CA2807374A1

CA2807374A1 - Aliskiren in form of a solid dispersion

Info

Publication number: CA2807374A1
Application number: CA2807374A
Authority: CA
Inventors: Ralph Stefan; Dominique Meergans
Original assignee: Ratiopharm GmbH
Current assignee: Ratiopharm GmbH
Priority date: 2010-04-21
Filing date: 2011-04-19
Publication date: 2011-10-27
Also published as: EP2382967A1; EP2590627A1; WO2011131348A1

Abstract

The invention relates to an intermediate, containing Aliskiren and substrate, wherein the Aliskiren is present in the form of a solid dispersion. The invention further relates to methods of producing a solid dispersion of Aliskiren base and pharmaceutical formulations containing Aliskiren in the form of a solid dispersion.

Description

Aliskiren in Form of a Solid Dispersion Background The invention is related to an intermediate, containing Aliskiren as a free base and a substrate, the Aliskiren being present in form of a solid dispersion. The invention further relates to methods of producing a solid dispersion of Aliskiren base and pharmaceutical formulations, especially tablets, containing Aliskiren base in form of a solid dispersion.

Aliskiren (IUPAC name: (2 S,4 S ,5 S,7S)-5-amino-N-(2-carbamoy1-2-methyl-propy1)-4-hydroxy-7- [4-methoxy-3 -(3 -methoxypropoxy)phenyl] methy11-8-methy1-2-propane-yl-nonanamide) is reported to be a direct renin inhibitor. Aliskiren is currently employed as a medicament for hypertension and is marketed by Novartis under the brand name TEKTURNA'. Aliskiren has the following chemical structure, formula (I):

CH, o H 3 C CH
OH H HC CH

133 C 0 41111H 3c CH, formula (I) A method of synthesising Aliskiren in form of the hemifumarate salt is described in EP
0 678 503 Al. It has, however, become clear that Aliskiren, especially in the form of the hemifumarate salt, is difficult to formulate, because crystalline Aliskiren is hygroscopic, amongst other properties, and exhibits poor flowability, cf. WO 2005/089729 A1. For this reason, amorphous Aliskiren has also been proposed in WO 2009/64479 A1.
One problem in this context, however, is that the stability, compared to the crystalline state, is disadvantageous (cf. WO 2005/089729 Al, p. 2).

The objective of the present invention was therefore to overcome the above-mentioned disadvantages. The intention is to provide the active agent in a form possessing good flowability and allowing good compression into tablets. It is also the intention to pro-vide the active agent in a form, which does not have a tendency to agglomerate. In ad-dition, it is intended to enable an even distribution of the active agent. It is intended to avoid micronisation of the active agent in order to avoid the disadvantages usually associated with micronisation.

In addition, the intention is to provide Aliskiren in a form that makes it possible to achieve a high level of uniformity of the content (content uniformity), especially with a high content of active agent (drug load).

While developing Aliskiren formulations, the inventors of the present application were also confronted with the fact that crystalline Aliskiren hemifitmarate - as described in WO 2009/064479 - can exist in different polymorphic forms. The different polymorphs are not stable, however, but have a tendency to convert into other polymorphs, for example under the influence of heat or in a moist environment. Moreover, the different polymorphic forms have different dissolution profiles.

In a patient, the different dissolution profile leads to an undesirable, uneven rise in the concentration of the active agent. It was therefore an objective of the present invention to provide Aliskiren in a form enabling as even a rise as possible in the concentration in the patient. The aim was to avoid both inter-individual and also intra-individual devi-ations to a great extent.
The intention is also to provide the active agent in a form, which possesses good solu-bility and good bioavailability with good storage stability at the same time.

Summary of the invention According to the invention, the above objectives are achieved by providing Aliskiren in the form of a solid dispersion, with Aliskiren being used not as a pharmaceutically acceptable salt, but rather in the form of the free base.

The subject matter of the invention is therefore an intermediate, containing Aliskiren and substrate material, the Aliskiren being present in the form of a solid dispersion and preferably being used not as a pharmaceutically acceptable salt, but rather as a free base.
This intermediate of the invention is a solid dispersion of Aliskiren, especially Aliskiren base, in stabilised form.
The subject matter of the invention is also various methods of producing a solid disper-sion of Aliskiren base in the form of the intermediate of the invention.

Finally, the subject matter of the invention also comprises pharmaceutical formulations containing the Aliskiren base of the invention in form of a solid dispersion or in form of the intermediate of the invention.

Detailed description of the invention The term "solid dispersion" may be understood in the context of this invention as Aliskiren base being distributed on and/or in a substrate, which is preferably present in a solid aggregate state at 25 C.

In a preferred embodiment, Aliskiren base can be distributed substantially homogeneously on and/or in the substrate. This conventionally means that intermediates of this preferred embodiment exhibit a content uniformity with a standard deviation of <
6% (i.e. 94 % to 106 %). An embodiment is particularly preferred which is characterised by a content uniformity with a standard deviation of < 3 % (i.e.
97 % to 103 %). The "content uniformity" is determined in accordance with Ph. Eur.
6.0, section 2.9.6.

This intermediate of the invention is thus a solid dispersion of Aliskiren base in stabil-ised form.

