MXPA06010482A - Galenic formulations of organic compounds - Google Patents

Abstract

The present invention relates to a solid oral dosage form comprising a therapeutically effective amount of aliskiren or a pharmaceutically acceptable salt thereof, and wherein the active incredient is present in an amount of more than 46%by weight based on the total weight of the oral dosage form.

Description

GALENIC FORMULATIONS OF ORGANIC COMPOUNDS Description of the Invention The present invention relates to solid oral dosage forms comprising an orally active renin inhibitor, alisciren, or a pharmaceutically acceptable salt thereof, as the active ingredient in a suitable vehicle medium. In particular, the present invention provides galenic formulations comprising aliscirene, preferably, a hemi-fumarate salt thereof, alone or in combination with another active agent. The present invention also relates to methods for their preparation and for their use as medicaments. In the following, the term "alisciren", if not specifically defined, should be understood to be both the free base and a salt thereof, especially a pharmaceutically acceptable salt thereof, most preferably a hemi-fumarate thereof. Renin released from the kidneys cleaves angiotensinogen in the circulation to form decapeptide angiotensin I. This in turn is split by the angiotensin-converting enzyme in the lungs, kidneys, and other organs to form the octapeptide angiotensin I I. The octapeptide increases blood pressure both directly through arterial vasoconstriction, and indirectly by releasing the aldosterone hormone sodium retention from the adrenal glands, accompanied by an increase in the volume of extracellular fluid. Inhibitors of renin enzymatic activity produce a reduction in the formation of angiotensin I. As a result, a smaller amount of angiotensin II is produced. The reduced concentration of the active peptide hormone is the direct cause of, for example, the antihypertensive effect of the renin inhibitors. Accordingly, the renin inhibitors or their salts can be used, for example, as antihypertensive agents or for the treatment of congestive heart failure. The renin inhibitor, alisciren, in particular, a hemi-fumarate thereof, is known to be effective in the treatment to reduce blood pressure without regard to age, sex or race and is also very tolerated. The alisciren in the form of the free base is represented by the following formula: and chemically defined as 2 (S), 4 (S), 5 (S), 7 (S) -N- (3-amino-2,2-dimethyl-3-oxopropyl) -2,7-di (1 -methylethyl) -4-hydroxy-5-amino-8- [4-methoxy-3- (3-methoxy-propoxy) phenyl] -octanamide. As described above, the hemi-fumarate salt thereof is very preferred, which is specifically described in EP 678503 A as Example 83. Oral administration of such pharmaceutical agents as tablets or capsules has certain advantages over parenteral administration , such as iv or i.m. Diseases that require treatment with painful injectable formulations are considered to be more serious than those conditions that can be treated with oral dosage forms. However, the main advantage with oral formulations is that they maintain their stability for self-administration, whereas parenteral formulations have to be administered in most cases by a physician or paramedical personnel. However, alisciren is difficult to formulate and until now it has not been possible to make oral formulations in the form of tablets in a reliable and robust way. In a galenic formulation comprising alisciren, or a pharmaceutically acceptable salt thereof, a high amount of the drug substance (DS) is usually required with properties which make the formulation of the tablets difficult. For example, alisciren has a needle-shaped glass cover, which has a negative influence on the volume properties of the drug substance, e.g., flow properties and bulk density. The compression behavior of the drug substance is poor, leading to weak inter-particle bonds and changes of polymorphism under pressure. The alisciren has a strong elastic component that also leads to the weakening of bonds between particles. The high dose (up to 300 or 600 mg of the free base per tablet) makes a high drug loading necessary in order to obtain a reasonable tablet size. The quality of drug substance is very variable with effect on the processability of a tablet, for example, particle size distribution, bulk density, fluid wetting ability, surface area, and adherent tendency. In addition, alisciren is highly hygroscopic. In contact with water, the polymorphism of the drug substance changes to an amorphous state, which shows a lower stability compared to the crystalline state. The combination of these obstacles makes a standard tablet manufacturing process extremely difficult. Direct compression is not an advisable option for routine production, due to, for example, high hygroscopic capacity, needle-like particle structure, poor fluid capacity with resultant processability problems, and uniformity problems. dose. A roller compaction process leads to a reduction of the high bulk volume of the drug substance. Moreover, the pre-compression of the drug substance during roll compaction makes an additional compression in the tablets with sufficient hardness and resistance to friability without a high amount of excipients extremely difficult, due to the low compression capacity of the drug substance. A tablet with a load of alisciren drug greater than about 35% has been found not to lead to robust tablets (eg, viability, hardness) and a robust process (eg, adhesion and perforation during roller compaction and forming. of tablet). Accordingly, a suitable and robust galenic formulation which overcomes the above problems with regard to the properties of alisciren needs to be developed. The present invention has solved the above problems resulting in a robust formulation which avoids all previous disadvantages and in a process suitable for large scale manufacture of solid oral dosage forms. The present invention relates to a solid oral dosage form comprising a therapeutically effective amount of alisciren, or a pharmaceutically acceptable salt thereof, and wherein the active ingredient is present in an amount greater than 46% by weight, based on the Total weight of the oral dosage form, whether dependent on or not dependent on any coating or capsule material used. If it is not dependent on any coating or capsule used, the active ingredient is present in an amount greater than 48% by weight, based on the total weight of the oral dosage form. If dependent on any capsule coating used, the active ingredient is present in an amount greater than 46% by weight, based on the total weight of the oral dosage form. In a preferred embodiment of the present invention, the active agent is present in an amount ranging from 46 to 60% by weight, based on the total weight of the oral dosage form. In another preferred embodiment of the present invention, the active agent is present in an amount of greater than 46% to 56% by weight, based on the total weight of the oral dosage form. In a solid oral dosage form according to the present invention, wherein the active agent consists entirely of alisciren, or a pharmaceutically acceptable salt thereof, it is preferred if the active agent is present in an amount ranging from about 75 mg to about 600 mg of the free base per unit dose form.

