CA2654243A1 - Oral pharmaceutical composition of a poorly water-soluble active substance - Google Patents
Oral pharmaceutical composition of a poorly water-soluble active substance Download PDFInfo
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- CA2654243A1 CA2654243A1 CA002654243A CA2654243A CA2654243A1 CA 2654243 A1 CA2654243 A1 CA 2654243A1 CA 002654243 A CA002654243 A CA 002654243A CA 2654243 A CA2654243 A CA 2654243A CA 2654243 A1 CA2654243 A1 CA 2654243A1
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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
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
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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
- A61K9/20—Pills, tablets, discs, rods
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/485—Inorganic compounds
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
Abstract
Provided in the present invention are improved oral pharmaceutical compositions comprising at least one poorly water soluble active agent, preferably endothelin conversion enzyme (ECE) inhibitor and/or neutral endopeptidase (NEP) inhibitor in an amount greater than 10% w/w of the composition, more preferably, with the alkali system co mprising a mixture of at least two alkaline compounds in the ratio 1:20 to 20:1, the active agent is SLV-306 or its pharmaceutically acceptable salts, esters, hydrates, solvates, isomers or derivatives thereof; a 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. Also provided are process for preparation of such improved compositions and method of using such composition.
Description
ORAL PHARMACEUTICAL COMPOSITION OF A POORLY WATER-SOLUBLE ACTIVE SUBSTANCE
Field of the invention.
[0001] The present invention relates to an improved oral pharmaceutical compositions comprising at least one poorly water soluble active substance (also referred to as active agent), preferably an endothelin conversion enzyme (ECE) inhibitor and/or a neutral endopeptidase (NEP) inhibitor 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 preferably comprising a mixture of at least two alkaline compounds and optionally one or more pharmaceutically acceptable excipients.
Field of the invention.
[0001] The present invention relates to an improved oral pharmaceutical compositions comprising at least one poorly water soluble active substance (also referred to as active agent), preferably an endothelin conversion enzyme (ECE) inhibitor and/or a neutral endopeptidase (NEP) inhibitor 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 preferably comprising a mixture of at least two alkaline compounds and optionally one or more pharmaceutically acceptable excipients.
[0002] More preferably, with 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 N Mn+
Ri H H
2 N, C-COO
n general formula (I) wherein:
Ri is selected from the group consisting of (C1-C6)alkoxy(C1-C6)alkyl which may be substituted by a(Ci-C6)alkoxy, phenyl-(Ci-C6)-alkyl and phenyloxy-(C1-C6)-alkyl wherein the phenylgroup may be substituted with (C1-C6)alkyl, (C1-C6)alkoxy or halogen, and naphtyl-(C1-C6)-alkyl, R2 and R3 are both independently hydrogen or halogen, R4 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.
Even more preferably, with the alkali system comprising a mixture of at least two alkaline compounds in the ratio 1:20 to 20:1, the active agent is 1H-1-Benzazepine-l-acetic acid, 3-[[[1-[2-(ethoxycarbonyl)-4-phenylbutyl]cyclopentyl]carbonyl]amino]-2,3,4,5-tetrahydro-2-oxo- (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.
[0003] In the framework of the present invention suitable groups R4 forming biolabile 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. Where the group R4 forming a biolabile ester is lower alkyl, this can be a preferably unbranched alkyl group with 1 to 4, preferably 2, carbon atoms. Where 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. Where 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 R4 are phenyl, benzyl or indanyl.
Where R4 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).
Ri H H
2 N, C-COO
n general formula (I) wherein:
Ri is selected from the group consisting of (C1-C6)alkoxy(C1-C6)alkyl which may be substituted by a(Ci-C6)alkoxy, phenyl-(Ci-C6)-alkyl and phenyloxy-(C1-C6)-alkyl wherein the phenylgroup may be substituted with (C1-C6)alkyl, (C1-C6)alkoxy or halogen, and naphtyl-(C1-C6)-alkyl, R2 and R3 are both independently hydrogen or halogen, R4 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.
Even more preferably, with the alkali system comprising a mixture of at least two alkaline compounds in the ratio 1:20 to 20:1, the active agent is 1H-1-Benzazepine-l-acetic acid, 3-[[[1-[2-(ethoxycarbonyl)-4-phenylbutyl]cyclopentyl]carbonyl]amino]-2,3,4,5-tetrahydro-2-oxo- (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.
[0003] In the framework of the present invention suitable groups R4 forming biolabile 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. Where the group R4 forming a biolabile ester is lower alkyl, this can be a preferably unbranched alkyl group with 1 to 4, preferably 2, carbon atoms. Where 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. Where 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 R4 are phenyl, benzyl or indanyl.
Where R4 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).
[0004] The 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.
Background of the invention.
Background of the invention.
[0005] Endothelins (ETs) 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 isoforms of these metalloproteases have been identified; they all share a significant amino acid sequence identity with neutral endopeptidase (NEP), another metalloprotease. Therefore the majority of ECE inhibitors also possess potent NEP
inhibitory activity. To date, 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.
inhibitory activity. To date, 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.