In the intermediate of the invention, Aliskiren base can be applied to and/or deposited in the substrate. The expression "applied to" in this context means bound to the surface of the substrate by physicochemical interactions, such as van der Waals forces, hydrogen bonds, or charge transfer interactions. The expression "deposited in" in this context means (at least partially) enclosed in the interior of the substrate structure by physico-chemical interactions, such as van der Waals forces, hydrogen bonds, or charge transfer interactions. It is preferable that at least 50 %, more preferably at least 70 %, even more preferably at least 90 %, especially at least 95 % of the substrate are wetted with Aliski-ren base.

The Aliskiren base applied to the substrate and/or deposited in the substrate may be present in liquid or solid form. Aliskiren is preferably present in the intermediate of the invention in solid form.

Alternatively, the term "solid dispersion" may be understood in the context of this invention as Aliskiren base, stabilized on a solid support.

Also alternatively the term "substrate" may be understood in the context of this invention as material used as solid support.

It is further preferred that the intermediate of the invention (containing Aliskiren base in the form of a solid dispersion) contains substantially no crystalline Aliskiren. In particu-lar, the intermediate of the invention contains less than 15 % by weight, more preferably less than 5 % by weight, of crystalline Aliskiren base, based on the total weight of the Aliskiren base present in the intermediate.
In particular, the intermediate of the invention consists substantially of disperse Aliski-ren base and substrate. If - as described below - a crystallisation inhibitor is used in addition, the intermediate of the invention may consist substantially of molecularly disperse Aliskiren base, substrate and crystallisation inhibitor. The word "substantially"
in this case indicates that small amounts of solvent etc. may also be present where applicable.

The substrate is generally a substance which is capable of stabilising Aliskiren base in form of a solid dispersion, especially by acting as a support and/or enclosing it. The substrate is preferably a polymer or an inorganic material. In addition, the substrate also includes substances which behave like polymers.

In a preferred embodiment, the substrate is a substance, which can be non-water-soluble. The non-water-soluble substrate is generally a pharmaceutical excipient specified in the European Pharmacopoeia which exhibits a water-solubility of less than 50 mg/1, measured at 25 C, more preferably of 25 mg/ml or less, even more preferably of 5 mg/ml or less, especially 0.01 to 4 mg/1 . Water-solubility is generally determined using the column elution method in accordance with EU Directive DIR 67-548 EEC, Annex V, Chap. A6.
In a further preferred embodiment, the substrate can be a brittle substrate.
Pharmaceutical excipients (for example substrates) can generally be classified with regard to the change in the shape of the particles under compression pressure (compaction): plastic excipients are characterised by plastic deformation, whereas when compressive force is exerted on brittle excipients, the particles tend to break into smaller particles. Brittle behaviour on the part of the substrate can be quantified by the increase in the surface area in a moulding. In the art, it is customary to classify the brittleness in terms of the "yield pressure". According to a simple classification, the values for the "yield pressure" here are low for plastic substances but high in the case of friable substances on the other hand (Duberg, M., Nystrom, C., 1982, "Studies on direct compression of tablets VI. Evaluation of methods for the estimation of particle fragmentation during compaction.", Acta Pharm. Suec. 19, 421-436; Humbert-Droz P., Mordier D., Doelker E., "Methode rapide de determination du comportement à la compression pour des etudes de preformulation", Pharm. Acta Hely., 57, 136-143 (1982)). The "yield pressure" describes the pressure that has to be reached for the excipient (i.e. preferably the substrate) to begin to flow plastically.

The "yield pressure" is preferably calculated using the reciprocal of the gradient of the Heckel plot, as described in York, P., Drug Dev. Ind. Pharm. 18, 677 (1992).
The meas-urement in this case is preferably made at 25 C and a deformation rate of 0.1 mm/s.

In the context of the present invention, an excipient (especially a substrate) is deemed a non-brittle excipient if it has a "yield pressure" of no more than 120 MPa, preferably no more than 100 MPa, particularly preferably 5 to 80 MPa. An excipient is usually de-1 0 scribed as a brittle excipient if it has a "yield pressure" of more than 80 MPa, preferably more than 100 MPa, particularly preferably more than 120 MPa, especially more than 150 MPa. Brittle excipients may exhibit a "yield pressure" of up to 300 MPa or up to 400 MPa or even up to 500 MPa.

Examples of non-brittle substrates are mannitol or starch.

Examples of brittle substrates are microcrystalline cellulose or calcium hydrogen phosphate, silicates or aluminosilicates. Especially preferred are fumed silica, for example, Aerosil 200, or magnesium aluminosilicate, for example, Neusilin .
Neusilin can be represented by the empirical formula A1203-Mg0.1.7SiO2xH20.
Preferably, a substrate, more preferably a brittle substrate, for example fumed silica, with a specific surface of 50 to 400 m2/g, more preferably 150-250 m2/g, is used, wherein the specific surface is preferably determined by gas adsorption according Ph.Eur., 6th edition, chapter 2.9.26.
Brittle substrates are preferably used in the preparation of the intermediate of the invention.

