EP2309977A1

EP2309977A1 - Bitablets comprising compacted polyallylamine polymer and method for the production thereof

Info

Publication number: EP2309977A1
Application number: EP09768863A
Authority: EP
Inventors: Maria Genth; Max-Werner Scheiwe
Original assignee: Ratiopharm GmbH
Current assignee: Ratiopharm GmbH
Priority date: 2008-06-25
Filing date: 2009-03-20
Publication date: 2011-04-20
Also published as: WO2009156014A8; CA2731853A1; US20110189121A1; JP2011525501A; WO2009156014A1; DE102008030046A1

Abstract

The invention relates to a method for producing tablets comprising a polyallylamine polymer, comprising the steps (i) providing a polyallylamine polymer or pharmaceutically compatible salts thereof, optionally mixed with one or more pharmaceutical additives; (ii) compacting to a slug; (iii) granulating the slug; and (iv) compressing the resulting granulate into tablets; and tablets, sachets, and slugs comprising a compacted polyallylamine polymer. The invention further relates to tablets comprising a polyallylamine polymer, particularly sevelamer, having a bimodal pore size distribution.

Description

Compacted polyallylamine polymer

The invention relates to a process for the preparation of tablets comprising a polyallylamine polymer comprising the steps of (i) providing a polyallylamine polymer or pharmaceutically acceptable salts thereof, optionally in admixture with one or more pharmaceutical excipients; (ü) compaction to a school; (iii) granulation of the slug; and (iv) compression of the resulting granules into tablets; and tablets, granules and slugs containing a compacted polyallylamine polymer. Furthermore, the invention relates to tablets comprising a polyallylamine polymer, in particular sevelamer, with a bimodal pore size distribution.

Sevelamer (INN) is a polyallylamine polymer known in the art which has phosphate binding properties. The use as a medicament was first described in EP 0 716 606 B1. Sevelamer hydrochloride is located under the name "Renagel ^®" in the trade, and (hyperphosphatemia) is used for binding of the phosphate from the diet especially in dialysis patients with excess phosphate in the blood.

The formulation of sevelamer into the commercially available tablets is usually by direct compression.

EP 1 153 940 A1 describes sevelamer with a density of 1.18 to 1.24 g / cm ³ . It has been found that sevelamer with this density can be processed by direct compression into tablets having an advantageous hardness. However, it was found that the hardness of the tablets is insufficient when sevelamer is used at a density of 1.25 g / cm ³ , see Table 1 of EP 1 153 940.

EP 1 239 837 B1 also discloses the direct compression of sevelamer into high-active-ingredient tablets. It has been found that it is particularly important to precisely adjust the water content of the sevelamer polymer. Especially at a water content of 5 to 7 wt .-% good tablet properties would be achieved. If the water content is below 5% by weight, the tablets show an undesirably low hardness. At a water content above 8%, the disintegration time is undesirably prolonged.

Further, EP 1 304 104 B1 relates to sevelamer-containing tablets prepared by direct compression. It has been found that (depending on the water content of the sevelamer) tablets with favorable hardness and disintegration time can only be prepared if about 30% by weight of crystalline cellulose are added to the active agent polymer, see for example FIGS. 1 and 2 of EP 1 3 04 104 B1. Tablets containing 200 mg of active ingredient and 100 mg of filler were prepared.

Finally, WO 2006/050315 A2 describes the preparation of sevelamer carbonate formulations, tablet tabletting likewise taking place by means of direct compression. It has been found that the disintegration time after 3 weeks of storage is only acceptable when sevelamer carbonate is mixed with sevelamer hydrochloride. However, the addition of sevelamer hydrochloride reduces the hardness of the resulting tablets, see Table 1.

It can thus be concluded that the processes described in the prior art for the preparation of polyallylamine polymer-containing tablets have numerous disadvantages, for example due to special requirements on the water content, the density or the salt composition of the active ingredient, or the need for special excipients. The object of the invention was therefore to overcome the disadvantages occurring in the prior art.

In particular, it was an object of the invention to provide a process for the preparation of tablets containing polyallylamine polymer, in particular sevelamer tablets, wherein a polyallylamine polymer, in particular sevelamer, with a variable water content is to be advantageously processed, for example with a water content from 1 to 14%. In particular, it should be possible to tablets both with rapid disintegration time (Less than 15 minutes, preferably less than 10 minutes, in particular less than 8 minutes, eg 5 to 7.5 minutes) as well as having an advantageous hardness (more than 100 Newton (N), preferably more than 120 Newton, in particular more than 150 Newton), to provide the water content may vary, for example 1 to 14% may be.