In a preferred embodiment of the present invention, the active agent consists entirely of alisciren, or a pharmaceutically acceptable salt thereof, and is present in an amount of about 75 to about 300 mg of the free base per unit dose form. In a further embodiment of the present invention, the dose of alisciren is in the form of a hemi-fumarate thereof and is present in an amount of about 83, about 166, about 332 or about 663 mg per unit dosage form. The solid oral dosage forms according to the present invention provide for the administration of the active ingredient in a smaller oral form than hitherto possible for a given unit dose of the active agent. Furthermore, the oral dosage forms obtained are stable both for the production process and during storage, for example, for about 2 years in a conventional package, for example, packets of sealed aluminum ampoules. The terms "effective amount" or "therapeutically effective amount" refer to the amount of the active ingredient or agent that stops or reduces the progress of the condition being treated or that otherwise completely or partially cures or acts palliatively in the condition . The alisciren, or a pharmaceutically acceptable salt thereof, can, for example, be prepared in a manner known per se, especially as described in EP 678503 A, for example, in Example 83. A solid oral dosage form it comprises a capsule or very preferably a tablet or a tablet covered with film. A solid oral dosage form according to the invention comprises additives or excipients which are suitable for the preparation of solid oral dosage form according to the present invention. Auxiliaries can be used to form tablets, commonly used in the formulation of tablets, and reference is made to the extensive literature on the subject, see in particular Fiedler's "Lexicon der Hilfstoffe", 4th.

Edition, ECV Aulendorf 1996, which is incorporated here by reference. These include, but are not limited to, fillers, binders, disintegrating agents, lubricants, slip agents, stabilizing agents, renegers or diluents, surfactants, film formers, softeners, pigments, and the like. In a preferred embodiment, the solid oral dosage form according to the present invention comprises an additive and a filler. In a preferred embodiment, the solid oral dosage form according to the present invention comprises an additive, in addition to a filler, and a disintegrating agent. In a preferred embodiment, the solid oral dosage form according to the present invention comprises as an additive, in addition to a filler and disintegrating agent, lubricant. In a preferred embodiment, the solid oral dosage form according to the present invention comprises as an additive, in addition to a filler, a disintegrating agent and lubricant, a slip agent. In a preferred embodiment, the solid oral dosage form according to the present invention comprises as an additive, in addition to a filler, a disintegrating agent, lubricant and glidant, binder. As fillers, mention may be made in particular of starches, for example, potato starch, wheat starch, corn starch, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose (HPMC) and, preferably, microcrystalline cellulose, for example, products available under the trademarks of AVICEL, FILTRAK, HEWETEN or PHARMACEL. As binders for wet granulation, polyvinylpyrrolidones (PVP), for example, PVP K 30, HPMC, for example, of viscosity grades of 3 or 6 cps, and polyethylene glycols (PEG), for example, PEG 4000, can be mentioned. A highly preferred binder is PVP K 30. As the disintegrating agents, particularly can be mentioned carboxymethylcellulose calcium, (CMC-Ca), sodium carboxymethylcellulose (CMC-Na), interlaced PVP (e.g.