In a further preferred embodiment, the substrate is a swellable substrate. The swellable substrate is preferably a swellable polymer or a swellable substance with polymer-like properties. The swellable substrate preferably has a swelling index of 1.2 to 6.0, prefer-ably 1.5 to 4.5, more preferably 2.0 to 4Ø The swelling index indicates the volume in millilitres which 1 g substance, including any mucilage that may be adhering to it, oc-cupies after swelling in an aqueous solution for 4 hours. The swelling index is deter-mined in accordance with Ph. Eur. 4th edition, Chapter 2.8.4.

It is especially preferred that the substrate is a brittle and non-water-soluble or a brittle, non-water-soluble and swellable substrate.

In addition, the substrate used for the preparation of the intermediate of the invention may be a polymer which preferably has a glass transition temperature (Tg) higher than 20 C, more preferably 25 C, especially 35 C. A polymer with an appropriately se-lected glass transition temperature causes immobilisation, which prevents the reversion of the Aliskiren base dispersion into larger, and hence no longer dispersely distributed particles.

The term "glass transition temperature" (Tg) is used to describe the temperature at which amorphous or partially crystalline polymers change from the solid state to the liquid state. In the process, a distinct change in physical parameters, for example hardness and elasticity, occurs. Below the glass transition temperature, a polymer is usually glassy and hard, whereas above the glass transition temperature, it changes into a rubber-like to viscous state. The glass transition temperature is determined in the context of this invention by means of dynamic differential scanning calorimetry (DSC).

For this purpose a Mettler Toledo DSC 1 apparatus can be used. The work is performed at a heating rate of 1-20 C/min, preferably 5-15 C/min, and at a cooling rate of 5-C/min, preferably 10-20 C/min.

In addition, the polymer to be used for the preparation of the intermediate preferably has 20 a weight-average molecular weight of 1,000 to 500,000 g/mol, more preferably from 2,000 to 90,000 g/mol. The weight-average molecular weight is preferably determined in the context of this application by means of gel permeation chromatography.
When the polymer used in the preparation of the intermediate is dissolved in water in an amount of 2 % by weight, the resulting dispersion preferably has a viscosity of 0.1 to 18 mPaxs, 25 more preferably 0.5 to 15 mPaxs, especially 1 to 8 mPaxs, measured at 25 C and preferably determined in accordance with Ph. Eur. 6.0, Chapter 2.2.10.

Hydrophilic polymers are preferably used for the preparation of the intermediate. This means polymers which possess hydrophilic groups. Examples of suitable hydrophilic groups are hydroxy, alkoxy, acrylate, methacrylate, sulphonate, carboxylate and quater-nary ammonium groups. Hydroxy groups are preferred.

The intermediate of the invention may, for example, comprise the following hydrophilic polymers as the substrate: polysaccharides, such as hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC, especially sodium and calcium salts), methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC); microcrystalline cellulose, polyvinyl pyrrolidone, polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, vinyl pyrrolidone-vinyl acetate copolymers (such as Kollidon VA64, BASF), polyalkylene glycols, such as polypropylene glycol or preferably polyethylene glycol, co-block polymers of polyethylene glycol, especially co-block polymers of polyethylene glycol and polypropylene glycol (Pluronic , BASF), polyethylene oxide and mixtures of the polymers mentioned.

Preferable substances used as substrates are polyvinyl pyrrolidone, preferably with a weight-average molecular weight of 10,000 to 60,000 g/mol, especially 12,000 to 40,000 g/mol, a copolymer of vinyl pyrrolidone and vinyl acetate, especially with a weight-average molecular weight of 40,000 to 70,000 g/mol and/or polyethylene glycol, especially with a weight-average molecular weight of 2,000 to 10,000 g/mol, and HPMC, especially with a weight-average molecular weight of 20,000 to 90,000 g/mol and/or preferably a content of methyl groups of 10 to 35 % and a content of hydroxy groups of 1 to 35 %. In addition microcrystalline cellulose can preferably be used, especially one with a specific surface area of 0.7 - 1.4 m2/g. The specific surface area is determined by means of the gas adsorption method according to Brunauer, Emmet and Teller.

Furthermore, the substrate also includes solid, non-polymeric compounds which prefer-ably contain polar side groups. Examples of these are sugar alcohols or disaccharides.
Examples of suitable sugar alcohols and/or disaccharides are mannitol, sorbitol, xylitol, isomalt, glucose, fructose, maltose and mixtures thereof. The term "sugar alcohols" in this context also includes monosaccharides. In an alternative embodiment, cyclodextrins can be used, for example alpha-cyclodextrin, beta-cyclodextrin or gamma-cyclodextrin.

In principle, all mixtures of the substrates mentioned are also possible.
Silicates, more preferably magnesium aluminosilicates and most preferably A1203=Mg0-1.7Si02-xH20, are used as particularly preferred substrates.

