THEIR PROCESS OF MANUFACTURING FIELD OF THE TECHNOLOGY

The present invention relates generally to pharmaceutical compositions enabling improved oral delivery of aliskiren and methods of using such compositions.

BACKGROUND 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. However, aliskiren is poorly absorbed in conventional formulations (bioavailability about 2.5%) with an approximate accumulation half-life of 24 hours.

Additionally, aliskiren is a drug substance difficult to formulate due to its physicochemical properties, and it is not trivial to make oral formulations in a reliable and robust way. Since the bioavailability is low, a high drug loading is necessary and this is technically difficult to achieve and makes for increased costs. Hence, the need exists for an efficient, specific, oral formulation for the improved oral delivery of aliskiren.

SUMMARY

Described herein are novel aliskiren compositions, processes for making these compositions, and methods of treating subjects using these compositions. The present inventors have devised a process for producing a pharmaceutical composition (bulk drug product) which involves preparing a water soluble composition comprising a therapeutically effective amount of the therapeutic agent aliskiren, a medium chain fatty acid salt and a matrix forming polymer, drying (e.g. by lyophilization) the water soluble composition to obtain a solid powder, and suspending the lyophilized material (the solid powder) in a hydrophobic (oily) medium, preferably castor oil or glyceryl tricaprylate (including other ingredients e.g. surfactants (viscosity modifiers) - see below, to produce an oily suspension containing, in solid form, the therapeutic agent, the medium chain fatty acid salt and the matrix forming polymer, thereby producing the bulk drug product. The solid form may comprise a particle (e.g., consists essentially of particles, or consists of particles). The particle may be produced by lyophilization or by granulation or by other means. The bulk drug product may then be encapsulated in capsules which may be coated by a pH sensitive coating and may be used for oral delivery. A typical generic process for producing the claimed formulations is shown in Figure 1.

The inventors of the present invention have discovered that the absorption of certain therapeutic agents (such as aliskiren or other renin inhibitor) in a subject can be improved when administered in the compositions described herein. For example, aliskiren administered in a formulation in accordance with one or more embodiments exhibits an improved bioavailability (B A) relative to the same therapeutic agent administered via a similar route but in a composition substantially free of the components described herein or having a lower amount of the components described herein; such components are e.g., a medium chain fatty acid salt, a matrix forming polymer, a hydrophobic medium. Such improvement in relative BA may be on the order of at least about 1.5-, 2-, 3-, 5- ,7-, 10-, 20 or more fold. In at least one aspect, a composition described herein improves bioavailability by enhancing the GI wall barrier permeability to the drug molecules. For example, an aliskiren composition described herein may enhance absorption by permeating the GI wall barrier via unsealing of the tight junctions between GI epithelial cells, allowing paracellular absorption in addition to the existing transcellular absorption.

The present invention demonstrates delivery of aliskiren to the intestine, which is a model for oral delivery, and from there to the bloodstream with high bioavailability.

Still other aspects, embodiments, and advantages are discussed in detail below. Moreover, it is to be understood that both the foregoing information and the following detailed description are merely illustrative examples of various aspects and embodiments, and are intended to provide an overview or framework for understanding the nature and character of the claimed aspects and embodiments. The accompanying drawing is included to provide illustration and a further understanding of the various aspects and embodiments, and is incorporated in and constitutes a part of this specification. The drawing, together with the remainder of the specification, serves to explain principles and operations of the described and claimed aspects and embodiments.

Throughout this application, various publications, including United States patents, are referenced by author and year and patents and applications by number. The disclosures of these publications, patents and patent applications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.

BRIEF DESCRIPTION OF THE DRAWINGS

Various aspects of at least one embodiment are discussed below with reference to the accompanying Figure 1. The Figure is provided for the purposes of illustration and explanation and is not intended as a definition of the limits of the invention. Figure 1 presents a generic process for production of a formulation of a composition of the invention in accordance with one or more embodiments as referenced in the accompanying Examples.

DETAILED DESCRIPTION

Aliskiren: The present invention relates to oral dosage forms comprising an orally active renin inhibitor, aliskiren, or a pharmaceutically acceptable salt thereof (or other renin inhibitor) as the active ingredient in an improved carrier medium. In particular, the present invention provides formulations comprising aliskiren, preferably a hemi-fumarate salt thereof, alone or in combination with another active agent. The present invention also relates to the processes for their preparation and to their use as medicaments.

Throughout the application, 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, most preferably a hemi-fumarate thereof.

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 II 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 formula (I) in WO 2009/040373A2 and is referred to as 2(S),4(S),5(S),7(S)-N-(3-amino-2,2-dimethyl-3- oxopropyl)-2,7-di(l-methylethyl)-4-hydroxy-5-amino-8-[4-meth oxy-3-(3-methoxy- propoxy)phenyl]-octanamide. As described above, most preferred is the hemi-fumarate salt thereof which is specifically disclosed, and can be prepared as described, in EP 678503 A; see Example 83. See also related US patent No 5,559,111. Throughout the application, 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, orotate or nitrate, most preferably a hemi-fumarate thereof.

Administration of such a pharmaceutical agent via the oral route is preferred to parenteral administration because it allows self-administration by patients whereas parenteral formulations are generally administered by a physician or paramedical personnel. However, aliskiren is poorly absorbed in conventional formulations (bioavailability about 2.5%) with an approximate accumulation half life of 24 hours. Steady state blood levels are reached in about 7-8 days. Additionally, aliskiren is a drug substance difficult to formulate due to its physicochemical properties and it is not trivial to make oral formulations in a reliable and robust way. Since the bioavailability is low, a high drug loading is necessary and this is technically difficult to achieve and makes for increased costs. Accordingly, a suitable and robust formulation overcoming the above problems related to the properties of aliskiren is desirable. Thus, the present invention relates to a novel oral dosage form comprising a therapeutically effective amount of aliskiren, or a

pharmaceutically acceptable salt thereof, wherein the bioavailability is improved over existing formulations. Preferably, the bioavailability is above 3%. In preferred embodiments of the present invention, the bioavailability is from 5% - 40%, e.g. the bioavailability is about 5-10%, about 10 -15%, about 15-20%, about 20-25%, about 25-30% or above 30%.

In a preferred embodiment of the present invention, the active agent consists entirely of aliskiren, or a pharmaceutically acceptable salt thereof, and is present in an amount ranging from about 5-600 mg, or more specifically is present in an amount of about 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg or 600 mg of the free base per unit dosage form.

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 ranging from about 5-650 mg per unit dosage form or less, i.e. corresponding to about 5- 600 mg or less of the free base per unit dosage form. 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 ranging from about 5-75 mg per unit dosage form, or about 75-150 mg per unit dosage form, or about 150-300 mg per unit dosage form, or about 300-600 mg per unit dosage form or more specifically is present in an amount of about 5 mg, 10 mg, 20 mg, 30 mg, 40mg, 50 mg 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg or 600 mg per unit dosage form.

Oral dosage forms according to the present invention provide for the administration of the active ingredient at a lower level of loading than was heretofore possible for a given unit dose of the active agent. Furthermore, the oral dosage forms obtained are stable both during the production process and during storage. The percentages given above and below are based on using a salt such as the hemifumarate, and if the free acid or other salts are used, the percentages will be adapted accordingly. For the percentages as used herein, the numbers refer to aliskiren, thus referring to the free acid or the salt, in particular they refer to the hemi- fumarate.

Pharmaceutical compositions: The pharmaceutical compositions described herein include aliskiren (or other renin inhibitor), a medium chain fatty acid salt and a matrix forming polymer in intimate contact or association with a substantially hydrophobic medium. For example, the therapeutic agent, the medium chain fatty acid or derivative thereof and the matrix forming polymer may be coated, suspended, sprayed by or immersed in a

substantially hydrophobic medium forming a suspension. The compositions of the invention are not emulsions. Almost all the compositions of the invention are oily suspensions (and rarely solutions) and the amount of water in the compositions is very low. The suspension may be a liquid suspension incorporating solid material, or a semi-solid suspension incorporating solid material (an ointment).

Many of the compositions described herein comprise a suspension which comprises an admixture of a hydrophobic medium and a solid form wherein the solid form comprises a therapeutically effective amount of a therapeutic agent, at least one salt of a medium chain fatty acid and a matrix forming polymer, wherein the medium chain fatty acid salt is present in the composition at an amount of 10% or more by weight. The solid form may comprise a particle (e.g., consist essentially of particles, or consist of particles). The particle may be produced by lyophilization or by granulation or by spray-drying or similar. In some embodiments, preferably after milling about 10% (v/v) of the particles are above aboutl20- 140 microns, and about 50% (v/v) of the particles are above about 40-50microns.

A cargo compound is a therapeutic agent (e.g. aliskiren) or a test compound (e.g. high molecular weight dextran) which is formulated as described herein within the compositions of the invention.

In some preferred embodiments, the compositions of the invention include only excipients which are generally recognized as safe, based on available data on human use, animal safety and regulatory guidelines (e.g. GRAS excipients). Some compositions of the invention may have other types of excipients (e.g. non-GRAS). In some embodiments, the compositions of the invention have amounts of excipients that are within the maximum daily doses as noted in such available data for each specific excipient.

The medium chain fatty acid salt may generally facilitate or enhance permeability and/or absorption of the therapeutic agent. The matrix forming polymer (see below) serves to increase the effect of the permeability enhancer. In some embodiments, the medium chain fatty acid salts include derivatives of medium chain fatty acid salts. The therapeutic agent, the medium chain fatty acid salt and the matrix forming polymer are in solid form, for example, a solid particle such as a lyophilized particle, granulated particle, pellet or micro- sphere. In preferred embodiments, the therapeutic agent, the medium chain fatty acid salt and the matrix forming polymer are all in the same solid form, e.g., all in the same particle. In other embodiments, the therapeutic agent, the medium chain fatty acid salt and the matrix forming polymer may each be in a different solid form, e.g. each in a distinct particle or in various combinations thereof. The compositions described herein are substantially free of any "membrane fluidizing agents" defined as linear, branched, aromatic and cyclic medium chain alcohols, in particular geraniol and octanol. For example, the compositions preferably include no membrane fluidizing agents but certain embodiments may include, for example, less than 1% or less than 0.5% or less than 0.1% by weight of membrane fluidizing agents.

Unlike emulsions, where water is an essential constituent of the formulation, the compositions described herein provide a solid form such as a particle containing the therapeutic agent, which is then associated with the hydrophobic (oily) medium. The amount of water in the compositions is generally less than 3% by weight, usually less than about 2% or about 1% or less by weight.

The compositions described herein are suspensions which comprise an admixture of a hydrophobic medium and a solid form wherein the solid form comprises a therapeutically effective amount of aliskiren, at least one salt of a medium chain fatty acid and a matrix forming polymer. The solid form may be a particle (e.g., consist essentially of particles, or consist of particles). The particle may be produced by lyophilization or by granulation or by other means. The medium chain fatty acid salt is generally present in the compositions described herein at an amount of 10% or more by weight. In certain embodiments the medium chain fatty acid salt is present in the composition at an amount of 10%-50% ₅ preferably 11%-18%, about 11%-17%, 12%-16%, 12%-15%, 13%-16%, 13%-15%, 14%- 16%, 14%-15%, 15%-16% or most preferably 15% or 16% by weight, and the medium chain fatty acid has a chain length from about 6 to about 14 carbon atoms preferably 8, 9 or 10 carbon atoms.