CROSPOVI DON E, POLYPLASDONE or KILLIDON XL), algic acid, sodium alginate and guar gum, most preferably PVP interlaced (CROSPOVIDONE), CMC interlaced (Ac-Di-Sol), carboxymethyl starch-NA (Pi RI MOJEL and EXPLO ). A highly preferred disintegrating agent is CROSPOVI DONE.

As slip agents, mention may be made in particular of colloidal silica, such as colloidal silicon dioxide, for example, AEROSIL, magnesium trisilicate (Mg), powdered cellulose, starch, talc and tribasic calcium phosphate or combinations thereof with fillers. or binders, for example, silicified microcrystalline cellulose (POSOLV). A highly preferred glidant is colloidal silicon dioxide (e.g., AEROSIL 200). As fillers of diluents, sugar confectionery, compressible sugar, dextrins, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, in particular, having a density of about 0.45 g / cm 3, for example, AVICEL, powdered cellulose, can be mentioned. , sorbitol, sucrose and talc. A very preferred filler is microcrystalline cellulose. As lubricants, mention may in particular be made of magnesium stearate, aluminum (Al) stearate or Ca stearate, PEG 4000 to 8000 and talc, hydrogenated castor oil, stearic acid and its salts, glycerol esters, sodium steryl fumarate, hydrogenated cottonseed, and others. A highly preferred lubricant is magnesium stearate. The additives that will be used as film coating materials comprise polymers such as HPMC, PEG, PVP, polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), polyvinyl alcohol (PVA), and sugar as film formers. A most preferred coating material is HPMC, especially HPMC 3 cps (preferred amount 5-6 mg / cm2) and mixtures thereof with other additives, for example, those available under the trade name OPADRY. Other additives include pigments, dyes, lakes, highly preferred T, O2, and iron oxides, anti-adhesion agents, such as talc and softeners such as PEG 3350, 4000, 6000, 6000, 8000, or others. The most preferred additives are talc and PEG 4000. The present invention also relates to a solid oral dosage form comprising a therapeutically effective amount of alisciren, or a pharmaceutically acceptable salt thereof, as an active agent, and a filler as a additive. Other additives include, but are not limited to, binders, disintegrating agents, lubricants, slip agents, stabilizing agents, diluents, surfactants, film formers, pigments, softeners and anti-adhesion agents, and the like. The amounts of the active ingredient and other additives are preferably those defined above. The present invention also relates to a solid oral dosage form comprising a therapeutically amount of alisciren, or a pharmaceutically acceptable salt thereof, as an active agent, and a filler and a disintegrating agent as additives. Other additives include, but are not limited to, binders, lubricants, slip agents, stabilizing agents, diluents, surfactants, film formers, pigments, softeners, and anti-adhesion agents, and the like. The amounts of the active ingredient and other additives are preferably those defined above. The present invention also relates to a solid oral dosage form comprising a therapeutically effective amount of alisciren or a pharmaceutically acceptable salt thereof; as an active agent, and a filler, a disintegrating agent and a lubricant as an additive. Other additives include, but are not limited to, binders, slip agents, stabilizing agents, diluents, surfactants, film formers, pigments, softeners and anti-adhesion agents, and the like. The amounts of the active ingredient and other additives are preferably those defined above. The present invention also relates to a solid oral dosage form comprising a therapeutically effective amount of alisciren, or a pharmaceutically acceptable salt as an active agent, and a filler, a disintegrating agent, lubricant and glidant as additives. Other additives include, but are not limited to, binders, stabilizing agents, diluents, surfactants, film formers, pigments, softeners and anti-adhesion agents, and the like. The amount of the active ingredient and other additives are preferably those defined above. The present invention also relates to a solid oral dosage form comprising a therapeutically effective amount of alisciren, or a pharmaceutically acceptable salt thereof, as an active agent, and a filler, a disintegrating agent, a lubricant, an agent of slip and a binder as additives. Other additives include, but are not limited to, stabilizing agents, diluents, surfactants, film formers, pigments, softeners and anti-adhesion agents, and the like. The amounts of the active ingredient and other additives are preferably those defined above.