A further object of the invention is to provide a process for the preparation of tablets containing polyallylamine polymer, in particular sevelamer tablets, wherein a polyallylamine polymer, in particular sevelamer, having a density of greater than 1.24 g / cm ³ is to be processed advantageously, for example with a density of 1, 25 to 1, 30 g / cm ³ . In particular, it should be possible to provide tablets both with rapid disintegration time (less than 15 minutes, preferably less than 10 minutes) and with advantageous hardness (more than 100 Newton, preferably more than 120 Newton), the Sevelamer with this high Density included.

It was a further object of the invention to provide a process for the preparation of sevelamer-containing tablets which show advantageous paintability. When painting the tablets according to the invention there should be no "chipping".

A further object of the invention is to provide a process for the preparation of tablets containing polyallylamine polymer, in particular of sevelamer tablets, it being possible, for example, to advantageously process lactose and mannitol or derivatives thereof. It should also be possible to use other fillers which are an alternative to cellulose. In particular, it should be possible to use tablets both with rapid disintegration time (less than 15 minutes, preferably less than 10 minutes, in particular less than 8 minutes, eg 5 to 7.5 minutes) and with advantageous hardness (more than 100 Newtons, preferably more than 120 Newton, in particular more than 150 Newton), which contain a polyallylamine polymer, in particular Sevelamer, as active ingredient and, for example, lactose and / or mannitol as auxiliary. Furthermore, it was an object of the invention to provide a process for the preparation of tablets containing polyallylamine polymer, in particular sevelamer tablets, wherein a high proportion of active compound can be advantageously processed, for example an active ingredient content of 80 to 95%. In particular, it should be possible to provide tablets with a high proportion of active ingredient, which have both a rapid disintegration time and an advantageous hardness.

Incidentally, it was an object of the invention to provide a method for the production of Sevelamertabletten, wherein the carbonate salt of sevelamer is to be processed advantageously, preferably as the sole active ingredient without mixing with sevelamer hydrochloride. In particular, it should be possible to provide tablets containing sevelamer carbonate, which have both a disintegration time which remains stable over time (disintegration time after 3 weeks storage under 30 minutes, preferably less than 15 minutes) and also an advantageous hardness.

Also, there should be provided a granular formulation of polyallylamine polymer, especially sevelamer, which can be advantageously used to prepare an oral suspension. The granules should flow well, do not segregate during storage and allow an exact dosage of single and multidose containers.

All of the above tasks should be accomplished (for example, in terms of process economics, occupational safety and environmental protection) as much as possible without the use of alcoholic solvents.

The tasks could be solved by compaction of a polyallylamine polymer, in particular by compaction of sevelamer, into a rag.

The invention therefore provides a scarf comprising a polyallylamine polymer, in particular Sevelamer, obtainable by a process comprising the steps (I) providing the polyallylamine polymer or pharmaceutically acceptable salts thereof, optionally in admixture with one or more pharmaceutical excipients and (ii) compaction into a slug.

In step (ii), in this case the polyallylamine polymer or preferably the mixture of polyallylamine polymer and one or more pharmaceutical excipients is compacted.

The invention further relates to a process for the preparation of

Tablets containing a polyallylamine polymer, in particular sevelamer, comprising the steps

(i) providing a polyallylamine polymer or pharmaceutically acceptable

Salts thereof, optionally in admixture with one or more pharmaceutical excipients;

(ii) compaction into a slug;

(iii) granulation of the slug; and

(iv) compression of the resulting granules into tablets, optionally with the addition of further pharmaceutical excipients.

The tablets produced by the process according to the invention may optionally be film-coated in a further, optional step (v).

Also, tablets and film-coated tablets obtainable by the method of the present invention are the subject of this invention.

Finally, the invention comprises a granulate, in particular for filling in

Sachets containing a polyallylamine polymer, in particular sevelamer, obtainable by a process comprising the steps

(i) providing the polyallylamine polymer or pharmaceutically acceptable

Salts thereof, optionally with one or more pharmaceutical

auxiliaries; (ii) compaction into a slug; and (iii) granulation of the slug.

While or preferably after step (iii), optional further adjuvants may be added. In particular, adjuvants are used to improve fluidity, tack, disintegration, taste and / or wettability therefor.

The resulting granules are preferably used for the preparation of an oral suspension. It is preferably filled into a suitable packaging. Examples of packaging materials are bottles, cans or preferably sachets. In the case of bottles or cans, these may include a daily dose. Alternatively, multi-day doses, e.g. a weekly dose or a monthly dose in bottles or cans.

The process according to the invention for producing tablets comprising a polyallylamine polymer, in particular sevelamer, is explained in more detail below. The remarks on the steps (i) and (ii) also apply to the production of the scarf according to the invention. The remarks on the steps (i) to (iii) are also used for the preparation of the granules according to the invention.

