EP2303239A1

EP2303239A1 - Directly pressed aliskiren tablets

Info

Publication number: EP2303239A1
Application number: EP09780419A
Authority: EP
Inventors: Jana Pätz; Frank Muskulus
Original assignee: Ratiopharm GmbH
Current assignee: Ratiopharm GmbH
Priority date: 2008-07-11
Filing date: 2009-07-10
Publication date: 2011-04-06
Also published as: IL210574A0; US20110165235A1; WO2010004022A1; RU2010154501A; JP2011527316A; CA2730112A1; EP2143425A1

Abstract

The invention relates to pharmaceutical compositions that contain the ingredient Aliskiren and to dry pressing suitable for the manufacture of tablets so that prior wet granulation can be eliminated. The invention also relates to tablets that are obtained through dry pressing of said pharmaceutical compositions, and a method for manufacturing said tablets. The invention further relates to the use of the novel pharmaceutical compositions and tablets for treating hypertension and illnesses associated therewith.

Description

Direct pressed aliskiren tablets

The invention relates to pharmaceutical compositions containing the active substance aliskiren and are suitable for Direktverpressung or dry processing, so that can be dispensed with a prior Naßgranulierung the active ingredient with excipients. Furthermore, the invention relates to tablets which are obtainable by direct compression of these pharmaceutical compositions, as well as a process for the preparation of these tablets. Furthermore, the invention relates to the use of the new pharmaceutical compositions and tablets for the treatment of hypertension and associated diseases.

Aliskiren (lUPAC name: (2S, 4S, 5S, 7S) -5-amino-Λ / - (2-carbamoyl-2-methyl-propyl) -4-hydroxy-7 - {[4-methoxy-3-one 3-methoxypropoxy) phenyl] methyl} -8-methyl-2-propan-2-ynonanamide) is a direct renin inhibitor used to lower elevated blood pressure. Aliskiren has the following chemical structure:

In particular, the hemifumarate salt of aliskiren is known, as disclosed for example in EP 678,503 in Example 83. The hemifumarate has the following structure:

Unless otherwise indicated, the term "aliskiren" in this application includes the free base as well as salts and solvates thereof,

In the prior art administration forms of aliskiren are known which have a high active ingredient content and release the active substance substantially without a time delay. WO 2004/002466 A1 describes the addition of surface-active agents ("surfactants") for increasing the bioavailability of aliskiren. Aliskiren is classified as a class III drug under the Biopharmaceutics Classification System (BCS). That is, the active ingredient has poor permeability but high solubility. The limiting factor for bioavailability is therefore the permeation rate.

WO 2005/089729 A2 and US 2006/0018960 A1 disclose fast-dissolving aliskiren tablets and aliskirent tablets with immediate release, which are characterized by an active ingredient content of> 46%, based on the total weight of the formulation. It is described that aliskiren hemifumarate is difficult to process, i.a. because of its needle shape, it is prone to interparticular bridging and consequently exhibits poor flowability and processability. To prevent problems with the uniform distribution of the drug in the drug form must therefore be worked with an active ingredient content> 46%. Furthermore, the processing by wet granulation is described, which is also intended to counteract the poor properties of the drug.

The two documents expressly disclose that direct compression or dry compaction of the active ingredient is not possible due to the high hygroscopicity, the acicular particle structure and the poor flowability of the active ingredient. Similarly, WO 2005/089729 A2 and US 2006/0018960 A1 disclose a wet granulation process for the preparation of medicaments containing more than 46% aliskiren. The multi-stage process of wet granulation, drying and subsequent compression to tablets is generally relatively unproblematic in terms of its feasibility. Thus, in general, moist granules can be tabletted most reliably and without complications, especially in the case of low-dose dosage forms. Therefore, wet granulation is usually the drug of choice, and wet granules are the usual intermediate in the manufacture of tablets.

A disadvantage of wet granulation, however, is that special machines must be used for granulation, solvents are required for the preparation of the moist mass and the active ingredient is exposed to a prolonged period of granulation until completion of drying. This can lead to stability problems. Furthermore, the drying step subsequent to the granulation requires additional energy, as a result of which the active ingredient is exposed to thermal influences over a relatively long period of time. Overall, the method of wet granulation in a tendency to polymorphism and stability-unstable drug with respect to the influence of moisture is unsuitable.

The document WO 2005/089729 A2 teaches that direct compression of aliskiren is not possible (page 2, last paragraph). As a solution, it is proposed to subject a high concentration of aliskiren to wet granulation (claim 1, claim 19).

WO 2007/147596 A1 teaches that direct compression of aliskiren is not possible (page 3, first paragraph). As a solution, it is proposed to use a carbohydrate as a filler. Even so, however, a wet granulation should be carried out (claim 30).

WO 2008/074001 A1 relates to the use of aliskiren for the treatment of obese patients. This document does not address the difficult processability of aliskiren, but merely refers to commonly used manufacturing processes.

EP 1 972 335 A1 describes processes for the production of medicaments containing aliskiren, in which initially a granulate is produced by a melt. This method has the disadvantage that it is expensive and exposes the ingredients to higher temperatures, which can lead to partial degradation of the active ingredient. The Further disadvantages are the special requirements placed on the machines on a large-scale and the high unintentional introduction of energy around the melt.

There is therefore a need for pharmaceutical dosage forms which contain the active substance aliskiren and have advantages over the administration forms of the prior art. The pharmaceutical dosage forms should in particular be simple and economical to produce and nevertheless have good administration properties. For this purpose, the drug should be distributed as evenly as possible within the pharmaceutical dosage form, even at an active ingredient content below 46 wt .-%.

This object is solved by the subject matter of the claims. It has surprisingly been found that a pharmaceutical composition containing the active substance aliskiren can be tabletted without prior wet granulation if the active ingredient has been mixed and / or comminuted before tabletting with a brittle excipient or a large amount of lubricant.

Unexpectedly, the tablets produced according to the invention do not tend to "cap" during tabletting even at high compression pressures. Lids are the breaking off of one or more layers from the tablet surface during ejection from the matrix. In the case of active substances such as aliskiren, which have high plasticity and poor flowability, a high tendency to cover is observed in the case of dry compression by customary methods, which is attributable to the high elastic re-expansion of plastic substances at the end of the press process.