One or more of these additives may be selected and used by one skilled in the art with respect to the particular desired properties of the solid oral dosage form through routine experimentation and without undue danger. The amount of each type of additive used, e.g., slip agent, binder, disintegrating agent, filler or diluent and lubricant or film coating can vary within conventional scales in the art. In this way, for example, the amount of lubricant can vary within a range of 0.2 to 5% by weight, in particular, for magnesium stearate of 0.5 to 2.0% by weight, for example from 0.8 to 1.5% by weight. weight; the amount of binder may vary within a range of from 0 to about 20% by weight, for example from 3 to 4% by weight; the amount of the disintegrating agent may vary within a range of from 0 to about 20%, for example, from 13.5 to 16% by weight; the amount of filler or diluent may vary within a range of from 0 to about 80% by weight, for example from 20 to 32% by weight; while the amount of slip agent may vary within a range of from 0 to about 5% by weight, for example from 0.4 to 0.6% by weight; and the amount of film coating can vary within a range of 0 to 20 mg / cm2, for example 4 to 7 mg / cm2. It is a feature of the present solid oral dosage forms that they contain only a relatively small amount of additives given the high content of the active agent. This allows the production of physically small unit dose forms. The total amount of additives in a given uncovered unit dose may be about 60% or less by weight, based on the total weight of the solid oral dosage form, more particularly about 54% or less. Preferably, the additive content is in the range of about 35 to 55% by weight, more particularly, the additive content ranges from about 50 to about 52% by weight. A preferred amount of a filler, especially microcrystalline cellulose, ranges from about 20 to 32% by weight per unit dosage form. A preferred amount of a binder, especially PVK K 30, ranges from about 3 to 4% by weight per unit dosage form.

A preferred amount of a disintegrating agent, especially CROSPOVIDONE, ranges from about 13.5 to 15% by weight per unit dosage form. A preferred amount of a slip agent, especially colloidal silicon dioxide, ranges from about 0.4 to 0.6% by weight per unit dosage form. A preferred amount of a lubricant, especially magnesium stearate, ranges from about 0.8 to 1.5% by weight per unit dosage form. A preferred amount of a film coating, especially of HPMC 3 cps, ranges from about 4 to 7 mg / cm 2 per unit dosage form. Preferred amounts of alisciren and additives are also shown in the illustrative examples. The absolute amounts of each additive and the relative amounts with other additives are similarly dependent on the desired properties of the solid oral dosage form and can also be selected by one skilled in the art through routine experimentation without undue danger. For example, the solid oral dosage form can be selected to exhibit an accelerated and / or delayed release of the active agent with or without quantitative control of the release of the active agent. In this way, when an accelerated release, a disintegrating agent, such as interlaced PVP, is desired, for example, those products available under the trademarks of POLYPLASDONE XL or KOLLIDON CL, in particular, having a molecular weight in excess of 1. , 000,000, more particularly, having a particle size distribution of less than 400 microns or, preferably, less than 74 microns, or comprising reactive additives (effervescent mixtures) which effect rapid disintegration of the tablet in the presence of water, for example, the so-called effervescent tablets containing an acid in solid form, usually citric acid, which acts in water in a base containing chemically combined carbon dioxide, for example, sodium hydrogen carbonate, or sodium carbonate, and liberates carbon dioxide. While the delayed release is desired, coating technology for multiparticulates (e.g., pellets, mini tablets), wax matrix systems, polymer matrix tablets or polymer coatings or other technologies conventional in the art can be used.

Quantitative control of the release of the active agent can be achieved by conventional techniques known in the art.

Such dosage forms are known as oral osmotic systems (e.g., OROS), coated tablets, matrix tablets, coated tablets under pressure, multi-layer tablets, and the like. In a solid oral dosage form, wherein the active agent consists entirely of alisciren, or a pharmaceutically acceptable salt thereof, or a combination of alisciren with other active pharmaceutical agents, the preferred additives with microcrystalline cellulose, hydroxypropylcellulose, interlaced PVP, PVP , PEG, CMC-Na or CMC-Ca, magnesium stearate, calcium stearate or aluminum stearate, anhydrous colloidal silica, talc, titanium dioxide and iron oxide pigments. The amounts of additive used will depend on how much active agent is going to be used. Stearate, for example magnesium stearate, is preferably used in amounts of 0.8 to 1.5% by weight. While silica preferably is used in an amount of 0.4 to 0.6% by weight. The amount of alisciren in the form of its hemi-fumarate within the total weight of the uncovered unit dose form ranges from, preferably, about 83 to 663 mg, most preferably, the amount of alisciren hemi-fumarate is about 83, approximately 1 66 or approximately 332 mg per unit dose form. The amount of binder within the total weight of the unit dose form not covered is preferably 2 to 5%, most preferably 3 to 4% by weight per unit dosage form.