It is advantageous for the substrate to be used in particulate form, the average particle diameter (D50) of the substrate particles being 1 to 250 mm, preferably 10 to 200 m, more preferably 40 to 150 pm. The expression "average particle diameter"
always relates in the context of this invention to the D50 value of the volume-average particle diameter determined by means of laser diffractometry. In particular, a Malvern Instru-ments Mastersizer 2000 was used to determine the diameter (wet measurement with ultrasound for 60 sec., 2,000 rpm, the evaluation using the Fraunhofer method, and preferably using a dispersant in which the substance to be measured does not dissolve at 20 C). The average particle diameter, which is also referred to as the D50 value of the integral volume distribution, is defined in the context of this invention as the particle diameter at which 50 % by volume of the particles have a smaller diameter than the diameter which corresponds to the D50 value. Similarly, 50 % by volume of the parti-cles then have a larger diameter than the D50 value.

In a preferred embodiment, the intermediate of the invention contains Aliskiren base and substrate, the weight ratio of Aliskiren base to substrate being 10 : 1 to 1 : 10, more preferably 5 : 1 to 1 : 5, especially 3 : 1 to 1 : 3.

It is preferable that that type and quantity of the substrate and the quantity of the Aliski-ren base should be selected such that the resulting intermediate has a glass transition temperature (Tg) of more than 20 C, preferably more than 30 C. Furthermore, the glass transition temperature of the intermediate should not be higher than 260 C, pref-erably below 210 C.

In a preferred embodiment, in addition to Aliskiren base and substrate, the intermediates of the invention can also contain a crystallisation inhibitor based on an inorganic salt, an organic acid or a high-molecular-weight polymer with an average molecular weight of more than 500,000 g/mol.

These polymers, which are suitable as crystallisation inhibitors, are also referred to in the context of this invention as "high-viscosity polymers". Their weight-average molecular weight is usually less than 5,000,000 g/mol. A preferred high-viscosity polymer is povidone.

The crystallisation inhibitor is preferably ammonium chloride, citric acid or Povidone K

90 (in accordance with Ph. Eur. 6.0).

The crystallisation inhibitor can generally be used in an amount of 0 to 30 %
by weight, preferably 2 to 25 % by weight, more preferably 5 to 20 % by weight, based on the total weight of the intermediate.

The intermediates of the invention are obtainable by a variety of preparation methods.

Depending on the preparation method, the intermediates are obtained in different parti-cle sizes. Normally, the intermediates of the invention are present in particulate form and have an average particle diameter (D50) of 10 to 350 pm, depending on the prepa-ration method concerned.

The subject matter of the invention is also a method of preparing an intermediate con-taining Aliskiren and substrate, wherein Aliskiren base is present as a solid dispersion, comprising the steps of (a) dissolving Aliskiren base in a solvent or mixture of solvents, and con-tacting the solution with substrate, (b) removing the solvent or mixture of solvents, (c) optionally granulating the mixture obtained in step (b).

In step (a) Aliskiren base is dissolved, preferably completely dissolved, in a solvent or mixture of solvents and contacted with the substrate. The substrate described above is preferably likewise suspended or dissolved, preferably suspended, in this solvent or mixture of solvents (i.e. containing Aliskiren base). The Aliskiren base and substrate are thus preferably contacted in a solvent or mixture of solvents. Where necessary, this can be done accompanied by stirring, for example for 1 minute to 1 hour.

Suitable solvents are, for example, water, alcohol (for example methanol, ethanol, isopropanol), dimethyl sulphoxide (DMSO), acetone, butanol, ethyl acetate, heptane, pentanol, chlorinated solvent (for example dichlormethane, chloroform) or mixtures thereof. Preferably, the solvent is ethanol or a mixture of water and alcohol, preferably ethanol, the weight ratio of alcohol : water being especially 50 : 50 to 99 :
1.

In an alternative embodiment, step (a) may also be arranged such that the Aliskiren base solution is applied to the substrate, such as by spraying.
In the subsequent step (b), the solvent or mixture of solvents is removed. The removal of the mixture of solvents may, for example, be achieved by raising the temperature (for example 50 to 150 C) and/or by reducing the pressure (for example 0.001 to 0.9 bar).

In a preferred embodiment, the solution, or preferably the suspension, from step (a) is spray-dried in step (b). The spray-drying can be carried out in a spray tower.
As an example, a Bilchi B-191 is suitable (Biichi Labortechnik GmbH, Germany).
Preferably an inlet temperature of 50 C to 150 C, more preferably 70 C to 130 C, is chosen.
The amount of air is, for example, 500 to 700 litres/hour, and the aspirator preferably runs at 80 to 100 %. In an alternative embodiment, the solution, or preferably the sus-pension, from step (a) is freeze-dried in step (b).

After the solvent has been removed, the mixture obtained in step (b) can be granulated, where applicable, in the optional step (c). The granulation may preferably also take place during removal of the solvent, i.e. steps (b) and (c) may be performed simulta-neously.

Steps (b) and (c) can preferably be performed in a fluidised bed granulator, such as a Glatt GPCG 3 (Glatt GmbH, Germany). Work is preferably performed with air inlet temperatures of 60 C to 80 C, with product temperatures of 30 C to 40 C
and with a spray pressure of 1 to 1.5 bar.

In accordance with the above alternative embodiment, an Aliskiren base solution may be applied to (for example sprayed on) the substrate particles while they are located in the fluidised bed, i.e. steps (a), (b) and (c) may be performed simultaneously.