The inventors unexpectedly found that, in the compositions of the invention described herein, PVP, in particular PVP-12, serves to increase the effect of the permeability enhancer in a synergistic manner. Furthermore, increasing the level of PVP-12 to 10% increased the absorption of APIs into the blood due to the improved bioavailability of the formulations. The inventors demonstrated that dextran had a similar (but lower) effect as PVP did. Other matrix forming polymers also have a similar effect. Instead of PVP in the formulation, a range of matrix forming polymers were substituted e.g., Carbopol polymer or alginate or hyaluronate or polyacrylic acid sodium salt; glucosamine or glucose was also substituted (see Tables B-l and B-2). All formulations displayed bioavailability. Carbopol polymers are polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol. Carbopol® 934P Polymer is a high molecular weight polymer of acrylic acid crosslinked with allyl ethers of sucrose. PVA is a water-soluble synthetic polymer of vinyl alcohol monomers.

Replacing PVP-12 in the formulation by e.g. Carbopol 934P or by PVA, or by some of the other matrix forming polymers indicated, reduces the total amount of matrix forming polymer in the particle phase (i.e. the solid form) of the formulation (the hydrophilic fraction) and thus bestows the ability to load more aliskiren into the formulation, which may be desirable in order to achieve desired blood levels or reduce capsule size and number.

The amount of solid form (i.e. hydrophilic fraction) in the formulations of the invention is normally from about 10% to about 50% of the formulation (w/w). In certain aspects of the invention, the amount of solid form is from about 17% to about 36%. In some embodiments of the compositions described above, the solid form including the therapeutic agent also includes an aliskiren stabilizer.

In a particular embodiment of the compositions described herein, the therapeutic agent is aliskiren and the salt of the fatty acid is sodium octanoate and the hydrophobic medium is glyceryl tricaprylate. In another particular embodiment, the composition further comprises PVP. In another particular embodiment, the composition further comprises a bile salt (e.g. sodium taurocholate or sodium deoxycholate or sodium glycocholate or sodium chenodeoxycolate or sodium cholate or sodium lithocholate) and lecithin and at least one aliskiren stabilizer. Therapeutic agents; The pharmaceutical compositions described herein can be used with a variety of therapeutic agents (also termed active pharmaceutical ingredient =API). In some embodiments, the pharmaceutical composition includes a plurality of therapeutic agents (effectors). The therapeutic agents can either be in the same solid form (e.g., in the same particle), or the therapeutic agents can each be in an independent solid form (e.g., each in different particles. In preferred embodiments, the therapeutic agent is in the form of a particle, for example, a granulated or solid particle. The particle is associated with or is in intimate contact with a substantially hydrophobic medium, for example, a hydrophobic medium described herein. The preferred therapeutic agents described herein are renin inhibitors and in particular aliskiren. Other therapeutic agents can be combined with the renin inhibitor e.g., ATi-receptor antagonists, HMG-Co-A reductase inhibitors, angiotensin converting enzyme (ACE) inhibitors, calcium channel blockers, aldosterone synthase inhibitors, aldosterone antagonists, dual angiotensin converting enzyme/neutral endopetidase (ACE/NEP) inhibitors, endothelin antagonists or diuretics.

The AT receptor antagonist may, for example, be selected from valsartan, losartan, eprosartan, irbesartan, telmisartan, candesartan, saprisartan and salts thereof.

The HMG-Co-A reductase inhibitor may, for example, be selected from atorvastatin, cerivastatin, compactin, dalvastatin, dihydrocompactin, fluindostatin, fluvastatin, lovastatin, pitavastatin, mevastatin, pravastatin, rivastatin, simvastatin, and velostatin. The ACEI may, for example, be selected from alacepril, benazepril, benazeprilat, captopril, ceronapril, cilazapril, delapril, enalapril, enaprilat, fosinopril, imidapril, lisinopril, moveltopril, perindopril, quinapril, ramipril, spirapril, temocapril, trandolapril and salts thereof.

The calcium channel blocker may, for example, be selected from amlodipine, felodipine, ryosidine, isradipine, lacidipine, nicardipine, nifedipine, niguldipine, niludipine, nimodipine, nisoldipine, nitrendipine, and nivaldipine. The aldosterone synthase inhibitor may, for example, be selected from non-steroidal aromatase inhibitors anastrozole, fadrozole (including the (+)-enantiomer thereof), as well as the steroidal aromatase inhibitor exemestane. The aldosterone antagonist may, for example, be selected from eplerenone or spironolactone. The dual angiotensin converting enzyme/neutral endopetidase (ACE/NEP) inhibitor may, for example, be selected from omapatrilate (cf. EP 629627), fasidotril or fasidotrilate, or Z 13752A (cf. WO 97/24342). The endothelin antagonist may, for example, be selected from bosentan, enrasentan, atrasentan, darusentan, BMS 193884 (cf. EP 702012 A), sitaxentan, especially sitaxsentan sodium, YM 598 (cf. EP 882719 A), S 0139 (cf. WO 97/27314), J 104132 (cf. EP 714897 A or WO 97/37665), furthermore, tezosentan. The diuretic may, for example, be selected from a thiazide diuretic, such as chlorothiazide, hydrochlorothiazide, methylclothiazide, or chlorothalidon.

In some embodiments of the compositions described herein, the solid form including the therapeutic agent also includes a stabilizer, in particular an aliskiren stabilizer.

Medium chain fatty acid salt; The compositions described herein include the salt of a medium chain fatty acid or a derivative thereof in a solid form. For example, the salt of the medium chain fatty acid is in the form of a particle such as a solid particle. In some embodiments, the particle may be characterized as a granulated particle. In at least some embodiments, the solid form may generally result from a spray drying or evaporation process. In preferred embodiments, the salt of the medium chain fatty acid is in the same particle as the therapeutic agent. For example, the therapeutic agent and the salt of the medium chain fatty acid can be prepared together by first preparing a solution such as an aqueous solution comprising both the therapeutic agent and the salt of the medium chain fatty acid and co-lyophilizing the solution to provide a solid form or particle that comprises both the therapeutic agent and the salt of the medium chain fatty acid (and other ingredients). As described above, the resulting solid particles are associated with a hydrophobic medium. For example, the solid particles may be suspended or immersed in a hydrophobic medium.

In different embodiments of the compositions described herein, the medium chain fatty acid salt and the matrix forming polymer (see below) may be in the same particle or in a different particle than that of the API. It was found that bioavailability of a cargo compound was lower if the medium chain fatty acid was in a different particle than the therapeutic agent i.e., there was improved bioavailability if the medium chain fatty acid salt and the cargo compound were dried after solubilization together in the hydrophilic fraction. In one embodiment, the medium chain fatty acid salt, the matrix forming polymer and the cargo compound are all in the same particle in the final powder.

Medium chain fatty acid salts include those having a carbon chain length of from about 6 to about 14 carbon atoms. Examples of fatty acid salts are sodium hexanoate, sodium heptanoate, sodium octanoate (also termed sodium caprylate), sodium nonanoate, sodium decanoate, sodium undecanoate, sodium dodecanoate, sodium tridecanoate, and sodium tetradecanoate. In some embodiments, the medium chain fatty acid salt contains a cation selected from the group consisting of potassium, lithium, ammonium and other monovalent cations e.g., the medium chain fatty acid salt is selected from lithium octanoate or potassium octanoate or arginine octanoate or other monovalent salts of the medium chain fatty acids. The inventors had previously determined that raising the amount of medium chain fatty acid salt increased the bioavailability of the resulting formulation. In particular, raising the amount of medium chain fatty acid salt, in particular sodium octanoate, above 10% to a range of about 12% to 15 % increased the bioavailability of the therapeutic agents in the

pharmaceutical compositions described herein.

In general, the amount of medium chain fatty acid salt in the compositions described herein may be from 10% up to about 50% by weight of the bulk pharmaceutical composition. For example, the medium chain fatty acid salt may be present at an amount of about

10%-50%, or at an amount of about 10%-20% or about 10%- 15% or and amount of about 15%-20% preferably about 11%-40% most preferably about 11 %-28% by weight for example at about 12%-13%, 13%-14%, 14%-15%, 15%-16%, 16%-17%, 17%-18%, 18%- 19%, 19%-20%, 20%-21%, 21%-22%, 22%-23%, 23%-24%, 24%-25%, 25%-26%, 26%- 27%, or 27%-28% by weight of the bulk pharmaceutical composition. In other embodiments the medium chain fatty acid salt may be present at an amount of at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15% at least about 16%,at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27% or at least about 28% by weight of the bulk pharmaceutical composition. In specific embodiments the medium chain fatty acid salt (sodium, potassium, lithium or ammonium salt or a mixture thereof) is present at about 12%-21% by weight of the bulk pharmaceutical composition preferably 11%-18% about 11%-17%, 12%-16%, 12%- 15%, 13%-16%, 13%-15%, 14%-16%, 14%-15%, 15%-16% or most preferably 15% or 16%. In specific embodiments, the medium chain fatty acid salt (having a carbon chain length of from about 6 to about 14 carbon atoms particularly 8, 9 or 10 carbon atoms) is present at about 12%-21 % by weight of the bulk pharmaceutical composition preferably 11 %- 18% about 11%-17%, 12%-16%, 12%-15%, 13%-16%, 13%-15%, 14%-16%, 14%-15%, 15%- 16% or most preferably 15% or 16%. In specific embodiments, the medium chain fatty acid salt (for example salts of octanoic acid, salts of suberic acid, salts of geranic acid) is present at about 12%-21% by weight of the bulk pharmaceutical composition preferably 11%-18% about 11%-17%, 12%-16%, 12%-15%, 13%-16%, 13%-15%, 14%-16%, 14%-15%, 15%- 16% or most preferably 15% or 16%. In certain embodiments, the medium chain fatty acid salt is present in the solid powder at an amount of about 30% to 90%, preferably at an amount of 40% to 60%.

One embodiment of the invention comprises a composition comprising a suspension which consists essentially of an admixture of a hydrophobic medium and a solid form wherein the solid form comprises a therapeutically effective amount of a therapeutic agent, at least one salt of a medium chain fatty acid and a matrix forming polymer, and wherein the medium chain fatty acid salt is not a sodium salt. The salt may be the salt of another cation e.g. lithium, potassium or arginine; an arginine salt is preferred. Matrix forming polymer: In certain embodiments, the composition of the invention comprises a suspension which comprises an admixture of a hydrophobic medium and a solid form wherein the solid form comprises a therapeutically effective amount of a therapeutic agent, at least one salt of a medium chain fatty acid and a matrix forming polymer. In certain embodiments, the composition comprises a suspension which consists essentially of an admixture of a hydrophobic medium and a solid form wherein the solid form comprises a therapeutically effective amount of a therapeutic agent, at least one salt of a medium chain fatty acid and a matrix forming polymer. The matrix forming polymer is preferably present in the composition at an amount of about 0.5% to about 10% by weight, most preferably at an amount of about 1 % to about 10% by weight.