The amount of the disintegrating agent within the total weight of the unit dose form not covered is preferably 0 to 20%, most preferably 1 3.5 to 16% by weight per unit dosage form. The amount of the slip agent within the total weight of the unit dose form not preferably covered is from 0 to 5%, most preferably from 0.4 to 0.6% by weight per unit dosage form. The amount of lubricant within the total weight of the unit dose form not preferably covered is from 0.2 to 5%, most preferably from 0.8 to 1.5% by weight for magnesium stearate by weight per unit dosage form. A preferred amount of a film coating, especially of HPMC 3 cps, is from about 4 to about 7 mg / cm 2 per unit dose form. The weight ratio of alisciren to the binder preferably ranges from about 8: 1 to about 25: 1, most preferably from about 1 1: 1 to about 15: 1. Most preferably the weight ratio is 12.5: 1. The weight ratio of alisciren to the disintegrating agent preferably ranges from about 2: 1 to about 4: 1, most preferably from about 2.5: 1 to about 3.7: 1.

Most preferably, the weight ratio is about 3.1: 1. The weight ratio of alisciren to slip agent preferably ranges from 75: 1 to about 125: 1, more preferably from about 80: 1 to about 90: 1. Most preferably, the weight ratio is about 83.3: 1.

The weight ratio of alisciren to the lubricant preferably ranges from about 25: 1 to about 63: 1, most preferably from about 30: 1 to about 50: 1. Most preferably, the weight ratio is about 30: 1. The solid oral dosage forms according to the present invention may also be in the form of tablets or film coated dragees, in which case, the solid oral dosage form is provided with a coating, usually a polymer such as HPMC, PVP, or the like, sugar, shellac or other film coating completely conventional in the art. Attention is paid to numerous known methods of coating used in the art, for example, spray coating in a fluidized bed, for example, through known methods using apparatus available from Aeromatic, Glatt, Wurster or Hüttlin, in a perforated tray coater, for example, by known methods using the apparatus of Accela Cota, Glatt, Driam, or others. , or other conventional methods in the art. The additives commonly used for clothing can be used in such methods. A further embodiment of the present invention is a method for the manufacture of a solid oral dosage form according to the present invention. Wet granulation of alisciren with excipients using water and / or an aqueous binder solution leads to a change in the polymorphism of the drug substance which partially changes to the amorphous state and causes a lower chemical stability of the drug product (DP) . However, the wet granulation of alisciren uses a mixture of organic solvents or an organic binder solution has been found to be the best way to manufacture suitable solid dosage forms of alisciren, especially tablets, showing the following advantages: Wet granulation reduces bulk volume of alisciren during granulation; • influences of a drug substance quality change are minimized; • a high drug loading above 46% by weight per unit dosage form can be easily obtained; • the formulation of tablets with sufficient hardness, resistance to friability, disintegration time, dissolution speed, etc. , it's possible; • the adherent tendency and the poor flow of the drug substance are reduced to a minimum; • A robust DP manufacturing procedure is achieved; • a formulation and procedure range is achieved resulting in reproducible DP operation; and • sufficient stability is achieved to obtain a reasonable storage life. The excipients can be partially distributed in the internal phase (granular) and partially in the external phase, which is the case in the invention described. The microcrystalline cellulose (filler) and CROSPOVI DONE (disintegrating agent) are partially in the interior and partially in the external phase, PVP k 30 (binder) is only part of the internal phase, the binder being during the granulation, while the Colloidal silicon dioxide (slip agent) and magnesium stearate (lubricant) are only part of the external phase. The internal phase excipients, for example, filler, binder and disintegrating agent, and the drug substance are mixed and granulated with an ethanolic solution of the binder and additional ethanol. The granulate is dried and sieved. The external phase containing, for example, the disintegrating agent, the filler, the slip agent and the lubricant, is sieved with the dry granulator and mixed. The mixture is compressed to tablets. The cores can optionally be covered with a film coating. The granulation phase is defined as the