The intermediate of the invention (i.e. Aliskiren base of the invention in the form of a solid dispersion) can be employed to prepare a pharmaceutical formulation.
This is preferably a pharmaceutical formulation for oral administration, especially in the form of a tablet.

The subject matter of the invention is therefore a pharmaceutical formulation containing intermediate of the invention and pharmaceutical excipients.

These are the excipients with which the person skilled in the art is familiar, such as those, which are described in the European Pharmacopoeia.

Examples of excipients used are disintegrants, anti-sticking agents, emulsifiers, pseudo-emulsifiers, fillers, additives to improve the powder flowability, glidants, wetting agents and/or lubricants. Where appropriate, further excipients can also be used.

The ratio of active agent to excipients can preferably be selected such that the resulting formulations contain 10 to 90 % by weight, more preferably 20 to 70 % by weight, especially 35 to 55 % by weight Aliskiren base, and 10 to 90 % by weight, more preferably 30 to 80 % by weight, especially 45 to 65 % by weight pharmaceutically acceptable excipients.

In these ratios specified, the amount of substrate optionally used to prepare the interme-diate of the invention can be counted as an excipient. This means that the amount of active agent refers to the amount of Aliskiren base contained in the formulation.

It has been shown that the intermediates of the invention can be suitable for serving both as a basis for a dosage form with immediate release (or "IR" for short) and also with modified release (or "MR" for short) .In a preferred embodiment for an IR

formulation, a relatively large amount of disintegrant can be used. In that preferred embodiment, the pharmaceutical formulation of the invention therefore can contain 5 to 30 % by weight, more preferably 10 to 25 % by weight, especially 12 to 22 % by weight disintegrant, based on the total weight of the formulation.

"Disintegrants" is the term generally used for substances, which accelerate the disinte-gration of a dosage form, especially a tablet, after it is placed in water.
Suitable disintegrants are, for example, organic disintegrants such as carrageenan, croscarmellose and crospovidone. Alkaline disintegrants are likewise used. The term "alkaline disintegrants" means disintegrants, which, when dissolved in water, produce a pH level of more than 7Ø

More preferably, inorganic alkaline disintegrants are used, especially salts of alkali and alkaline earth metals. Preferred examples here are sodium, potassium, magnesium and calcium. As anions, carbonate and/or hydrogen carbonate, for example, are preferred.
Examples are sodium hydrogen carbonate, sodium hydrogen phosphate, calcium hydro-gen carbonate and the like.

Sodium hydrogen carbonate can particularly preferably be used as a disintegrant, especially in the above-mentioned amounts.

In a preferred embodiment for an MR formulation, a relatively small amount of disin-tegrant is used. In that preferred embodiment, the pharmaceutical formulation of the invention therefore can contain 0 to 10 % by weight, more preferably 0.1 to 5 % by weight, especially 1 to 4 % by weight disintegrant, based on the total weight of the formulation.

In the case of the MR formulation, croscarmellose or crospovidone is preferred as the disintegrant.
In addition the conventional retardation techniques can be used for the MR
formulation.

Furthermore, the pharmaceutical formulation (both for IR and for MR) preferably con-tains one or more of the above-mentioned excipients. These will be explained in more detail below.

In a preferred embodiment, the formulation of the invention can contain 0 to 8 % by weight, more preferably 2 to 7 % by weight, especially 4 to 6 % by weight anti-sticking agent, based on the total weight of the formulation. This embodiment can be used especially for the production of tablets. "Anti-sticking agents" are usually understood to mean substances which reduce agglomeration in the core bed. Examples are talcum, silica gel, polyethylene glycol (preferably with 2,000 to 10,000 g/mol weight-average molecular weight) and/or glycerol mono alpha-cyclodextrin stearate.

The formulation of the invention can preferably contain fillers. "Fillers"
generally means substances, which serve, for example, to form the body of the tablet in the case of tablets with small amounts of active agent (for example less than 70 % by weight).
This means that fillers "dilute" the active agents in order to produce an adequate tablet-compression mixture. The normal purpose of fillers, therefore, is to obtain a suitable tablet size.

Examples of preferred fillers are lactose, lactose derivatives, starch, starch derivatives, treated starch, talcum, calcium phosphate, dicalcium phosphate, sucrose, magnesium carbonate, magnesium oxide, maltodextrin, calcium sulphate, dextrates, dextrin, dex-trose, hydrogenated vegetable oil, kaolin, sodium chloride, and/or potassium chloride.
Similarly, microcrystalline cellulose and/or siliconated microcrystalline cellulose (for example obtainable as Pros lv Rettenmaier & Sohne, Germany) can be used as a filler.

Fillers can generally be used in an amount of 0 to 60 % by weight, preferably 10 to 40 %
by weight, especially 15 to 35 % by weight, based on the total weight of the formula-tion.

Further, an additive to improve the powder flowability can be present in the pharmaceutical formulation. One example of an additive to improve the powder flowability can be disperse silicon dioxide. Additives to improve the powder flowability can be used in an amount of 0.1 to 3 % by weight, based on the total weight of the formulation.