[0006] 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 1-(carboxyalkyl) cyclopentyl-carbonylamino radical. These compound and their salts and biolabile esters fall under the scope of protection of the present invention and have NEP-inhibitory effects on the heart, as described in Waldeck et al., US
5,677,297 and EP 0733642. The benzazepine-N-acetic acid compounds used in the present invention are known from EP 0733642, EP 0830863, WO 00/48601 and WO 01/03699, and can be produced by the methods described in said US 5,677,297 and EP
0733642.
These patents are related to these compounds and their physiologically acceptable salts as such and to the use of the compound in heart insufficiency. WO 03/059939 relates to specific salts of these compounds, especially to the calcium salt. EP 0830863, W000/48601 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.
5,677,297 and EP 0733642. The benzazepine-N-acetic acid compounds used in the present invention are known from EP 0733642, EP 0830863, WO 00/48601 and WO 01/03699, and can be produced by the methods described in said US 5,677,297 and EP
0733642.
These patents are related to these compounds and their physiologically acceptable salts as such and to the use of the compound in heart insufficiency. WO 03/059939 relates to specific salts of these compounds, especially to the calcium salt. EP 0830863, W000/48601 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.
[0007] Various active substances have a very poor solubility in the gastric fluid. When these active substances are administered to the body, they often have a poor bio-availability due to the poor solubility in the digestive fluid. In order to solve this problem several methods were developed, such as micronization, inclusion in cyclodextrins, the use of inert water-soluble carriers, the use of solid dispersions (WO
00/00179) or solid solutions or nanocrystalline or amorphous forms of an active substance. Also the compounds described in US 5,677,297 and EP 0733642, including SLV-306 are poorly bio-available drugs due to the poor solubility in the gastric fluid.
Even when SLV-306 is used in its salt form, it forms a gel like structure in the acid gastric fluid. The gel like structure formed is very difficult to solubilize again even under alkaline conditions, leading to a low overall bioavailability.
00/00179) or solid solutions or nanocrystalline or amorphous forms of an active substance. Also the compounds described in US 5,677,297 and EP 0733642, including SLV-306 are poorly bio-available drugs due to the poor solubility in the gastric fluid.
Even when SLV-306 is used in its salt form, it forms a gel like structure in the acid gastric fluid. The gel like structure formed is very difficult to solubilize again even under alkaline conditions, leading to a low overall bioavailability.
[0008] 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. Although 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.
[0009] 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. Especially when docusate sodium is used as the surfactant a good bioavailability of the active substance is obtained.
Summary of the invention [0010] It is the objective of the present invention to provide an alternative oral formulation for the compounds with a low oral bio availability, especially for endothelin conversion enzyme (ECE) inhibitors and/or neutral endopeptidase (NEP) inhibitors with a significant increase in bio-availability compared with said active substance in a traditionally formulated form, the new oral formulation being sufficiently stable for commercial use and also being useful in the preparation of formulations with a high content of active substance with a reasonable size and optionally without the use of a surfactant. It is a further objective of the present invention to provide a formulation which can be prepared using normal formulation procedures and equipment, so that no substantial investment is not necessary.
[0011 ] It is another objective of the present invention to provide a process for the preparation of such improved compositions.
[0012] It is also an objective of the present invention to provide 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.
[0013] It is a further objective of the present invention to provide 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.
[0014] It is an even further objective of the present invention to provide 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, preferably 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 in the ratio 1:20 to 20:1 and optionally one or more pharmaceutically acceptable excipients.
[0015] 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.
[0016] It is another objective of the present invention to provide a process for the preparation of such improved compositions which comprises of the following steps:
i) mixing the active agent and alkali system optionally with one or more pharmaceutically acceptable excipients, and ii) formulating of the mixture produced in (i) into a suitable dosage form.
[0017] It is yet another objective of the present invention to provide a method of using such composition which comprises administering to a patient in need thereof an effective amount of the composition.
[0018] The improved compositions of the present invention are easier to formulate and possess improved solubility and stability.
Detailed description of the invention.
[0019] 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.
Preferably the alkaline system comprises a mixture of at least two alkaline compounds.
[0020] In the framework of the present description surfactants are defined as molecules with well defined polar and non-polar regions that allow them to aggregate in solutions to form micelles. Depending on the nature of the polar area, surfactants can be non-ionic, anionic, cationic and zwitterionic. Examples of non-ionic hydrophilic surfactants are polyoxyethylene sorbitan esters, cremophores and poloxamers. Examples of anionic surfactants are sodium lauryl sarcosinate, docusate and pharmaceutically acceptable docusate salts such as docusate calcium, docusate sodium and docusate potassium.
[0021] 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.
[0022] In a further embodiment of the present invention, 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.
[0023] Preferably 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.
[0024] In a preferred embodiment of the present invention, 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.