internal phase, the excipients added to the granulator are defined as the external phase of the tablet-forming mixture. The invention also relates to a process for the preparation of solid oral dosage forms as defined above. Such a solid oral dosage form can be produced by processing the components defined above in the appropriate amounts, to form unit dosage forms. Accordingly, the present invention provides a method for the manufacture of a solid oral dosage form of the present invention, comprising: 1) mixing the active ingredient and additives and granulating such components with a granulation liquid; 2) drying a resulting granulator; 3) mix the dry granulator with external phase excipients; 4) compressing a resulting mixture to form a solid oral dose as a core tablet; and 5) optionally coating a resulting core tablet to give a film coated tablet. Preferably, the additives in step (1) are selected from a filler, disintegrating agent and binder; and the external phase excipients in step (3) are selected from a filler, a disintegrating agent, a lubricant and a slip agent. The granulation liquid can be ethanol, a mixture of ethanol and water, a mixture of ethanol, water and isopropanol, or a solution of PVP in the aforementioned mixtures. A preferred mixture of ethanol and water ranges from about 50/50 to about 99/1 (% w / w), most preferably it is about 94/6 (w / w). A preferred mixture of ethanol, water and isopropanol ranges from about 45/45/5 to about 98/1/1 (% w / w / w), preferably from about 88.5 / 5.5 / 6.0 to about 91.5 / 4.5 / 4.0. (% p / p / p). A preferred concentration of PVP in the named mixtures ranges from about 5 to about 30% by weight, preferably from about 15 to about 25%, most preferably about 16 to 22%. Attention must be paid to the numerous known methods for granulation, drying and mixing, used in the art, for example, spray granulation in a fluidized bed, wet granulation in a high shear mixer, melt granulation, drying in a fluidized bed dryer, mixing in a free fall or stirring mixer, the compression to tablets in a single perforator or a rotary tablet press. The manufacture of the granulate can be carried out in standard equipment suitable for organic granulation processes. The manufacture of the final mixture and the compression of the tablets can also be carried out in standard equipment. For example, step (1) can be performed through a high shear granulator, for example, Collette Gral; The phase (2) can be conducted in a fluid bed dryer; step (3) can be performed through a free fall mixer (e.g., container mixer, stirring mixer); and step (4) can be performed using a dry compression method, for example, a rotary tablet press. As described above, the core tablets can then optionally be film coated. Due to the high hygroscopic capacity and water sensitivity of aliscirens with respect to changes in polymorphism, the use of water is preferably avoided in order to prevent the drug substance from changing into polymorphism for the reasons stated above (amorphous state). , lower chemical stability). One solution to such a problem is to apply a process of coating organic film. Surprisingly, it has been found that an aqueous film coating process using a standard film coating composition can be applied to alisciren core tablets without changes in polymorphism. The film coating preferably consists of HPMC as the polymer, iron oxide pigments, titanium dioxide as a PEG coloring agent as a softener and talc as an anti-adhesion agent. The use of coloring agents or dyes can serve to improve the appearance as well as to identify the compositions. Other dyes suitable for normal use include carotenoids, chlorophyll and lacquers. The film coating conditions which have to ensure that the tablet cores do not absorb considerable amounts of moisture and that the drug substance within the tablets does not remain in close contact with water droplets. This is achieved through process parameter determinations that reduce the amount of moisture that goes to the tablet cores. The solid oral dosage forms of the present invention are useful for reducing blood pressure, either systolic or diastolic, or both. Conditions for which the present invention is useful include, without limitation, hypertension (either malignant, essential, reno-vascular, diabetic, isolated systolic, or other secondary type), congestive heart failure, angina (either stable or unstable). ), myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal failure, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction (such as Alzheimer's) and stroke, headache and chronic heart failure.