Moreover, it is possible to produce tablets with the method according to the invention, which show a very rapid release of active ingredient in the range up to about 30 minutes. Therefore, the tablets according to the invention are outstandingly suitable as "immediate release" preparations This effect is observed in particular in formulations which are free of carbohydrates as fillers. SUMMARY OF THE INVENTION

The present invention relates, in a first aspect, to a pharmaceutical composition suitable for dry compression into tablets comprising the active substance aliskiren or one of its pharmaceutically acceptable solvates or salts and at least 10% by weight of a brittle adjuvant, based on the total weight of the pharmaceutical Composition.

Another aspect of the invention is a pharmaceutical composition suitable for dry compression into tablets comprising the active ingredient aliskiren or one of its pharmaceutically acceptable solvates or salts and at least 5% by weight of a lubricant, based on the total weight of the pharmaceutical composition.

The invention in another aspect relates to a pharmaceutical composition suitable for direct compression or dry processing in tablets comprising the active substance aliskiren or one of its pharmaceutically acceptable solvates or salts or a solvate of a salt in free-flowing form. That is, aliskiren is in a formulation with at least one other substance that is free-flowing.

Another aspect of the invention is a pharmaceutical composition suitable for dry compression into tablets comprising the active substance aliskiren or one of its pharmaceutically acceptable solvates or salts, characterized in that the pharmaceutical composition is free of carbohydrates as a filler. Preferably, the pharmaceutical composition is completely free of carbohydrates.

The invention also relates to the tablets obtainable by direct compression from these pharmaceutical compositions and to the process by which the compositions are compressed into tablets.

The invention in a further aspect relates to a process for the preparation of a tablet comprising the direct compression or dry compacting of a pharmaceutical composition of the present invention. The invention further relates to a process for the preparation of a medicament, comprising the following steps:

(a) mixing crystalline or partially crystalline aliskiren with 50-150% by weight of a brittle adjuvant or with at least 10% by weight of a lubricant, based in each case on the total amount of aliskiren in the medicament, and optionally with further excipients;

(b) optionally compacting the mixture obtained in (a) and mixing the compacted aliskiren with one or more excipients;

(c) dry-pressing the composition obtained in (a) or (b) into a tablet; and

(d) optionally coating the tablet thus obtained.

Another aspect of the invention is a tablet obtainable by a method of the present invention.

Another aspect of the invention is a tablet containing aliskiren, 20-70% by weight of a brittle inorganic adjuvant, based on the total weight of the tablet, and at least one disintegrant.

Another aspect of the invention is a tablet containing aliskiren, at least 5% by weight of a lubricant, based on the total weight of the tablet, and at least one disintegrant.

Another aspect of the present invention is the use of a pharmaceutical composition or a tablet according to the invention for the manufacture of a medicament for the treatment of hypertension or a disease associated therewith. DETAILED DESCRIPTION OF THE INVENTION

Active Ingredient (s)

The pharmaceutical compositions according to the invention contain as active substance aliskiren. All crystal forms of aliskiren can be used, e.g. For example, the crystal forms of aliskirene hemifumarate described in WO 2008/061622 A1. The disclosure of WO 2008/061622 A1 is incorporated by reference into the disclosure of the present application.

The concentration of aliskiren in the pharmaceutical composition of the invention may be about 10 to 80% by weight, based on the total weight of the pharmaceutical composition. Preferably, the concentration of aliskiren in the pharmaceutical composition is about 10 to <46% by weight, more preferably about 20 to 45%, most preferably about 35 to 42% by weight, based on the total weight of the pharmaceutical composition. Unless otherwise indicated, weights of aliskiren refer to the salt or solvate, not the free base.

The compositions of the invention may contain, in addition to aliskiren, one or more other active ingredients selected from the group consisting of AT ₁ receptor antagonists, ACE inhibitors, beta-blockers, calcium channel blockers, aldosterone synthase inhibitors, aldosterone receptor antagonists, and diuretics. Examples of these agents are well known to those skilled in the art. Preferred diuretic is hydrochlorothiazide (HCT). Most preferably, aliskiren is combined with HCT. The HCT may be in a formulation with aliskiren, which is preferred. In another embodiment, aliskiren and HCT are in separate formulations but in a drug combination. The concentration of HCT is usually in the range of 5 to 50 mg per unit dosage form, preferably in the range of 10 to 40 mg, more preferably in the range of 12.5 to 30 mg, most preferably in the range of 12.5 to 25 mg. The weight ratio of aliskiren to HCT is usually in the range of from 3: 1 to 40: 1, preferably from 5: 1 to 30: 1, more preferably from 7: 1 to 25: 1, most preferably from 10: 1 to 20: 1. Aliskiren with brittle excipient

The first aspect of the invention is a pharmaceutical composition suitable for dry compression into tablets comprising the active ingredient aliskiren or one of its pharmaceutically acceptable solvates or salts and at least 10% by weight of a brittle adjuvant, based on the total weight of the pharmaceutical composition.

According to this aspect of the invention, the active substance aliskiren is mixed with at least one brittle adjuvant. It has surprisingly been found that the pharmaceutical composition has a better compressibility in the presence of a brittle adjuvant than in the absence of the brittle adjuvant. As a result, the formulation can be easily compressed into tablets or processed in a dry granulation. It could be shown that with different settings of the pressing force, the hardness of the tablet increases without inclining to cover, shown in a pressing force-hardness profile (see FIG. 1). Based on this graph, a lid tilt of the tablet would become visible through the formation of a pietational phase. A wet granulation is therefore not required.