In step (i) of the process according to the invention, first a "polyallylamine polymer" is provided.

For purposes of this invention, the term "polyallylamine polymer" includes a polymer obtainable preferably by polymerization of monomers comprising an allylamine moiety or derivatives thereof, such as alkylated polyallylamine polymers. In the context of this invention, it is preferable to use a cross-linked polyallylamine polymer. In particular, the polyallylamine polymer of the present invention is sevelamer (INN) or colesevelam (INN) and their pharmaceutically acceptable salts. The polyallylamine polymer preferably has phosphate-binding properties. The alkylated polyallylamine polymer preferably has bile acid binding properties.

Polyallylamine polymers are known in the art and described for example in EP 0 716 606 B1. Derivatives of polyallylamine polymers are described, for example, in EP 0 764 174 B1.

The polyallylamine polymer, preferably crosslinked, of the present invention usually has a weight-average molecular weight of 1,000 to 5 million, preferably 2,000 to 2 million, more preferably 5,000 to 1 million, more preferably 10,000 to 250,000 g / mole.

The polyallylamine polymer preferably comprises the following repeating structural unit:

The polyallylamine polymer is preferably crosslinked by reaction with epichlorohydrin. The crosslinked polyallylamine polymer particularly preferably comprises 5 to 15% by weight, more preferably 9 to 10% by weight, in particular 9.0 to 9.8% by weight, of epichlorohydrin units, based on the total weight of the polymer.

In a preferred embodiment, the crosslinked polyallylamine polymer has the following structure (shown schematically):

In the above formula, the ratio (x + y) is preferably: z = 45: 1 to 2: 1, more preferably 15: 1 to 5: 1, especially 9.

Further, in the above formula, m indicates the number of repeating units. Preferably, m is chosen so that the number average molecular weight described above is achieved.

In principle, in the context of this application, the terms "polyallylamine polymer", "sevelamer" or "colesevelam" include both the corresponding polymers and pharmaceutically acceptable salts thereof. This may be one or more salts, which may also be present in a mixture. By "salt" is meant herein that one or more amine groups of the polymer are protonated to form a positively charged nitrogen atom associated with a corresponding counter anion.

The salts used are preferably acid addition salts. Examples of suitable salts are hydrochlorides, carbonates, bicarbonates, acetates, Lactates, butyrates, propionates, sulfates, citrates, tartrates, nitrates, sulfonates, oxalates and / or succinates.

Most preferably, in the case of sevelamer, the pharmaceutically acceptable salt is sevelamer hydrochloride. Also most preferably, the pharmaceutically acceptable salt is sevelamer carbonate. Finally, it is particularly preferably a mixture of sevelamer hydrochloride and sevelamer carbonate. In a preferred embodiment, this mixture of sevelamer hydrochloride and sevelamer carbonate contains 0.01 to 10% by weight, preferably 0.1 to 5% by weight, of sevelamer hydrochloride and 90 to 99.99% by weight, preferably 95 to 99.9% by weight of sevelamer carbonate, based on the total weight of the mixture.

In a preferred embodiment, 10 to 60%, more preferably 30 to 50%, especially about 40% of the amino groups are protonated.

In the case of sevelamer hydrochloride, the following structure (shown schematically) may be present:

In the above formula, the ratio (x + y) is preferably: z = 45: 1 to 2: 1, more preferably 15: 1 to 5: 1, especially 9. Further, in the above formula, m indicates the number of repeating units. Preferably, m is chosen so that the number average molecular weight described above is achieved.

Averaged over all units, n is preferably 0.1 to 0.6, more preferably 0.3 to 0.5, especially about 0.4.

In the case of colesevelam, the pharmaceutically acceptable salt is particularly preferably colesevelam hydrochloride.

In a preferred embodiment, 1 to 90%, more preferably 5 to 50%, especially 10 to 30% of the amino groups are alkylated. The alkylation is preferably carried out by reacting the polyallylamine polymer with 1-bromo-decane and / or (6-bromo-hexyl) -trimethylammonium bromide. In the case of colesevelam hydrochloride, the following structure (shown schematically) may be present:

In the above formula, the units (a) are unalkylated allylamine units, (b) are allylamine units crosslinked with epichlorohydrin, (c) are allylamine units alkylated with a decyl group, and (d) is (a) methylammonium) -hexyl group alkylated allylamine units. The proportions of these units add up to 100%, with each species preferably present in the total polymer at least 1%, more preferably at least 5%, especially at least 10%. Furthermore, the formula does not represent a particular order of units (a) - (d) because the crosslinking and alkylation of the units occurs along the polymer chain in a random fashion. A proportion (preferably less than 10%) of the amines is optionally dialkylated (not shown). A proportion of the amines (preferably 10 to 90%, in particular 30 to 70%) is optionally protonated. In the above formula, the polymer is represented as hydrochloride. However, bromide can optionally also be present in the polymer instead of chloride.