[0025] In another embodiment, with the alkali system comprising 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) R4 p p Rs y N Mn+
Ri H H N
n Formula-1 Wherein:
Ri is a selected from the group consisting of (C1-C6) alkoxy(C 1 -C6) alkyl which may be substituted by a(C1-C6) alkoxy, phenyl-(C1-C6)-alkyl and phenyloxy-(C1-C6)-alkyl wherein the phenyl group may be substituted with (C1-C6)alkyl, (C1-C6) alkoxy or halogen, and naphtyl-(C1-C6)-alkyl, R2 and R3 are both independently hydrogen or halogen, R4 is a biolabile ester forming group, M is a hydrogen or a metal ion, preferably a bivalent metal ion nisl,2or3;
[0026] In a preferred embodiment, with the alkali system comprising a mixture of at least two alkaline compounds in the ratio 1:20 to 20:1, the active agent is the endothelin conversion enzyme (ECE) inhibitor and neutral endopeptidase (NEP) inhibitor, SLV-306, of chemical formula 3-(1-(2'-(Ethoxycarbonyl)-4'-phenyl-butyl)-cyclopentan-l- carbonylamino)-2,3,4,5-tetrahydro-2-oxo-1H-l-benzazepin-l-acetic acid or at least one pharmaceutically acceptable salt, esters hydrate, solvate, isomer or derivative thereof.
[0027] In a more preferred embodiment, with the alkali system comprising a mixture of at least two alkaline compounds in the ratio 1:20 to 20:1 w/w, the active agent is SLV-306 in its calcium salt form .
[0028] 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 (1H-1-Benzazepine-l-acetic acid, 3[[[1-[2-(ethoxycarbonyl)-phenylbutyl] -cyclopentyl] carbonyl] amino] -2,3,4,5-tetrahydro-2-oxo-) is referred to as Compound S-H, the corresponding sodium salt is referred to as Compound S-Na.
[0029] In one embodiment, 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.
[0030] In further preferred embodiment, 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. Primarily, 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 C temperature. This protection mechanism provided by the heat stable sodium sesquicarbonate prevents early effervescent reaction at ambient and elevated temperature storage conditions.
[0031] Surprisingly the inventors of the present invention have found that using an alkaline compound in the formulation, alone or in a mixture e.g. Effer-SodaTM-12, even without any surfactant in the composition prevents the difficult to solubilize gel formation in the acid gastric fluid, thereby enhancing the solubility of SLV-306 as evidenced during in vitro dissolution studies in a biphasic dissolution model (see Example 1a), which indicates an improvement in the in vivo solubility as well and thus improvement in bioavailability. Further the compositions have a good stability upon storage. Further since the Effer-SodaTM-12 is granular in nature, its use in formulating the compositions of the present invention has improved the flow properties and compressibility of material used to formulate the desired dosage form and also improved its machinability.
[0032] Specific 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. In the present invention the composition preferably does not contain an acidic compound.
[0033] In another embodiment of the present invention, 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.
[0034] 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.
[0035] 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.
[0036] 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.
[0037] 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.
[0038] 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. 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(t VA 64; polar solvent; and the like used either alone or in combination.
[0039] The present invention also relates to a process of preparing the formulation as described above. In a first embodiment of this aspect of the present invention, 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.
[0040] In a preferred embodiment of the process of the present invention, 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.
and 45% of the total weight of the formulation. Especially when docusate sodium is used as the surfactant a good bioavailability of the active substance is obtained.
Summary of the invention [0010] It is the objective of the present invention to provide an alternative oral formulation for the compounds with a low oral bio availability, especially for endothelin conversion enzyme (ECE) inhibitors and/or neutral endopeptidase (NEP) inhibitors with a significant increase in bio-availability compared with said active substance in a traditionally formulated form, the new oral formulation being sufficiently stable for commercial use and also being useful in the preparation of formulations with a high content of active substance with a reasonable size and optionally without the use of a surfactant. It is a further objective of the present invention to provide a formulation which can be prepared using normal formulation procedures and equipment, so that no substantial investment is not necessary.
[0011 ] It is another objective of the present invention to provide a process for the preparation of such improved compositions.
[0012] It is also an objective of the present invention to provide 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.
[0013] It is a further objective of the present invention to provide 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.
[0014] It is an even further objective of the present invention to provide 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, preferably 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 in the ratio 1:20 to 20:1 and optionally one or more pharmaceutically acceptable excipients.
[0015] 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.
[0016] It is another objective of the present invention to provide a process for the preparation of such improved compositions which comprises of the following steps:
i) mixing the active agent and alkali system optionally with one or more pharmaceutically acceptable excipients, and ii) formulating of the mixture produced in (i) into a suitable dosage form.
[0017] It is yet another objective of the present invention to provide a method of using such composition which comprises administering to a patient in need thereof an effective amount of the composition.
[0018] The improved compositions of the present invention are easier to formulate and possess improved solubility and stability.
Detailed description of the invention.
[0019] 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.
Preferably the alkaline system comprises a mixture of at least two alkaline compounds.