Hiifsstoffe can generally about their behavior, resp. the change in the particle shape can be classified under pressing pressure (compression): plastic materials are characterized by plastic deformation, while brittle materials show a fracture of the particles into smaller particles under the influence of a pressing force. A brittle behavior of the excipient can be quantified by the increase of the surface in the pressing. In the literature, it is common to classify the deformation mechanisms by means of the so-called "yield pressure". According to a simple classification, the values for the "yield pressure" are small for plastic substances, but large for brittle substances [Duberg, M., Nyström, 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. Methodology rapid determination of comportment I Ia compression pour des etudes de preformulation. Pharm. Acta HeIv., 57, 136-143 (1982)). The "yield pressure" describes the tension that has to be reached in order for the substance to begin to flow plastically or can be regarded as a measure of the internal resistance. He knows about the reciprocal value of Slope of the Heckel plots are determined. "Yield pressure" values below 80 MPa are considered to be an indicator of plastic flow behavior (York, P., Drug Dev. Ind. Pharm. 18, 677 (1992); Crystal engineering and particle design for the powder compaction process In the present invention, an adjuvant is considered to be a brittle adjuvant when it has a yield pressure of at least 80 MPa as determined by the ejected tablef method, see WA Ritschel and A. Bauer-Brandl, The Tablet, 2nd Ed , Editio Cantor Verlag Aulendorf, 2002, page 442 and the references cited therein.

Preferably, the brittle adjuvant is an inorganic brittle adjuvant. As brittle auxiliaries, among others, inorganic, pharmaceutically acceptable salts of calcium or magnesium, e.g. Calcium carbonate, calcium phosphate, calcium sulfate, gastric oxide, are used. Preferred is calcium phosphate, especially calcium hydrogen phosphate, most preferably anhydrous

Calcium hydrogen phosphate (e.g., available as Di-Cafos AN from Chemische Fabrik Budenheim).

The concentration of the brittle adjuvant in the pharmaceutical composition is typically about 10 to 80 wt.%, Preferably 20 to 70 wt.%, More preferably 30 to 65 wt.%, Most preferably 40 to 60 wt. z. B. about 50 wt .-%, each based on the total weight of the pharmaceutical composition.

The weight ratio of aliskiren to brittle adjuvant is usually 1: 5 to 5: 1, preferably 1: 3 to 3: 1, more preferably 1: 2 to 2: 1, most preferably 1: 1 to 1: 1.5.

Aliskiren with a high amount of lubricant

The second aspect of the invention is a pharmaceutical composition suitable for dry compression into tablets comprising the active substance aliskiren or one of its pharmaceutically acceptable solvates or salts and at least 5% by weight of a brittle adjuvant, based on the total weight of the pharmaceutical composition. This aspect of the invention may be combined with the other aspects described herein. According to this aspect of the invention, the active substance aliskiren is mixed with a relatively high proportion of at least one lubricant. It has been found that by mixing with a high level of lubricant aliskiren can be converted into a formulation which can be easily compressed into tablets or processed in a dry granulation.

As lubricant, it is possible to use all customary pharmaceutical auxiliaries - preferably magnesium stearate or dehydrated vegetable oils (for example Lubritab®). As a lubricant, it is also possible to use stearic acid, sodium stearyl fumarate and / or polyethylene glycol (PEG).

The amount of lubricant according to this aspect of the invention should be at least 5% by weight, preferably 5 to 30% by weight, more preferably 10 to 20% by weight, based in each case on the total weight of the pharmaceutical composition. For the other aspects of the invention, the lubricant content may be lower, as indicated below.

Crushing of aliskiren

In this embodiment of the invention, which can be combined with all others, the active ingredient is processed by comminution technologies prior to direct compression or dry compaction. This alters the crystal habit of the drug and prevents bridging. Since aliskiren fumarate tends under mechanical action to convert into the amorphous active ingredient, which has a lower stability, attention must be paid to the temperature during the comminution. The temperature should be below 40 ^° C., preferably below 35 ^° C., during comminution. B. at about 10 to about 34 ⁰ C or about 20 to about 30 ⁰ C, to prevent degradation.

The active ingredient comminution preferably takes place in the form of a cover grinding with a surface-stabilizing auxiliary. Here, the addition of gum arabic has proved to be a surface stabilizing adjuvant in the cover grinding. The active ingredient is incorporated during the cover milling in the excipient. Other possible surface stabilizers are mentioned below. All known methods of pharmaceutical micronization or cover milling can be used, for example using an air jet mill or ball mill. When using an air jet mill, it is preferable to work with a process air of 4-6 bar. Processing under a protective gas atmosphere is also possible. The crushed crystals preferably have a mean size of 3 to 250 μm, preferably 5 to 150 μm, most preferably 10 to 120 μm.

The average particle size can be determined by laser diffraction according to Pharm. Eur. 2.9.31. Version 6.6, z. In a Malvern Mastersizer.

The micronization, resp. Cover milling can be carried out with or without surface stabilizer. Possible agglomeration of the micronized active ingredient can be counteracted by the addition of one or more surface stabilizers. These can be added before or during comminution. As surface stabilizers it is possible to use pharmaceutically acceptable organic or inorganic auxiliaries which are polymers or contain low molecular weight oligomers or nonionic, ionic, zwitterionic surface-active substances. They are added in an active ingredient: adjuvant weight ratio of from 1: 1 to 1: 100, preferably from 1: 2 to 1:50. Examples of Öberflächenstabilisatoren the purposes of the present invention are hydroxypropyl methylcellulose (HPMC), casein, gelatin, polyvinylpyrrolidone (PVP), sodium dodecyl sulfate (SDS), tragacanth, Stearinsäue, gum arabic, Polaxomer, polyethylene glycol (PEG), Tween ^®, polysaccharides, alginates, phospholipids etc.

Coating of aliskiren

In a further embodiment, the crystal habit and the surface of the crystals of the active ingredient can be changed by a coating such that bridge formation is prevented and the flowability and thus the dose accuracy is increased. For this purpose, all common pharmaceutically acceptable polymers can be used, for example, polymers based on cellulose, methacrylates or polyvinyl alcohol (PVA). Examples of pharmaceutically acceptable polymers are cellulose ethers such as hydroxypropylcellulose, hydroxymethylcellulose, methylcellulose and hydroxypropylmethylcellulose, cellulose acetate phthalate, wherein Hydroxypropylmethylcellulose is particularly preferred. suitable

Hydroxypropylmethylcelluloses are available, for example, under the name "Methocel". It is also referred to "Fiedler - Encyclopedia of adjuvants", Editio Cantor-Verlag Aulendorf, 5th edition 2002.

Owing to the good solubility properties of the aliskiren, this method also leads to a smoothing due to phenomena of dissolution on the surface of the crystals, which in turn is advantageous for further processing by direct compression. Furthermore, the addition of such polymers, which are also considered as hydrophilizing, to improve the bioavailability of the drug. The coating of the active ingredient is preferably carried out in fluidized bed or by spray drying.

