MX2008016418A - Oral pharmaceutical composition of a poorly water-soluble active substance. - Google Patents

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 AN ACTIVE SUBSTANCE SOLELY SOLUBLE IN WATER FIELD OF THE INVENTION The present invention relates to improved oral pharmaceutical compositions comprising at least one active substance (which also bears the designation of active agent), sparingly soluble in water, preferably an inhibitor of the endothelin conversion enzyme (ECE, endothelin conversion enzyme ) and / or a neutral endopeptidase inhibitor (NEP, neutral endopeptidase), in an amount greater than 10% w / w of the composition, an alkaline system in an amount greater than 10% w / w of the composition, which preferably contains a mixture of at least two alkaline compounds, and optionally one or more pharmaceutically acceptable excipients. More preferably, the alkali system comprising a mixture of at least two alkali compounds in the ratio 1: 20 to 20: 1, the active agent is a compound of the general formula (i) wherein: Ri has been selected from the group consisting of alkoxy (Cr C6) alkyl (Ci-C6) which may be substituted by a (C6) alkoxy, phenyl-alkyl (CrC6) and phenyloxy-alkyl (Ci-C6) , wherein the phenyl group may be substituted by alkyl (CrC6), alkoxy (Ci-C6) or halogen, and naphthyl-alkyl (Ci-C6), R2 and R3, independently of each other, are both 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 their pharmaceutically acceptable hydrates or solvates. With the alkaline system comprising a mixture of at least two alkaline compounds in the ratio 1: 20 to 20: 1, it is even more preferable that the active agent be 3 - [[[1 - [2- (ethoxycarbonyl)] - 4-phenylbutyl] cyclopentyl] carbonyl] amino] -2,3,4,5-tetrahydro-2-oxo-1 H-1-benzazepin-1-acetic acid (SLV 306). A still more preferred compound is said compound in 3S, 2'R form. The most preferred compound is SLV-306 in the form of its Ca2 + salt, or its pharmaceutically acceptable hydrates and solvates. In the context of the present invention, suitable R4 groups that form biollabile esters include lower alkyl groups, phenyl or phenyl-lower alkyl groups which are optionally substituted on the phenyl ring by lower alkyl or by an alkylene chain lower bound 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 in the oxymethyl group by lower alkyl. If the group R4 which forms a biolabile ester is lower alkyl, it may be an alkyl group, preferably unbranched, with 1 to 4 carbon atoms, preferably with 2 carbon atoms. If the group forming a biolabile ester is a phenyl-lower alkyl group, optionally substituted, its alkylene chain may contain from 1 to 3 carbon atoms, preferably 1 carbon atom. If the phenyl group is substituted by a lower alkylene chain, it may contain from 3 to 4 carbon atoms, preferably 3 carbon atoms. Particularly suitable phenyl substituents R4 are phenyl, benzyl or indanyl. If R 4 is an optionally substituted alkanoyloxymethyl group, its alkanoyloxy group may contain from 2 to 6 carbon atoms, preferably from 3 to 5 carbon atoms, and is preferably branched, and may be, for example, a pivaloyloxymethyl radical (ternary radical). butylcarbonyloxymethyl). The compositions of the present invention are easy to formulate, and exhibit improved solubility and stability. The present invention also describes methods for the preparation of such improved compositions, and methods for using such compositions.