Matrix forming polymers include polyvinylpyrrolidone (PVP), a polymer of linear chains of N-vinylpyrrolidone which is known to generate "matrix-like" structures, and cross- linked PVP (cross-povidones); ionic polysaccharides (for example hyaluronic acid/ hyaluronates and alginic acid/ alginates); neutral polysaccharides (for example dextran, methyl cellulose and hydroxypropyl methylcellulose (HPMC)); linear polyacrylic acid polymers including polymethacrylic acid polymers; cross-linked polyacrylic acid polymers (carbomers); amino- polysaccharides (e.g. chitosans); S-containing polymers (thiomers); and high molecular weight linear and bridged organic alcohols (for example linear polyvinyl alcohol).

Carbomer is a generic name for cross-linked polymers of acrylic acid; carbomers may be homopolymers of acrylic acid, cross-linked with, for example, an allyl ether

pentaerythritol, or allyl ether of sucrose or allyl ether of propylene or allyl sucrose or other sugars or allyl pentaerythritol or a polyalkenyl ether or divinyl glycol.

In particular embodiments, the matrix forming polymer is polyvinylpyrrolidone (PVP), carbomer, polyvinyl alcohol (PVA), dextran, alginate salt, hyaluronate salt or polyacrylic acid salt or a combination thereof. In certain particular embodiments the matrix forming polymer is polyvinylpyrrolidone (PVP), Carbopol polymer or polyvinyl alcohol (PVA) or a combination thereof.

In particular embodiments, the polyvinylpyrrolidone is present in the composition at an amount of about 2% to about 20% by weight, preferably at an amount of about 3% to about 18 % by weight, more preferably at an amount of about 5% to about 15 % by weight, most preferably at an amount of about 10 % by weight. In certain particular embodiments, the polyvinylpyrrolidone is PVP- 12 and/or has a molecular weight of about 3000, and is present in the composition at an amount of about 2% to about 20% by weight, preferably at an amount of about 5% to about 15 % by weight, most preferably at an amount of about 10 % by weight.

In one aspect of the invention, the matrix forming polymer is a cross-linked acrylic acid polymer (also termed carbomer). Carbopol polymers are examples of cross-linked polymers of acrylic acid. The viscosity of the cross-linked acrylic acid polymer is about 2000-80000 cP, preferably 4000-65000, most preferably 25000-45000 cP; the viscosity is measured in cP, 0.5% solution at pH7.5. In one particular aspect of the invention, the cross- linked acrylic acid polymer is an allyl sucrose-linked carbomer, of viscosity about 29000 to about 40000, particularly Carbopol 934P. The cross-linked acrylic acid polymers maybe present in the composition at an amount of about 0.1 % to about 6% by weight, preferably at an amount of about 0.5% to about 4 % by weight, e.g. at an amount of about 1 % or about 2% or about 3% by weight.

In another aspect of the invention, the matrix forming polymer is polyvinyl alcohol of molecular weight 10000 - 60000 Da, preferably 20000 - 30000 Da. In particular

embodiments the polyvinyl alcohol is polyvinyl alcohol of molecular weight of about 27000 Da, and may be present in the composition at an amount of about 0.1 % to about 6% by weight, preferably at an amount of about 0.5% to about 4 % by weight, e.g. at an amount of about at an amount of about 1 %, about 2 %, or about 3% by weight.

Glucose and/or other sugars and/or mannitol may be substituted in certain

embodiments instead of a matrix forming polymer. Aliskiren stabilizers: The inventors found that, to reduce degradation of the aliskiren particularly on storage at about 25° C, a stabilizer had to be added to the formulations, particularly to the solid form. These stabilizers include metal salts and/or an amino acid or a combination hereof. Examples of a metal salt are a magnesium salt, a calcium salt and a zinc salt or a combination thereof. Particular examples of a metal salt are MgCl ₂ , ZnCl ₂ , CaCl ₂ , Zn acetate, Mg acetate and Ca acetate. Examples of amino acids are glycine and arginine. In other embodiments the hydrophobic medium may be selected to be a stabilizing medium for example glyceryl tricaprylate and other polar non-hydroxylic liquids. Hydrophilic fraction: In some embodiments, the above compounds, including the therapeutic agent, the medium chain fatty acid salt and the matrix forming polymer (or substitute) and optionally an aliskiren stabilizer are solubilized in an aqueous medium and then dried to produce a powder. The drying process may be achieved, for example, by lyophilization or granulation, spray drying or by other means. The powder obtained is termed the "hydrophilic fraction". In the hydrophilic fraction water is normally present at an amount of less than 6% and the water in the final bulk composition comprises residual water from the hydrophilic fraction.

Lyophilization may be carried out as shown in the Examples herein and by methods known in the art e.g., as described in Lyophilization: Introduction and Basic Principles , Thomas Jennings, published by Interpharm/CRC Press Ltd ( 1 99, 2002) The lyophilizate may optionally be milled (e.g. below 150 micron) or ground in a mortar. During industrial production the lyophilizate is preferably milled before mixing of the hydrophilic fraction and the hydrophobic medium in order to produce batch-to-batch reproducibility.

Granulation may be carried out as shown in the Examples herein and by methods known in the art e.g., as described in Granulation, Salman et al , eds, Elsevier (2006) and in Handbook of Pharmaceutical Granulation Technology, 2 ^nd edition, Dilip M. Parikh, ed., (2005). Various binders may be used in the granulation process as described in the previous two references.

Spray-drying may be carried out by methods known in the art e.g., as described by Patel et al. (2009) Indian Journal of Science and Technology 2(10) 44-47 and by Shabde, Vikram (2006) Ph.D. thesis, Texas Tech University.

Hydrophobic Medium:

Oil: As described above, in the compositions of the invention described herein the therapeutic agent and the medium chain fatty acid salt are in intimate contact or association with a hydrophobic medium. For example, one or both may be coated, suspended, immersed or otherwise in association with a hydrophobic medium. Suitable hydrophobic mediums can contain, for example, aliphatic, cyclic or aromatic molecules. Examples of a suitable aliphatic hydrophobic medium include, but are not limited to, mineral oil, fatty acid monoglycerides, diglycerides, triglycerides, ethers, esters, and combinations thereof. Examples of a suitable fatty acid are octanoic acid, decanoic acid and dodecanoic acid, also C7 and C9 fatty acids and di-acidic acids such as sebacic acid and suberic acid, and derivatives thereof. Examples of triglycerides include, but are not limited to, long chain triglycerides, medium chain triglycerides, and short chain triglycerides. For example, the long chain triglyceride can be castor oil or olive oil, and the short chain triglyceride can be glyceryl tributyrate and the medium chain triglyceride can be glyceryl tricaprylate or coconut oil. Monoglycerides are considered to be surfactants and are described below. Exemplary esters include ethyl isovalerate and butyl acetate. Examples of a suitable cyclic hydrophobic medium include, but are not limited to, terpenoids, cholesterol, cholesterol derivatives (e.g., cholesterol sulfate), and cholesterol esters of fatty acids. A non-limiting example of an aromatic hydrophobic medium includes benzyl benzoate.

In some embodiments of the compositions described herein, it is desirable that the hydrophobic medium include a plurality of hydrophobic molecules. In specific embodiments of the compositions described herein the hydrophobic medium also includes one or more surfactants (see below).

Surface Active Agents (surfactants): The compositions of this invention described herein can further include a surface active agent. For example, the surface active agent can be a component of the hydrophobic medium as described above, and/or the surface active agent can be a component of the solid form as described above, for example, in the solid form or particle that includes the therapeutic agent.

Suitable surface active agents include ionic and non-ionic surfactants. Examples of ionic surfactants are lecithin (phosphatidyl choline), bile salts (e.g. sodium taurocholate, sodium deoxycholate, sodium glycocholate, sodium chenodeoxycolate, sodium cholate, sodium lithocholate) and detergents. Examples of non-ionic surfactants include monoglycerides, cremophore, a polyethylene glycol fatty alcohol ether, a sorbitan fatty acid ester, a polyoxyethylene sorbitan fatty acid ester, Solutol HS15, a poloxamer, alkyl- saccharides ( e.g. octyl glycoside, terra decyl maltoside), or a combination thereof. Examples of monoglycerides are glyceryl monocaprylate (also termed glyceryl monooctanoate), glyceryl monodecanoate, glyceryl monolaurate, glyceryl monomyristate, glyceryl

monostearate, glyceryl monopalmitate, and glyceryl monooleate. Examples of sorbitan fatty acid esters include sorbitan monolaurate, sorbitan monooleate, and sorbitan monopalmitate (Span 40), or a combination thereof. Particular examples of polyoxyethylene sorbitan fatty acid esters include polyoxyethylene sorbitan monooleate (Tween 80), polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate or a combination thereof. The commercial preparations of monoglycerides that were used also contain various amounts of diglycerides and triglycerides.

Compositions described herein including a surface active agent generally include less than about 12% by weight of total surface active agent (e.g., less than about 10%, less than about 8%, less than about 6%, less than about 4%, less than about 2%, or less than about

1%). In particular embodiments of the invention, the total sum of all the surfactants is about 6-7% by weight in the composition. In certain embodiments, the surfactants include Tween 80 at about 2% by weight and glyceryl monocaprylate at about 4-5% by weight. In particular embodiments the surfactants include lecithin in the hydrophobic (lipophilic) medium and a bile salt in particular sodium taurocholate in the hydrophilic (solid) faction.

Methods of making pharmaceutical compositions and the compositions produced: Also included in the invention are methods of producing the compositions described herein. Thus one embodiment of the invention is a process for producing a pharmaceutical composition which comprises preparing a water-soluble composition comprising a therapeutically effective amount of at least one therapeutic agent (renin inhibitor/aliskiren), a medium chain fatty acid salt and a matrix forming polymer or substitute (as described above), drying the water soluble composition to obtain a solid powder, and suspending the solid powder in a hydrophobic medium, to produce a suspension containing in solid form the therapeutic agent, the medium chain fatty acid salt and the matrix forming polymer, thereby producing the pharmaceutical composition, wherein the pharmaceutical composition normally contains about 10% -15% by weight of medium chain fatty acid salt. See Figure 1.

One embodiment is a process for producing a pharmaceutical composition which comprises providing a solid powder of a therapeutically effective amount of at least one therapeutic agent (renin inhibitor/aliskiren), a solid powder comprising a medium chain fatty acid salt and a solid powder comprising matrix forming polymer, and suspending the solid powders in a hydrophobic medium, to produce a suspension containing in solid form the therapeutic agent and the medium chain fatty acid salt, thereby producing the pharmaceutical composition, wherein the pharmaceutical composition contains 10% or more by weight of medium chain fatty acid salt.

In one embodiment of the processes and compositions described herein, the water- soluble composition is an aqueous solution. In certain embodiments, the drying of the water- soluble composition is achieved by lyophilization or by granulation or by spray -drying or by other means. In the granulation process, a binder may be added to the water soluble composition before drying. In certain embodiments, the drying step removes sufficient water so that the water content in the pharmaceutical composition is lower than about 6% by weight, about 5% by weight, about 4% by weight, about 3%, about 2 % or about 1% by weight. In certain embodiments of the processes and compositions described herein, the drying step removes an amount of water so that the water content in the solid powder is lower than 6%, 5%, 4% or 3% or preferably lower than 2% by weight. The water content is normally low and the water may be adsorbed to the solid phase during lyophilization i.e., the water may be retained by intermolecular bonds. In certain embodiments the water soluble composition additionally comprises a stabilizer, in particular an aliskiren stabilizer.