The polymers are preferably used for coating in an amount of 2 to 20% by weight, more preferably 5 to 15% by weight, most preferably 7 to 12% by weight, based in each case on the weight of the active ingredient. The coating solution is prepared based on an organic solvent. Suitable organic solvents are ethanol or isopropanol.

Depending on the polymer used is usually worked with a product temperature between 30 and 45 ° C or between 35 and 40 ⁰ C.

Another advantage of this processing method is the stabilization of the active ingredient against external influences, such as e.g. Moisture that promotes conversion to the thermolabile amorphous state. This allows the drug to be marketed in more cost-effective packaging.

A modification of this technology is the incorporation of the active ingredient in an adjuvant (preferably a polymer) and the application of this solution to a carrier. For this purpose, the active ingredient is dissolved or suspended in a solution of a pharmaceutically acceptable excipient (eg polymer) in a solvent and applied to an inert core, by known layering techniques such as e.g. the fluidized bed. Any kind of "multiple units" pellets, minitablets, particles and so on are possible.

For a fast-release formulation, a mixture of a water-soluble and a water-insoluble excipient is preferably used. It is also possible to use only water-insoluble or only water-soluble excipients. Examples of suitable water-soluble auxiliaries are HPMC, povidone, povidone VA 64 (copolymer of polyvinylpyrrolidone with polyvinyl acetate, available commercially from BASF), mannitol, sorbitol. Suitable water-insoluble auxiliaries are, for example, polyvinyl alcohol, cellulose acetate phthalate, various methacrylates, etc.

This possibility combines both the improved stabilization of the active ingredient by an intimate embedding in a polymer, as well as the improved processability of the carrier-drug mixture. As a result, bridging of the active substance does not occur, reproducible production with regard to uniform distribution of the active ingredient is ensured.

Aliskiren in a formulation without carbohydrates as a filler

Another aspect of the invention, preferably combined with one or more of the aspects described above, is a pharmaceutical composition suitable for dry compression into tablets comprising the active substance aliskiren or one of its pharmaceutically acceptable solvates or salts, characterized that the pharmaceutical composition is free of carbohydrates as a filler. Preferably, the pharmaceutical composition is completely free of carbohydrates.

The term "carbohydrates" for the purposes of the present invention encompasses monosaccharides, disaccharides, oligosaccharides, polysaccharides and sugar alcohols Modified carbohydrates are not carbohydrates for the purposes of this application. Modified carbohydrates are to be understood as meaning chemical derivatives of carbohydrates, in particular not naturally occurring but artificially produced carbohydrates Derivatives (eg, croscarmellose, HPMC, HPC, HEC, CMC, carboxymethyl starch, methyl cellulose, etc.).

In another embodiment, the pharmaceutical composition is free of carbohydrates as a bulking agent and free of modified carbohydrates as a bulking agent. In yet another embodiment, the pharmaceutical composition is completely free of carbohydrates and completely free of modified carbohydrates. These embodiments also have the advantage that they contain no lactose and thus can be taken by patients with lactose intolerance.

Properties of the pharmaceutical compositions

Contrary to the presentation in WO 2005/089729, the properties of aliskiren with respect to flowability and processability can be improved by the measures described above, so that direct compression or dry compacting is possible. It is thus possible to produce reproducible debris and tamped densities, which ensure volume-metered processing by tabletting and thus "content uniformity". It was found that in particular the addition of a brittle excipient can greatly improve this effect or also has a positive influence on the stability.

The combination of adjuvants should be chosen so that the dry loss of the tableting mixture is between 0.2-6%, preferably between 1.0-0.4%. The drying loss is determined according to Pharm. Eur. 6.0 - 2.5.32. For this purpose, a temperature gradient with 5 7min of 50 -85 ⁰ C is applied.

Due to the pretreatment of the active ingredient, the ready-mixed mixtures show good reproducibility with regard to the density of debris and tapped material and the quotient of the same. The bulk density is preferably between 0.4 and 0.8 kg / l and the quotient of tamped and bulk density between 1, 01 and 1, 3 or between 1, 1 and 1.3.

Pressing / tableting

The invention relates to a process for the preparation of a medicament, comprising the following steps:

(A) mixing crystalline or partially crystalline aliskiren with 50 to 150 wt .-% of a brittle excipient or at least 10 wt .-% of a lubricant, each based on the total amount of aliskiren in the drug, and optionally with other excipients; (b) optionally compacting or dry granulating the mixture obtained in (a) and mixing the compacted aliskiren with one or more excipients;

(c) dry-pressing the composition obtained in (a) or (b) into a tablet; and

(d) optionally coating the tablet thus obtained.

If step (b) is performed, it is a dry compaction or dry granulation. If step (b) is not carried out, it is a direct compression without granulation or precompacting.

Preferred is a process for the preparation of a medicament comprising the following steps:

(a) mixing crystalline or semi-crystalline aliskiren with 50-150% by weight of a brittle adjuvant or with at least 10% by weight of a lubricant, each based on the total amount of aliskiren in the drug;

(b) directly compressing the composition obtained in (a) into a tablet; and

(c) optionally coating the tablet thus obtained.

The pharmaceutical compositions of the present invention prepared by mixing and optionally compacting can thus be dry-pressed into tablets. For this purpose, all current Trockenkompaktierverfahren can be used by roll compaction or briquetting. Care should be taken that the pressing force is between 2 - 50 kN, preferably between 3 and 30 kN, e.g. 5 - 2O kN, lies.

Thus, the drug can be compressed with common pharmaceutical excipients to form a tablet, which can be coated after the taste lamination of the bitter drug still.

Unless stated above, the following adjuvants may be used: The binder used is preferably a water-soluble adjuvant, for example povidone, HPMC, HPC. As a water-soluble excipient, any pharmaceutically acceptable, tasteless material can be used. The amount of binder may be about 10 to 25% by weight, preferably 15 to 25% by weight, most preferably 17 to 24% by weight, based in each case on the total weight of the pharmaceutical composition.