BACKGROUND OF THE INVENTION Endothelin (ETs) are potent vasoconstrictors, promitogens, and inflammatory mediators. It has been considered that they intervene in the pathogenesis of various cardiovascular diseases, renal, pulmonary, and central nervous system. Since the final step of the biosynthesis of ETs is catalyzed by a family of ECEs (enzymes that convert endothelin), inhibitors of these enzymes may represent new therapeutic agents. At present, seven isoforms of these metalloproteases have been identified: all of them have in common a significant amino acid identity with NEP (neutral endopeptidase), which is another metalloprotease. Therefore, most ECE inhibitors also possess a potent NEP inhibitory activity. To date, three classes of ECE inhibitors have been synthesized: the dual inhibitors of ECE / NEP, the triple inhibitors of ECE / NEP / ACE, and the selective ECE inhibitors. An agent that suppresses the production of endothelin, such as an ECE inhibitor, or that inhibits the binding of endothelioma to an endothelin receptor, such as an endothelin receptor antagonist, antagonizes various physiological effects of endothelin, and It produces beneficial effects in a variety of therapeutic areas. Therefore, endothelin receptor antagonists and ECE inhibitors are useful in the treatment of a variety of diseases affected by endothelin. A list, not exhaustive, of such diseases includes the chronic heart failure, myocardial infarction, cardiogenic shock, systemic and pulmonary hypertension, ischemia-reperfusion injury, atherosclerosis, coronary and systemic vasospastic disorders, cerebral vasospasm, subarachnoid hemorrhage, and the like. SLV-306 (daglutril) is an orally active inhibitor of the NEP endopeptidase neutral) and ECE (enzyme that converts endothelin). It is part of the class of benzazepine, benzoxazepine and benzothiazepine-N-acetic acid derivatives, which contain an oxo group in the alpha position with respect to the nitrogen atom and which are substituted in position 3 by a 1 - (carboxyalkyl) radical cyclopentyl-carbonylamino. These compounds and their biolabile salts and esters fall under the scope of protection of the present invention, have inhibitory effects of NEP in the heart, as described in: Waldeck et al., US 5,677,297 and EP 0733642. Benzazepine-N-acetic acid used in the present invention are known from EP 0733642, EP 0830863, WO 00/48601 and WO 01/03699, and it is possible to produce them by the methods described in said documents US Pat. No. 5,677,297 and EP 0733642. Patents refer to said compounds and their physiologically acceptable salts as such, and to the use of the compound in heart failure. WO 03/059939 relates to specific salts of these compounds, especially the calcium salt. EP 0830863, WO 00/48601 and WO 01/03699 relate to the use of the aforementioned compounds for the improvement of blood flow gastrointestinal, in the treatment of hypertension and in the treatment and prophylaxis of cardiac damage caused by adriamycin and by comparable anti-cancer drugs, respectively. Various active substances have a very low solubility in the gastric fluid. When these active substances are administered in the body, they frequently have a poor bioavailability, due to their poor dissolubility in the digestive fluid. In order to solve this problem, several methods have been developed, such as micronization, inclusion in cyclodextrins, the use of water-soluble inert carriers, the use of solid dispersions (WO 00/00179) or of solid solutions or of nanocrystalline or amorphous forms of an active substance. Also the compounds described in US 5,677,297 and EP 0773642, which include SLV-306, are drugs of low bioavailability due to their poor solubility in gastric fluid. Even if SLV-306 is used in the form of salts, it forms a structure similar to a gel in acidic gastric fluid. Again, the formed structure, similar to a gel, is difficult to solubilize even under alkaline conditions, which leads to a low overall bioavailability. WO 03/068266 describes an oral solid solution formulation of compounds of Formula (I) having a reinforced bioavailability compared to said active substance in the form of a traditional formulation. Although this formulation has superior bioavailability properties, it has the drawback that It is formed by a molten mixture, which leads to some restrictions: it must be formulated either in a capsule, or in a tablet, by means of a melt extrusion technique. In addition, the size of the formulation will be too large for higher doses. WO 2006/067150 (not published previously) describes an oral immediate release formulation, of compounds of Formula (I) comprising the active substance in an amount of up to 60% of the total weight of the formulation, so less 10% w / w of an alkaline compound or a mixture of alkaline compounds, between 0.1 and 10% w / w of one or more surfactants, and optionally auxiliary materials in an amount between 1% and 45%. % of the total weight of the formulation. In particular, if docusate sodium is used as a surfactant, a good bioavailability of the active substance is obtained.

