WO2009040427A1

WO2009040427A1 - Galenical formulations of organic compounds

Info

Publication number: WO2009040427A1
Application number: PCT/EP2008/062959
Authority: WO
Inventors: Marie-Christine Wolf; Petra Gisela Rigassi-Dietrich; Matthias Willmann
Original assignee: Novartis Ag
Priority date: 2007-09-28
Filing date: 2008-09-26
Publication date: 2009-04-02

Abstract

The present invention relates to a solid oral dosage form comprising a therapeutically effective amount of aliskiren or a pharmaceutically acceptable salt thereof, a therapeutically effective amount of Valsartan or a pharmaceutically acceptable salt thereof, wherein the oral dosage form has a disintegration time for both of components (a) and (b) of equal to or less than 25 min.

Description

Galenical Formulations of Organic Compounds

The present invention relates to solid oral dosage forms comprising an orally active renin inhibitor, aliskiren, or a pharmaceutically acceptable salt thereof, and Valsartan as the active ingredients in a suitable carrier medium. In particular, the present invention provides galenical formulations comprising the hemi-fumarate salt aliskiren in combination with valsartan. The present invention also relates to the processes for their preparation and to their use as medicaments.

Renin released from the kidneys cleaves angiotensinogen in the circulation to form the decapeptide angiotensin I. This is in turn cleaved by angiotensin converting enzyme in the lungs, kidneys and other organs to form the octapeptide angiotensin II. The octapeptide increases blood pressure both directly by arterial vasoconstriction and indirectly by liberating from the adrenal glands the sodium-ion-retaining hormone aldosterone, accompanied by an increase in extracellular fluid volume. Inhibitors of the enzymatic activity of renin bring about a reduction in the formation of angiotensin I. As a result a smaller amount of angiotensin Il is produced. The reduced concentration of that active peptide hormone is the direct cause of, e.g., the antihypertensive effect of renin inhibitors. Accordingly, renin inhibitors, or salts thereof, may be employed, e.g., as antihypertensives or for treating congestive heart failure.

The renin inhibitor, aliskiren, in particular, a hemi-fumarate thereof, is known to be effective in the treatment of reducing blood pressure irrespective of age, sex or race and is also well tolerated. Aliskiren in form of the free base is represented by the following formula

and chemically defined as 2(S),4(S),5(S),7(S)-Λ/-(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, most preferred is the hemi-fumarate salt thereof which is specifically disclosed in EP 678503 A as Example 83. Valsartan is a known Angiotensin receptor blocker (ARB, angiotensin Il antagonist) and the combination with Aliskiren is described, e.g. in WO02/40007.

Angiotensin Il is a hormone that causes blood vessels to constrict. This, in turn, can result in high blood pressure and strain on the heart. It is known that angiotensin Il interacts with specific receptors on the surface of target cells. Two receptor subtypes for angiotensin II, namely AT1 and AT2, have been identified thus far. In recent times, great efforts have been made to identify substances that bind to the AT1 receptor. Angiotensin receptor blockers (ARBs, angiotensin Il antagonists) are now known to prevent angiotensin Il from binding to its receptors in the walls of blood vessels, thereby resulting in lower blood pressure. Because of the inhibition of the AT1 receptor, such antagonists can be used, therefore, as anti-hypertensives or for the treatment of congestive heart failure, among other indications.

The oral administration of such pharmaceutical agents as tablets or capsules has certain advantages over parenteral administration such as i.v. or i.m. Diseases requiring treatment with painful injectable formulations are considered to be more serious than those conditions which can be treated with oral dosage forms. However, the major advantage with oral formulations is held to be their suitability for self administration whereas parenteral formulations have to be administered in most cases by a physician or paramedical personnel.

However, aliskiren is difficult to formulate and it is not trivial to make oral formulations in the form of tablets in a reliable and robust way. In a galenical formulation comprising aliskiren, or a pharmaceutically acceptable salt thereof, a high amount is normally needed of the drug substance (DS) with properties that make the formulation of tablets difficult.

For example, aliskiren has a needle shaped crystal habit, which has a negative influence on the bulk properties of the drug substance, e.g., flow properties and bulk density. The compression behavior of the drug substance is poor, leading to weak interparticulate bonds and polymorphism changes under pressure. Aliskiren has a strong elastic component that also leads to weakening of interparticulate bonds. The high dose (up to 300 or 600 mg of the free base per tablet) makes a high drug loading necessary in order to achieve a reasonable tablet size. The drug substance quality is very variable with effect on the processability of a tablet, e.g., particle size distribution, bulk density, flowability, wetting behavior, surface area and sticking tendency. Moreover, aliskiren is highly hygroscopic. After contact with water and removal of the water, the drug substance polymorphism changes to an amorphous state, which shows inferior stability compared to the crystalline state. The combination of these hurdles makes a standard tablet manufacturing process extremely difficult. A solid oral dosage form of Aliskiren is described in WO2005/089729.

The difficulties encountered with Aliskiren to prepare oral formulations in the form of tablets in a reliable and robust way are believed to be potentiated when using it in combination with other therapeutic agents, in particular valsartan. Furthermore, when using a formulation containing Aliskiren and Valsartan, the disintegration time and dissolution rates of both therapeutic agents must be controlled to be within an acceptable range and these dissolution rates must be balanced with a sufficient hardness and friability characteristics. In particular, it was found that when two therapeutic agents such as aliskiren and valsartan are present, they may affect each others' disintegration time compared to a formulation containing only one therapeutic agent in that the disintegration time may be unsuitably increased for one or both of the agents.