Lubricants can be used in addition. Lubricants are generally used to reduce sliding friction. In particular, the intention is to reduce the sliding friction found during tablet pressing between the punch moving up and down in the die and the die wall, on the one hand, and between the edge of the tablet and the die wall, on the other hand.
Suitable lubricants are, for example, stearic acid, adipic acid, sodium stearyl fumarate (Pruv ) and/or magnesium stearate.
Lubricants can generally be used in an amount of 0.1 to 3 % by weight, based on the total weight of the formulation.

In a preferred embodiment, the pharmaceutical formulation of the invention therefore can comprise (i) 50 to 95 % by weight intermediate of the invention, preferably 60 to 90 % by weight intermediate, (ii) 5 to 25 % by weight, preferably 8 to 15 % by weight disintegrant, (iii) 0 to 50 % by weight, preferably 10 to 35 % by weight filler, based on the total weight of the formulation.

In addition, it is preferred that the pharmaceutical formulation of the invention may also contain one or more further active agents. In a preferred embodiment, the pharmaceuti-cal formulation of the invention contains 0.1 to 10 % by weight, more preferably 0.5 to 8 % by weight of a further active agent, based on the total weight of the formulation.
The further active agent can be, for example, an ATI receptor antagonist, ACE
inhibitor, beta blocker, calcium channel blocker, aldosterone synthase inhibitor, aldosterone re-ceptor antagonist or preferably a diuretic. It is particularly preferably hydrochlorothi-azide (HCT, HCTZ or HCZ for short).

The pharmaceutical formulation of the invention can preferably be pressed into tablets.
The intermediates of the invention are therefore pressed into tablets by means of direct compression or are subjected to granulation, for example wet granulation or dry granulation, before being pressed into tablets. Intermediates with a bulk density of less than 0.5 g/ml are preferably processed by dry granulation or wet granulation.

The tabletting conditions are preferably selected such that the resulting tablets have a ratio of tablet height to weight of 0.005 to 0.3 mm/mg, particularly preferably 0.05 to 0.2 mm/mg.

In addition, the resulting tablets preferably have a hardness of 50 to 200 N, particularly preferably 80 to 150 N. The hardness is determined in accordance with Ph. Eur.
6.0, section 2.9.8.
In addition, the resulting tablets preferably have a friability of less than 5 %, particularly preferably less than 2 %, especially less than 1 %. The friability is determined in accordance with Ph. Eur. 6.0, section 2.9.7.

Finally, the tablets of the invention usually have a "content uniformity" of 90 to 110 %
of the average content, preferably 95 to 105 %, more preferably 98 to 102 %, especially 99 to 101 %. The "content uniformity" is determined in accordance with Ph.
Eur.6.0, section 2.9.6.

In the case of an IR formulation, the release profile of the tablets of the invention accor-ding to the USP method (paddle, 0.1 n HC1, 75 rpm) after 10 minutes usually indicates a content released of at least 30 %, preferably at least 60 %, especially at least 80 %.

In the case of an MR formulation, the release profile of the tablets of the invention ac-cording to the USP method (paddle, 0.1 n HC1, 75 rpm) after 60 minutes usually indi-cates a content released of not more than 20 %, preferably not more than 30 %, espe-cially not more than 40 %. Within 8 hours, however, preferably at least 80 %, more preferably at least 90 %, has been released.

The above details regarding hardness, friability, content uniformity and release profile preferably relate here to the non-film-coated tablet for an IR formulation.
For a modi-fied-release tablet, the release profile relates to the total formulation.

The tablets produced by the method of the invention may be tablets which can be swal-lowed unchewed (non-film-coated or preferably film-coated). They may likewise be chewable tablets or dispersible tablets. "Dispersible tablet" here means a tablet to be used for producing an aqueous suspension for swallowing.

In the case of tablets which are swallowed unchewed, it is preferable that they are coat-ed with a film layer. For this purpose, the methods of film-coating tablets, which are standard in the state of the art, may be employed. The above-mentioned ratios of active agent to excipient, however, relate to the uncoated tablet.

For film-coating, macromolecular substances can preferably be used, such as modified celluloses, polymethacrylates, polyvinyl pyrrolidone, polyvinyl acetate phthalate, zein and/or shellack or natural gum, such as carrageenan.

The thickness of the coating is preferably 1 to 100 m, more preferably 5 to 60 m.

Possible dosage forms for the pharmaceutical formulations of the invention for oral administration include tablets, capsules, dispersions, suspensions and similar formula-tions. Tablets are preferred. The dosage of the active agent or the combination of active agents may be varied, for example because of the nature of the disorder to be treated, the severity of the disorder and the dosage form.
In treating the diseases which are indicated for the active agent or the combination of active agents in the formulations of the invention, satisfactory results are usually ob-tained if the active agent Aliskiren contained is administered in a daily dose of 10 mg to 1,000 mg, preferably 50 mg to 600 mg, particularly preferably 75 mg to 300 mg and/or if the optionally contained active agent HCT is administered in a daily dose of 5 mg to 50 mg, preferably 10 mg to 25 mg. In addition, it is preferable for the daily dose to be administered once a day or for the daily dose to be administered spread over two to five doses. In the same doses, applications less than once a day are possible, such as every two, three or four days, for example in a delayed-release formulation. The dosing regi-men may be varied within or even outside this frame in order to achieve the optimum treatment results.