BRIEF DESCRIPTION OF THE INVENTION The aim of the present invention is to provide an alternative oral formulation for compounds of low oral bioavailability, especially for inhibitors of ECE (enzyme that converts endothelin) and / or for inhibitors of NEP (neutral endopeptidase), together with a significant increase in bioavailability in comparison with said active substance in a traditional formulation form, which is sufficiently stable for commercial use and which can also be used to prepare formulations with a high content of active substance, of a reasonable size, and without the use of a surfactant. Another objective of the present invention is to provide a formulation that can be prepared by using normal formulation methods and equipment, so that large investments are not necessary. Another objective of the present invention is to provide a process for the preparation of said improved compositions. It is also an object of the present invention to provide improved oral pharmaceutical compositions comprising at least one poorly soluble active agent, preferably an endothelin converting enzyme (ECE) inhibitor and / or a neutral endopeptidase (NEP) inhibitor, other than of the compound of the above-mentioned general Formula (I), in an amount greater than 10% w / w of the composition, an alkaline system in an amount greater than 20% w / w of the composition, and optionally, one or more excipients pharmaceutically acceptable Another objective of the present invention is to provide improved oral pharmaceutical compositions comprising at least one poorly soluble active agent, preferably an endothelin converting enzyme (ECE) inhibitor and / or a neutral endopeptidase (NEP) inhibitor, other than composed of the above-mentioned general Formula (I), in an amount greater than 10% w / w of the composition, an alkaline 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. And yet another objective of the present invention is to provide improved oral pharmaceutical compositions comprising at least one poorly soluble active agent, preferably an endothelin converting enzyme (ECE) inhibitor and / or a neutral endopeptidase inhibitor (NEP). ), preferably a compound of the above-mentioned general Formula (I), in an amount greater than 10% w / w of the composition, an alkaline system in an amount greater than 20% w / w of the composition comprising a mixture of at least two alkaline compounds in a ratio of 1: 20 to 20: 1, and optionally, one or more pharmaceutically acceptable excipients. Another objective of the present invention is to provide improved oral pharmaceutical compositions comprising SLV-306 or its pharmaceutically acceptable salts, esters, hydrates, solvates, isomers or derivatives, as an active agent in an amount greater than 10% w / w. of the composition, an alkaline 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 excipients pharmaceutically acceptable Another object of the present invention is to provide a process for the preparation of such improved compositions, comprising the following steps: i) - mixing the active agent and the alkaline system, optionally together with one or more pharmaceutically acceptable excipients; and ii) the formulation of the mixture in a suitable dosage form. And yet another objective of the present invention is to provide a method for using said composition, which comprises administering to a patient in need, an effective amount of the composition. The improved compositions of the present invention are easier to formulate, and possess improved solubility and stability.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides improved oral pharmaceutical compositions comprising at least one active agent sparingly soluble in acid, preferably an inhibitor of the endothelin converting enzyme (ECE) and / or a neutral endopeptidase inhibitor (NEP), other than the compound of the invention. General formula (I) mentioned above, in an amount greater than 10% w / w of the composition, an alkaline system in an amount greater than 10% w / w of the composition, and optionally, one or more excipients pharmaceutically acceptable It is preferable that the alkaline system comprises a mixture of at least two alkaline compounds. By definition, within the scope of the present invention surfactants are molecules with well-defined polar and non-polar regions that allow their aggregation in solutions, so as to form micelles. Depending on the nature of the polar area, the surfactants can be non-ionic, anionic, cationic and zwitterionic. Examples of non-ionic hydrophilic surfactants include polyoxyethylene sorbitan esters, cremophores and poloxamers. Examples of anionic surfactants include sodium lauryl sarcosinate, docusate and pharmaceutically acceptable docusate salts such as docusate calcium, docusate sodium and docusate potassium. Within the scope of the present invention, a neutral endopeptidase (NEP) inhibitor and / or endothelin converting enzyme (ECE) inhibitor includes, but is not limited to: CGS 26303, phosphoramidone, FR901533, TMC-66, SM-19712, SLV-306, KC-12615, KC-90095-1 -AC, CGS-26303, CGS-30440, CGS-3 447, CGS-26670, Sch-54470, and pharmaceutically, salts, esters, isomers, derivatives and prodrugs acceptable, of the same. In another embodiment of the present invention, the alkaline system comprises an alkaline compound or a mixture of at least two alkaline compounds selected without limitation from the group consisting of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, magnesium carbonate; calcium carbonate, buffer tris, triethanolamine; alkali 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. It is preferable that the alkaline system is present in an amount greater than 10% w / w of the composition, more preferably, greater than 20% w / w, or that it is present in an amount greater than 30% w / w , 40% weight / weight, 50% weight / weight, 55% weight / weight, or 66% weight / weight, of the composition. In a preferred embodiment of the present invention, the alkaline system of the composition comprises a mixture of at least two alkali compounds in the ratio 1: 20 to 20: 1 w / w. In another embodiment, with the alkaline system comprising a mixture of at least two alkaline compounds in the ratio 1: 20 to 20: 1 w / w, the inhibitor of ECE (endothelin converting enzyme) or the neutral endopeptidase inhibitor ( NEP), has the following general Formula (Formula I): Formula 1 wherein: Ri has been selected from the group consisting of (C6) alkoxy alkyl (CrC6) which may be substituted by a (C6) alkoxy, phenyl (C6) alkyl and phenyloxy (Ci-C6) alkyl, wherein the phenyl group may be substituted by (C6) alkyl, (C6) alkoxy or halogen, and naphthyl-C1-C2), R2 and R3, independently of each other, are both 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. In a preferred embodiment, if the alkali system comprises a mixture of at least two alkali compounds in the ratio 1: 20 to 20: 1, the active agent is the inhibitor of ECE (endothelin converting enzyme) and the NEP inhibitor (neutral endopeptidase), SLV-306, of the chemical formula 3- (1 - (2 '- (ethoxycarbonyl) -4'-phenyl-butyl) -cyclopentan-1-carbonylamino) -2,3,4,5-tetrahydro-2 -oxo-1 H-1-benzazepin-1-acetic acid or its pharmaceutically acceptable salts, esters, hydrates, solvates, isomers or derivatives thereof. In a more preferred embodiment, the alkaline 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.