A formulation is provided as an embodiment wherein the hydrophobic medium consists essentially of glyceryl tricaprylate; in a further embodiment of the basic formulation the hydrophilic fraction consists essentially of aliskiren, PVP-12 and sodium octanoate.

A particular formulation is provided as an embodiment wherein the hydrophobic (lipophilic) medium consists essentially of glyceryl tricaprylate and surfactant in particular lecithin, and the hydrophilic fraction consists essentially of aliskiren, PVP-12 and sodium octanoate and optionally a bile salt. Another particular formulation is provided as an embodiment wherein the hydrophobic medium comprises glyceryl tricaprylate and surfactant in particular lecithin and the hydrophilic fraction consists essentially of aliskiren, PVP-12, sodium octanoate, optionally a bile salt in particular sodium taurocholate, and optionally an aliskiren stabilizer, for example a metal salt or an amino acid or a combination thereof.

Many of the compositions described herein comprise a suspension which comprises an admixture of a hydrophobic medium and a solid form wherein the solid form comprises a therapeutically effective amount of aliskiren, a matrix forming polymer and at least one salt of a medium chain fatty acid, and wherein the medium chain fatty acid salt is present in the composition at an amount of 10% or more by weight. The solid form may be a particle (e.g., consist essentially of particles, or consists of particles). The particle may be produced by lyophilization or by granulation or by spray-drying or by other means.

In a particular embodiment, the formulation consists essentially of a suspension which comprises an admixture of a hydrophobic medium and a solid form wherein the solid form comprises about 1-20% preferably about 5-10% aliskiren, about 10-20% preferably 15% medium chain fatty acid salt preferably sodium octanoate, about 5- 10% preferably 10% PVP- 12, about 0.1-2.0% preferably 0.5% bile salt preferably sodium taurocholate and optionally a stabilizer of aliskiren; and wherein the hydrophobic medium comprises about 20-80% , preferably 50-70% triglyceride preferably glyceryl tricaprylate or glyceryl tributyrate or castor oil or a combination thereof, about 3-10% surfactants, preferably about 6%, preferably lecithin . The stabilizer of aliskiren may be a metal salt or an amino acid or a combination thereof. Examples of a metal salt are a magnesium salt, a calcium salt and a zinc salt or a combination thereof, present at an amount of about 1-10%, preferably about 2-6%. Particular examples of metal salt are MgCl ₂ , ZnCl ₂ , CaCl ₂ , Zn acetate, Mg acetate and Ca acetate. Examples of an amino acid are glycine, aspartic acid and arginine present at an amount of about 1 -10%, preferably about 3-7%.

Another particular embodiment is a pharmaceutical composition comprising a suspension which comprises an admixture of a hydrophobic medium and a solid form wherein the solid form comprises a therapeutically effective amount of aliskiren, at least one salt of a medium chain fatty acid, a matrix forming polymer, and optionally a surfactant and optionally an aliskiren stabilizer. The hydrophobic medium contains at least one surfactant, preferably lecithin, preferably present at about 3% -9% by weight preferably at about 6% by weight. The salt of the medium chain fatty acid is sodium octanoate, the matrix forming polymer is PVP-12, and the surfactant is a bile salt preferably sodium taurocholate. The aliskiren stabilizer is an amino acid or a metal salt or a combination thereof. The sodium octanoate is present at an amount of 10%-20% by weight, preferably about 15% by weight, and the PVP is present at about 5-15% by weight preferably about 10%. The sodium taurocholate is present at an amount of 0.1%-2% by weight, preferably about 0.5% by weight and the aliskiren is present at an amount of 1% - 20% by weight, preferably about 5-10% by weight, or about 10% by weight. In some embodiments, the pharmaceutical composition additionally comprises a second therapeutic agent or a third therapeutic agent.

In particular embodiments, the aliskiren is present at an amount of less than 33%, or less than 25%, or less than 10%, or less than 1% or less than 0.1%. The solid form may be a particle (e.g., consist essentially of particles, or consists of particles). The particle may be produced by lyophilization or by granulation or by spray drying. In a particular embodiment, the solid form may be a particle and may be produced by lyophilization or by granulation or spray drying.

In all the above formulations, the percentages recited are weight/weight and the solid form may be a particle (e.g., consist essentially of particles, or consists of particles). The particles may be produced by lyophilization or by granulation or by spray drying or by other means.

Once administered to the intestine the therapeutic agent is protected from damage by the GI environment since the formulations are oil-based. Thus, a separate local environment is created in the intestine where the therapeutic agent is contained in oil droplets, which confers stability in vivo.

Particular embodiments of the invention comprise an oral dosage form comprising the pharmaceutical composition, in particular an oral dosage form which is enteric coated. Further embodiments of the invention comprise a capsule or a tablet containing the compositions of the invention, and in various embodiments the capsule is a hard gel or a soft gel capsule, and generally the capsule is enteric-coated. Other embodiments of the invention comprise a rectal dosage form comprising the pharmaceutical composition, in particular a suppository, or a buccal dosage form. A kit comprising instructions and the dosage form is also envisaged.

The therapeutic agent or medium chain fatty acid salt or matrix forming polymer, or surfactant (e.g. a bile salt) or any combination of therapeutic agent and other components, such as an aliskiren stabilizer, can be prepared in a solution of a mixture (e.g., forming an aqueous solution or mixture) which can be lyophilized together and then suspended in a hydrophobic medium. Other components of the composition can also be optionally lyophilized or added during reconstitution of the solid materials. Alternatively the ingredients can be provided in dry form and mixed into the hydrophobic medium thus forming a suspension.

In some embodiments, the therapeutic agent is solubilized in a mixture, for example, including one or more additional components such as a medium chain fatty acid salt, a matrix forming polymer, a stabilizer and/or a surface active agent( surfactant), and the solvent is removed to provide a resulting solid powder (solid form), which is suspended in a hydrophobic medium. In some embodiments, the therapeutic agent and/or the medium chain fatty acid salt and /or the matrix forming polymer may be formed into a granulated particle that is then associated with the hydrophobic medium (for example suspended in the hydrophobic medium or coated with the hydrophobic medium). In general, the compositions described herein are substantially free of "membrane fluidizing agents" such as medium chain alcohols.

"Membrane fluidizing agents" are defined as medium chain alcohols which have a carbon chain length of from 4 to 15 carbon atoms (e.g., including 5 to 15, 5 to 12, 6, 7, 8, 9, 10, or 11 carbon atoms). For example, a membrane fluidizing agent can be a linear (e.g., saturated or unsaturated), branched (e.g., saturated or unsaturated), cyclical (e.g., saturated or unsaturated), or aromatic alcohol. Examples of suitable linear alcohols include, but are not limited to, butanol, pentanol, hexanol, heptanol, octanol, nonanol, decanol, undecanol, dodecanol, tridecanol, tetradecanol, and pentadecanol. Examples of branched alcohols include, but are not limited to, geraniol, farnesol, rhodinol, citronellol. An example of a cyclical alcohol includes, but is not limited to, menthol, terpineol, myrtenol, perillyl and alcohol. Examples of suitable aromatic alcohols include, but are not limited to, benzyl alcohol, 4-hydroxycinnamic acid, thymol, styrene glycol, and phenolic compounds.

Examples of phenolic compounds include, but are not limited to, phenol, m-cresol, and m- chlorocresol.

If desired, the pharmaceutical composition may also contain minor amounts of nontoxic auxiliary substances such pH buffering agents, and other substances such as for example, sodium acetate and triethanolamine oleate.

In some embodiments the process for producing a pharmaceutical composition comprises preparing a water-soluble composition comprising a therapeutically effective amount of at least one therapeutic agent (renin inhibitor/aliskiren), a medium chain fatty acid salt and a matrix forming polymer, drying the water soluble composition to obtain a solid powder, and dissolving the solid powder in a solution consisting essentially of octanoic acid, thereby producing the pharmaceutical composition, which is a suspension at the

concentration of solids exemplified. At a lower concentration of solids (below the saturation threshold) a solution is obtained. In some embodiments, the solid form may be a particle (e.g., consist essentially of particles, or consists of particles). In some embodiments, the particle may be produced by lyophilization or by granulation. In some embodiments of this process, the octanoic acid is present in the composition at a level of about 50 % to about 90% or at a level of about 55 to about 85% preferably about 58%. In some embodiments of this process, the fatty acid salt is sodium octanoate. In further embodiments of this process, the medium chain fatty acid salt is present in the composition at an amount of about 11% to about 40% by weight or at an amount of about 11% to about 28% by weight or at an amount of about 15% by weight. The matrix forming polymer may be present as described above. The composition may in addition include surfactants as described above. The pharmaceutical products of these processes are further embodiments of the invention.

Capsules and tablets: Preferred pharmaceutical compositions are oral dosage forms or suppositories. Exemplary dosage forms include gelatin or vegetarian capsules like starch hydroxylpropyl-methylcellulose ("HPMC") capsules, enteric coated, containing the bulk drug product. Capsules which may be used to encapsulate the compositions of this invention are known in the art and are described for example in Pharmaceutical Capsules edited by Podczech and Jones, Pharmaceutical Press (2004) and in Hard gelatin capsules today - and tomorrow, 2nd edition, Steggeman ed published by Capsugel Library (2002). Tablets comprising solid forms of the bulk drug product, and tabletted with suitable excipients as known in the art, are also envisaged; the tablets should be enteric-coated. An oral dosage form according to the invention comprises additives or excipients that are suitable for the preparation of the oral dosage form according to the present invention and may be prepared as described herein.

Further embodiments of the invention comprise a capsule or tablet containing the compositions of the invention, and in various embodiments the capsule is a hard gel or a soft gel capsule, and generally the capsule or tablet is enteric-coated. An enteric coating is resistant to stomach acid thus allowing intact capsule or tablet to pass the stomach and reach the intestine in which it dissolves in the less acidic area of the intestines, thus releasing the therapeutic agent. Examples of enteric coatings are Acryl-EZE™ (a methacrylic acid copolymer type C), Opadry™ Enteric series 91 (a polyvinyl acetate phthalate) Sureteric™ ( also a polyvinyl acetate phthalate), Opadry™ Enteric series 94 (methacrylic acid-methyl methacrylate 1:1 copolymer), Opadry™ Enteric series 95 (methacrylic acid-methyl methacrylate 1 :2 copolymer) - all from Colorcon; Eudragit™ series (polymethylacrylates) from Evonik Rohm Gmbh; Aquacoat CPD (cellulose acetate phthalate) from FMC

Biopolymer, USA; Eastman C-A-P Cellulose Ester (cellulose acetate phthalate) from

Eastman; HPMCP -50(hydroxypropyl methylcellulose phthalate) and HPMCAS Shin-Etsu AQOAT (hydroxypropyl methylcellulose acetate succinate) - both from Shin Etsu,

Japan; and CMEC (carboxymethyl cellulose) from Freund, Japan.

Capsules can be coated with the same materials as tablets (sometimes a sub-coat or binder for better adhesion of enteric polymer is needed). A kit comprising instructions and the dosage form is also envisaged. It was found that stability of encapsulated aliskiren is similar to stability of non- encapsulated bulk drug product.