[0020] In the framework of the present description surfactants are defined as molecules with well defined polar and non-polar regions that allow them to aggregate in solutions to form micelles. Depending on the nature of the polar area, surfactants can be non-ionic, anionic, cationic and zwitterionic. Examples of non-ionic hydrophilic surfactants are polyoxyethylene sorbitan esters, cremophores and poloxamers. Examples of anionic surfactants are sodium lauryl sarcosinate, docusate and pharmaceutically acceptable docusate salts such as docusate calcium, docusate sodium and docusate potassium.
[0021] 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.
[0022] In a further embodiment of the present invention, 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.
[0023] Preferably 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.
[0024] In a preferred embodiment of the present invention, 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.
[0025] In another embodiment, with the alkali system comprising 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) R4 p p Rs y N Mn+
Ri H H N
n Formula-1 Wherein:
Ri is a selected from the group consisting of (C1-C6) alkoxy(C 1 -C6) alkyl which may be substituted by a(C1-C6) alkoxy, phenyl-(C1-C6)-alkyl and phenyloxy-(C1-C6)-alkyl wherein the phenyl group may be substituted with (C1-C6)alkyl, (C1-C6) alkoxy or halogen, and naphtyl-(C1-C6)-alkyl, R2 and R3 are both independently hydrogen or halogen, R4 is a biolabile ester forming group, M is a hydrogen or a metal ion, preferably a bivalent metal ion nisl,2or3;
[0026] In a preferred embodiment, with the alkali system comprising a mixture of at least two alkaline compounds in the ratio 1:20 to 20:1, the active agent is the endothelin conversion enzyme (ECE) inhibitor and neutral endopeptidase (NEP) inhibitor, SLV-306, of chemical formula 3-(1-(2'-(Ethoxycarbonyl)-4'-phenyl-butyl)-cyclopentan-l- carbonylamino)-2,3,4,5-tetrahydro-2-oxo-1H-l-benzazepin-l-acetic acid or at least one pharmaceutically acceptable salt, esters hydrate, solvate, isomer or derivative thereof.
[0027] In a more preferred embodiment, with the alkali system comprising a mixture of at least two alkaline compounds in the ratio 1:20 to 20:1 w/w, the active agent is SLV-306 in its calcium salt form .
[0028] 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 (1H-1-Benzazepine-l-acetic acid, 3[[[1-[2-(ethoxycarbonyl)-phenylbutyl] -cyclopentyl] carbonyl] amino] -2,3,4,5-tetrahydro-2-oxo-) is referred to as Compound S-H, the corresponding sodium salt is referred to as Compound S-Na.
[0029] In one embodiment, 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.
[0030] In further preferred embodiment, 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. Primarily, 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 C temperature. This protection mechanism provided by the heat stable sodium sesquicarbonate prevents early effervescent reaction at ambient and elevated temperature storage conditions.
[0031] Surprisingly the inventors of the present invention have found that using an alkaline compound in the formulation, alone or in a mixture e.g. Effer-SodaTM-12, even without any surfactant in the composition prevents the difficult to solubilize gel formation in the acid gastric fluid, thereby enhancing the solubility of SLV-306 as evidenced during in vitro dissolution studies in a biphasic dissolution model (see Example 1a), which indicates an improvement in the in vivo solubility as well and thus improvement in bioavailability. Further the compositions have a good stability upon storage. Further since the Effer-SodaTM-12 is granular in nature, its use in formulating the compositions of the present invention has improved the flow properties and compressibility of material used to formulate the desired dosage form and also improved its machinability.
[0032] Specific 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. In the present invention the composition preferably does not contain an acidic compound.
[0033] In another embodiment of the present invention, 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.
[0034] 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.
[0035] 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.
[0036] 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.
[0037] 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.
[0038] 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. 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(t VA 64; polar solvent; and the like used either alone or in combination.
[0039] The present invention also relates to a process of preparing the formulation as described above. In a first embodiment of this aspect of the present invention, 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.
[0040] In a preferred embodiment of the process of the present invention, 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.
[0041] In a further preferred embodiment of the process of the present invention, 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.
[0042] In a further embodiment, 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. In a preferred embodiment of the present invention, 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. In an embodiment, the compositions of the present invention are in the form of compacted tablets, compressed tablets, moulded tablets, and the like.
[0043] When the 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.
[0044] 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.
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.
[0042] In a further embodiment, 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. In a preferred embodiment of the present invention, 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. In an embodiment, the compositions of the present invention are in the form of compacted tablets, compressed tablets, moulded tablets, and the like.
[0043] When the 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.
[0044] 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.
[0045] The improved compositions of the present invention are easier to formulate and possess improved solubility and stability.
[0046] The following examples are only intended to further illustrate the invention, in more detail, and therefore these Examples are not deemed to restrict the scope of the invention in any way.
[0047] EXAMPLES.
[0048] Example 1. Materials and methods [00491 Materials.
S-Ca were prepared according to the prescription given in Examples 2 and 3 of W003/059939 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.
[00501 Methods.
Description of the bi-phase in-vitro dissolution method.