Several methods were found unsuitable to solve the object of the present invention to prepare the claimed formulation. In particular, if aiming to counter-balance the increased disintegration times with the use of more disintegrant in the formulation, stability issues may be observed due to a potential water uptake of the disintegrant leading to a negative effect on the stability of the moisture-sensitve aliskiren drug substance.

In addition the therapeutic ranges in which both valsartan and aliskiren can be used are comparatively high, so that when combined it is highly desired that the amounts of excipients are kept at a minimum to avoid excessively large formulations. Despite that fact, the formulation should still fulfill all of the above requirements.

Accordingly, a suitable and robust galenical formulation overcoming the above problems relating to the properties of aliskiren in particular when formulated together with valsartan need to be developed. The present invention has solved the above problems resulting in a robust formulation avoiding all the above 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) a therapeutically effective amount of Aliskiren, or a pharmaceutically acceptable salt thereof,

b) a therapeutically effective amount of Valsartan, or a pharmaceutically acceptable salt thereof,

wherein the oral dosage form has a disintegration time for both of components (a) and (b) of equal to or less than 20 min.

It was surprisingly found that such suitable disintegration times could be achieved by selecting suitable amounts and ratios of the two therapeutic agents as set forth below without having to use an excessive amount of disintegrant which would have a deleterious effect on the stability. It was found that valsartan had a positive influence on the disintegration time of aliskiren, and surprisingly in fact decreased the disintegration time of aliskiren compared to aliskiren monotherapy formaulations or aliskiren/hydrochlorothiazide formulations. Aliskiren, on the other hand may impair the disintegration time of valsartan compared to monotherapy. Preferably, these properties can be achieved by formulating component a) and component b) in a monolithic oral dosage form, such as a monolayer tablet. Thus, component a) and component b) are preferably in contact with each other in the oral dosage form so as to influence each others properties, in particular the individual disintegration times.

In a preferred embodiment of the present invention, component (a) is present in an amount ranging from 10 to 45, such as 10 to 35%, by weight based on the total weight of the oral dosage form.

In another preferred embodiment of the present invention component (a) is present in an amount of 12 to 45, such as 12 to 40, in one embodiment 12 to 30, such as 12 to 25% by weight based on the total weight of the oral dosage form. It is preferred that component (a) is present in an amount ranging from about 75 mg to about 300 mg of the free base per unit dosage form.

In a preferred embodiment of the present invention, component (a) is present in an amount ranging from 75 to 300mg, such as 75 to150 mg, of the free base per unit dosage form, in particular 75, 150 or 300 mg, such as 75 or 150 mg.

In a further preferred embodiment of the present invention, the dosage of aliskiren is in the form of a hemi-fumarate thereof and is present in an amount of 83, 166 or 332 mg, such as 83 or 166 mg, per unit dosage form.

In a preferred embodiment of the present invention, component (b) is present in an amount ranging from 8 to 45 %, such as 10 to 30 %, in particular 12 to 27 %, by weight based on the total weight of the oral dosage form.

In a preferred embodiment of the present invention, component (b) is present in an amount of 20 to 40, such as 20 to 30%, by weight based on the total weight of the oral dosage form.

It is preferred that component (b) is present in an amount ranging from 100 to 350mg, such as 100 to 200 mg, more preferably 80 mg to 320 mg, such as 80 to 160 mg, per unit dosage form, in particular 80, 160 or 320 mg, such as 80 or 160 mg.

The weight ratio of component (a) to component (b) preferably ranges from about 1 :0.001 to about 1 :5, more preferably from about 1 :0.5 to about 1 :4 or 1 :0.03 to 1 :0.07. Most preferably, the weight ratio is about 1 :1.0 to1.1 ; 1 :2.1 to 2.2; or 1 :0.005 to 0.006 based on the free acids of (a) and (b). Most preferably, components (a) and (b), are used in amounts of 75/80 mg, 75/160 mg, 150/80 mg, 150/160 mg, 300/320 mg, 300/160 mg or 150/320 mg, most preferably 75/160 mg of (a)/(b), based on the free acids of (a) and (b). In one embodiment it is preferred to use a high drug load using 300 mg of (a) and/or 320 mg of (b), most preferably 300/320 mg of of (a)/(b).

When using a salt such as the hemifumarate for component (a), the ratios will be adapted accordingly. For the following ratios, the numbers refer to component (a), thus referring to the free acid or the salt, in particular the hemifumarate.

The solid oral dosage forms according to the present invention have a desirable disintegration property. Preferably the disintegration time for at least one, preferably both, components (a) and (b) is equal to or less than 15 min, more preferably equal to or less than 10 min, such as equal to or less than 8 min. Such short times ensure good dissolution rates and thus faster drug uptake. For the purpose of this invention, disintegration does not imply complete dissolution of the solid oral dosage form or even its active constituents. Complete disintegration is defined herein as that state in which any residue of the solid oral dosage form, except fragments of insoluble coating or capsule shell, if present, remaining on the screen of the test apparatus is a soft mass having no palpably firm core in accordance with USP<701>. The fluid for determining the disintegration property is water, such as tap water or deionized water. The disintegration time is measured by standard methods known to the person skilled in the art, see the harmonized procedure set forth in the pharmacopeias USP <701> and EP 2.9.1 and JP. In particular the following procedure is applied:

The apparatus consists of a basket-rack assembly, a 100 ml, low-form beaker, 138 to 155 mm in height and having an inside diameter of 97 to 110 mm for the immersion fluid, a thermostatic arrangement for heating the fluid from 35 to 39 ⁰C, and a device for raising and lowering the basket in the immersion fluid at a constant frequency rate of 29 to 32 cycles per minute through a distance of not less than 5.3 cm and not more than 5.7 cm. The volume of the fluid in the vessel is such that at the highest point of the upward stroke the wire mesh of the assembly remains at least 2.5 cm below the surface of the fluid and descends not less than 2.5 cm from the bottom of the vessel on the downward stroke. The time required for the upward stroke is equal to the time required for the downward stroke, and the change in stroke direction is a smooth transition, rather than an abrupt reversal of motion. The basket- rack assembly moves vertically along its axis. There is no appreciable horizontal motion or movement of the axis from the vertical. The basket-rack assembly consists of 6 open-ended transparent tubes, each 7.75+0.25 cm long and having an inside diameter of 20.7 to 23 mm and a wall 1.0 to 2.8 mm thick; the tubes are held in a vertical position by two plastic plates, each 8.8 to 9.2 cm in diameter and 5 to 7 mm in thickness, with 6 holes, each 22 to 26 mm in diameter, equidistant from the center of the plate and equally spaced from each other. Attached to the under surface of the lower plate is a woven stainless steel wire cloth, which has a plain square weave with 1.8- to 2.2-mm apertures and with a wire diameter of 0.63+0.03 mm. The parts of the apparatus are assembled and rigidly held by means of three bolts passing through the two plastic plates. A suitable means is provided to suspend the basket-rack assembly from the raising and the lowering device using a point on its axis. One tablet is placed in each of the six tubes of the basket and the apparatus is operated using water maintained at 37+2 ⁰C as the immersion fluid. After 25 min the basket is lifted from the water and the tablets are observed. If 1 or 2 of the tablets failed to disintegrate completely, the test is repeated on 12 additional tablets. Not less than 16 of the tested 18 tablets have to disintegrate completely.

The solid oral dosage forms according to the present invention show desirable dissolution , rate (DR) properties due to the decreased disintegration time. Preferably, the DR is at least 75 %, more preferably at least 80%, after 45 min. for component (a). Preferably, the DR is at least 70 %, more preferably at least 75%, after 60 min. for component (b). The DR is measured by standard methods known to the person skilled in the art, see the harmonized procedure set forth in the pharmacopeias USP <711> and EP 2.9.3 and JP.

The solid oral dosage forms according to the present invention also have a low friability. Preferably the friability is not more than 0.8%. The friability is measured by standard methods known to the person skilled in the art, see the harmonized procedure set forth in the pharmacopeias USP <1216> and EP 2.9.7 and JP.

The solid oral dosage forms according to the present invention also have a sufficient hardness. Preferably the hardness is in arrange so as to ensure a low friability, good coatability, desirably fast disintegration times and thus high dissolution rates time. The actual values for the hardness are dependent on the size of the oral dosage form. For oral dosage forms with 75 mg of aliskiren based on the free acid, preferred ranges are between 50 to 250N, more preferably 60 to 230N, such as 65 to 220N. For oral dosage forms with 150 or 300 mg of aliskiren based on the free acid, preferred ranges are between 180 to 280N, more preferably 190 to 260N, such as 200 to 250N. The cited hardness refers to the hardness of the core of a solid oral dosage form. The hardness is measured by standard methods known to the person skilled in the art, using e.g. equipment from Erweka and Pharmatest.

Solid oral dosage forms according to the present invention provide for the administration of the active ingredient in a relatively small oral form of sufficient hardness and short disintegration times. Furthermore, the oral dosage forms obtained are stable both to the production process and during storage, e.g., for about 2 years in conventional packaging, e.g., sealed aluminium blister packs. The terms "effective amount" or "therapeutically effective amount" refers to the amount of the active ingredient or agent which halts or reduces the progress of the condition being treated or which otherwise completely or partly cures or acts palliatively on the condition.

In the above and in the following the term "aliskiren", if not defined specifically, is to be understood both as the free base and as a salt thereof, especially a pharmaceutically acceptable salt thereof, such as a hemi-fumarate, hydrogen sulfate or nitrate, most preferably a hemi-fumarate thereof.

Aliskiren, or a pharmaceutically acceptable salt thereof, can, e.g., be prepared in a manner known per se, especially as described in EP 678503 A, e.g., in Example 83.

In the following the term "valsartan", if not defined specifically, is to be understood both as the free base and as a salt thereof, especially a pharmaceutically acceptable salt thereof, as described below.

Valsartan , or a pharmaceutically acceptable salt thereof, can, e.g., be prepared in a manner known per se. Preferred salts forms include acid addition salts. The compounds having at least one acid group (e.g., COOH or 5-tetrazolyl) can also form salts with bases. Suitable salts with bases are, e.g., metal salts, such as alkali metal or alkaline earth metal salts, e.g., sodium, potassium, calcium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, e.g., ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine, or a mono-, di- or trihydroxy lower alkylamine, e.g., mono-, di- or tri- ethanolamine. Corresponding internal salts may furthermore be formed. Salts which are unsuitable for pharmaceutical uses but which can be employed, e.g., for the isolation or purification of free compounds I or their pharmaceutically acceptable salts, are also included. Even more preferred salts are, e.g., selected from the mono-sodium salt in amorphous form; di-sodium salt of valsartan in amorphous or crystalline form, especially in hydrate form, thereof.