The pharmaceutical formulations of the invention are usually characterised by a release and absorption that lead to advantageous figures for the AUC ("area under curve"), the area under the curve of the plasma level 0 to 48 hours after peroral administration), ad-vantageous figures for the Cmax (maximum plasma level) and advantageous figures for the T. (time when the maximum plasma level is reached after peroral administration).

In a preferred embodiment, the peroral administration of the formulations of the inven-tion to a human patient can lead to a plasma level profile characterised by a Tmax regard-ing the active agent Aliskiren of about 0.5 to 3 hours.

In a preferred embodiment, the peroral administration of the formulations of the inven-tion to a human patient can lead to a plasma level profile characterised by a T. regard-ing the active agent HCT of about 0.5 to 3 hours.
In a preferred embodiment, the peroral administration of the formulations of the inven-tion to a human patient can lead to a plasma level profile characterised by a C. regard-ing the active agent Aliskiren of about 10 to 90 ng/ml, preferably 20 to 80 ng/ml.

In a preferred embodiment, the peroral administration of the formulations of the inven-tion to a human patient can lead to a plasma level profile characterised by a C. regard-ing the active agent HCT of about 100 to 200 ng/ml, preferably 115 to 185 ng/ml.

In a preferred embodiment, the peroral administration of the formulations of the inven-tion to a human patient can lead to a plasma level profile characterised by an AUC re-garding the active agent Aliskiren of about 300 to 1,500 ngxh/ml, preferably 400 to 1,300 ngxh/ml.

In a preferred embodiment, the peroral administration of the formulations of the inven-tion to a human patient can lead to a plasma level profile characterised by an AUC
regarding the active agent HCT of about 500 to 1,500 ngxh/ml, preferably 650 to 1,350 ngxh/ml.

The above-mentioned plasma level figures are preferably average values, obtainable by examining blood samples from a group of 10 candidates (with an average body weight of 70 kg), the corresponding blood samples being taken 0, 1, 3, 4, 6, 8, 24 and 48 hours after the peroral administration of the formulation of the invention. The plasma level figures can preferably be determined by means of appropriate HPLC-MSMS
methods.
The AUC can be calculated by, for example, using a computer program such as the Microsoft Excel program.

In a preferred embodiment, the pharmaceutical formulations of the invention can be used to treat essential hypertension or cardiac insufficiency either as a mono-preparation or in combination with diuretics or ACE inhibitors. It is particularly preferable to treat patient groups in which the therapy with other antihypertensive agents, particularly preferably a monotherapy with diuretics or ACE inhibitors or a combined therapy of diuretics and ACE inhibitors, has not produced satisfactory results.

The subject matter of the invention is thus also a tablet containing 50 to 500 mg Aliski-ren base and optionally 5 to 50 mg HCT, the tablet having a hardness of 50 to 250 N, a friability of less than 5 % and content uniformity of 95 to 105 %, and wherein the ad-ministration regarding the active agent Aliskiren leads to a T. of 0.5 to 3 hours, a Cmax of 10 to 90 ng/ml and an AUC of about 300 to 1,500 ngxh/ml, and wherein, where applicable, the administration regarding the active agent HCT leads to a T. of 0.5 to 3 hours, a Cmax of 100 to 200 ng/ml and an AUC of about 500 to 1,500 ngxh/ml. In the tablet of the invention, Aliskiren is preferably present in the form of the intermediate of the invention. The tablet of the invention accordingly preferably contains a pharmaceutical composition of the invention, especially in accordance with any of claims 10 to 14. The administration of the tablet of the invention is preferably once a day.
The invention will now be illustrated with reference to the following examples.

EXAMPLES
Example 1 1. Aliskiren base 150 mg 2. Microcrystalline cellulose 150 mg 3. Et0H 96 % q.s.
4. Microcrystalline cellulose 100 mg 5. Aerosil 200 5 mg 6. Crospovidone 30 mg 7. Magnesium stearate 15 mg Aliskiren base was dissolved with a sufficient quantity of ethanol 96 % and mixed with item 2. After sufficient agitating and subsequent drying, the dried cake was passed through a 0.8 mm screen and the screened (0.8 mm) items 4 - 6 were added. The mixture was mixed for 15 min in the Turbula . After that, item 7 was added via a screen (0.8 mm) and mixed for 15 min in the Turbula .

The finished mixture was pressed into tablets of 11 mm diameter each;
hardness 90-120 N.

Example 2: Formulation example for Aliskiren free base in combination with HCT

1. Aliskiren base 300 mg 2. Hydrochlorothiazide (HCT) 12.5 mg 3. Neusilin US2 130 mg 4. Di Cafose AN 152.5 mg 5. Aerosil 200 5 mg 6. Kollidon" CL 40 mg 7. Magnesium stearate 10 mg 8. Et0H 96% q.s.
Aliskiren base was dissolved in Et0H (96%) in a weight ratio of 1:1. Neusilin was granulated with the solution of Aliskiren and Et0H in a high shear mixer (Diosna P1/6) at 200 rpm mixer speed. After drying in a cabinet dryer at 40 C for 12 h, the granules were sieved (mesh size 1.0 mm) and mixed with the sieved (mesh size 1.0 mm) Di Cafos AN, HCT, Aerosil" 200 and Kollidon CL in a tumble blender (Turbula TB10) for 15 min. Magnesium stearate was added through a sieve (mesh size 0.5 mm) and mixed to the final blend for a further 5 min.