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 C using Vankel VK7010 equipment.
The dissolution of the formulations was started in 500 m10.1 M hydrochloric acid (4.2 ml concentrated hydrochloric acid (HC1) in 500 ml water)(phase 1). After 0, 5, 15 and minutes a sample was taken. After 30 minutes 500 ml 1 M phosphate buffer (32.4 gram sodium di-hydrogen phosphate NaH2PO4 and 124.8 gram di-sodium hydrogen phosphate (NazHPO4) in 1000 ml water was added to phase 1. Addition of the 30 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.
All the samples were filtered through a Pall Zymark Acrodisc PSF, GxF/GHP, 0.45 m or a Millipore Millex-FH (hydrophobic PTFE 0.45 m) filter.
[0046] The following examples are only intended to further illustrate the invention, in more detail, and therefore these Examples are not deemed to restrict the scope of the invention in any way.
[0047] EXAMPLES.
[0048] Example 1. Materials and methods [00491 Materials.
S-Ca were prepared according to the prescription given in Examples 2 and 3 of W003/059939 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.
[00501 Methods.
Description of the bi-phase in-vitro dissolution method.
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 C using Vankel VK7010 equipment.
The dissolution of the formulations was started in 500 m10.1 M hydrochloric acid (4.2 ml concentrated hydrochloric acid (HC1) in 500 ml water)(phase 1). After 0, 5, 15 and minutes a sample was taken. After 30 minutes 500 ml 1 M phosphate buffer (32.4 gram sodium di-hydrogen phosphate NaH2PO4 and 124.8 gram di-sodium hydrogen phosphate (NazHPO4) in 1000 ml water was added to phase 1. Addition of the 30 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.
All the samples were filtered through a Pall Zymark Acrodisc PSF, GxF/GHP, 0.45 m or a Millipore Millex-FH (hydrophobic PTFE 0.45 m) filter.
The quantity of the dissolved daglutril in the filtered samples was analyzed by off-line UV measurements at 240 nm using external standardization.
In an earlier comparative study with the calcium salt of the compound SLV306 (S-Ca), it has been shown that this bi-phase in vitro dissolution method has a good correlation with in-vivo results.
[0051 ] Example 2: Preparation of a traditionally formulated coated tablet of SLV-306.
Ingredients Quantity (mg/tablet) S-Ca 414.25 Micro crystalline cellulose PH301 249.00 Cross-linked polyvinylpyrrolidon 14.00 Sodium stearyl fumarate 1.75 Opadry II Yellow coating 21.00 Tablet weight 700.00 [0052] Procedure:
i) Compact S-Ca and pass the compact through a 1.0 mm sieve.
ii) Mix material of step (i) with micro crystalline cellulose PH301, cross-linked polyvinylpyrrolidon and sodium stearyl fumarate to obtain a uniform mixture.
iii) Compress the material of step (ii) using a tablet compression machine.
iv) Coat the tablets from step (iii) in suitable coating equipment.
[0053] Example 3: Preparation of tablets of SLV-306 containing Effer-SodaTM-12 Ingredients Quantity (mg/tablet) Tablet I Tablet II
S-Ca 622.5 622.5 Effer-SodaTM-12 299.5 599.5 Magnesium stearate 10.0 13.0 Sodium starch glycolate 33.0 65.0 Opadry II Yellow coating 35.0 47.2 Tablet weight 1000.0 1347.2 [0054] Procedure:
i) Sift S-Ca, Effer-SodaTM-12, Magnesium stearate and Sodium starch glycolate through an appropriate sieve, e.g. a #40 mesh sieve.
ii) Mix the S-Ca, Effer-SodaTM-12 and a portion of Magnesium stearate and Sodium starch glycolate sifted above to obtain a uniform mixture.
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.
v) 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.
[00551 Example 4. Comparative dissolution study for SLV306 formulation with Effer-SodaTM-12 and a traditionally formulated tablet 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(I) and Tablet C, prepared as described in Example 3 (II)).
The release profile of these formulations is given in the Table below and depicted in Figure 1. From this study it can be concluded that a formulation of S-Ca with a high drug load and a favorable release profile can be prepared.
Time Drug Release in %
(min) Tablet A Tablet B Tablet C
0 0 -0.02 0.00 5 1.1 -0.02 0.10 15 1.6 -0.03 0.15 1.9 -0.07 0.08 30 35 31.4 51.99 60.88 45 49.1 76.76 75.73 60 57.4 88.27 87.79 [0056] Example 5: Preparation of film-coated tablets of SLV-306 containing Effer-Soda.