Mono-potassium salt of valsartan in amorphous form; di-potassium salt of valsartan in amorphous or crystalline form, especially in hydrate form, thereof. Calcium salt of valsartan in crystalline form, especially in hydrate form, primarily the tetrahydrate thereof; magnesium salt of valsartan in crystalline form, especially in hydrate form, primarily the hexahydrate thereof; calcium/magnesium mixed salt of valsartan in crystalline form, especially in hydrate form; jb/s-diethylammonium salt of valsartan in crystalline form, especially in hydrate form; jb/s-dipropylammonium salt of valsartan in crystalline form, especially in hydrate form; jb/s-dibutylammonium salt of valsartan in crystalline form, especially in hydrate form, primarily the hemihydrate thereof; mono-L- arginine salt of valsartan in amorphous form; b/s-L-arginine salt of valsartan in amorphous form; mono-L-lysine salt of valsartan in amorphous form; b/s-L-lysine salt of valsartan in amorphous form.

Most preferably, valsartan is used as the free acid.

A solid oral dosage form comprises a capsule or more preferably a tablet or a film-coated tablet.

A solid oral dosage form according to the invention comprises additives or excipients that are suitable for the preparation of the solid oral dosage form according to the present invention. Tabletting aids, commonly used in tablet formulation can be used 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 herein by reference. These include, but are not limited to, fillers, binders, disintegrants, lubricants, glidants, stabilising agents, fillers 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 as an additive a disintegrant.

In a preferred embodiment the solid oral dosage form according to the present invention comprises as an additive, e.g. in addition to a disintegrant, a filler.

In a preferred embodiment the solid oral dosage form according to the present invention comprises as an additive, e.g. in addition to a filler and a disintegrant, a lubricant.

In a preferred embodiment the solid oral dosage form according to the present invention comprises as an additive, e.g. in addition to a filler, a disintegrant and a lubricant, a glidant.

In a preferred embodiment the solid oral dosage form according to the present invention comprises as an additive, e.g. in addition to a filler, a disintegrant, a lubricant and a glidant, a binder. As fillers one can particularly mention celluloses, e.g., hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose (HPMC) and, preferably, microcrystalline cellulose, e.g., products available under the registered trade marks AVICEL, FILTRAK, HEWETEN or PHARMACEL.

As binders for wet granulation, one can particularly mention polyvinylpyrrolidones (PVP), e.g., PVP K 30, HPMC, e.g., viscosity grades 3 or 6 cps, and polyethylene glycols (PEG), e.g., PEG 4000. A most preferred binder is PVP K 30.

As disintegrants one can particularly mention carboxymethylcellulose calcium (CMC-Ca), carboxymethylcellulose sodium (CMC-Na), crosslinked PVP (e.g. CROSPOVI DONE, POLYPLASDONE or KOLLIDON XL), alginic acid, sodium alginate and guar gum, most preferably crosslinked PVP (CROSPOVIDONE), crosslinked CMC (Ac-Di-SoI), carboxymethylstarch-Na (PIRIMOJEL and EXPLOTAB). A most preferred disintegrant is CROSPOVIDONE.

As glidants one can mention in particular colloidal silica, such as colloidal silicon dioxide, e.g., AEROSIL, magnesium (Mg) trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate or combinations of these with fillers or binders, e.g., silicified microcrystalline cellulose (PROSOLV). A most preferred glidant is colloidal silicon dioxide (e.g. AEROSIL 200) as well as talc.

As lubricants one can mention in particular Mg stearate, aluminum (Al) or Ca stearate, PEG 4000 to 8000 and talc, hydrogenated castor oil, stearic acid and salts thereof, glycerol esters, Na-stearylfumarate, hydrogenated cotton seed oil and others. A most preferred lubricant is Mg stearate.

Additives to be used as filmcoating 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 further additives, e.g., those available under the registered trade mark OPADRY. Further additives comprise pigments, dies, lakes, most preferred TiO₂ and iron oxides, anti-tacking agents like talc and softeners like PEG 3350, 4000, 6000, 8000 or others. Most preferred additives are talc and PEG 4000. The present invention likewise relates to a solid oral dosage form comprising a therapeutically effective amount of aliskiren, or a pharmaceutically acceptable salt thereof, as an active agent and a therapeutically effective amount of valsartan, or a pharmaceutically acceptable salt thereof. Further additives include, but are not limited to, fillers, binders, disinteg rants, lubricants, glidants, stabilising agents, diluents, surfactants, film formers, pigments, softeners and antitacking agents and the like. The amounts of the active ingredient and further additives are preferably those as defined above or below.

The present invention likewise relates to a solid oral dosage form comprising a therapeutically effective amount of aliskiren, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of valsartan, or a pharmaceutically acceptable salt thereof, and a disintegrant as an additive. Further additives include, but are not limited to, fillers, binders, lubricants, glidants, stabilising agents, diluents, surfactants, film formers, pigments, softeners and antitacking agents and the like. The amounts of the active ingredient and further additives are preferably those as defined herein above or below.

The present invention likewise relates to a solid oral dosage form comprising a therapeutically effective amount of aliskiren, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of valsartan, or a pharmaceutically acceptable salt thereof, a disintegrant and a filler as additives. Further additives include, but are not limited to, binders, lubricants, glidants, stabilising agents, diluents, surfactants, film formers, pigments, softeners and antitacking agents and the like. The amounts of the active ingredient and further additives are preferably those as defined herein above or below.