It can be added to a filler or diluent: z. As lactose and / or other sugar alcohols or carbohydrates. These can be combined with a proportion of water-insoluble fillers, preferably with microcrystalline cellulose. Also conceivable as fillers are inorganic salts: calcium carbonate, calcium hydrogen phosphate, etc. The amount of filler may be about 10 to 80 wt .-%, preferably 10 to 70 wt .-%, most preferably 15 to 60 wt .-%, each based on the total weight of the pharmaceutical composition.

In order to ensure rapid decay and the correlated release, a disintegrant should be used. Preferably cross-povidone,

Sodium carboxymethyl starch or similar superdesintegrants. The amount of disintegrant is usually about 1 to 20 wt .-%, preferably 2 to 10 wt .-%, most preferably 3 to 8 wt .-%, each based on the total weight of the pharmaceutical composition.

As lubricant, it is possible to use all customary pharmaceutical auxiliaries - preferably magnesium stearate or dehydrated vegetable oils (for example Lubritab®). As a lubricant, it is also possible to use stearic acid, sodium stearyl fumarate and / or polyethylene glycol (PEG). The amount of lubricant may be about 1 to 10% by weight, preferably 2 to 8% by weight, most preferably 3 to 7% by weight, based in each case on the total weight of the pharmaceutical composition.

The ingredients are usually mixed together in a free-fall mixer (Turbula) and then pressed on a rotary press (fats) into tablets. The tabletting mixtures showed good compressibility. The applied main compressive forces are usually in the range of 2 to 50 kN, preferably 5 to 12 kN, depending on the size and type of press used. The present invention further relates to a process for the preparation of a medicament, comprising the following steps:

Crushing aliskiren crystals or semi-crystalline aliskiren with or without surface stabilizer;

optionally mixing the comminuted aliskiren crystals with one or more excipients;

Direct compression of the composition thus obtained to obtain a tablet, and

optionally coating the tablet thus obtained.

The invention further relates to a process for the preparation of a medicament, comprising the following steps:

Coating crystalline aliskiren or semi-crystalline aliskiren with at least one pharmaceutically acceptable polymer;

optionally mixing the coated aliskiren with one or more excipients;

Direct compression of the composition thus obtained into a tablet; and

optionally coating the tablet thus obtained

Compacting crystalline aliskiren or semi-crystalline aliskiren with at least one pharmaceutically acceptable excipient;

optionally mixing the compacted aliskiren with one or more excipients;

Direct compression of the composition thus obtained into a tablet; and

optionally coating the tablet thus obtained.

In preferred embodiments of the processes according to the invention, no wet granulation or wet granulation is carried out, in particular no aqueous wet or moist granulation. If dry granulation is carried out, the temperature during granulation is preferably below the melting point of all auxiliaries used. For example, the temperature below 40 ⁰ C, or below 35 ° C. A so-called "hot-melt" granulation is therefore not preferred.

Properties of the tablets

The tablets according to the invention generally have a hardness between 60-160 N, preferably 60-120 N, more preferably 70-110 N. The hardness can be determined by methods known per se, for. B. Pharm. Eur. 6.0 <2.9.8>.

The tablets of the invention show a low rolling and Schüttelverschleiß (friability) or a good abrasion resistance. The friability is preferably less than 1% (for example 0.1 to 0.8%, preferably 0.2 to 0.5%). The friability can be determined by methods known per se, e.g. according to Pharm. Eur. 4.0 / 2.09.07.00.

The tablets according to the invention generally have a geometry which is adapted to the amount of active substance contained.

A particular advantage of the tablets according to the invention is their advantageous release profile. The tablets release a substantial proportion of the active ingredient within 30 minutes, measured according to USP 28, Method <711>, Apparatus 2, in 500 ml of 0.1 HCl pH 1, 1 at 37 ° C. and 75 rpm. In a first embodiment, the tablets show a drug release of at least 15% at 5 minutes, at least 40% at 10 minutes, at least 60% at 15 minutes, and at least 70% at 20 minutes, determined according to USP 28, method <711 >, Apparatus 2, in 500 ml of 0.1 HCl pH 1, 1 at 37 ° C and 75 rpm.

In a second embodiment, the tablets show a drug release of at least 20% at 5 minutes, at least 50% at 10 minutes, at least 70% at 15 minutes, and at least 80% at 20 minutes, determined according to USP 28, method <711 >, Apparatus 2, in 500 ml of 0.1 HCl pH 1, 1 at 37 ° C and 75 rpm.

In a third embodiment, the tablets show a drug release of at least 20% after 5 minutes, of at least 50% after 10 minutes, of at least 80% after 15 minutes, and of at least 90% after 20 minutes, determined according to USP 28, Method <711>, Apparatus 2, in 500 ml of 0.1 HCl pH 1, 1 at 37 ° C and 75 rpm.

In a fourth embodiment, after 5 minutes, the tablets show a drug release of at least 10%, preferably at least 15%, most preferably at least 20%, as determined by USP 28, Method <711>, Apparatus 2, in 500 ml of 0.1 HCl pH 1, 1 at 37 ⁰ C and 75 rpm.

In a fifth embodiment, after 10 minutes the tablets show a drug release of at least 30%, preferably at least 40%, more preferably at least 50%, most preferably at least 60% or even at least 75% as determined by USP 28, method <711> , Apparatus 2, in 500 ml of 0.1 HCl pH 1, 1 at 37 ° C and 75 rpm.

In a sixth embodiment, after 15 minutes, the tablets show a drug release of at least 50%, preferably at least 60%, more preferably at least 70%, most preferably at least 80% or even at least 90%, determined according to USP 28, Method <711> , Apparatus 2, in 500 ml of 0.1 HCl pH 1, 1 at 37 ° C and 75 rpm.

In a seventh embodiment, after 20 minutes the tablets show a drug release of at least 70%, preferably at least 75%, more preferably at least 80%, most preferably at least 90%, determined according to USP 28, method <711>, Apparatus 2, in 500 ml of 0.1 HCl pH 1, 1 at 37 ° C and 75 rpm.

After 30 minutes, the tablets usually show a drug release of at least 90%, usually of at least 95%, determined according to USP 28, Method <711>, Apparatus 2, in 500 ml of 0.1 HCl pH 1, 1 at 37 ⁰ C and 75 rpm.

