fr) * 2002-02-14 2003-08-21 Solvay Pharmaceuticals B.V. Formulation de solution solide orale d'une substance active faiblement hydrosoluble
WO2004062692A1 (fr) * 2003-01-13 2004-07-29 Solvay Pharmaceuticals B.V. Formulation de substances actives a faible hydrosolubilite
WO2007054975A1 (fr) * 2005-11-08 2007-05-18 Panacea Biotec Ltd Compositions pharmaceutiques destinees au traitement de troubles cardiovasculaires et d'autres troubles associes

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW200633713A (en) * 2004-12-23 2006-10-01 Solvay Pharm Bv Oral immediate release formulation of a poorly water-soluble active substance

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002087621A1 (fr) * 2001-04-30 2002-11-07 Shire Laboratories Inc. Preparation pharmaceutique comprenant des inhibiteurs de l'ace/nep et des renforcateurs de biodisponibilite
WO2003068266A1 (fr) * 2002-02-14 2003-08-21 Solvay Pharmaceuticals B.V. Formulation de solution solide orale d'une substance active faiblement hydrosoluble
WO2004062692A1 (fr) * 2003-01-13 2004-07-29 Solvay Pharmaceuticals B.V. Formulation de substances actives a faible hydrosolubilite
WO2007054975A1 (fr) * 2005-11-08 2007-05-18 Panacea Biotec Ltd Compositions pharmaceutiques destinees au traitement de troubles cardiovasculaires et d'autres troubles associes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP2037890A1 *

Also Published As

Publication number Publication date
NO20090265L (no) 2009-01-22
KR20090033246A (ko) 2009-04-01
EP2037890A1 (fr) 2009-03-25
JP2009541267A (ja) 2009-11-26
AU2007263016A1 (en) 2007-12-27
EA200970045A1 (ru) 2009-06-30
CA2654243A1 (fr) 2007-12-27
IL195653A0 (en) 2009-09-01

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