The present invention likewise relates to a solid oral dosage form comprising a therapeutically effective amount of aliskiren, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of valsartan, or a pharmaceutically acceptable salt thereof, a disintegrant, a filler and a lubricant as additives. Further additives include, but are not limited to, binders, glidants, stabilising agents, diluents, surfactants, film formers, pigments, softeners and antitacking agents and the like. The amounts of the active ingredient and further additives are preferably those as defined herein above or below.

The present invention likewise relates to a solid oral dosage form comprising a therapeutically effective amount of aliskiren, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of valsartan, or a pharmaceutically acceptable salt thereof, a disintegrant, a further filler, a lubricant and a glidant as additives. Further additives include, but are not limited to, binders, stabilising agents, diluents, surfactants, film formers, pigments, softeners and antitacking agents and the like. The amounts of the active ingredient and further additives are preferably those as defined herein above or below.

The present invention likewise relates to a solid oral dosage form comprising a therapeutically effective amount of aliskiren, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of valsartan, or a pharmaceutically acceptable salt thereof, a disintegrant, a further filler, a lubricant, a glidant and a binder as additives. Further additives include, but are not limited to, stabilising agents, diluents, surfactants, film formers, pigments, softeners and antitacking agents and the like. The amounts of the active ingredient and further additives are preferably those as defined herein above or below.

One or more of these additives can be selected and used by a person skilled in the art having regard to the particular desired properties of the solid oral dosage form by routine experimentation and without any undue burden.

The amount of each type of additive employed, e.g., glidant, binder, filler or diluent and lubricant or film coat may vary within ranges conventional in the art.

Thus, for example, the amount of lubricant may vary within a range of from 0.2 to 5% by weight, in particular, for Mg stearate from 0.5 to 2.0% by weight, e.g., from 0.8 to 1.8% by weight; the amount of binder may vary within a range of from 0 to about 20% by weight, e.g., from 0.3 to 1.0% by weight; the amount of disintegrant may vary within a range of from 0 to about 20% by weight, e.g., from 8 to 15% by weight; the amount of filler or diluent may vary within a range of from 0 to about 80% by weight, e.g., from 30 to 50% by weight; whereas the amount of glidant may vary within a range of from 0 to about 3% by weight, e.g. from 0.5 to 1.0% by weight; and the amount of film coat may vary within a range of 0 to 10 % , e.g. 2 to 6 %.

It is a characteristic 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 enables the production of physically small unit dosage forms. The total amount of additives in a given uncoated unit dosage may be about 70% or less by weight based on the total weight of the solid oral dosage form, more particularly about 65% or less. Preferably, the additive content is in the range of about 50 to 64% by weight, more particularly, the additive content ranges from about 55 to about 63% by weight. A preferred amount of a filler, especially of microcrystalline cellulose, ranges from about 30 to 50, more preferably 35 to 45, % by weight per unit dosage form. This amount of filler can contribute to a desired hardness of the oral dosage form.

A preferred amount of a binder, especially of PVP K 30, ranges from about 0.3 to 1.0, more preferably 0.4 to 0.95, % by weight per unit dosage form.

A preferred amount of a disintegrant, especially of CROSPOVIDONE, ranges from about 5 to 20, more preferably 8 to 15, most preferably 10 to 14, such as 13.0 to 13.5, % by weight per unit dosage form. The amount of disintegrant can be used appropriately to counterbalance any increase in the dissolution time caused by the combined use of aliskiren and valsartan in one formulation so as to avoid an undesirable disintegration profile. It is preferred that the amount of disintegrant is kept reasonably low using the amounts stated above, so that the disintegrant does not have a negative impact on the later aqueous coating.

A preferred amount of a glidant, especially of colloidal silicon dioxide, ranges from about 0 to 3, more preferably 0.2 to 1.5, most preferably 0.5 to 1.0, % by weight per unit dosage form.

A preferred amount of a lubricant, especially of Mg stearate, ranges from about 0.8 to 1.8, more preferably 0.95 to 1.6, % by weight per unit dosage form.

The amounts provided herein for the additives apply equally for the uncoated unit dosage form as well as the final coated unit dosage form.

A preferred amount of a film coat, especially of HPMC 3 cps, ranges from about 2 to 6% per unit dosage form.

Preferred amounts of components (a) and (b) and additives are further shown in the illustrative Examples.

The absolute amounts of each additive and the amounts relative to other additives is similarly dependent on the desired properties of the solid oral dosage form and may also be chosen by the skilled artisan by routine experimentation without undue burden. For example, the solid oral dosage form may be chosen to exhibit accelerated and/or delayed release of the active agent with or without quantitative control of the release of active agent. Thus, where accelerated release is desired a disintegrant such as crosslinked PVP, e.g., those products available under the registered trade marks 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) that effect rapid disintegration of the tablet in the presence of water, for example so-called effervescent tablets that contain an acid in solid form, typically citric acid, which acts in water on a base containing chemically combined carbon dioxide, for example sodium hydrogencarbonate or sodium carbonate, and releases carbon dioxide.

Whereas if delayed release is desired one may employ coating technology for multiparticulates (e.g. pellets, minitablets), wax matrix systems, polymer matrix tablets or polymer coatings or other technologies conventional in the art.

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, press-coated tablets, multilayer tablets and the like.