Additional formulations: The compositions of the invention may be formulated using additional methods known in the art, for example, as described in the following publications: Pharmaceutical Dosage Forms Vols 1-3 ed. Lieberman, Lachman and Schwartz, published by Marcel Dekker Inc, New York(1989); Water-insoluble Drug Formulation 2 ^nd edition, Liu, editor, published by CRC Press, Taylor and Francis Group (2008); Therapeutic Peptides and Proteins: Formulation, Processing and Delivery Systems, 2 ^nd edition by Ajay K. Banga (author) published by CRC Press , Taylor and Francis Group (2006); Protein Formulation and Delivery, 2 ^nd edition, McNally and Hasted eds , published by Informa Healthcare USA Inc(2008); and Advanced Drug Formulation to Optimize Therapeutic Outcomes, Williams et al eds, published by Informa Healthcare USA (2008).

The compositions of the invention may be formulated using microparticulate technology for example as described in Microparticulate Oral Drug Delivery, Gerbre-

Selassie ed., published by Marcel Dekker Inc (1994) and in Dey et al, Multiparticulate Drug Delivery Systems for Controlled Release-, Tropical Journal of Pharmaceutical Research, September 2008; 7 (3): 1067-1075. Methods of treatment: The aliskiren formulations of the invention may be used for the treatment of hypertension, hypertension with diabetes, congestive heart failure, angina, myocardial infarction, artherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, albuminuria, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, stroke, headache and chronic heart failure.

One aspect of the invention is a method for the treatment of hypertension, hypertension with diabetes, congestive heart failure, angina, myocardial infarction, artherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, albuminuria, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, stroke, headache and chronic heart failure, which method comprises administering a therapeutically effective amount of an oral dosage form according to the invention to a patient in need thereof.

Another aspect of the invention is the use of the aliskiren formulations of the invention for the manufacture of a medicament for the treatment of hypertension, hypertension with diabetes, congestive heart failure, angina, myocardial infarction, artherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, albuminuria, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, stroke, headache and chronic heart failure.

Another aspect of the invention is combining a second therapeutic agent within the aliskiren compositions/formulations of the invention wherein the second therapeutic agent is selected from the group consisting of ATi-receptor antagonists, HMG-Co-A reductase inhibitors, angiotensin converting enzyme (ACE) inhibitors, calcium channel blockers, aldosterone synthase inhibitors, aldosterone antagonists, dual angiotensin converting enzyme/neutral endopetidase (ACE/NEP) inhibitors, endothelin antagonists and diuretics.

Another aspect of the invention is combining a third therapeutic agent within the aliskiren compositions/formulations of the invention wherein the third therapeutic agent is selected from the group consisting of AT ₁ -receptor antagonists, HMG-Co-A reductase inhibitors, angiotensin converting enzyme (ACE) inhibitors, calcium channel blockers, aldosterone synthase inhibitors, aldosterone antagonists, dual angiotensin converting enzyme/neutral endopetidase (ACE/NEP) inhibitors, endothelin antagonists and diuretics.

The dosage regimen utilizing the compounds is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

Compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, four, five or six times daily.

A representative product of the invention is an aliskiren-based formulation orally administered as an enteric coated-capsule: each capsule contains a solid form comprising aliskiren, PVP, sodium octanoate, an aliskiren stabilizer and a bile salt preferably sodium taurocholate which solid form is suspended in a hydrophobic (lipophilic) medium comprising preferably glyceryl tricaprylate and at least one surfactant, preferably lecithin. In another representative product of the invention a metal salt or an amino acid or a combination thereof is present in the solid form as the aliskiren stabilizer. The compositions described herein can be administered to a subject i.e., a human or an animal, in order to treat the subject with a pharmacologically or therapeutically effective amount of a therapeutic agent described herein. The animal may be a mammal e.g. a mouse, rat, pig horse, cow or sheep. As used herein the terms "pharmacologically effective amount" or "therapeutically effective amount" or "effective amount" means that amount of a drug or pharmaceutical agent (the therapeutic agent) that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher or clinician and /or halts or reduces the progress of the condition being treated or which otherwise completely or partly cures or acts palliatively on the condition.

The formulations of the invention allow incorporation of the aliskiren into the formulation without any chemical modification of the aliskiren. Furthermore, the

formulations of the invention allow for high flexibility in loading of the aliskiren. Finally, the formulations of the invention protect the cargo compounds from inactivation in the GI environment.

It is also envisaged that two or more therapeutic agents may be in the same dosage form or may be given separately, in conjunction with each other. By "in conjunction with" is meant prior to, simultaneously or subsequent to. Accordingly, the individual components of such a combination can be administered either sequentially or simultaneously from the same or separate pharmaceutical formulations. The dosage form may be an oral formulation, which has bioavailability. In particular the dosage form to be administered to the subject is an oral dosage form of the invention.

Summary of the Embodiments: The pharmaceutical composition of the invention comprises a suspension which comprises an admixture of a hydrophobic medium and a solid form wherein the solid form comprises a therapeutically effective amount of aliskiren and optionally a second and optionally a third therapeutic agent and at least one salt of a medium chain fatty acid; an additional constituent may be selected from the group consisting of a matrix forming polymer and a sugar; the solid form comprises a particle; and the particle is produced by lyophilization or by granulation or spray drying or by other means. The water content in the pharmaceutical composition is lower than about 6 % by weight, preferably lower than about 2 % by weight, and the water content in the solid form is lower than about 6% by weight, preferably lower than 2% by weight. The medium chain fatty acid salt has a chain length from about 6 to about 14 carbon atoms, and is sodium hexanoate, sodium heptanoate, sodium octanoate, sodium nonanoate, sodium decanoate, sodium undecanoate, sodium dodecanoate, sodium tridecanoate or sodium tetradecanoate, or a corresponding potassium or lithium or ammonium salt or a combination thereof, in particular sodium octanoate. The medium chain fatty acid salt is present in the composition at an amount of 11% to 40% by weight preferably 12% to 18% by weight, most preferably aboutl5% by weight. The medium chain fatty acid salt is present in the solid form at an amount of 50% to 90% by weight preferably at an amount of 70% to 80% by weight. The matrix forming polymer is present in the composition at an amount of about 0.5% to 15% by weight, preferably about 1% to 10% by weight, and is selected from the group consisting of polyvinylpyrrolidone, carbomer (e.g. Carbopol polymer), polyvinyl alcohol, dextran, alginate salt, hyaluronate salt and polyacrylic acid salt and a combination thereof, in particular polyvinylpyrrolidone, carbomer and polyvinyl alcohol and a combination thereof.

The polyvinylpyrrolidone is preferably PVP-12, and preferably has a molecular weight of about 3000, and is present in the composition at an amount of about 2% to about 20% by weight, preferably at an amount of about 5% to about 15 % by weight, most preferably at an amount of about 10 % by weight. The carbomer is preferably Carbopol 934P, and is present in the composition at an amount of about 0.1% to about 6% by weight, preferably at an amount of about 0.5% to about 4 % by weight, most preferably at an amount of about the polyvinyl alcohol is preferably polyvinyl alcohol of molecular weight of about 27000 Da, and is present in the composition at an amount of 4 % by weight, most preferably at an amount of about 1-2 % by weight. The pharmaceutical composition of the invention is free of a medium chain alcohol and is free of a membrane fiuidizing agent.

The pharmaceutical composition of the invention additionally comprises a surfactant, which is an ionic surfactant or a non-ionic surfactant or a combination thereof. In some embodiments the surfactant is lecithin or a bile salt (e.g. sodium taurocholate) or a detergent (e.g. Tween- 80) or a combination thereof; a monoglyceride, a cremophore, a polyethylene glycol fatty alcohol ether, a sorbitan fatty acid ester, a polyoxyethylene sorbitan fatty acid ester, Solutol HS15 (polyoxyethylene esters of 12-hydroxystearic acid), an alkyl-saccharide (e.g. octyl glycoside, terra decyl maltoside) or a poloxamer or a combination thereof. The monoglyceride is glyceryl monocaprylate, glyceryl monoocatnoate, glyceryl monodecanoate, glyceryl monolaurate, glyceryl monomyristate, glyceryl monopalmitate or glyceryl monooleate or glyceryl monostearate or a combination thereof. The sorbitan fatty acid ester comprises sorbitan monolaurate, sorbitan monooleate or sorbitan monopalmitate or a combination thereof. The polyoxyethylene sorbitan fatty acid ester comprises

polyoxyethylene sorbitan monooleate (Tween 80), polyoxyethylene sorbitan monostearate or polyoxyethylene sorbitan monopalmitate or a combination thereof. In some embodiments the surfactant is a bile salt, and the bile salt is selected from sodium taurocholate, sodium deoxycholate, sodium glycocholate, sodium chenodeoxycolate, sodium cholate, sodium lithocholate and a combination thereof, in particular sodium taurocholate. In some embodiments, the main component by weight of the hydrophobic medium is glyceryl tricaprylate . In some embodiments the hydrophobic medium comprises an aliphatic, olefinic, cyclic or aromatic compound; and /or the hydrophobic medium comprises a mineral oil, a paraffin, a fatty acid such as octanoic acid, a monoglyceride, a diglyceride, a triglyceride, an ether or an ester (e.g. a low molecular weight ester, preferably ethyl isovalerate or butyl acetate), or a combination thereof. The triglyceride is a long chain triglyceride, or a medium chain triglyceride or a short chain triglyceride or a combination thereof.

In some embodiments the pharmaceutical composition additionally comprises an aliskiren stabilizer, e.g. an amino acid, and the amino acid is selected from the group consisting of glycine, aspartic acid and arginine and a combination thereof, in particular arginine. In some embodiments the aliskiren stabilizer is a metal salt and the metal salt is selected from the group consisting of a magnesium salt, a calcium salt and a zinc salt and a combination thereof or the metal salt is selected from the group consisting of MgCl , ZnCl ₂ , CaCl ₂ , Zn acetate, Mg acetate and Ca acetate, in particular the metal salt is a zinc salt, preferably zinc acetate. In some embodiments the aliskiren stabilizer is in the solid form of the pharmaceutical composition. In some embodiments the pharmaceutical composition consists essentially of aliskiren, a medium chain fatty acid salt and a matrix forming polymer and a hydrophobic medium and/or the solid powder consists essentially of aliskiren, a medium chain fatty acid salt and a matrix forming polymer. In some embodiments the hydrophobic medium consists essentially of glyceryl tricaprylate and the hydrophobic medium additionally contains a surfactant.

In some embodiments the pharmaceutical composition comprises a suspension which consists essentially of an admixture of a hydrophobic medium and a solid form wherein the solid form comprises a therapeutically effective amount of aliskiren, at least one salt of a medium chain fatty acid and a matrix forming polymer; the hydrophobic medium comprises a triglyceride or a monoglyceride or a combination thereof. In some embodiments the pharmaceutical composition comprises a suspension which comprises an admixture of a hydrophobic medium and a solid form wherein the solid form comprises a therapeutically effective amount of aliskiren, at least one salt of a medium chain fatty acid, a matrix forming polymer, and optionally a surfactant and optionally an aliskiren stabilizer. The hydrophobic medium contains at least one surfactant, preferably lecithin, preferably present at about 3% - 9% by weight preferably at about 6% by weight; the salt of the medium chain fatty acid is sodium octanoate, the matrix forming polymer is PVP-12, and the surfactant is a bile salt preferably sodium taurocholate; the aliskiren stabilizer is an amino acid or a metal salt or a combination thereof; the sodium octanoate is present at an amount of 10%-20% by weight , preferably about 15% by weight, and the PVP is present at about 5-15% by weight preferably about 10%; the sodium taurocholate is present at an amount of 0.1%-2% by weight, preferably about 0.5% by weight; the aliskiren is present at an amount of 1% - 20% by weight, preferably about 5-10% by weight, or about 10% by weight; the aliskiren is preferably aliskiren hemifurnarate.