The present invention also relates to a method for treating hypertension (either malignant, essential, reno-vascular, diabetic, isolated systolic, or other secondary type), congestive heart failure, angina (either stable or unstable), infarction to the myocardium, atherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, for example, Alzheimer's, attack, headache and chronic heart failure, which comprises administering to an animal, including a human, with the need for such treatment, a therapeutically effective solid oral dosage form according to the present invention. The present invention also relates to the use of a solid oral dosage form according to the present invention for the manufacture of a medicament for the treatment of hypertension (either malignant, essential, reno-vascular, diabetic, isolated systolic, or another secondary type), congestive heart failure, angina (either stable or unstable), myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal failure, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction (such as Alzheimer's) and attack, headache and chronic heart failure. The present invention also relates to a pharmaceutical composition for the treatment of hypertension (whether malignant, essential, reno-vascular, diabetic, isolated systolic, or other secondary type), congestive heart failure, angina (either stable or unstable), myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal failure, vascular disease peripheral, left ventricular hypertrophy, cognitive dysfunction (such as Alzheimer's) and attack, headache and chronic heart failure, comprising a solid oral dose according to the present invention. Finally, the exact dose of the active agent and the particular formulation that will be administered depends on a number of factors, for example, the condition to be treated, the desired duration of treatment and the rate of release of the active agent. For example, the amount of active agent required and the rate of release thereof can be determined based on known in vitro or in vivo techniques, determining how much of the particular active agent concentration remains in the blood plasma at an acceptable level for a therapeutic effect. The above description fully describes the invention, including its preferred embodiments. Modifications and improvements of the modalities specifically described herein are within the scope of the following claims. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, use the present invention to its fullest extent. Therefore, the examples herein are to be construed merely as illustrative and not as limiting the scope of the present invention in any way.

EXAMPLE 1 Alisciren composition, 150 mg (free base) tablets not covered in mg / unit. Tablet Shape Form Form compacted by dose 1 dose 2 roll dose 3 Component Alisciren Hemi-fumarate 165,750 165,750 165,750 165,750 Cellulose microcrystalline 220,650 84,750 72,250 107,250 Polyvinylpyrrolidone K 30 - - 12,000 12.00 Crospovidone 84,000 45,000 44,000 48,200 Aerosol 200 4,800 1,500 1,500 1,800 Magnesium stearate 4,800 3,000 4,500 5,000 Total weight 480,000 300,000 300,000 340,000 Composition of alisciren 1 50 mg (free base) tablets not covered in percentage by weight. Tablet Shape Form of compacted dosage form 1 dose 2 doses 3 per roll Component Hemisamiderate alisciren 34.53 55.25 55.25 48.75 Microcrystalline cellulose 45.97 28.25 24.08 31,545 Polyvinylpyrrolidone K 30 - - 4 3.53 Crospovidone 17.5 15 14.67 14.175 Aerosol 200 1 0.5 0.5 0.53 Magnesium stearate 1 1 1.5 1.47 Total weight 100.00 100.00 100.00 100.00 Composition of alisciren 1 50 mg (free base) tablets not covered in mg / unit (divided into internal / external phase). Tablet Shape Form of compacted dose 1 dose 2 doses 3 per roll Component Internal phase Hemi-fumarate 165.75 165.75 165.75 165.75 alisciren Microcrystalline cellulose 220.65 84.75 72.25 90.25 Polyvinylpyrrolidone K 30 - - 12.00 12.25 Crospovidone 36.00 - - 14.20 Aerosol 200 - - - - Magnesium stearate 2.40 - - - External phase Crospovidone 48.00 45.00 44.00 34.00 Microcrystalline cellulose - - - 17.00 Aerosol 200 4.80 1.50 1.50 1.80 Magnesium stearate 2.40 3.00 4.50 5.00 Total weight 480.00 300.00 300.00 340.00 Alisciren composition 150 mg (free base) tablets not covered in percentage by weight (divided into internal / external phase).

Tablet Shape Form Form compacted by dose 1 dose 2 doses 3 roll Component Internal phase Almisciren Hemi-fumarate 34.53 55.25 55.25 48.75 Microcrystalline cellulose 45.97 28.25 24.08 26.545 Polyvinylpyrrolidone K 30 - - 4 3.530 Crospovidone 7.5 - - 4.175 Aerosol 200 - - - - Magnesium stearate 0.5 - - - External phase Crospovidone 10 15 14.67 10 Microcrystalline cellulose - - - 5 Aerosol 200 1 0.5 0.5 0.53 Magnesium stearate 0.5 1 1.5 1.47 Total weight 100.00 100.00 100.00 100.00 EXAMPLE 2 Alisciren composition (dose form 3) tablets covered with film in mg / unit.