In a solid oral dosage form preferred additives are microcrystalline cellulose, hydroxypropylcellulose, crosslinked PVP, PVP, PEG, CMC-Na or CMC-Ca, Mg stearate, Ca stearate or Al stearate, anhydrous colloidal silica, talc, titatium dioxide and iron oxide pigments. The amounts of additive employed will depend upon how much active agent is to be used. The stearate, e.g., Mg stearate is preferably employed in amounts of 0.8 to 1.8% by weight. Whereas the silica is preferably employed in an amount of from 0.4 to 2.0% by weight.

The amount of aliskiren in the form of the hemi-fumarate thereof within the total weight of the uncoated unit dosage form ranges, preferably, from about 83 to about 332 mg, most preferably, the amount of aliskiren hemi-fumarate is about 83, about 166 or about 332 mg per unit dosage form.

The weight ratio of component (a) to the binder preferably ranges from about 10:1 to about 40:1 , more preferably from about 20:1 to about 35:1. Most preferably, the weight ratio is about 25-30:1. The weight ratio of component (a) to the disintegrant preferably ranges from about 0.5:1 to about 4:1 , more preferably from about 0.8:1 to about 3:1. Most preferably, the weight ratio is about 1.0-2.0:1.

The weight ratio of component (a) to the filler preferably ranges from about 0.1 :1 to about 1 :1 , more preferably from about 0.2:1 to about 0.8:1. Most preferably, the weight ratio is about 0.3-0.6:1.

The weight ratio of component (a) to the glidants preferably ranges from about 10:1 to about 80:1 , more preferably from about 15:1 to about 40:1. Most preferably, the weight ratio is about 18-38:1.

The weight ratio of component (a) to the lubricant preferably ranges from about 2:1 to about 40:1 , more preferably from about 5:1 to about 35:1. Most preferably, the weight ratio is about 7-28:1.

The weight ratio of component (b) to the binder preferably ranges from about 5:1 to about 70:1 , more preferably from about 10:1 to about 60:1. Most preferably, the weight ratio is about 24-55:1.

The weight ratio of component (b) to the disintegrant preferably ranges from about 0.1 :1 to about 5:1 , more preferably from about 0.5:1 to about 3:1. Most preferably, the weight ratio is about .0.7-2.5:1.

The weight ratio of component (b) to the filler preferably ranges from about 0.05:1 to about 1 : 1 , more preferably from about 0.15:1 to about 0.8:1. Most preferably, the weight ratio is about 0.2-0.75:1.

The weight ratio of component (b) to the glidants preferably ranges from about 8:1 to about 60: 1 , more preferably from about 10:1 to about 50:1. Most preferably, the weight ratio is about 15-45:1.

The weight ratio of component (b) to the lubricant preferably ranges from about 5:1 to about 30:1 , more preferably from about 8:1 to about 25:1. Most preferably, the weight ratio is about 10-20:1.

The solid oral dosage forms according to the present invention may also be in the form of film-coated tablets or dragees in which case the solid oral dosage form is provided with a coating typically a polymer like HPMC, PVP or the like, sugar, shellac or other film-coating entirely conventional in the art. Attention is drawn to the numerous known methods of coating employed in the art, e.g., spray coating in a fluidized bed, e.g., by the known methods using apparatus available from Aeromatic, Glatt, Wurster or Hϋttlin, in a perforated pan coater, e.g., by the known methods using apparatus from Accela Cota, Glatt, Driam or others, or other methods conventional in the art. The additives commonly used in confectioning may be employed in such methods.

A further embodiment of the present invention is a process for the manufacture of a solid oral dosage form according to the present invention.

Thus, the present invention provides a process for the manufacture of a solid oral dosage form of the present invention comprising: i) granulating

b) a therapeutically effective amount of valsartan, or a pharmaceutically acceptable salt thereof, and additives optionally with a granulation liquid; ii) optionally drying a resulting granulate; iii) mixing the granulate with outer phase excipients; iv) compressing a resulting mixture to form a solid oral dosage as a core tablet; and v) optionally coating a resulting core tablet to give a film-coated tablet.

By performing this process, a monolayer tablet can be obtained where both components a) and b) are present in the same layer.

This process has been found to be the best way of manufacturing suitable aliskiren + valsartan solid oral dosage forms, especially tablets, in contrast to other methods described before. The resulting formulation shows the following advantages:

A relatively high drug loading may easily be achieved;

The formulation of tablets with sufficient hardness, resistance to friability, disintegration time, dissolution rate etc. is possible;

The sticking tendency and poor flow of the drug substance is reduced to a minimum; A robust manufacturing process of the DP is achieved;

Scale-up of formulation and process resulting in a reproducible DP performance is achieved; and

Sufficient stability to achieve a reasonable shelf life is achieved.

The excipients or additives may be distributed partly in the inner (granular) phase and partly in the outer phase, which is the case in the described invention. Microcrystalline cellulose (filler), Mg stearate (lubricant) and colloidal silicon dioxide (glidant) are preferably partly in the inner and partly in the outer phase, PVP K 30 (binder) and CROSPOVIDONE (disintegrant) are preferably only part of the inner phase.

The inner phase excipients, e.g., filler, binder, glidant, lubricant, disintegrant, and the drug substance are mixed and granulated to form the granular or inner phase. Preferably, two granular phases are obtained separately, one containing component (a), the other containing component (b).