Ingredients Quantity (mg/ tablet) S-Ca 311.25 Effer-SodaTM-12 300.00 Microcrystalline cellulose (Avicel 310.00 Croscarmellose sodium 20.00 Isopropyl alcohol q.s (lost in processing) Hydrogenated castor oil (Lubritab(t) 7.50 Purified talc 7.50 Colloidal silicon dioxide 7.50 Opadry II Yellow 85F22185 30.00 Purified water q.s. (lost in processing) [0057] Procedure:
i) Sift S-Ca, Effer-SodaTM-12, Microcrystalline cellulose (Avicel(t PH 101) and Croscarmellose sodium through an appropriate sieve, e.g. a #40 mesh sieve and mix.
ii) Granulate the mixture using Isopropyl alcohol followed by sifting through an appropriate sieve, e.g. a #24 mesh sieve and drying.
iii) Sift Hydrogenated castor oil (Lubritab(t), Purified talc and Colloidal silicon dioxide through an appropriate sieve, e.g. a #40 mesh sieve and mix.
iv) Add the material of step (iii) to the material of step (ii) and mix.
v) 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 suspension in water on the tablets followed by drying the tablets.
[0058] Example 6: Preparation of capsules of SLV-306.
Ingredients Quantity (mg/ capsule) S-Ca 311.25 Magnesium carbonate 150.00 Dicalcium phosphate 131.25 Sodium starch glycolate 30.00 Magnesium stearate 10.00 [0059] Procedure:
i) Sift S-Ca, Magnesium carbonate, Dicalcium phosphate, Sodium starch glycolate and Magnesium stearate through an appropriate sieve, e.g. a #40 mesh sieve and mix.
ii) Compact the material of step (i) and pass the compacts through #30 mesh sieve.
iii) Lubricate the material of step (ii) with #60 mesh sieve passed Magnesium stearate.
iv) Fill the material of step (iii) into a hard gelatin capsule.
In an earlier comparative study with the calcium salt of the compound SLV306 (S-Ca), it has been shown that this bi-phase in vitro dissolution method has a good correlation with in-vivo results.
[0051 ] Example 2: Preparation of a traditionally formulated coated tablet of SLV-306.
Ingredients Quantity (mg/tablet) S-Ca 414.25 Micro crystalline cellulose PH301 249.00 Cross-linked polyvinylpyrrolidon 14.00 Sodium stearyl fumarate 1.75 Opadry II Yellow coating 21.00 Tablet weight 700.00 [0052] Procedure:
i) Compact S-Ca and pass the compact through a 1.0 mm sieve.
ii) Mix material of step (i) with micro crystalline cellulose PH301, cross-linked polyvinylpyrrolidon and sodium stearyl fumarate to obtain a uniform mixture.
iii) Compress the material of step (ii) using a tablet compression machine.
iv) Coat the tablets from step (iii) in suitable coating equipment.
[0053] Example 3: Preparation of tablets of SLV-306 containing Effer-SodaTM-12 Ingredients Quantity (mg/tablet) Tablet I Tablet II
S-Ca 622.5 622.5 Effer-SodaTM-12 299.5 599.5 Magnesium stearate 10.0 13.0 Sodium starch glycolate 33.0 65.0 Opadry II Yellow coating 35.0 47.2 Tablet weight 1000.0 1347.2 [0054] Procedure:
i) Sift S-Ca, Effer-SodaTM-12, Magnesium stearate and Sodium starch glycolate through an appropriate sieve, e.g. a #40 mesh sieve.
ii) Mix the S-Ca, Effer-SodaTM-12 and a portion of Magnesium stearate and Sodium starch glycolate sifted above to obtain a uniform mixture.
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.
v) 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.
[00551 Example 4. Comparative dissolution study for SLV306 formulation with Effer-SodaTM-12 and a traditionally formulated tablet 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(I) and Tablet C, prepared as described in Example 3 (II)).
The release profile of these formulations is given in the Table below and depicted in Figure 1. From this study it can be concluded that a formulation of S-Ca with a high drug load and a favorable release profile can be prepared.
Time Drug Release in %
(min) Tablet A Tablet B Tablet C
0 0 -0.02 0.00 5 1.1 -0.02 0.10 15 1.6 -0.03 0.15 1.9 -0.07 0.08 30 35 31.4 51.99 60.88 45 49.1 76.76 75.73 60 57.4 88.27 87.79 [0056] Example 5: Preparation of film-coated tablets of SLV-306 containing Effer-Soda.
Ingredients Quantity (mg/ tablet) S-Ca 311.25 Effer-SodaTM-12 300.00 Microcrystalline cellulose (Avicel 310.00 Croscarmellose sodium 20.00 Isopropyl alcohol q.s (lost in processing) Hydrogenated castor oil (Lubritab(t) 7.50 Purified talc 7.50 Colloidal silicon dioxide 7.50 Opadry II Yellow 85F22185 30.00 Purified water q.s. (lost in processing) [0057] Procedure:
i) Sift S-Ca, Effer-SodaTM-12, Microcrystalline cellulose (Avicel(t PH 101) and Croscarmellose sodium through an appropriate sieve, e.g. a #40 mesh sieve and mix.
ii) Granulate the mixture using Isopropyl alcohol followed by sifting through an appropriate sieve, e.g. a #24 mesh sieve and drying.
iii) Sift Hydrogenated castor oil (Lubritab(t), Purified talc and Colloidal silicon dioxide through an appropriate sieve, e.g. a #40 mesh sieve and mix.
iv) Add the material of step (iii) to the material of step (ii) and mix.
v) 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 suspension in water on the tablets followed by drying the tablets.