In another embodiment, the tablets have a release profile similar to that of the drug Rasilez®, or substantially the same as the release profile of Rasilez®. By per se known formulation additives, the skilled person can slow down the very rapid drug release of the tablets described above so that a release profile is obtained, which is similar to that of Rasilez® or similar (in each case at most 10% deviation of the drug release after 5, 10, 15, 20 and 30 minutes).

uses

Furthermore, the invention relates to the use of the above-described pharmaceutical composition or tablet for the treatment of hypertension or a disease associated therewith. These conditions include congestive heart failure, cardiac hypertension, cardiofibrosis, postinfarct cardiomyopathy, complications of diabetes such as nephropathy, vasculopathy and neuropathy, coronary artery disease, restenosis after angioplasty, increased intraocular pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, anxiety, and cognitive disorders.

The invention further relates to the use of aliskiren for the manufacture of a medicament for the treatment of hypertension or a disease associated therewith, characterized in that an aliskiren-containing pharmaceutical composition is directly compressed into tablets. Preferably, the active substance aliskiren is coated before direct compression by at least one pharmaceutically acceptable polymer. Alternatively, the aliskiren crystals or partially crystalline aliskiren may be comminuted prior to direct compression, for example by micronization as described above.

According to the invention, it is also possible that the pharmaceutical compositions and tablets described herein are administered in a combination therapy. The medicaments according to the invention can be administered simultaneously with another active ingredient or at intervals. Other active ingredients include, for example, the following active ingredient categories: AT ₁ receptor antagonists, ACE inhibitors, beta blockers, calcium channel blockers, aldosterone synthase inhibitors, aldosterone receptor antagonists, and diuretics. Examples of these agents are well known to those skilled in the art. Preferred diuretic is hydrochlorothiazide (HCT).

Most preferably, aliskiren is combined with HCT. The HCT may be in a formulation with aliskiren, which is preferred. In another embodiment Aliskiren and HCT in separate formulations, but in a drug combination. The concentration of HCT is usually in the range of 5 to 50 mg per unit dosage form, preferably in the range of 10 to 40 mg, more preferably in the range of 12.5 to 35 mg, most preferably in the range of 12.5 to 25 mg.

The weight ratio of aliskiren to HCT is usually in the range of from 3: 1 to 40: 1, preferably from 5: 1 to 30: 1, more preferably from 7: 1 to 25: 1, most preferably from 10: 1 to 20: 1.

The present invention further relates to the following items (1) to (16):

(1) A pharmaceutical composition suitable for directly compressing tablets comprising the active substance aliskiren or one of its pharmaceutically acceptable solvates or salts in free-flowing form.

(2) The pharmaceutical composition according to (1), characterized in that the active ingredient is in micronized form.

(3) A pharmaceutical composition according to (1) or (2), characterized in that the active ingredient is coated by a pharmaceutically acceptable polymer.

(4) The pharmaceutical composition according to (3), characterized in that the pharmaceutically acceptable polymer is selected from the group consisting of cellulose-based polymers, methacrylates and polyvinyl alcohol.

(5) The pharmaceutical composition according to (3) or (4), characterized in that the content of the pharmaceutically acceptable polymer is 2 - 20 wt .-% based on the weight of the active ingredient.

(6) The pharmaceutical composition according to any one of the preceding items (1) to (5), characterized in that it contains a binder.

(7) The pharmaceutical composition according to any one of the preceding items (1) to (6), characterized in that the bulk density of the composition is between 0.4 and 0.7 kg / L. (8) Pharmaceutical composition according to one of the preceding items (1) to (7), characterized in that the quotient of tamped density and bulk density between 1, 1 and 1, 3 is.

(9) A process for producing a tablet which comprises directly compressing a pharmaceutical composition according to any one of the preceding items (1) to (8).

(10) Method according to (9), characterized in that the pressing force during direct compression is between 2 and 50 kN.

(11) Tablet obtainable by a method according to (9) or (10).

(12) A tablet containing micronized or pharmaceutically acceptable polymer coated aliskiren.

(13) Use of a pharmaceutical composition according to any one of items (1) to (8) or a tablet of (11) or (12) for the manufacture of a medicament for the treatment of hypertension or a disease associated therewith.

(14) Use according to (13), characterized in that the hypertensive disease is selected from the group consisting of congestive heart failure, cardiac hypertension, cardiofibrosis, postinfarct cardiomyopathy, complications due to diabetes such as nephropathy, vasculopathy and neuropathy, coronary artery disease, Restenosis after angioplasty, increased intraocular pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, anxiety and cognitive disorders.

(15) Use according to (13) or (14), characterized in that the pharmaceutical composition or tablet is administered in combination with another active ingredient. (16) Use according to (15), characterized in that the further active ingredient is selected from the group consisting of ATV receptor antagonists, ACE inhibitors, beta-blockers, calcium channel blockers, aldosterone synthase inhibitors, aldosterone receptor antagonists, and diuretics.

The above objects (1) to (16) can be further combined with the aspects and embodiments described in the present application.

Figure 1 shows a press force-hardness diagram with results of Example 8.

Figures 2 and 3 show the release profiles determined in Examples 11a and 11b, respectively.

The invention is further illustrated by the following examples:

Example 1: Dry Compaction with Calcium Phosphate

Quantities are calculated based on the single dose.

The active ingredient was compacted with 300 mg calcium phosphate, 5 mg Aerosil, 40 mg Crosscarmellose and 20 mg magnesium stearate in the compactor at 15-45 kN. The compact was crushed with a sieve and mixed with the remaining amounts of calcium phosphate, magnesium stearate and Aerosil on a free-fall mixer. This finished mixture was pressed on a rotary press into tablets. These had a hardness of 70 -110 N combined with a friability of less than 1%. Subsequently, the tablets were coated in a drum coater. For this purpose, a suspension of HPMC, PEG, talc, titanium dioxide and the dye was prepared. Table 1

'corresponds to 300 mg aliskirene base

Example 2: Active ingredient coating

The active ingredient was introduced into a fluid-bed apparatus (Glatt GPC3) and coated with an isopropanolic solution of HPMC. The product temperature was between 35-40 ° C with applied supply air temperature of 40-80 ⁰ C. The spray pressure was set with 1-2 bar. Subsequently, the coated active substance was premixed with Avicel, Aerosil and Crosscarmellose for 30 min on a free fall mixer. The final mixture was prepared with the addition of magnesium stearate. For this purpose, it was mixed again for 3 min. The finished mixture was then pressed on a rotary press into tablets (Fette 102i) having a hardness of 60-120 N.