Further, in the above formula, m indicates the number of repeating units. Preferably, m is chosen so that the number average molecular weight described above is achieved. The polyallylamine polymer (or polyallylamine polymer salt) used may contain water. It usually comprises from 1 to 15% by weight of water, preferably from 2 to 12% by weight of water, based on the total weight of the polymer. Furthermore, the polyallylamine polymer (or polyallylamine polymer salt) used in the process according to the invention has a density of greater than 1.24 g / cm ³ , preferably a density of from 1.25 g / cm ³ to 1.30 g / cm ³ . The term "density" refers to the true density and is determined as described below. In particular, sevelamer hydrochloride or sevelamer carbonate of the above-mentioned density is used.

In step (i) of the process according to the invention, only the polyallylamine can be provided. In a preferred embodiment, however, one or more pharmaceutical excipients are provided in addition to the polyallylamine polymer. These are preferably mixed with the polyallylamine. These are the adjuvants known to those skilled in the art, for example those described in the European Pharmacopoeia.

Examples of auxiliaries are binders, disintegrants, flow control agents, mold release agents, lubricants, wetting agents, gelling agents, film coating agents and / or lubricants.

In a preferred embodiment, polyallylamine polymer in step (i) of the process according to the invention is mixed with one or more fillers and / or binders.

Fillers are generally to be understood as substances which serve to form the tablet body. That is, fillers produce by "stretching" of the active ingredients sufficient Tablettiermasse. So fillers are usually used to obtain a suitable tablet size.

Examples of preferred fillers are lactose, lactose derivatives, starch, starch derivatives, treated starch, talc, calcium phosphate, sucrose, sugar alcohols such as mannitol, isomalt, xylitol, sorbitol and / or maltitol; Calcium carbonate, magnesium carbonate, magnesium oxide, maltodextrin, calcium sulfate, dextrates, dextrin, dextrose, hydrogenated vegetable oil, kaolin, polymethacrylates, sodium chloride, and / or potassium chloride. Also, (microcrystalline) cellulose or derivatives thereof (such as Prosolv ^®, Rettenmaier & Sohne, Germany) may be used. Furthermore, mixtures of the abovementioned substances can be used. For example, a spray-dried mixture of lactose monohydrate (preferably 85% by weight) and corn starch (preferably 15% by weight) is preferably used. Such a mixture is commercially available under the trade designation "StarLac ^®".

Preferably, sugar alcohols are used as fillers, in particular mannitol, isomalt and / or maltitol.

Binders are usually used to increase the strength of the tablets. Binders may generally further contribute to the plastic deformation of the tabletting material during compression, e.g. by forming or enlarging the interparticle surfaces where bonds can form.

Possible binders are polysaccharides, such as hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC, in particular sodium and calcium salts), ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose (HPC); Guar gum, alginic acid and / or alginates; synthetic polymers such as polyvinylpyrrolidone (Kollidon ^®), polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), polymers of acrylic acid and salts thereof, polyacrylamide, polymethacrylates, vinylpyrrolidone-vinyl acetate copolymers (copolyvidone), 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) and mixtures of the polymers mentioned. If polymeric binders are used, they preferably have a weight-average molecular weight of from 5,000 to 120,000 daltons, more preferably from 10,000 to 70,000 daltons. Examples of preferred binders are gelatin, alginic acid, carbomer, dextrin, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, glucose, MgAl silicate, maltodextrin, methyl cellulose, polymethacrylate, povidone and derivatives thereof, pregelatinized starch, sodium alginate and / or Polyvinyl alcohol (PVA).

It is in the nature of pharmaceutical excipients that they partially perform multiple functions in a pharmaceutical formulation. Therefore, individual adjuvants can serve, for example, both as a filler and as a binder.

In a preferred embodiment, in step (i) of the method according to the invention

(A) 20 to 99 wt .-%, more preferably 30 to 95 wt .-%, in particular 40 to 90 wt .-% polyallylamine polymer or pharmaceutically acceptable salts thereof and

(B) 1 to 80 wt .-%, more preferably 5 to 70 wt .-%, in particular 10 to 60 wt .-% pharmaceutically acceptable excipients.

The mixing can be done in conventional mixers. Alternatively, the mixing of active substances and auxiliaries can also take place after the granulation step (iii). Alternatively, it is possible that the polyallylamine polymer is mixed with a part of the auxiliaries (e.g., 50 to 95%) before compaction (ii) and that the remaining part of the adjuvants is added after the granulation step (iii). In the case of Mehrfachkompaktierung the admixing of the excipients should preferably take place before the first compacting step, between several Kompaktiersch or after the last granulation step.