The granulation of each phase preferably takes place by dry, aqueous or organic wet granulation. Preferably the granular phase containing component (a) undergoes organic wet granulation and/or the granular phase containing component (b) undergoes dry granulation. The granulation liquid for the organic wet granulation can be ethanol, a mixture of ethanol and water, a mixture of ethanol, water and isopropanol, or a solution of PVP in the before mentioned 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), most preferably from about 88.5/5.5/6.0 to about 91.5/4.5/4.0 (% w/w/w). In a preferred embodiment, the granulation is effected by an ethanolic solution of the binder and additional ethanol. The dry granulation of component (b) refers preferably to roller compaction. For details of this method it is referred to WO 97/49394. In particular, Compression to form a coprimate requires the compaction of the dry ground components. Compaction may be carried out using a slugging technique or preferably, roller compaction. Roller compaction apparatus is conventional and essentially utilises two rollers which roll towards each other. A hydraulic ram forces one of the rollers against the other to exert a compacting force against the ground particles fed into the roller compactor via a screw conveyor system. A compaction force of between 25 and 65 kN is preferably used. The granulate is dried, if a wet granulation technique is used, and preferably sieved. If the granular phase is provided as two separate granular phases, the two are preferably mixed together prior to addition of the outer phase excipients.

The outer phase containing, e.g., filler, disintegrant, giidant and lubricant, is screened to the dried granulate and mixed. The mixture is compressed into tablets (cores). The cores may optionally be coated with a film-coat.

Preferably, the lubricant is added separately to the mixture and more preferably it is added last of all the components of the outer phase to the mixture. It is preferred that at first only part of the granular phase, such as 50%, is mixed with the components of the outer phase, preferably without the lubricant. After blending, the remaining portion of the granular phase is added to the mixture and blended.

The granulate phase is defined as the inner phase, the excipients added to the granulate are defined as the outer phase of the tabletting mixture.

The invention likewise relates to a process for the preparation of solid oral dosage forms as described herein above. Such solid oral dosage form may be produced by working up components as defined herein above in the appropriate amounts, to form unit dosage forms.

Preferably, the additives in step (i) are selected from a filler, a disintegrant, a glidant, a lubricant and a binder; and the outer phase excipients in step (iii) are selected from a filler, a disintegrant, a lubricant and a glidant.

Attention is drawn to the numerous known methods of granulating, drying and mixing employed in the art, e.g., 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 tumble blender, compressing into tablets on a single-punch or rotary tablet press.

The manufacturing of the granulate can be performed on standard equipment suitable for aqueous or organic granulation processes. The manufacturing of the final blend and the compression of tablets can also be performed on standard equipment.

For example, step (i) may be carried out by a high-shear granulator, e.g., Collette Gral or Diosna; step (i) may be conducted in a fluid-bed dryer; step (iii) may be carried out by a free- fall mixer (e.g. container blender, tumble blender); and step (iv) may be carried out using a dry compression method, e.g., a rotary tablet press.

As described above, the core tablets may then be optionally film-coated.

Due to the high hygroscopicity and water sensitivity of aliskiren with respect to changes in polymorphism, the use of water has preferably to be avoided in order to prevent the drug substance from changes in polymorphism for the above stated reasons (amorphous state, inferior chemical stability). A solution for said problem is to apply an organic film-coating process.

The film-coat preferably consists of HPMC as the polymer, iron oxide pigments, titanium dioxide as coloring agent, PEG as softener and talc as anti-tacking agent. The use of coloring agents or dyes may serve to enhance the appearance as well as to identify the compositions. Other dyes suitable for use typically include carotinoids, chlorophyll and lakes.

The film coating conditions have to assure that the tablet cores do not take up considerable amounts of moisture and that the drug substance within the tablets does not closely get into contact with water droplets. This is achieved by process parameter settings that reduce the amount of humidity which gets onto the tablet cores.

The solid oral dosage forms of the present invention are useful for lowering the blood pressure, either systolic or diastolic or both. The conditions for which the instant invention is useful include, without limitation, hypertension (whether of the malignant, essential, renovascular, diabetic, isolated systolic, or other secondary type), congestive heart failure, angina (whether stable or unstable), myocardial infarction, artherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction (such as Alzheimer's) and stroke, headache and chronic heart failure.

The present invention likewise relates to a method of treating hypertension (whether of the malignant, essential, reno-vascular, diabetic, isolated systolic, or other secondary type), congestive heart failure, angina (whether stable or unstable), myocardial infarction, artherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, e.g., Alzheimer's, stroke, headache and chronic heart failure comprising administering to an animal, including human patient, in need of such treatment a therapeutically effective solid oral dosage form according to the present invention.

The present invention likewise 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 (whether of the malignant, essential, reno-vascular, diabetic, isolated systolic, or other secondary type), congestive heart failure, angina (whether stable or unstable), myocardial infarction, artherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, e.g., Alzheimer's, stroke, headache and chronic heart failure.

The present invention likewise relates to a pharmaceutical composition for the treatment of hypertension (whether of the malignant, essential, reno-vascular, diabetic, isolated systolic, or other secondary type), congestive heart failure, angina (whether stable or unstable), myocardial infarction, artherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, e.g., Alzheimer's, stroke, headache and chronic heart failure, comprising a solid oral dosage form according to the present invention.

Ultimately, the exact dose of the active agent and the particular formulation to be administered depend on a number of factors, e.g., the condition to be treated, the desired duration of the treatment and the rate of release of the active agent. For example, the amount of the active agent required and the release rate thereof may be determined on the basis of known in vitro or in vivo techniques, determining how long a particular active agent concentration in the blood plasma remains at an acceptable level for a therapeutic effect.