The most preferred compound, the alkaline system comprising a mixture of at least two alkali compounds in the ratio 1: 20 to 20: 1 w / w, is the calcium salt of SLV-306 in its 3S, 2'R form. This compound is called Compound S-Ca, the corresponding acid, 3 [[[1 - [2- (ethoxycarbonyl) -4-phenylbutyl] -cyclopentyl] carbonyl] amino] -2,3,4,5-tetrahydro -2-oxo-1 H-1-benzazepin-1-acetic is designated as Compound SH, and the corresponding sodium salt bears the designation Compound S-Na. In one embodiment, the active agent of Formula I is present in the composition in an amount of 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 in micronized form, or can optionally be used in micronized form. In another preferred embodiment, the alkaline system comprises a mixture of sodium bicarbonate and sodium carbonate (Effer-Soda ™ -2) marketed by SPI Pharma. Effer-Soda ™ -12 is a surface modified sodium bicarbonate powder, very stable. It is produced by converting the surface of the particles of sodium bicarbonate into sodium carbonate. Basically, Effer-Soda ™ -12 contains 83-90% weight / weight of sodium bicarbonate and 10-17% weight / weight of sodium carbonate. The outer layer of sodium carbonate absorbs moisture (from the atmosphere or composition), and forms sesquicarbonate sodium, which is Stable up to a temperature of 70 ° C. This protection mechanism, provided by the sodium sesquicarbonate, thermostable, prevents an early effervescent reaction under storage conditions at room temperature and at elevated temperatures. The inventors of the present invention have surprisingly discovered that by using an alkaline compound in the formulation, alone or in the form of a mixture, for example Effer-Soda ™ -12, even without any surfactant in the composition, the difficulty of solubilizing gel formation in acidic gastric fluid is avoided, thereby reinforcing the solubility of SLV-306, particularly as evidenced during in vitro dissolution studies in a two-phase dissolution model (see Example 1 a), which also indicates an improvement in in vivo solubility, and therefore an improvement in bioavailability. In addition, the compositions have a good stability under storage. On the other hand, since the Effer-Soda ™ -12 is of a granular nature, its use in the formulation of the compositions of the present invention has improved the flow properties and the compressibility of the material used to formulate the desired dosage form , and it has also improved its machinability. Specific solid alkali compounds such as bicarbonates and carbonates, such as those mentioned above, are frequently used in combination with solid acidic compounds (eg, 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 hydrogen citrate and disodium hydrogen citrate) in effervescent compositions. In the present invention, it is preferable that the composition does not contain an acid compound. In another embodiment of the present invention, the pharmaceutical compositions of the present invention optionally comprise one or more pharmaceutically acceptable excipients selected without limitation from a group consisting of diluents, disintegrants, binders, polymers, solubilizers, fillers, bulking agents, anti-adhesives. , antioxidants, buffering agents, dyes, flavoring agents, coating agents, plasticizers, surfactants, organic solvents, stabilizers, preservatives, lubricants, slip agents, chelating agents, and the like known in the art, used alone or in the form of combinations thereof. Diluents that may be used in the present invention include: lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrans, dextran, starches, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, and the like, or mixtures thereof. Binders such as acacia, alginic acid and salts thereof, cellulose derivatives, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyethylene glycol, gums, polysaccharide acids, gelatin, polyvinylpyrrolidone, polyvinylpyrrolidone / vinyl acetate copolymer, polymethacrylates, hydroxypropyl