The polyallylamine polymer used in step (i) may have a volume-average particle size (d (50)) of, for example, 70 to 400 μm, preferably 100 to 300 μm.

The polyallylamine polymer used may alternatively be micronized. The micronization is preferably carried out before the compaction or before Mixing the polyallylamine polymer with the excipients. The micronization usually leads to an increase in the surface roughness. The micronization takes place, for example, in pin mills or air impact mills. The micronization can also be done by wet milling in ball mills. The micronized polyallylamine polymer preferably has a volume-average particle size (d (50)) of 0.5 to 20 .mu.m, preferably from 1 to 10 .mu.m. The volume average particle size is determined by laser diffractometry (using a Mastersizer 2000 from Malvern Instruments, dispersing module Scirocco 2000 (A) with air as dispersant and 1.5 bar dispersion air pressure, for the calculation an absorbance of 0.1 and a refractive index of 1, 52 was used). The average particle diameter, 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 corresponding to the D50 value. Likewise, then 50% by volume of the particles have a larger diameter than the D50 value. Analogously, the D90 value of the integral volume distribution is defined as the particle diameter at which 90% by volume of the particles have a smaller diameter than the diameter corresponding to the D90 value.

In step (ii) of the process according to the invention, the polyallylamine polymer from step (i) or, preferably, the mixture comprising polyallylamine and pharmaceutical excipients from step (i) is compacted to form the rag according to the invention. It is preferred that this is a dry compaction.

The compaction is preferably carried out in the absence of solvents, in particular in the absence of organic solvents.

The compaction conditions in step (ii) are preferably selected so that the slug has a density of 1.18 g / cm ³ to 1.50 g / cm ³ , more preferably from 1.19 g / cm ³ to 1.40 g / cm ³ , in particular from 1.20 g / cm ³ to 1.30 g / cm ³ . The term "density" here preferably refers to the "true density" (ie not to the bulk density or tamped density). The true density can be determined with a gas pycnometer. The gas pycnometer is preferably a helium pycnometer, in particular the device AccuPyc 1340 helium pycnometer manufactured by Micromeritics, Germany is used.

The compaction is preferably carried out in a roll granulator.

The rolling force is preferably 2 to 20 kN / cm, more preferably 3 to 15 kN / cm, especially 4 to 12 kN / cm.

The gap width of the rolling granulator is, for example, 0.8 to 5 mm, preferably 1 to 4 mm, more preferably 1, 5 to 3 mm, in particular 1, 8 to 2.8 mm.

The compacting device used preferably has a cooling device. In particular, it is cooled in such a way that the temperature of the compactate 55 does not exceed ⁰ ° C.

In step (iii) of the method according to the invention, the slug is granulated. The granulation can be carried out by methods known in the art.

In a preferred embodiment, the granulation conditions are selected so that the resulting particles (granules) have a volume average particle size (d (50) value) of 50 to 600 microns, more preferably 60 to 400 microns, even more preferably 70 to 250 microns , in particular from 80 to 150 microns. The volume average particle size is determined by laser diffractometry (using a Mastersizer 2000 from Malvern Instruments, measuring conditions as described above). Furthermore, the resulting particles (granules) usually have a d (20) value of the particle size distribution of from 20 to 80 .mu.m, preferably from 30 to 70 .mu.m, particularly preferably from 40 to 60 .mu.m. Finally, the resulting particles (granules) usually have a d (90) value of Particle size distribution of 100 to 800 .mu.m, preferably from 150 to 600 .mu.m, more preferably from 200 to 500 .mu.m.

In a preferred embodiment, the granulation is carried out in a sieve mill. In this case, the mesh size of the sieve insert is usually 0.1 to 5 mm, preferably 0.5 to 3 mm, more preferably 0.75 to 2 mm, in particular 0.8 to 1, 8 mm.

Optionally, the polyallylamine polymers may have a surface that is not sufficiently rough so that the compaction step (ii) described above is made more difficult. Therefore, depending on the surface condition, the compaction step (ii) and the granulation step (iii) may be repeated if necessary.

In a preferred embodiment, therefore, the inventive method is adapted so that a Mehrfachkompaktierung takes place, wherein the granules resulting from step (iii) is recycled one or more times for compaction (ii).

The granules from step (iii) are preferably recycled 1 to 5 times, in particular 2 to 3 times.

In the case of multiple compaction, the rolling forces can be up to 25 kN / cm.

In the case of multiple compaction, granulation (iii) preferably takes place by means of a so-called Frewitt sieve. It is preferably screened with mesh diameters of 50 to 250 microns.