In some embodiments the pharmaceutical composition additionally comprises a second therapeutic agent, and optionally a third therapeutic agent. In certain embodiments, the medium chain fatty acid salt in the water-soluble composition has the same fatty acid radical as the medium chain monoglyceride or as the medium chain triglyceride or a combination thereof. In certain of these embodiments the medium chain fatty acid salt is sodium caprylate (sodium octanoate) and the monoglyceride is glyceryl monocaprylate and the triglyceride is glyceryl tricaprylate.

One embodiment of the invention is a process for producing a pharmaceutical composition which comprises preparing an aqueous solution comprising a therapeutically effective amount of aliskiren and optionally a second therapeutic agent, and optionally a third therapeutic agent; and a medium chain fatty acid salt, drying the aqueous solution to obtain a solid powder, and suspending the solid powder in a hydrophobic medium, to produce a suspension containing in solid form the aliskiren and the medium chain fatty acid salt thereby producing the pharmaceutical composition. In further embodiments, the process further comprises a matrix forming polymer in the water-soluble solution; the solid form comprises a particle and the drying is achieved by lyophilization or by granulation or by spray-drying or by other means.

In some embodiments of the process, the drying step removes sufficient water so that the water content in the pharmaceutical composition is lower than about 5 % by weight, preferably lower than about 2 % by weight and/or the drying step removes an amount of water so that the water content in the solid powder is lower than 6% by weight preferably lower than 2% by weight. In some embodiments of the process the medium chain fatty acid salt has a chain length from about 6 to about 14 carbon atoms and /or is sodium hexanoate, sodium heptanoate, sodium octanoate, sodium nonanoate, sodium decanoate, sodium undecanoate, sodium dodecanoate, sodium tridecanoate or sodium tetradecanoate, or a corresponding potassium or lithium or ammonium salt or a combination thereof, preferably sodium octanoate; and the medium chain fatty acid salt is present in the composition at an amount of about 11% to about 40% by weight preferably 11% to about 28% by weight preferably about 15% by weight and/or the medium chain fatty acid salt is present in the solid powder at an amount of 30% to 90% by weight preferably 40% to 80% by weight.

In some embodiments of the process the matrix forming polymer is selected from the group consisting of polyvinylpyrrolidone, carbomer ( e.g. Carbopol polymer), polyvinyl alcohol, dextran, alginate salt, hyaluronate salt, and polyacrylic acid salt and a combination thereof, in particular polyvinylpyrrolidone, carbomer and polyvinyl alcohol and a

combination thereof. The polyvinylpyrrolidone is preferably PVP-12, and preferably has a molecular weight of about 3000, and is present in the composition at an amount of about 2% to about 20% by weight, preferably at an amount of about 5% to about 15 % by weight, most preferably at an amount of about 10 % by weight. In some embodiments of the process the carbomer is preferably Carbopol 934P, and is present in the composition at an amount of about 0.1% to about 6% by weight, preferably at an amount of about 0.5% to about 4 % by weight, most preferably at an amount of about 1 % by weight. In some embodiments of the process the polyvinyl alcohol is preferably polyvinyl alcohol of molecular weight of about 27000 Da, and is present in the composition at an amount of about 0.1% to about 6% by weight, preferably at an amount of about 0.5% to about 4 % by weight, most preferably at an amount of about 2 % by weight or 1%. In the process the composition is substantially free of a medium chain alcohol and /or of a membrane fluidizing agent. In some embodiments, the process additionally comprises a surfactant; the hydrophobic medium comprises castor oil or glyceryl tricaprylate or glyceryl tributyrate or octanoic acid or a combination thereof; the main component by weight of the hydrophobic medium is castor oil or glyceryl tricaprylate or octanoic acid; the hydrophobic medium comprises an aliphatic, olefinic, cyclic or aromatic compound, in particular an aliphatic compound; the hydrophobic medium comprises a mineral oil, a paraffin, a fatty acid such as octanoic acid, a monoglyceride, a diglyceride, a triglyceride, an ether or an ester, or a combination thereof. In some embodiments the ester in the hydrophobic medium is a low molecular weight ester, preferably ethyl isovalerate or butyl acetate; the triglyceride is a long chain triglyceride, a medium chain triglyceride or a short chain triglyceride or a mixture thereof or the long chain triglyceride is castor oil or coconut oil or a combination thereof. In some embodiments the short chain triglyceride is glyceryl tributyrate and the medium chain triglyceride is glyceryl tricaprylate.

In some embodiments the process additionally comprises at least one surfactant, an ionic surfactant or a non-ionic surfactant or a combination thereof. In some embodiments of the process the surfactant is lecithin or a bile salt (e.g. sodium taurocholate) or a detergent or a combination thereof; or the surfactant is a monoglyceride, a cremophore, a polyethylene glycol fatty alcohol ether, a sorbitan fatty acid ester, a polyoxyethylene sorbitan fatty acid ester, Solutol HS15 (polyoxyethylene esters of 12-hydroxystearic acid), an alkyl-saccharide (e.g. octyl glycoside, tetra decyl maltoside) or a poloxamer or a combination thereof. In some embodiments the monoglyceride is glyceryl monocaprylate, glyceryl monoocatnoate, glyceryl monodecanoate, glyceryl monolaurate, glyceryl monomyristate, glyceryl monopalmitate or glyceryl monooleate or glyceryl monostearate or a combination thereof; or the sorbitan fatty acid ester comprises sorbitan monolaurate, sorbitan monooleate or sorbitan monopalmitate or a combination thereof; or the polyoxyethylene sorbitan fatty acid ester comprises polyoxyethylene sorbitan monooleate (Tween 80), polyoxyethylene sorbitan monostearate or polyoxyethylene sorbitan monopalmitate or a combination thereof.

The surfactant is in the solid form or it is in the hydrophobic medium or it is in both the solid form and the hydrophobic medium. In some embodiments the surfactant is lecithin or a bile salt ( e.g. sodium taurocholate or a detergent ( e.g. Tween- 80) or a combination thereof. In some embodiments of the process the composition consists essentially of aliskiren, a medium chain fatty acid salt, and a matrix forming polymer and a hydrophobic medium and /or the solid powder consists essentially of aliskiren, a medium chain fatty acid salt and a matrix forming polymer. In some embodiments of the process the hydrophobic medium consists essentially of glyceryl tricaprylate and optionally additionally contains a surfactant In some embodiments of the process the solid powder consists essentially of aliskiren and a medium chain fatty acid salt and a surfactant and optionally the hydrophobic medium consists essentially of glyceryl tricaprylate. In some embodiments of the process, the composition additionally comprises an aliskiren stabilizer; the aliskiren stabilizer is in particular an amino acid or a metal salt or a combination thereof. The amino acid is glycine or aspartic acid or arginine or a combination thereof, in particular arginine and the metal salt is a magnesium salt, a calcium salt or a zinc salt or a combination thereof in particular the metal salt is selected from the group consisting of MgCl ₂ , ZnCl ₂ , CaCl ₂ , Zn acetate, Mg acetate and Ca acetate.

One embodiment is a process for producing a pharmaceutical composition which comprises providing a solid powder comprising a therapeutically effective amount of aliskiren and optionally a second and optionally a third therapeutic agent; at least one salt of a medium chain fatty acid; suspending the solid powder in a hydrophobic medium, to produce a suspension containing in solid form the therapeutic agent and the medium chain fatty acid salt, thereby producing the pharmaceutical composition; and optionally providing a matrix forming polymer and an aliskiren stabilizer in the solid powder optionally further comprises providing at least one surfactant in the composition. The medium chain fatty acid salt, matrix forming polymer, stabilizer and surfactant are as described above.

One embodiment is a pharmaceutical composition produced by the processes of any of the embodiments of the invention. One embodiment is an oral dosage form comprising the composition of any of the embodiments of the invention, which is additionally enteric coated. One embodiment is a kit comprising instructions and the dosage form of the invention. One embodiment is a capsule containing the composition of the invention, and the capsule is a hard gel or a soft gel capsule; the capsule is enteric-coated. The oral dosage form of the invention is used for the treatment of hypertension, hypertension with diabetes, congestive heart failure, angina, myocardial infarction, artherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, albuminuria, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, stroke, headache and chronic heart failure.

One embodiment is a method for the treatment of hypertension, hypertension with diabetes, congestive heart failure, angina, myocardial infarction, artherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, albuminuria, 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 of the invention to a patient in need thereof. One embodiment is the use of an oral dosage form of the invention for the manufacture of a medicament for the treatment of hypertension, hypertension with diabetes, congestive heart failure, angina, myocardial infarction, artherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, albuminuria, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, stroke, headache and chronic heart failure. One embodiment is any of the above compositions which have optionally a second and optionally a third therapeutic agent wherein the second or third therapeutic agent is selected from the group consisting of AT] -receptor antagonists, HMG-Co-A reductase inhibitors, angiotensin converting enzyme (ACE) inhibitors, calcium channel blockers, aldosterone synthase inhibitors, aldosterone antagonists, dual angiotensin converting enzyme/neutral endopetidase (ACE/NEP) inhibitors, endothelin antagonists and diuretics. One embodiment is a unit dosage form comprising aliskiren for use in oral delivery and the aliskiren is present in an amount ranging from about 5-75 mg per unit dosage form, or about 75-150 mg per unit dosage form, or about 150-300 mg per unit dosage form, or about 300-600 mg per unit dosage form. One embodiment is an unit dosage form where the resulting bioavailability of aliskiren on oral administration of the unit dosage form is greater than 3% or greater than 4%, or greater than 5% or greater than 6%.

The function and advantages of these and other embodiments will be more fully understood from the following examples. These examples are intended to be illustrative in nature and are not to be considered as limiting the scope of the systems and methods discussed herein.

EXAMPLES

Example 1 : Detailed production process of the formulations

The production of two formulations of aliskiren is described below. The production process for all the formulations in the following Examples is essentially as described in Figure 1 and in this Example 1.

A. A formulation of aliskiren including PVP-12

Production of the hydrophilic fraction

To a beaker containing 100 mL water the following ingredients were slowly added one by one (with 2-3 minutes mixing between each ingredient or until a clear solution was obtained): 10.08g aliskiren hemifumarate (content 99.2%), 10.00 g of PVP-12 and 15.00 g of sodium octanoate. The solution was mixed for another 5 min and then transferred into a stainless steel lyophilization tray. The tray was frozen at -80°C for 1.5-2h and then lyophilized for about 24 h. This procedure produced about 35 g of the hydrophilic fraction.