methylcellulose, ethylcellulose, tragacanth, starch, pregelatinized starch, tragacanth, dextrin, microcrystalline cellulose, sucrose or glucose, and the like or mixtures thereof. The disintegrating agents useful in the present invention are selected by way of non-limiting among: starches, pregelatinized starch, celluloses, crosslinked carboxymethyl cellulose, crospovidone, cross-linked polyvinyl pyrrolidone, a calcium or sodium alginate complex, clays, alginates, sodium starch glycolate , croscarmellose sodium, and the like, or mixtures thereof. Lubricants such as 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. Slip agents such as talc, colloidal silica, or the like can be used. Additionally, they can also be used in the formulation of the compositions of the present invention: polymers such as cellulose 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, arabinogalactin, pectin, tragacanth, scleroglutane, dextran, amylase, amylopectin, dextrin, and the like, or mixtures thereof. Solubilizers such as polyethylene glycol and its derivatives can also be used in the present invention, 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 trade names of the Brij® and Cetomacrogol® Series; polyvinylpyrrolidone K-30, polyvinylpyrrolidone K-90 or Kollidon® VA 64; polar solvent; and similar, used only in combination. The present invention also relates to a process for preparing the formulation according to the above described. In a second embodiment of this aspect of the present invention, the process for the preparation of such improved compositions comprises the following steps: i) mixing the active agent and the alkaline system, optionally with one or more pharmaceutically acceptable excipients; and ii) the formulation of the mixture in a suitable dosage form. In a preferred embodiment of the process of the present invention, this method comprises the following steps: i) mixing the active agent, the alkaline system, and the lubricant, with each other; ii) optionally, adding one or more pharmaceutically acceptable excipients, and Ü) Formulation of the mixture in a suitable dosage form. In another preferred embodiment of the process of the present invention, the process comprises the following steps: i) mixing SLV-306 or its pharmaceutically acceptable salts, esters, hydrates, solvates, isomers or derivatives; the alkaline system, the disintegrating agent and the lubricant, ti) optionally, adding one or more other pharmaceutically acceptable excipients, and iii) formulating the mixture in a suitable dosage form. In another embodiment, the composition of the present invention is in the form of a solid dose form such as tablets, capsules, patches, or the like, preferably in the form of tablets. It is possible to prepare the tablets either by 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 can be aqueous or non-aqueous. The non-aqueous solvent used is selected from a group comprising ethanol, isopropyl alcohol, ethyl acetate, MTBE (methyl t-butyl ether), and methyl chloride. In one embodiment, the compositions of the present invention are in the form of compacted tablets, compressed tablets, molded tablets, and the like. When the formulations of the present invention are provided in tablet form, they have decay times of between 5 and 10. minutes and 90 minutes. It is preferable that the disintegration times be less than 60 minutes, and it is more preferable that they be less than 45 minutes. It is possible to prepare formulations with short disintegration times by using a mixture of sodium bicarbonate and sodium carbonate, such as that available in the Effer-Soda ™ -12. The present invention also provides a method for using such a 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-reperfusion injuries, 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. The following examples are merely for the purpose of illustrating the invention in greater detail, so it is considered that these Examples do not restrict the scope of the invention in any way.