In the case of multiple compaction, it is also possible that the amounts of excipients specified above are only partially added in step (i), with the remaining portions being added prior to further compacting operations. In step (iv) of the process according to the invention, the granules obtained in step (iii) are compressed into tablets, ie they are compressed into tablets. The compression can be done with tableting machines known in the art.

Process step (iv) is preferably carried out in the absence of solvents, in particular organic solvents, i. as dry compression.

In step (iv) of the process according to the invention, auxiliaries can be added to the granules from step (iii).

Examples of suitable excipients include, for example, additives to improve powder flowability (e.g., particulate silica), tablet lubricants (e.g., talc, stearic acid, adipic acid, sodium stearyl fumarate, and / or magnesium stearate) and disintegrants (e.g., croscarmellose, crospovidone). Furthermore, the auxiliaries mentioned under step (i) may also be added.

An example of an additive to improve the powder flowability (flow regulator) is dispersed silica, such as known under the trade name Aerosil ^®. Flow control agents usually have the task of reducing both the friction (cohesion) between the individual powder particles or granules and the adhesion of these to the wall surfaces of the pressing device.

Additives to improve the powder flowability are usually used in an amount of 0.1 to 3 wt .-%, based on the total weight of the formulation.

Furthermore, lubricants can be used. Lubricants are generally used to reduce sliding friction. In particular, the sliding friction is to be reduced, the tabletting on the one hand between the in the die bore moving up and down punches and the Matrizenwand and on the other hand between tablet web and Matrizenwand exists. Suitable lubricants are, for example, stearic acid, adipic acid, sodium stearyl fumarate and / or magnesium stearate.

Lubricants are usually used in an amount of from 0.1 to 3% by weight, based on the total weight of the formulation.

As disintegrants are generally referred to substances which accelerate the disintegration of a dosage form, in particular a tablet, after introduction into water. Suitable disintegrants are e.g. organic disintegrants such as carrageenan, croscarmellose and crospovidone.

Disintegrating agents are usually used in an amount of from 0.1 to 10% by weight, preferably from 1 to 5% by weight, based on the total weight of the formulation.

The amount of excipients added in step (iv) usually depends on the type of tablet to be prepared and on the amount of excipients already added in steps (i) or (ii).

The ratio of active ingredients to auxiliaries is preferably chosen so that the resulting tablets

(A) 65 to 99 wt .-%, more preferably 75 to 95 wt .-%, in particular 80 to 93 wt .-% polyallylamine polymer or its pharmaceutically acceptable salts and

(B) 1 to 35 wt .-%, more preferably 5 to 25 wt .-%, in particular 7 to 20 wt .-% pharmaceutically acceptable excipients.

These amounts are particularly preferred when tablets are produced by the method according to the invention, which are swallowed whole. The tablets produced by the process according to the invention may therefore be tablets which are swallowed whole (unfiltered or preferably film-coated). It can also be chewable tablets or disperse tablets. "Disperstablette" is here understood to mean a tablet for the production of an aqueous suspension for oral use.

In an alternative embodiment, therefore, chewing tablets can be produced by the method according to the invention. In this case, the ratio of active ingredients to adjuvants is preferably chosen so that the resulting chewable tablets

(a) 35 to 80% by weight, more preferably 45 to 70% by weight, in particular 55 to 65% by weight, of polyallylamine polymer or pharmaceutically acceptable salts thereof and

(B) 20 to 65 wt .-%, more preferably 30 to 55 wt .-%, in particular 35 to 45 wt .-% pharmaceutically acceptable excipients.

In a further alternative embodiment, disperse tablets can be produced by the method according to the invention. In this case, the ratio of active ingredients to adjuvants is preferably chosen so that the resulting Disperstabletten

(a) 35 to 60% by weight, more preferably 40 to 55% by weight, especially 42 to 51% by weight of polyallylamine polymer or pharmaceutically acceptable salts thereof and

(B) 40 to 65 wt .-%, more preferably 45 to 60 wt .-%, in particular 49 to 58 wt .-% of pharmaceutically acceptable excipients.

If granules according to the invention are prepared, which are preferably used for the preparation of an oral suspension, the ratio of active ingredients to auxiliaries is preferably chosen so that the resulting granules

(a) 25 to 90% by weight, more preferably 40 to 80% by weight, especially 52 to 74% by weight of polyallylamine polymer or pharmaceutically acceptable salts thereof and (B) 10 to 75 wt .-%, more preferably 20 to 60 wt .-%, in particular 26 to 48 wt .-% pharmaceutically acceptable excipients.