Production of the hydrophobic medium:

2.2 g Tween 80, 4.4 g of glyceryl monocaprylate, and 64,0 g of glyceryl tricaprylate were mixed together. This procedure produced about 70 g of hydrophobic (lipophilic) medium. Production of the bulk drug product: Mixing of the liydrophilic fraction and the hydrophobic medium was performed using a mortar. 57.8 g of hydrophobic medium was poured into the mixing bowl. 32.2 g of the hydrophilic fraction was slowly added while mixing. After addition of the entire hydrophilic fraction, the suspension was mixed for about lh until a smooth viscous suspension was obtained, which was stored below 25°C. This is formulation I in Table B in Example 4.

B. A formulation of aliskiren including PVA

PVA of molecular weight 27000 Da was obtained from Aldrich. It was virtually completely hydrolyzed (~98-99%).

Production of the hydrophilic fraction:

To a beaker containing 100 mL water, 2.00g of PVA was added while stirring. The mixture was heated to about 60°C. After all the PVA was dissolved, the solution was cooled to RT and 15.00 g of sodium octanoate was added while mixing. After the sodium octanoate was dissolved, 10.08 g of aliskiren hemifumarate (content 99.2%) was added while mixing. The tray was frozen at -80°C for 1.5-2h and then lyophilized for about 24 h. This procedure produced about 27 g of hydrophilic fraction.

Production of the hydrophobic medium: 2.2 g Tween 80, 4.4 g of glyceryl monocaprylate, and 73.0 g of glyceryl tricaprylate were mixed together. This procedure produced about 80 g of hydrophobic medium.

Production of the bulk drug product: Mixing of the hydrophilic fraction and the hydrophobic medium was performed using a mortar. 65.1 g of the hydrophobic medium was poured into the mixing bowl and 24.9 g of the hydrophilic fraction was slowly added while mixing. After addition of the entire hydrophilic fraction, the suspension was mixed for about lh till a smooth viscous suspension/ semi-solid was obtained, which was stored below 25°C. This is formulation V in Table B in Example 4.

Example 2; Animal models for testing the bioavailability of a range of different formulations containing a variety of active ingredients In order to test the capability of the formulation platform, the bioavailability of formulations containing different cargo compounds or active ingredients (APIs) was tested in the following animal model: jejunal administration to conscious (non- anesthetized) rats.

To test the bioavailability of formulations in the jejunum of conscious rats, a specialized rat model was established in which two different cannulas are surgically implanted in male Sprague-Dowley rats (other rats may also be used):

1- jejunal cannula to bypass the stomach and enable direct formulation administration to the jejunum; and

2- jugular vein cannula to determine the systematic levels of the administered dextran following jejunal administration.

Rats were allowed to recover for 4 days before the study and were deprived of food for 18 hours before the start of the study.

Formulation containing API was administered to the jejunum of conscious rats, as described above, and separately saline solution containing API was administered

intravenously or subcutaneously as reference. Blood samples were drawn from the jugular vein at an appropriate series of times post jejunal administration and post IV administration,

(or post SC administration), plasma was prepared and levels of active ingredient were determined in each sample. The average absolute Bioavailability (aBA) achieved after jejunal administration of the formulation was calculated as described below.

Exposure values, AUC (0-T), are calculated from the area under the serum concentration versus time curve (AUC) and are determined for jejunal and intravenous administration (or

SC administration). T= final time at which measurement was made.

The absolute Bioavailability (aBA) is determined according to the following equation:

aBA= (jejunal AUC _(0-T) )/ (iv AUC _(0-T) ) )* (iv dose/ jejunal dose)

The relative Bioavailability (rBA) is determined according to the following equation rBA = Gejunal AUC _(0-T ) /SC AUC _(0-T) ) * (SC dose/ jejunal dose)

Data is normally presented as Mean ± SD (n > 5 rats per group). Example 3: Formulation for dextran

A formulation containing FD4 (Sigma) was made essentially as described in Example 1, except that the ingredients listed below in Table A were used. The Carbopol (obtained from Lubrizol) has to be neutralized (unlike the PVP-12 and the PVA). The FD4 is FITC-labeled dextran with an average MW of 4.4kDa.

The formulation containing FD4 was tested as described in Example 2, and, as indicated, the absolute BA for FD4 was 12.5%. A formulation similar to Formulation I (see Example 1 and Table B in Example 4) with FD4 from the same lot gave BA of 12.0%±7.2%, N=6.

Example 4: Formulations for aliskiren

Various formulations of aliskiren (Novartis) were devised as described in Table B below, and all five formulations were prepared. The formulations were prepared essentially as described in Example 1, wherein the ingredients in the hydrophilic fraction and in the hydrophobic medium for each formulation were as listed in Table B. The neutralization step was used only for the Carbopol formulation (Formulation II) and was omitted from the other formulations. Each formulation contains 10% of aliskiren free base.

In Formulation I, a major constituent of the hydrophilic fraction is PVP. The significance of PVP as a structuring element was examined by replacing it with different matrix forming polymers, namely, Carbopol and polyvinyl alcohol (27 kDa PVA) and Formulations II and V respectively. Formulation IV, based on octanoic acid, was made as described for the other four formulations see e.g. Figure 1 and appears to be a semi- transparent liquid, but still a suspension.

The above formulations in Table B were tested for bioavailability in the animal model described in Example 2(i) namely, by jejunal administration to conscious (non-anesthetized) rats. Aliskiren was measured using LC/MS/MS and the bioavailability for each formulation was determined as described. This was then compared with the bioavailability of the unformulated oral aliskiren solution given by gavage, which gave the following results: AUC _(0-240min) /dose/kg =990, CV=53%, N=l 0

These results are shown in the above Table B. All the formulations tested showed an increase in aliskiren bioavailability compared to an unformulated oral solution of aliskiren. Additionally, the 10% P VP formulation, Formulation I, was prepared in two versions, the lyophilized version described above, and a non-lyophilized version I (Formulation I-NL) which gave the following results:

AUC _(0-240min) /dose/kg =1654, CV=122%, N=9, fold from Aliskiren oral solution=1.7

Stability data: Three of the above formulations in Table B, and also Formulation I-NL were tested for stability by incubation at 25°C for two months. The identification of individual impurities and degradants was performed using HPLC. The total IDD results (Impurities and Degradants Determination) were as follows: Formulation I = 4.57%, Formulation III =

7.29%, Formulation IV = 3537%, and Formulation I- NL lost homogeneity after two weeks and could not be measured.

Formulation I was chosen as the candidate on which to base future development, based on stability and bioavailability data.

Example 5: Variation of amount of permeability enhancer and PVP

Permeability enhancer: Medium chain fatty acid salts are key excipients for increased absorption in the formulations of the invention, and in particular sodium octanoate (sodium caprylate) is used. Earlier formulation work done by the inventors showed that bioavailability increased in a linear relationship with the concentration of sodium octanoate (from 3 to 12%). When further increase in sodium octanoate was tested (12, 15 and 18% sodium octanoate) the results clearly demonstrated highest bioavailability at 15% sodium octanoate concentration. All this experiments were performed with different APIs, wherein significantly lower loading was needed (about 0.05 - 0.1% compared to about 10% for aliskiren). The assumption was that probably higher permeability enhancer concentration might be needed for these levels of loading.

In order to verify this, Formulation IA was made, which had increased sodium octanoate concentration (20%) and reduced PVP concentration (2.75%) in order "to make room" for the sodium octanoate ; this formulation resulted in reduction of about 30% in bioavailability compared to Formulation I, as shown in Table C.

PVP: Another consideration was regarding the level of PVP. The API loading must be maintained relatively high in order to achieve therapeutic aliskiren blood concentrations. Thus it could be helpful to try to reduce the level of the matrix forming polymer in order to get more API loading capacity and reduce viscosity of the formulations. This was done with the non-lyophilized (NL) version of Formulation I, Formulation I-NL as shown in Table D. Formulation I-NL- 3% PVP is similar to Formulation I-NL except for reduction in amount of PVP to 3%.

As shown in Table D, the reduction in the amount of PVP resulted in a slight decrease in bioavailability and was therefore not implemented in future formulations.

Example 6: Investigation of polar compounds to replace octanoic acid.

As shown above, the octanoic acid based formulation (Formulation IV in Table B) displayed good bioavailability and prolonged PK profile (which is preferable), but also produced 35.37% total degradants after incubation at 25°C for two months.

In order to try to preserve the bioavailability advantages and improve stability, different polar lipophilic compounds were checked, which were less acidic and less polar than octanoic acid. These lipophilic compounds were glyceryl monocaprylate (GMC), ethyl octanoate, Captex 200 (propylene glycol dicaprylate/dicaprate) and Poloxamers 123, 124 and 181. The formulations were prepared based on Formulation I in Table B wherein the lipophilic (hydrophobic) phase was replaced by one of the compounds above. The formulations were checked for stability and/or bioavailability. The results are shown in Table E below.

These results show that using GMC as lipid phase gives good bioavailability.

Formulations which contained other polar lipophilic compounds were not checked for bioavailability either because there was a lack of stability improvement (ethyl octanoate, Poloxamer 124) or because the formulations were toxic to rats (Poloxamers 123 and

181).The polar lipophilic LFP approach is discussed in Example 9.

Example 7: Effect of different surfactants on bioavailability and stability of the formulations

Most of the formulas of the invention are a suspension of hydrophilic particles in a lipophilic (hydrophobic) medium. When the formulation is placed into the GI environment, it is exposed to an aqueous medium and an emulsion presumably will form. The properties of the emulsion, including the absorption ability, should be strongly linked to the properties of the surfactant blend. Several experiments were designed in order to optimize the surfactants in order to produce higher bioavailability/stability. HLB approach. Experiments were performed to optimize the HLB of the surfactants blend using different ratios of lipophilic and hydrophilic surfactants. A combination of Labrafil (HLB 4) and Lutrol F-68 (HLB 29) was used (at 6% overall surfactant concentration) and covered the HLB range from 5.3 to 27.8. These experiments resulted in formulations which were too viscous and had reduced bioavailability.

Bile mimicking. A series of formulations was prepared, based on Formulation I (in Table B) with 6 % lecithin as the single surfactant (replacing GMC and Tween 80) in the hydrophobic medium and with addition of various amounts of sodium taurocholate (Na-TC) to the solid (hydrophilic) phase. The formulations were checked for bioavailability as shown in Table F below.

Table F shows dose- response results for sodium taurocholate (designated Na-TC), and demonstrates that incorporation into the formulations of a bile component (sodium taurocholate) produces an improvement in bioavailability, with a maximum effect at 0.5% sodium taurocholate. Formulation I with 0 .5% Na-TC in the solid (hydrophilic) phase and 6% lecithin as the single surfactant is designated Formulation VI ; see Table J in Example 10 for its detailed composition. A similar sodium taurocholate dose-response experiment was performed using 2% aliskiren in a similar series of formulations but without lecithin; this experiment also demonstrated that a formulation comprising 0.5% Na-TC in the solid (hydrophilic) phase gave the highest bioavailability, in this case a 5.6 fold increase over gavage.

The stability of two of the formulations in Table F, Formulation I and Formulation VI (having 0.5% Na-TC, 6% lecithin) was then investigated. The formulations were maintained at 25°C for 4 weeks and at 40°C for 4 weeks and analyzed for degradants; see Example 8. The results of the two formulations were very similar and demonstrated that incorporation of lecithin and sodium taurocholate had no significant effect on stability.

Other surfactants: Surfactants that are blends of several components and include PEG- based were investigated (e.g. labrasol). The formulations were found not to be stable.