[0058] Example 6: Preparation of capsules of SLV-306.
Ingredients Quantity (mg/ capsule) S-Ca 311.25 Magnesium carbonate 150.00 Dicalcium phosphate 131.25 Sodium starch glycolate 30.00 Magnesium stearate 10.00 [0059] Procedure:
i) Sift S-Ca, Magnesium carbonate, Dicalcium phosphate, Sodium starch glycolate and Magnesium stearate through an appropriate sieve, e.g. a #40 mesh sieve and mix.
ii) Compact the material of step (i) and pass the compacts through #30 mesh sieve.
iii) Lubricate the material of step (ii) with #60 mesh sieve passed Magnesium stearate.
iv) Fill the material of step (iii) into a hard gelatin capsule.
Claims (18)
1. An improved oral pharmaceutical composition comprising at least one endothelin conversion enzyme (ECE) inhibitor and/or neutral endopeptidase (NEP) inhibitor as the active agent 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, with the proviso that the active agent is not a compound of the general formula wherein:
R1 is a selected from the group consisting of (C1-C6) alkoxy(C1-C6) alkyl which may be substituted by a(C1-C6) alkoxy, phenyl-(C1-C6)-alkyl and phenyloxy-(C1-C6)-alkyl wherein the phenyl group may be substituted with (C1-C6)alkyl, (C1-C6) alkoxy or halogen, and naphtyl-(C1-C6)-alkyl, R2 and R3 are both independently hydrogen or halogen, R4 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 a pharmaceutically acceptable salt, ester, hydrate, solvate, isomersor derivative thereof.
R1 is a selected from the group consisting of (C1-C6) alkoxy(C1-C6) alkyl which may be substituted by a(C1-C6) alkoxy, phenyl-(C1-C6)-alkyl and phenyloxy-(C1-C6)-alkyl wherein the phenyl group may be substituted with (C1-C6)alkyl, (C1-C6) alkoxy or halogen, and naphtyl-(C1-C6)-alkyl, R2 and R3 are both independently hydrogen or halogen, R4 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 a pharmaceutically acceptable salt, ester, hydrate, solvate, isomersor derivative thereof.
2. A composition according to claim 1, wherein the active agent is selected from a group comprising CGS 26303, phosphoramidon, FR901533, TMC-66, SM-19712, 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.
3. A composition according to claim 1 or 2 , wherein the alkali system is selected from a group comprising 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.
4. A composition according to any of claims 1 to 3, wherein the alkali system comprises a mixture of at least two alkaline compounds.
5. An improved oral pharmaceutical composition comprising at least one endothelin conversion enzyme (ECE) inhibitor and/or neutral endopeptidase (NEP) inhibitor as the active agent in an amount greater than 10% w/w of the composition, an alkali system comprising a mixture of at least two alkaline compounds in the ratio 1:20 to 20:1 w/w, in an amount greater than 10% w/w of the composition, and optionally one or more pharmaceutically acceptable excipients.
6. A composition according to claim 5, wherein the active agent is selected from a group comprising CGS 26303, phosphoramidon, FR901533, TMC-66, SM-19712, 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.
7. A composition according to claim 5, wherein the endothelin conversion enzyme (ECE) inhibitor and/or neutral endopeptidase (NEP) inhibitor is an active agent of the general formula wherein:
R1 is a selected from the group consisting of (C1-C6) alkoxy(C1-C6) alkyl which may be substituted by a(C1-C6) alkoxy, phenyl-(C1-C6)-alkyl and phenyloxy-(C1-C6)-alkyl wherein the phenyl group may be substituted with (C1-C6)alkyl, (C1-C6) alkoxy or halogen, and naphtyl-(C1-C6)-alkyl, R2 and R3 are both independently hydrogen or halogen, R4 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 a pharmaceutically acceptable salt, ester, hydrate, solvate, isomer or derivative thereof.
R1 is a selected from the group consisting of (C1-C6) alkoxy(C1-C6) alkyl which may be substituted by a(C1-C6) alkoxy, phenyl-(C1-C6)-alkyl and phenyloxy-(C1-C6)-alkyl wherein the phenyl group may be substituted with (C1-C6)alkyl, (C1-C6) alkoxy or halogen, and naphtyl-(C1-C6)-alkyl, R2 and R3 are both independently hydrogen or halogen, R4 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 a pharmaceutically acceptable salt, ester, hydrate, solvate, isomer or derivative thereof.
8. A composition according to claim 7, wherein M is calcium in its 2+ form.
9. A composition according to claim 7 or 8, wherein the active agent is the calcium salt of 1H-1-Benzazepine-l-acetic acid 3-[[[1-[2-(ethoxycarbonyl)-4-phenylbutyl]-cyclopentyl]carbonyl]-amino]-2,3,4,5-tetrahydro-2-oxo-, preferably in its 3S,2'R form.