EXAMPLES EXAMPLE 1 Materials and methods Materials. It is possible to prepare the S-Ca according to the indications given in Examples 2 and 3 of WO 03/059939, starting with the acid prepared according to Example 2 of EP 0733642. In all the examples the amount is indicated real S-Ca. 103.75 mg of S-Ca corresponds to 100 mg of S-H which is the active principle. Sodium bicarbonate is marketed by Sigma Aldrich or by Canton Labs, India. Effer-Soda ™ -12 can be provided by SPI Pharma, Newclastle, Delaware, USA. All other auxiliary materials are easily obtainable in commerce.

Methods Description of the in-vitro biphasic dissolution method. The biphasic solution was carried out with configuration 2 of the apparatus according to USP. The speed of the paddles was 50 rpm, and the temperature of the containers (and therefore, the temperature of the medium of the dissolution) was maintained at 37.0 ° C by using a Vankel VK7010 equipment. The dissolution of the formulations was started in 500 ml of 0.1 M hydrochloric acid (4.2 ml of concentrated hydrochloric acid (HCl) in 500 ml of water) (Phase 1). After 0, 5, 1 5 and 30 minutes, a sample was taken. After 30 minutes, to phase 1 500 ml of 1 M phosphate buffer (32.4 grams of sodium dihydrogen phosphate, NaH2P0, and 24.8 grams of disodium hydrogen phosphate (NaH2PO4) in 1000 ml of water were added. The addition of the phosphate buffer changed the pH of the solution 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. of 35, 45 and 60 minutes All the samples were filtered through a Pall filter Zymark Acrodisc PSF, GxF / GHP, 0.45 pm, or through a Millipore Millex-FH filter (hydrophobic PTFE, 0.45 pm). amount of daglutril dissolved in the filtered samples, by off-line UV measurements, at 240 nm, under the use of an external standardization In a previous comparative study with the calcium salt of the compound SLV306 (S-Ca) it has been demonstrated that this in vitro biphasic solution method has a good correlation ation with the results in vivo.

EXAMPLE 2 Preparation of a traditionally coated, SLV-306 tablet Procedure: i) Compact the S-Ca and pass the compacted material through a 1.0 mm sieve. ii) Mix the material from step (i) with microcrystalline cellulose PH301, cross-linked polyvinylpyrrolidone and sodium stearyl fumarate, in order to obtain a uniform mixture. iii) Compress the material of step (ii) by means of a compression machine for tablets. iv) Coat the tablets of step (iii) in a suitable coating equipment.