If necessary, the tablet can be coated equivalent to Example 1. Table 2

* corresponds to 300 mg aliskiren base

Example 3: Active ingredient comminution (cover grinding with gum arabic)

The active ingredient was comminuted together with gum arabic in the air jet mill. A process air between 4 -6 bar was created. After milling, the drug-excipient mixture was mixed with Aerosil, Crospovidone and Avicel for 30 min on a free-fall mixer. It was then mixed again with magnesium stearate for 3 min. The finished mixture was pressed analogously to the previous examples and optionally coated.

Table 3

^* corresponds to 300 mg aliskiren base

Example 4: Direct compression with calcium phosphate

Calcium hydrogen phosphate, Aerosil 200, Ac-Di-Sol and magnesium stearate were sieved through a 0.5 mm sieve into the mixing vessel. Aliskirene hemifumarate was added. It was then mixed for 15 minutes on a Turbula T10B mixer. The final mixture thus obtained was compressed by means of a hydraulic one-hand press (Specac hydraulic press) with the setting 0.5 kN.

Table 4

^* corresponds to 150 mg aliskiren base The final mixture showed good compressibility. The tablets had sufficient hardness.

Example 5: Direct compression without carbohydrate

Calcium hydrogen phosphate, Aerosil 200, Kollidon CL and magnesium stearate were sieved through a 0.5 mm sieve into the mixing vessel. Aliskirene hemifumarate was added. It was then mixed for 15 minutes on a Turbula T10B mixer. The final mixture thus obtained was compressed by means of a hydraulic one-hand press (Specac hydraulic press) with the setting 0.5 kN.

Table 5

* corresponds to 150 mg aliskiren base

The final mixture showed good compressibility. The tablets had sufficient hardness.

Example 6: Dry Compaction (Dry Granulation) with Calcium Phosphate

150 mg of calcium hydrogen phosphate, 2.5 mg of Aerosil 200, 20 mg of croscarmellose sodium and 10 mg of magnesium stearate were sieved through a 0.5 mm sieve into the mixing tank. Aliskirene hemifumarate was added. The mixture was then for 15 min mixed on a mixer (Turbula T10B). The mixture was pressed at about 0.1 kN on a hydraulic one-hand press (Specac). The compact was then crushed through a 1 mm sieve. The residual amounts of calcium hydrogen phosphate and Aerosil were added through a 0.5 mm sieve and mixed for an additional 15 minutes. The residual amount of magnesium stearate was also added through a 0.5 mm sieve and the entire mixture was mixed on a Turbula T10B mixer for 5 minutes. The final mixture was pressed by means of a hydraulic one-hand press (Specac hydraulic press) with the setting 10 kN.

Table 6

Example 7: Active ingredient comminution (cover grinding with gum arabic)

Aliskirene hemifumarate and gum arabic were mixed for 5 min in a Turbula T10B, followed by comminution in a mortar. Microcrystalline cellulose, Aerosil and Colidon CL were added through a 0.5 mm sieve and mixed for 15 minutes. Magnesium stearate was added through a 0.5 mm sieve and the mixture was mixed for a further 3 minutes. The final mixture was compressed at 6-8 kN with a hydraulic one-hand press (Specac). Table 7

Example 8: Direct compression at different compression forces

Three formulations A, B and C having the composition shown in Table 7 were prepared. The preparation was carried out as described in Example 4, with the difference that for pressing a "Riva piccola Rotary Press" was used with the parameters given in Table 8.

The composition of the tested formulations is shown below:

Table 8

The compression parameters of the three formulations are given in Table 9 below.

Table 9: Compression parameters and measured tablet properties

The compression pressure and the hardness are compared in Figure 1 in a diagram. The curve does not show a plateau at high pressures, indicating that the tablets are not prone to capping.

Example 9: Combination with HCT direct compression with calcium phosphate

Calcium hydrogen phosphate, Aerosil 200, calcium phosphate and magnesium stearate were sieved through a 0.5 mm sieve into the mixing vessel. Aliskirene hemifumarate and HCT were added. It was then mixed for 15 minutes on a Turbula T10B mixer. The final mixture thus obtained was compressed by means of a hydraulic one-hand press (Specac hydraulic press) with the setting 0.6-0.8 kN. Table 10

Example 10: Combination with HCT - Covermilling with PVP

Aliskirene hemifumarate, HCT and povidone were mixed for 5 min in a Turbula T10B, followed by crushing in a mortar and subsequent sieving over 0.5 mm. Microcrystalline cellulose, Aerosil and Kollidon CL were added through a 0.5 mm sieve and mixed for 15 minutes. Magnesium stearate was added through a 0.5 mm sieve and the mixture was mixed for a further 3 minutes. The final mixture was compressed at 6-8 kN with a hydraulic one-hand press (Specac).

Table 11

Example 11: Release profile

a) The drug release of the formulations according to Examples 4, 6 and 7 was determined according to USP 28, <711>, Apparatus 2 (Paddle). Also tested as a reference product was the commercially available formulation sold under the name "Rasilez® 150 mg". The tablets or the reference product prepared in Examples 4, 6 and 7 were each stirred in 500 ml of 0.1 N HCl, pH 1.1 at 37 ° C at 75 rpm. The amount of active ingredient dissolved was determined by HPLC. The results are summarized in FIG.

As can be seen from FIG. 2, the formulations according to the invention show a significantly more rapid release of active ingredient than the reference product, in particular for the period up to 30 minutes.

b) The drug release of the formulations of Examples 9 and 10 was determined according to USP 28, <711>, Apparatus 2 (Paddle). Also tested as a reference product was the commercially available formulation sold under the name "Tekturna®". The tablets or the reference product prepared in Examples 9 and 10 were each stirred in 900 ml of 0.1 N HCl, pH 1, 2 at 37 ° C at 75 rpm. The dissolved quantities of both active ingredients were determined by HPLC. The results are summarized in FIG.