The mixture was compressed to tablets of 11 mm diameter and a hardness of 170 N on a Riva Picola rotary press.

Example 3: Formulation example for Aliskiren free base in combination with HCT

1. Aliskiren base 300 mg 2. Di Cafos AN 300 mg 3. Hydrochlorothiazide (HCT) 12.5 mg 4. Di Cafos AN 20 mg 5. Di Cafos AN 50 mg 6. Aerosil 200 8 mg 7. Crospovidone 40 mg 8. Magnesium stearate 10 mg 9. Et0H 96 % q.s.

Aliskiren base was dissolved in Et0H, and Di Cafos AN (item 2.) was mixed with that solution and dried. After drying, the mixture was passed through a screen (0.8 mm) and mixed with Di Cafos AN (item 5.) for 10 min in the Turbula . HCT and Di Cafos AN
(item 4.) were passed through a screen (0.8 mm) and mixed for 10 min in the Turbula .
The mixture was added to the dried and screened mixture from items 1., 2. and 5., Aero-sil 200 and crospovidone were added via a screen and mixed for 10 min in the Turbu-, la . Magnesium stearate was added via a screen and mixed for 5 min.
The mixture was pressed into oblong tablets 18 x 8.5 mm, using a rotary tabletting press (Riva), with 50-120 N hardness.
Comparative Example:

Marketed prior art tablet (Tekturna HCT8).

Example 4: In vitro release The in vitro release of the tablets of Example 1, Example 2 and the comparative example was investigated (USP Method II, paddle, 500 ml 0.1 N HC1, pH 1.1, 37 C, 75 rpm).
Table 1 5 min 10 min 15 min 20 min 30 min 60 min Dissolution [IY0] of 99 100 Example 1 Dissolution [%] of 86 91 94 96 Example 2 Dissolution [%] of 18 37 55 72 comparative example As shown in Table 1, the tablets according to the present application show a superior dissolution profile in comparison to the prior art tablets.

Additionally, the tablets according the present application were manufactured without the need of a salt-forming step of Aliskiren free base with an acid (for example for the preparation of Aliskiren hemifumarate). Further, the method according to the application avoids melt extrusion and therewith the accompanying high temperatures causing possible degradation of the heat-sensitive Aliskiren. Another advantage of the this invention is the higher drug load of the pharmaceutical composition that can be achieved using the substrate of the present invention, preferably magnesium aluminosilicate, as compared to the polymers used in a melt extrusion process.

Claims

1. An intermediate, containing Aliskiren base and substrate, wherein Aliskiren base is present as a solid dispersion.

2. The intermediate as claimed in claim 1, wherein Aliskiren base is applied to the substrate and/or deposited in the substrate.

3. The intermediate as claimed in either of claims 1 or 2, wherein the weight ratio of Ali skiren base to substrate is 10 : 1 to 1 : 10.

4. The intermediate as claimed in any of claims 1 to 3, wherein the substrate is a brittle substrate with a yield pressure of more than 80 MPa.

5. The intermediate as claimed in any of claims 1 to 4, wherein a non-water-soluble substrate is used.

6. The intermediate as claimed in any of claims 1 to 5, wherein a swellable sub-strate is used.

7. A method of preparing an intermediate containing Aliskiren and substrate, wherein Aliskiren base is present as a solid dispersion, comprising the steps of (a) dissolving Aliskiren base in a solvent or mixture of solvents, and contact-ing the solution with a substrate, (b) removing the solvent or mixture of solvents, (c) optionally granulating the mixture obtained in step (b).

8. The method as claimed in claim 7, wherein step (b) is performed as a freeze-drying step or spray-drying step.

9. The method as claimed in claim 7, wherein steps (b) and (c) are performed in a fluidised-bed granulator.

10. An intermediate obtainable by a method as claimed in anyone of claims 7 to 9.

11. A pharmaceutical formulation containing Aliskiren base in the form of an inter-mediate as claimed in any of claims 1 to 6 and 10, and optionally at least one further pharmaceutical excipient.

12. The pharmaceutical formulation as claimed in claim 11 for oral administration, preferably in the form of a tablet.

13. The pharmaceutical formulation as claimed in either of claims 11 or 12, con-taining (i) 50 to 95 % by weight intermediate, (ii) 5 to 25 % by weight disintegrant, (iii) 0 to 50 % by weight filler, based on the total weight of the formulation.

14. The pharmaceutical formulation as claimed in any of claims 11 to 13, containing 0.1 to 10 % by weight of a further active agent, preferably hydrochlorothiazide.

15. A tablet containing 50 to 500 mg Aliskiren base, wherein the tablet has a hard-ness of 50 to 250 N, a friability of less than 5 % and a content uniformity of 95 to 105 %, wherein the administration regarding the active agent Aliskiren leads to a T max of 0.5 to 3 hours, a C max of 10 to 90 ng/ml and an AUC of about 300 to 1,500 ng×h/ml, and wherein the administration is performed once to twice daily.