10. A composition according to any of claims 4 to 9, wherein the alkali system comprises a mixture of sodium bicarbonate and sodium carbonate.
11. A composition according to claim 10, wherein the alkali system comprises between 83 and 90% w/w of sodium bicarbonate and between 10 and 17% w/w of sodium carbonate.
12. A composition according to any of claims 1 to 11, wherein the alkali system is present in an amount of at least 20% w/w of the composition.
13. A composition according to any of claims 1 to 12, wherein the pharmaceutically acceptable excipients are selected from a group comprising diluents, disintegrants, binders, polymers, solubilizers, fillers, bulking agents, anti-adherants, anti-oxidants, buffering agents, colorants, flavoring agents, coating agents, plasticizers, organic solvents, stabilizers, preservatives, lubricants, glidants, and chelating agents used either alone or in combination thereof.
14. A composition according to any of claims 1 to 13 which is in the form of granules, tablets or capsules.
15. A process of preparation of a composition according to any of claims 1 to 14, which 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.
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.
16. A process of preparation of a composition according to any of claims 1 to 14, which comprises of 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.
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.
17. A process of preparation of a composition according to any of claims 7 to 14, which comprises of the following steps:
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.
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.
18. A method of using the composition according to any of claims 7 to 14, which comprises administering to a patient in need thereof an effective amount of the composition.
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US81557906P | 2006-06-22 | 2006-06-22 | |
| US60/815,579 | 2006-06-22 | ||
| IN1473DE2006 | 2006-06-22 | ||
| EP06115881 | 2006-06-22 | ||
| IN1473/DEL/2006 | 2006-06-22 | ||
| EP06115881.2 | 2006-06-22 | ||
| PCT/EP2007/056207 WO2007147873A1 (en) | 2006-06-22 | 2007-06-21 | Oral pharmaceutical composition of a poorly water-soluble active substance |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2654243A1 true CA2654243A1 (en) | 2007-12-27 |
Family
ID=38475974
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002654243A Abandoned CA2654243A1 (en) | 2006-06-22 | 2007-06-21 | Oral pharmaceutical composition of a poorly water-soluble active substance |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP2037890A1 (en) |
| JP (1) | JP2009541267A (en) |
| KR (1) | KR20090033246A (en) |
| AU (1) | AU2007263016A1 (en) |
| CA (1) | CA2654243A1 (en) |
| EA (1) | EA200970045A1 (en) |
| IL (1) | IL195653A0 (en) |
| NO (1) | NO20090265L (en) |
| WO (1) | WO2007147873A1 (en) |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1397160A1 (en) * | 2001-04-30 | 2004-03-17 | Shire Laboratories Inc. | Pharmaceutical composition including ace/nep inhibitors and bioavailability enhancers |
| AR038681A1 (en) * | 2002-02-14 | 2005-01-26 | Solvay Pharm Bv | ORAL FORMULATION OF SOLID SOLUTION OF A POVERLY SOLUBLE ACTIVE SUBSTANCE IN WATER |
| WO2004062692A1 (en) * | 2003-01-13 | 2004-07-29 | Solvay Pharmaceuticals B.V. | Formulation of poorly water-soluble active substances |
| TW200633713A (en) * | 2004-12-23 | 2006-10-01 | Solvay Pharm Bv | Oral immediate release formulation of a poorly water-soluble active substance |
| WO2007054975A1 (en) * | 2005-11-08 | 2007-05-18 | Panacea Biotec Ltd | Pharmaceutical compositions for the treatment of cardiovascular and other associated disorders |
-
2007
- 2007-06-21 WO PCT/EP2007/056207 patent/WO2007147873A1/en active Application Filing
- 2007-06-21 EA EA200970045A patent/EA200970045A1/en unknown
- 2007-06-21 JP JP2009515884A patent/JP2009541267A/en not_active Withdrawn
- 2007-06-21 AU AU2007263016A patent/AU2007263016A1/en not_active Abandoned
- 2007-06-21 CA CA002654243A patent/CA2654243A1/en not_active Abandoned
- 2007-06-21 KR KR1020097001506A patent/KR20090033246A/en not_active Application Discontinuation
- 2007-06-21 EP EP07730293A patent/EP2037890A1/en not_active Ceased
-
2008
- 2008-12-02 IL IL195653A patent/IL195653A0/en unknown
-
2009
- 2009-01-16 NO NO20090265A patent/NO20090265L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| EP2037890A1 (en) | 2009-03-25 |
| JP2009541267A (en) | 2009-11-26 |
| NO20090265L (en) | 2009-01-22 |
| KR20090033246A (en) | 2009-04-01 |
| EA200970045A1 (en) | 2009-06-30 |
| AU2007263016A1 (en) | 2007-12-27 |
| IL195653A0 (en) | 2009-09-01 |
| WO2007147873A1 (en) | 2007-12-27 |
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Legal Events
| Date | Code | Title | Description |
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| FZDE | Discontinued |
Effective date: 20130621 |