The method according to the invention is particularly suitable for the preparation of tablets containing a large amount of polyallylamine polymer or pharmaceutically acceptable salts thereof.

In a preferred embodiment, the tablets according to the invention contain 600 mg or more, more preferably 800 to 1200 mg, in particular 800 to 1000 mg of polyallylamine polymer or pharmaceutically acceptable salts thereof. These amounts are particularly preferred when tablets are produced by the method according to the invention, which are swallowed whole.

In the case of tablets which are swallowed whole, it is preferred that they be coated with a film layer. In this case, the usual in the prior art method for filming tablets can be used. However, the above-mentioned ratios of active ingredient to excipient relate to the unpainted tablet.

Preferably, macromolecular substances are used for the coating, for example modified celluloses, polymethacrylates, polyvinylpyrrolidone, polyvinyl acetate phthalate, zein and / or shellac.

In principle, films without influence on the drug release, enteric films and slow release films are possible. Films without influence on the drug release are usually water-soluble (preferably they have a water solubility of more than 250 mg / ml). Enteric-coated films have a pH-dependent solubility. Retarder films are usually not water-soluble (preferably have a water solubility of less than 10 mg / ml).

Preferred examples of film formers which have no influence on the drug release are methylcellulose (MC), hydroxypropyl methylcelluslose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), polyvinylpyrrolidone (PVP) and mixtures thereof. The polymers mentioned should usually have a weight-average molecular weight of 10,000 to 150,000 g / mol. Particularly preferably used is HPMC (also referred to as hypromellose), in particular HPMC having a weight-average molecular weight of 10,000 to 150,000 g / mol and / or an average degree of substitution of -OCH ₃ groups of 1.2 to 2.0.

The layer thickness of the coating is preferably 10 to 100 μm, more preferably 15 to 50 μm or even more preferably 30 to 60 μm.

The tabletting conditions are further preferably selected in the process according to the invention such that the resulting tablets have a tablet height to weight ratio of 0.005 to 0.3 mm / mg, more preferably 0.005 to 0.012 mm / mg.

Furthermore, the tablets according to the invention preferably have a breaking strength of from 100 to 300 N, more preferably from 120 to 200 N, in particular from 140 to 180 N, on. The breaking strength is determined according to Ph. Eur. 6, edition Grundwerk 2008. 2.9.8.

In addition, the tablets according to the invention preferably exhibit a friability of less than 2%, particularly preferably less than 1%, in particular less than 0.5%. The friability is calculated according to Ph.Eur. 6.0, Section 2.9.7.

Finally, the tablets according to the invention preferably exhibit a disintegration time of less than 15 minutes (min), particularly preferably less than 10 minutes, in particular less than 8 minutes, e.g. 5 to 7.5 minutes, up. The decay time is calculated according to Ph.Eur. 6.0, Section 2.9.1 (Exam A).

The invention is not only the inventive method, but also the tablets produced by this method. It has been found that the tablets produced by this process preferably have a monomodal or bimodal pore size distribution. Subject of the The invention thus relates to tablets comprising a polyallylamine polymer, in particular sevelamer or colesevelam, or pharmaceutically acceptable salts thereof and optionally pharmaceutically acceptable auxiliaries, wherein the tablet has a monomodal or bimodal pore size distribution. By "bimodal pore size distribution" is meant that the pore size distribution has two maxima.

The tablet according to the invention is produced when the granules from method step (iii) are compressed. This compact consists of solid and pores. The pore structure can be further characterized by determining the pore size distribution.

The pore size distribution was determined by mercury porosimetry. Mercury porosimetry measurements were carried out with the "Poresizer" porosimeter from Micromeritics, Norcross, USA. The pore sizes were calculated assuming a surface tension of mercury of 485 mN / m. From the cumulative pore volume, the pore size distribution was calculated as the sum distribution or proportion of the pore fractions in percent. The average pore diameter (4V / A) was determined from the total specific mercury intrusion volume (VgeSj _nt ) and the total pore area (Agesp _por ) according to the following equation.

In a preferred embodiment, the slug according to the invention (obtainable in step (ii) of the process according to the invention) has a maximum pore size distribution of from 5 to 50 .mu.m, more preferably from 10 to 30 .mu.m, in particular from 11 to 25 .mu.m.

In a preferred embodiment, the granules according to the invention (obtainable in step (iii) of the process according to the invention) have a maximum pore size distribution of from 10 to 100 .mu.m, more preferably from 20 to 80 .mu.m, in particular from 30 to 60 .mu.m. In a preferred embodiment, the tablets according to the invention (obtainable in step (iv) of the process according to the invention) have a maximum pore size distribution of 1 to 10 μm, more preferably 2 to 8 μm, in particular 3 to 6 μm.