Incorporation of Lutrols (F-68, F-127) produced formulations with inferior bioavailability compare to 6% lecithin.

Thus the formulation with the best bioavailability was modified Formulation I, containing 0.5% sodium taurocholate in the solid form and 6% lecithin as sole surfactant in the hydrophobic medium, and this formulation was designated Formulation VI; see detailed composition of this formulation in Table J, in Example 10. Formulation VI was used as a basis for further development.

Example 8: Stability of the aliskiren formulations

Stability of the aliskiren was one of the major concerns in formulation development.

The three most probable reasons for degradant formation were investigated: a) residual water content in the excipient; b) residual acid content in the excipients; and c) metal catalysis:

a) Residual water: The water content of the hydrophilic fraction (HFP) of the formulations is controlled and does not exceed 2%. The only possibility to have additional residual water in the formulation is the water content of the lipidic excipients. Several excipients (GMC, GTC, Tween-80 and octanoic acid) were checked for water content by F titration, and the stability of aliskiren in each excipient was measured at 25 °C and 40°C at intervals up to 2 months. It was found that there was no correlation between water content in the excipient to aliskiren stability in the corresponding excipient.

b) Residual acidity: The correlation between the acid values of several excipients to the stability results was examined. Aliskiren was incubated separately with one of four excipients (octanoic acid, GMC, Tween-80 and GTC) having decreasing acid value, respectively, at 25 °C and at 40°C for up to two months, and the amount of impurities and degradants was measured. It was found that there indeed was a positive correlation between the acidity of the excipient to the destabilization produced by the excipient. In other words, the most acid medium, octanoic acid, produced the most impurities and degradants, while the least acid medium, GTC, produced the least impurities and degradants.

To investigate this point, two GTC based formulations were prepared. This was Formulation I without surfactants and with/without addition of 2% acetic acid. The stability results at 25°C for 4 weeks showed that addition of acidity to the formulation caused significant increase in degradation. Attempts were made to solve this problem by buffering the system, and different bases (organic amines) were added to aliskiren dispersion into GMC (imidazole, niacinamide and N,N-Diisopropylethylamine) or to Formulation I

(niacinamide or ethyl-nicotinate, either to hydrophilic fraction or lipophilic medium or both) without any noticeable stabilization effect. Apparently, residual acidity is not a major degradation source in this type of formulation.

c) Metal catalysis. The effect of residual metals on aliskiren stability was studied. In order to check the quantity of residual heavy metals, Inductively Coupled Plasma (ICP) analysis of the ingredients in Formulation I was performed; these ingredients are sodium octanoate, PVP-12, Tween 80, GMC and GTC. The only suspicious finding was a high boron level found in sodium octanoate. Boron was therefore investigated as a possible aliskiren destabilizer. It was found however, that borate at different pH values did not affect the aliskiren stability in solution.

Example 9: Additional approaches to produce stability of the aliskiren formulations

Following the lack of success of the above investigation (Example 8), the inventors attempted to solve the stability problem in the following ways:

(i) Antioxidants. Several antioxidants were tried in the early stage of the development with GMC based formulations. Antioxidants incorporated in the hydrophilic fraction (0.025% Torlox) or dispersed in the lipophilic medium (0.03% a-tocopherol, 0.02% BFIA) had no stabilizing effect.

(ii) Replacing GMC by GTC. GMC-based formulations showed the best bioavailability but limited stability. GTC-based formulations having GTC as the sole ingredient of the lipophilic phase were made and tested for stability by incubation at 25°C and at 40°C for two weeks, The identification of individual impurities and degradants was performed using HPLC. The total IDD results (Impurities and Degradants Determination) were as follows:

After incubation at 25°C for two weeks Formulation I with GTC only as lipophilic phase had IDD=1.12% and Formulation I with GMC only as lipophilic phase had IDD=1.74%.

After incubation at 40°C for two weeks, Formulation I with GTC only as lipophilic phase had IDD=3.04% and Formulation I with GMC only as lipophilic phase had IDD=7.01%.

(iii) Polar non hydroxylic substitutes for GTC in the lipophilic (hydrophobic) medium. GMC based formulations of the invention were shown to have the best bioavailability but limited stability, probably because of the high content of hydroxides. Therefore, it was decided to try to identify a polar, continuous phase that would give similar bioavailability without harming stability. Ethyl octanoate, Captex 200 (propylene glycol

dicaprylate/dicaprate) and Poloxamers 123 and 181 were all investigated as the lipid phase of formulations of the invention. There was no improvement in stability results in all three formulations. Moreover, there was no improvement in bioavailability i.e. the bioavailability was less than the corresponding formulation with GMC (see for example Table E above).

(iv) Metal salts. Different salts of divalent cations (magnesium, calcium and zinc compounds) were incorporated into the hydrophilic fraction of Formulation I (lipophilic medium GTC only) and of Formulation VI; different salt concentrations ( 1 :1 or 1 :2 molar ratio of aliskiren: stabilizer) were tested. They were then tested for stability by incubation at 25° for four weeks and at 40° for two weeks. The identification of individual impurities and degradants was performed using HPLC. The total IDD results (Impurities and Degradants Determination) were as follows, for 25° and for 40°, respectively: Formulation I alone = 2.00% and 2.80%; Formulation I plus 3.0% zinc acetate =0.74% and 1.95%; Formulation I plus 1.6 % magnesium chloride = 1.30% and 4.76%; Formulation VI plus 1.6 % magnesium chloride = 0.9% and 6.12%; Formulation VI plus 2.23 % zinc chloride = 1.17% and 5.59%; Formulation VI plus 4.47 % zinc chloride = 0.90% and 2.71 %; Formulation VI plus 1.82 % calcium chloride = 1.23% and 4.96%; Formulation VI plus 3.0% zinc acetate = 0.50%» and 2.21%; and Formulation VI plus 6.0% zinc acetate = 0.30% and 1.92%.

Addition of the following salts was also examined: ferrous acetate, ferric citrate and sodium acetate. There was no improvement in stability. Thus formulations containing zinc acetate showed the best stability. Following the encouraging stability results, several formulations of the above formulations were checked for bioavailability, and some of the results are shown in Table G below.

(v) Amino acids. The inventors postulated that amino acids (e.g. glycine, aspartic acid and arginine) might be used as stabilizers. Glycine (1.23%), arginine (2.86%) and aspartic acid (2.2%), were each added separately to the hydrophilic fraction of Formulation VI. These formulations and also Formulation VI without amino acid were tested for stability by incubation at 25°C for one week and at 40°C for one week. The identification of individual impurities and degradants was performed using HPLC The total IDD results (Impurities and Degradants Determination) were as follows for 25° and for 40° respectively: Formulation VI alone = 0.62% and 3.55%; Formulation VI plus glycine =0.44% and 2.93% ; Formulation VI plus arginine =0.36% and 1.59 %; and Formulation VI plus aspartic acid=0.66% and 5.02%. Guanidine was also tested but had no significant effect on stability.

Based on these results, higher arginine concentrations in Formulation VI were investigated for stability. The total IDD results at 25°C for 4 weeks and at 40°C for two weeks, respectively, were as follows: Formulation VI alone = 0.90 % and 6.12%;

Formulation VI plus 2.86% arginine = 1.07% and 3.57%; Formulation VI plus 5.72% arginine = 1.00 % and 3.27%. Arginine-containing formulations of the invention were then tested for bioavailability, and the results are shown in Table H. Table H

As the results in Table H above demonstrate, the formulations containing arginine have bioavailability. (vi) Combination formulations. Combination formulations are formulations including both metal salts and amino acids. Since arginine-containing formulations and ZnAc ₂ containing formulations (above) show significant decrease in degradant formation, it was decided to try to make combination formulations. Making the hydrophilic fraction including both Zn acetate and arginine was found to be problematic since sticky sediment formed during manufacture. Finally, a combination Zn acetate/arginine formulation was made which contained 3% Zn acetate/ 2.86% arginine, and it was prepared using two different hydrophilic fractions:

• 1 ^st hydrophilic fraction: Half the amount of aliskiren, half the amount of sodium taurocholate, all the PVP and all the Zn acetate were dissolved in half the amount of water, frozen and lyophilized.

• 2 ^nd hydrophilic fraction: Half the amount of aliskiren, half the amount of sodium taurocholate, all the sodium octanoate and all the arginine were dissolved in half the amount of water, frozen and lyophilized After lyophilization, both hydrophilic fractions were mixed together into the lipophilic medium to produce one bulk drug product.

The stability results were as follows: Incubation at 25°C for 3 months, IDD = 0.40%; incubation at 40°C for 4weeks, IDD = 0.79%; incubation at 4°C for 2 month, IDD = 0.08%. Thus this combination formulation is very stable, but on testing in the animal model this formulation was found to have low bioavailability, and showed no improvement over gavage.

Other combinations were made with arginine: magnesium acetate (using two different concentrations of both arginine and magnesium acetate), and calcium acetate. Other metal salts did not form the precipitation seen with zinc salts and could be made in the regular manner (producing one hydrophilic fraction), but a combination of other metal salts with arginine did not give such marked stability improvement as the combination formulation of zinc acetate/arginine.

(vii) Other approaches tested. Several additional approaches were tried in order to improve stability of the formulations. These approaches included: dry granulation instead of lyophilization (to reduce exposure of the aliskiren to water) and use of glycerol (addition as stabilizer to HFP or to LFP, or coating of HPF powder with glycerol before mixing with LFP). All these efforts did not result in any noticeable stabilization effect.

(iix Temperature effect. During the stability program, it was noticed that the degradation level at 40°C is not in line with the stability results at 25°C. It seems that degradation at 40°C is much higher than might be expected. Therefore, several formulations were investigated to explore the effect of incubation at 2-8°C. The results clearly indicated, that in each single formulation tested at refrigerator temperatures (2-8°C), no significant degradants formed even after 2 months of storage. The results of stability experiments at 4°C are as follows: Formulation VI, IDD = 0.15% at 4 weeks

Formulation VI-Ζη (Formulation VI with 3 ,0% zinc acetate), IDD = 0.10% at 2 months Formulation VI-Arg (Formulation VI with 5.72% arginine), IDD = 0.67% at 2 months

Example 10: Three aliskiren formulations Based on a combination of bioavailability and stability results, three key formulations were noted:

• Formulation VI: This was derived from Formulation I, with 0.5% sodium

taurocholate in the hydrophilic fraction and 6% lecithin instead of Tween/GMC in the lipophilic medium.

• Formulation VI-Ζη: Formulation VI with 3.0% zinc acetate as stabilizer

• Formulation VI-Arg: Formulation VI with 5.72% arginine as stabilizer.

For clarity, the composition of these three formulations is as shown in Table J:

In the process of arriving at these key formulations, 140 complete formulations of the invention were prepared (not including pre-formulation work when stability of the akiskiren was tested against various excipients). 65 of the formulations were tested in rats.

Having thus described several aspects of at least one embodiment, it is to be appreciated that various alterations, modifications, and improvements will readily occur to those skilled in the art. Such alterations, modifications, and improvements are intended to be part of this disclosure and are intended to be within the scope of the invention, Accordingly, the foregoing description and drawings are by way of example only, and the scope of the invention should be determined from proper construction of the appended claims, and their equivalents.