Dosage form 3 / strength 75 mg 150 mg 300 mg (free base) (free base) (free base) Component Alisciren Hemi-fumarate 82,875 165,750 331,500 Microcrystalline cellulose 53,625 107,250 214,500 Polyvinylpyrrolidone K 30 6,000 12,000 24,000 Crospovidone 24,100 48,200 96,400 Aerosol 200 0.900 1,800 3,600 Magnesium stearate 2,500 5,000 10,000 Total tablet weight 170,000 340,000 680,000 Opadry premix white 9.946 16.771 23.9616 Opadry premix red 0.024 0.238 1.8382 Opadry premix black 0.030 0.051 0.2002 Total weight of covered tablet 180,000 357,000 706,000 with film

Claims (10)

1 .- A solid oral dosage form comprising a therapeutically effective amount of alisciren, or a pharmaceutically acceptable salt thereof, wherein the active ingredient is present in an amount of greater than 46% by weight based on the total weight of the oral dosage form.

2. A solid oral dosage form according to claim 1, wherein the active ingredient is present in an amount of more than 48% by weight.

3. A solid oral dosage form according to claim 1, wherein the active ingredient is present in an amount ranging from about 46 to 60% by weight.

4. A solid oral dosage form according to claim 3, wherein the active ingredient consists entirely of alisciren or a pharmaceutically acceptable salt thereof, and is present in an amount ranging from about 75 to about 600 mg of the free base per unit dose form.

5. A solid oral dosage form according to claim 4, wherein the active ingredient consists entirely of alisciren or a pharmaceutically acceptable salt thereof, and is present in an amount ranging from about 75 to about 300 mg of the free base per unit dose form.

6. A solid oral dosage form according to claim 5, wherein the alisciren is in the form of a hemi-fumarate thereof, and is present in an amount of about 83, about 1 66 or about 332 mg per unit dose form.

7. A solid oral dosage form according to claim 6, wherein the dosage form further comprises a filler.

8. A solid oral dosage form according to claim 7, wherein the filler is microcrystalline cellulose.

9. A solid oral dosage form according to claim 7, wherein the dosage form further comprises a disintegrating agent.

10. A solid oral dosage form according to claim 9, wherein the dosage form further comprises a lubricant. 1 - A solid oral dosage form according to claim 10, wherein the dosage form further comprises a slip agent. 12. A solid oral dosage form according to claim 1, wherein the dosage form further comprises a binder. 1 3. A solid oral dosage form according to claim 12, for the treatment of hypertension, congestive heart failure, angina, myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal failure, peripheral vascular disease, hypertrophy left ventricle, cognitive dysfunction, attack, headache and chronic heart failure. 14. A solid oral dose form according to claim 1, for the treatment of hypertension, congestive heart failure, angina, myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal failure, peripheral vascular disease, ventricular hypertrophy left, cognitive dysfunction, attack, headache and chronic heart failure. 1 5.- A method for the treatment of hypertension, congestive heart failure, angina, myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal failure, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, attack, headache and chronic heart failure, such method comprises administering a therapeutically effective amount of a solid oral dosage form according to claim 1 to a patient in need thereof. 16.- A method for the treatment of hypertension, congestive heart failure, angina, myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal failure, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, attack, headache and chronic heart failure, the method comprises administering a therapeutically effective amount of a solid oral dosage form according to claim 12 to a patient in need thereof. 7. The use of a solid oral dosage form according to claim 1, for the manufacture of a medicament for the treatment of hypertension, congestive heart failure, angina, myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiac myopathy , renal failure, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, attack, headache and chronic heart failure. 1 8. The use of a solid oral dosage form according to claim 12, for the manufacture of a medicament for the treatment of hypertension, congestive heart failure, angina, myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiac myopathy , renal failure, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, attack, headache and chronic heart failure. 9. A method for manufacturing a solid oral dosage form according to claim 12, comprising: 1) mixing the active ingredient and additives and granulating such components with a granulation liquid; 2) drying a resulting granulator; 3) mix the dry granulator with external phase excipients; 4) compressing a resulting mixture to form a solid oral dose as a core tablet; and 5) optionally coating a resulting core tablet to give a film coated tablet. 20. A process according to claim 1, wherein the additives in step (1) are selected from a filler, disintegrating agent and binder; and the external phase excipients in step (3) are selected from a filler, disintegrating agent, lubricant and slip agent.