EXAMPLE 3 Preparation of SLV-306 tablets containing Effer-Soda ™ -12 Procedure: i) Screen the S-Ca, Effer-Soda ™ -12, magnesium stearate and sodium starch glycolate via a suitable sieve, for example a # 40 mesh screen. ii) Mix the S-Ca, the Effer-Soda ™ -12 and a portion of the magnesium stearate and the sieved sodium starch glycolate, as previously described, in order to obtain a uniform mixture. iii) Compact the material from step (ii), and pass the compacted material through a suitable screen, for example a # 30 mesh screen. iv) Mix the material from step (iii) with the remaining amount of magnesium stearate and sodium starch glycolate. v) Compress the material from step (iv) by using a tablet compression machine vi) Coat the tablets from step (v) by spraying an aqueous suspension of Opadry II Yellow 85F22185, followed by drying the tablets EXAMPLE 4 Comparative dissolution study for the formulation of SLV-306 with Effer-Soda ™ -12 and for a traditional formulation tablet A comparative dissolution study was carried out according to the method described in Example 1, on a batch of tablets formulated in the traditional manner (Tablet A, prepared as described in Example 2) and on two batches of the salt of calcium of SLV-306 (S-Ca) (Tablet B, prepared as described in Example 3 (l) and Tablet C, prepared as described in Example 3 (II)). The release profile of these formulations has been reported in the following table, and illustrated in Figure 1. From this study it can be concluded that it is possible to prepare an S-Ca formulation with a high drug loading and with a favorable release profile.

EXAMPLE 5 Preparation of SLV-306 tablets containing Effer-Soda, coated from a movie Ingredients Quantity (mg / tablet) S-Ca 31 1.25 Effer-Soda ™ -12 300.00 Microcrystalline cellulose (Avicel K) 310.00 Croscarmellose sodium 20.00 Isopropyl alcohol Qty. (lost in processing) Hydrogenated castor oil (Lubritab ®) 7.50 Purified talcum 7.50 Colloidal silicon dioxide 7.50 Opadry II Yellow 85F22185 30.00 Purified water Cant.suf. (lost in processing) Procedure: I) Screen the S-Ca, Effer-Soda ™ -12, microcrystalline cellulose (Avicel® PH 101) and croscarmellose sodium through a suitable screen, for example a # 40 mesh screen, and mix. I) Granulate the mixture by using isopropyl alcohol followed by screening through a suitable screen, for example a # 24 mesh screen, and drying. iii) Screen hydrogenated castor oil (Lubritab®), purified talc and colloidal silicon dioxide, through a suitable screen, for example a # 40 mesh screen, and mix. iv) Add the material from step (iii) to the material of step (ii), and mix. v) Compress the material of step (iv) by using a machine to compress tablets. vi) Coat the tablets of step (v) by spraying a suspension of Opadry II Yellow 85F22185 in water, followed by drying the tablets.

EXAMPLE 6 Preparation of SLV-306 capsules Procedure: I) Screen the S-Ca, magnesium carbonate, dicalcium phosphate, sodium starch glycolate, and magnesium stearate, through a suitable screen, for example a # 40 mesh screen, and mix. li) Compact the material from step (i), and pass the compacted material through a # 30 mesh screen. iü) Lubricate the material from step (ii) with magnesium stearate that passed through the # 60 mesh screen. iv) Introduce the material from step (iü) into a hard gelatin capsule.

Claims (10)

NOVELTY OF THE INVENTION CLAIMS

1 .- An improved oral pharmaceutical composition, comprising at least one inhibitor of ECE (endothelin converting enzyme) and / or an inhibitor of NEP (neutral endopeptidase) as an active agent in an amount greater than 10% w / w of the composition, an alkaline 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: Ri has been selected from the group consisting of alkoxy (d-C6) alkyl (CrC6) which may be substituted by a (C6) alkoxy, phenyl-alkyl (Ci-C6) and phenyloxy-alkyl (CrC6), that the phenyl group may be substituted by alkyl (C C6), alkoxy (CrC6) or halogen, and naphthyl-alkyl (CiC-6), R2 and R3, independently of each other, are both 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 their pharmaceutically acceptable salts, esters, hydrates, solvates, isomers or derivatives thereof.

2. The composition according to claim 1, further characterized in that the active agent has been selected from a group comprising CGS 26303, phosphoramidone, FR901533, TMC-66, SM-19712, KC-126 5, 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. The composition according to claim 1 or 2, further characterized in that the alkaline system has been selected from a group comprising sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, magnesium carbonate, carbonate of calcium, 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. The composition according to any of claims 1 to 3, further characterized in that the alkaline system comprises a mixture of at least two alkaline compounds.