The above description fully discloses the invention including preferred embodiments thereof. Modifications and improvements of the embodiments specifically disclosed 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, utilize the present invention to its fullest extent. Therefore, the Examples herein are to be construed as merely illustrative and not a limitation of the scope of the present invention in any way. Example 1 : Formulations

Compositions of aliskiren 75 or 150 mg or 300 mg (free base) and valsartan 80 or 160 mg or 320 mg tablets in mg/unit. The components are formulated to obtain a monolayer tablet as set forth in the description.

¹ salt factor 1.1.05

² removed during processing Example 2: Evaluation of 150/160 mq formulation parameter 150/160 mg hardness [N] 220 (201 - 249) thickness mean [mm] 6.7 friability [%] 0.1

Disint. time [min] 5'00" - 7'05"

Example 3: Evaluation of 75/160 mg formulation parameter 75/1160 mg hardness [N] 180 (149 - 196) thickness mean [mm] 6.2 friability [%] 0.0

Disint. time [min] 2'30" - 3'30"

Example 4: Evaluation of 150/80 mq formulation parameter 150/80 mg hardness [N] 207 (196 - 214) thickness mean [mm] 6.5 friability [%] 0.0

Disint. time [min] 5'30" - 6'55"

Example 5: Evaluation of 75/80 mq formulation parameter 75/80 mg

I hardness [N] 78 (66 - 89) thickness mean [mm] 4.6 -4.7 friability [%] 0.1

Disint. time [min] rO6" - 2'O8"

Claims

What is claimed is:

1. A solid oral dosage form comprising

c) a therapeutically effective amount of Aliskiren, or a pharmaceutically acceptable salt thereof,

d) a therapeutically effective amount of Valsartan, or a pharmaceutically acceptable salt thereof,

2. A solid oral dosage form according to claim 1 , wherein component (a) is present in an amount ranging from 10 to 45% by weight based on the total weight of the oral dosage form.

3. A solid oral dosage form according to claim 1 or 2, wherein component (a) is present in an amount ranging from 12 to 40% by weight based on the total weight of the oral dosage form.

4. A solid oral dosage form according to any of the preceding claims, wherein component (a) is present in an amount ranging from 75 to 350 mg of the free base per unit dosage form.

5. A solid oral dosage form according to any of the preceding claims, wherein component (a) is present in an amount ranging from 75 to 300 mg of the free base per unit dosage form.

6. A solid oral dosage form according to any of the preceding claims, wherein component

(a) is present in an amount of 83, 166 or 332 mg per unit dosage form.

7. A solid oral dosage form according to claim 1 , wherein component (b) is present in an amount ranging from 8 to 45% by weight based on the total weight of the oral dosage form.

8. A solid oral dosage form according to claim 1 or 2, wherein component (b) is present in an amount ranging from 10 to 40% by weight based on the total weight of the oral dosage form.

9. A solid oral dosage form according to any of the preceding claims, wherein component

(b) is present in an amount ranging from 80 to 320 mg per unit dosage form.

10. A solid oral dosage form according to any of the preceding claims, wherein the disintegration time for both of components (a) and (b) is equal to or less than 15 min.

1 1. A solid oral dosage form according to any of the preceding claims, wherein the disintegration time for both of components (a) and (b) is equal to or less than 10 min.

12. A solid oral dosage form according to any of the preceding claims, wherein the dosage form further comprises a filler.

13. A solid oral dosage form according to any of the preceding claims, wherein the filler is microcrystalline cellulose.

14. A solid oral dosage form according to any of the preceding claims, wherein the filler is present in an amount of 10 to 50, more preferably 20 to 45, % by weight per unit dosage form.

15. A solid oral dosage form according to any of the preceding claims, wherein the dosage form further comprises a disintegrant.

16. A solid oral dosage form according to any of the preceding claims, wherein the disintegrant is crosslinked PVP.

17. A solid oral dosage form according to any of the preceding claims, wherein the disintegrant is present in an amount of 5 to 15, most preferably 7 to 14, % by weight per unit dosage form.

18. A solid oral dosage form according to any of the preceding claims, wherein the dosage form further comprises a lubricant.

19. A solid oral dosage form according to any of the preceding claims, wherein the dosage form further comprises a glidant.

20. A solid oral dosage form according to any of the preceding claims, wherein the dosage form further comprises a binder.

21. A solid oral dosage form according according to any of the preceding claims for the treatment of hypertension, congestive heart failure, angina, myocardial infarction, artherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, stroke, headache and chronic heart failure.

22. A solid oral dosage form according according to any of the preceding claims for the treatment of hypertension.

23. A method for the treatment of hypertension, congestive heart failure, angina, myocardial infarction, artherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, stroke, headache and chronic heart failure which method comprises administering a therapeutically effective amount of a solid oral dosage form according to claims 1 to 22 to a patient in need thereof.

24. A method according to claim 23 for the treatment of hypertension.

25. Use of a solid oral dosage form according to claims 1 to 22 for the manufacture of a medicament for the treatment of hypertension, congestive heart failure, angina, myocardial infarction, artherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, stroke, headache and chronic heart failure.

26. Use according to claim 25 for the treatment of hypertension.

27. A process for the manufacture of a solid oral dosage form according to any of claims 1 to 22 comprising the steps of: i) granulating

28. A process according to claim 27, wherein the preparation of he granular phase in steps (i) and (ii) is performed as two separate phases, one containing the component (a), the other containing the component (b), whereby the two granular phases are combined prior to step (iii).