Example 12: Drying loss

The drying loss of the tablets prepared according to Examples 4 and 8 was determined according to Pharm. Eur. 2.2.32. The results are shown in Table 12 below.

Table 12 Abbreviations

CMC carboxymethylcellulose

HEC hydroxyethylcellulose

HPC hydroxypropyl cellulose

HPLC "High Performance Liquid Chromatography

HPMC hydroxypropyl methylcellulose

IR "Immediate Release"

Pharm. Eur. European Pharmacopoeia

RPM revolutions per minute

USP United States Pharmacopeia

Claims

claims

A pharmaceutical composition suitable for dry compression into tablets comprising the active ingredient Aiiskiren or one of its pharmaceutically acceptable solvates or salts and at least 10% by weight of a brittle adjuvant, based on the total weight of the pharmaceutical composition.

A pharmaceutical composition suitable for dry compression into tablets comprising the active substance aliskiren or one of its pharmaceutically acceptable solvates or salts and at least 5% by weight of a lubricant, based on the total weight of the pharmaceutical composition.

A pharmaceutical composition suitable for direct compression of tablets, comprising the active substance aliskiren or one of its pharmaceutically acceptable solvates or salts in free-flowing form.

4. Pharmaceutical composition according to one of the preceding claims, characterized in that the active ingredient is in micronized form.

5. Pharmaceutical composition according to one of claims 2 to 4, characterized in that it contains a brittle excipient.

6. Pharmaceutical composition according to claim 1 or 5, characterized in that the brittle excipient is selected from the group consisting of inorganic, pharmaceutically acceptable salts of calcium or magnesium.

7. A pharmaceutical composition according to claim 6, characterized in that the brittle excipient is selected from the group consisting of calcium carbonate, calcium phosphate, calcium sulfate and gastric oxide.

8. A pharmaceutical composition according to claim 7, characterized in that the brittle excipient is calcium hydrogen phosphate.

9. A pharmaceutical composition according to any one of claims 1 and 5 to 8, characterized in that the content of the brittle auxiliary 30 to 70 wt .-%, based on the total weight of the pharmaceutical composition is.

10. Pharmaceutical composition according to one of the preceding claims, characterized in that it is free of carbohydrates as a filler.

11. Pharmaceutical composition according to one of the preceding claims, characterized in that it is free of carbohydrates.

12. Pharmaceutical composition according to one of the preceding claims, characterized in that the aliskirengehalt, based on the total weight of the pharmaceutical composition, less than 46 wt .-% is.

13. Pharmaceutical composition according to one of the preceding claims, characterized in that it contains hydrochlorothiazide as further active ingredient.

14. Pharmaceutical composition according to one of the preceding claims, characterized in that the bulk density of the composition is between 0.4 and 0.8 kg / L.

15. Pharmaceutical composition according to one of the preceding claims, characterized in that the quotient of tamped density and bulk density between 1, 01 and 1, 3 is located.

16. A pharmaceutical composition according to any one of the preceding claims, characterized in that it comprises at least one further active ingredient selected from the group consisting of AT _r receptor antagonists, ACE inhibitors, beta-blockers, calcium channel blockers, aldosterone synthase inhibitors, aldosterone receptor antagonists and diuretics.

17. Pharmaceutical composition according to claim 16, characterized in that the further active ingredient is hydrochlorothiazide.

18. A process for producing a tablet which comprises directly compressing a pharmaceutical composition according to any one of claims 1 to 17.

19. The method according to claim 18, characterized in that the pressing force during direct compression between 2 and 50 kN.

20. A process for the preparation of a tablet, comprising the dry compaction of a pharmaceutical composition according to any one of claims 1 to 17.

21. A method of making a tablet, comprising the steps of:

(A) mixing crystalline or partially crystalline aliskiren with 50 to 150 wt .-% of a brittle excipient and / or with at least 10 wt .-% of a lubricant, each based on the total amount of aliskiren in the drug, and optionally with other excipients;

(b) optionally compacting or dry granulating the mixture obtained in (a) and mixing the compacted aliskiren with one or more excipients;

(c) dry-pressing the composition obtained in (a) or (b) into a tablet; and

(d) optionally coating the tablet thus obtained.

22. A tablet obtainable by a method according to any one of claims 18 to 21.

23. A tablet containing aliskiren, 20-70% by weight of a brittle inorganic adjuvant, based on the total weight of the tablet, and at least one disintegrant.

24. A tablet containing aliskiren, at least 5% by weight of a lubricant, based on the total weight of the tablet, and at least one disintegrant.

25. A tablet according to any one of claims 22 to 24, characterized in that it is free of carbohydrates.

26. A tablet according to any one of claims 22 to 25, characterized in that it has a drug release of at least 15% after 5 minutes, of at least 40% after 10 minutes, of at least 60% after 15 minutes, and of at least 70% after 20 minutes shows, determined according to USP 28, method <711>, Apparatus 2, in 500 ml of 0.1 HCl pH 1, 1 at 37 ⁰ C and 75 rpm.

27. A tablet according to any one of claims 22 to 26, characterized in that it has a hardness of at least 60 N, determined according to Pharm. Eur. 6.0, Method <2.9.8>.

28. Use of a pharmaceutical composition according to any one of claims 1-17 or a tablet according to any one of claims 22 to 27 for the manufacture of a medicament for the treatment of hypertension or a disease associated therewith.

29. Use according to claim 28, characterized in that the disease associated with hypertension is selected from the group consisting of congestive heart failure, cardiohypertension, cardiofibrosis, postinfarct cardiomyopathy, complications resulting from diabetes, such as nephropathy, vasculopathy and neuropathy, coronary vascular disease, restenosis Angioplasty, increased intraocular pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, anxiety and cognitive disorders.

30. Use according to claim 28 or 29, characterized in that the pharmaceutical composition or tablet is administered in combination with another active ingredient.

31. Use according to claim 30, characterized in that the further active ingredient is selected from the group consisting of ATrRezeptorantagonisten, ACE inhibitors, beta-blockers, calcium channel blockers, aldosterone synthase inhibitors, aldosterone receptor antagonists, and diuretics.

32. Use according to claim 31, characterized in that the further active ingredient is hydrochlorothiazide.