5. - An improved oral pharmaceutical composition, comprising at least one ECE inhibitor (converting enzyme of endothelin) and / or an inhibitor of NEP (neutral endopeptidase) as an active agent in an amount greater than 10% w / w of the composition, an alkaline system comprising a mixture of at least two alkaline compounds in a ratio of 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. - The composition according to claim 5, further characterized in that the active agent has been selected from the group comprising CGS 26303, phosphoramidone, FR901533, TMC-66, SM-1 9712, KC-2615, 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. - The composition of compliance with claim 5, further characterized in that the ECE (endothelin converting enzyme) inhibitor and / or a NEP inhibitor (neutral endopeptidase) is an active agent of the general Formula: where: Ri has been selected from the group consisting of alkoxy (Ci C6) alkyl (CrC6) which may be substituted by a (C6) alkoxy, phenyl (C6) alkyl and phenyloxy-alkyl (Cr6), wherein the phenyl group may be substituted by (C6) alkyl, alkoxy (C C6) or halogen, and naphthyl (Ci-C6) alkyl, R2 and R3, independently of each other, are both 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 salts, esters, hydrates, solvates, isomers or derivatives thereof, pharmaceutically acceptable.

8. The composition according to claim 7, further characterized in that M is calcium in its 2 + form.

9. The composition according to claim 7 or 8, further characterized in that the active agent is the calcium salt of 3 - [[[1 - [2- (ethoxycarbonyl) -4-phenylbutyl] -cyclopentyl] carbonyl] -amino] -2,3,4,5-tetrahydro-2-γ-1 H-1-benzazepin-1-acetic, preferably in its 3S, 2'R form.

10. The composition according to any of claims 4 to 9, further characterized in that the alkaline system comprises a mixture of sodium bicarbonate and sodium carbonate. eleven . - The composition according to claim 10, further characterized in that the alkaline system comprises between 83 and 90% weight / weight of sodium bicarbonate and between 10 and 17% weight / weight of sodium carbonate. 12. - The composition according to any of claims 1 to 11, further characterized in that the alkaline system is it is present in an amount of at least 20% w / w of the composition. 13. - The composition according to any of claims 1 to 12, further characterized in that the pharmaceutically acceptable excipients have been selected from a group consisting of diluents, disintegrants, binders, polymers, solubilizers, fillers, bulking agents, anti-adherents, antioxidants , buffering agents, colorants, flavoring agents, coating agents, plasticizers, organic solvents, stabilizers, preservatives, lubricants, slip agents, and chelating agents, used alone or in combination thereof. 14. The composition according to any of claims 1 to 13, further characterized in that it is in the form of granules, tablets or capsules. 15. A process for the preparation of the composition claimed in any of claims 1 to 14, comprising the following steps: i) mixing the active agent and the alkaline system, optionally with one or more pharmaceutically acceptable excipients; and ii) the formulation of the mixture in a suitable dosage form. 16. A process for the preparation of the composition claimed in any of claims 1 to 14, comprising the following steps: i) mixing the active agent, alkaline system, and lubricant, ü) optionally, adding one or more pharmaceutically acceptable excipients, and iii) formulating the mixture in a suitable dosage form. 17. A process for the preparation of the composition claimed in any of claims 7 to 14, comprising the following steps: i) mixing the SLV-306 or its salts, esters, hydrates, solvates, isomers or derivatives, pharmaceutically acceptable; the alkaline system, the disintegrating agent and the lubricant, ii) optionally, adding one or more other pharmaceutically acceptable excipients, and iii) formulating the mixture in a suitable dosage form. 18. The use of the composition claimed in any of claims 7 to 14, for the manufacture of a medicament useful for the treatment of a disease selected from chronic heart failure, myocardial infarction, cardiogenic shock, systemic hypertension and pulmonary, ischemia-reperfusion injuries, atherosclerosis, coronary and systemic vasospastic disorders, cerebral vasospasm and subarachnoid hemorrhage.