In the method according to the invention, therefore, the process parameters described above are preferably chosen such that the described pore sizes are achieved.

Finally, the subject matter of the invention is the tablets according to the invention, or granules for the treatment of hyperphosphatemia or hyperlipidemia and for the improvement of the glycemic control.

The invention will be illustrated by the following examples.

Examples

Examples 1.1 to 1.3: tablets that are swallowed whole

The following tablets were prepared according to the method of the invention.

The procedure in Example 1.1. was done as described below.

A mixture of sevelamer hydrochloride having a density of 1.26 g / cm ³ and lactose was prepared with a Lödige MTG30 high speed mixer by intimately mixing 6.4 kg of sevelamer hydrochloride, 1.6 kg of lactose in the mixer for 10 minutes , Subsequently, this mixture was crushed on a pharmaceutically compatible roller compactor with a gap width of 2 mm and over a crushing sieve with a mesh width of 1.0 mm. The resulting broken compactate (= granules) was mixed with fumed silica and croscarmellose after sieving, and finally mixed with magnesium stearate. After pressing on a high-performance rotary tablet press into tablets of specified size (formulation 1.1: oblong 20.0 by 9.4 mm, height 7.2 mm), the in-process controls customary for the pharmaceutical form were carried out.

The mass proved to be well tablettable, no glue or lid appeared, the results of the in-process controls were in the usual range, e.g. but not exclusively hardness at 121-145 Newton, decay time at 9-10 min.

Examples 1.2 and 1.3 were carried out analogously.

It was also possible to obtain tablets having a hardness of greater than 120 N and a disintegration time of less than 10 minutes if sevelamer hydrochloride having a water content of about 4% by weight or alternatively 9% by weight was used.

Examples 2.1 to 2.3: tablets swallowed whole

The following tablets were prepared according to the method of the invention.

The execution of Examples 2.1 to 2.3 was carried out as described below.

A mixture of sevelamer carbonate (substantially free of sevelamer hydrochloride) and copolyvidone was made with a high speed mixer. Subsequently, fumed silica (1) and stearic acid (1) were mixed in the free-fall mixer after sieving and the mixture was compacted on a roller compactor suitable for pharmaceuticals. After passing through a 1.5 mm crushing sieve, the resulting crushed compactate was mixed with fumed silica (2) and crospovidone after sieving and end mixed with stearic acid (2). After pressing on a high-performance rotary tablet press into tablets of predetermined size (formulation 2.1 oblong 20.0 by 9.4 mm, height 5.8 mm), the in-process controls customary for the pharmaceutical form were carried out.

The mass proved to be well tablettable, there were no adhesives or lids, the results of the in-process controls were in the desired range. For example, in the case of the formulation according to Example 2.1, a hardness at 100-123 Newton and a disintegration time of 4 to 7 min. detected. The tablets according to Example 2 were also stored for 3 weeks. After storage, the tablets had a disintegration time of less than 15 minutes.

The tablets of Examples 1 and 2 could optionally be coated with a conventional aqueous or aqueous-alcoholic film.

For this purpose, hypromellose was prepared with water, after dissolving with talc, polyethylene glycol and titanium dioxide added and this suspension coated in Lochtrommelcoater:

Moisture of the cores before coating: 2.7% Moisture of the film-coated tablets after coating: 2.8% Weight of the film application: 28 mg per tablet Hardness of the film-coated tablets from Example 1: 135-170 N Disintegration time of the film-coated tablets from Example 1: 17- 23 min.

None of the film-coated tablets showed chipping.

Examples 3.1 to 3.4: tablets that are swallowed whole

The following tablets were prepared according to the method of the invention.

The preparation of the tablets was carried out essentially as described in Example 1 and 2. In Example 3.1, however, only Sevelamer was compacted in this case together with colloidal silicon dioxide, while in Examples 3.2 to 3.4 Sevelamer together with colloidal silicon dioxide and binder (Kollidon ^®, ^® StarLac or isomalt) was compacted.

Average breaking strength, friability and decay were as follows:

Examples 4.1 to 4.3: Disperse tablets

The following Disperstabletten were prepared according to the inventive method.

A mixture of sevelamer hydrochloride and microcrystalline cellulose (1) was prepared with a high speed mixer. Subsequently, in the free-fall mixer, fumed silica (1) and sodium stearyl fumarate (1) were added after sieving and the mixture was compacted on a roller compactor suitable for pharmaceuticals. After passing through a crushing sieve 1, 25 mm, the resulting crushed compactate was fumed with fumed silica (2) and croscarmellose mixed after sieving, then mixed with sodium stearyl fumarate (2) and then compressed on a high performance rotary tablet press into tablets of specified size (for formulation 4.1 round, biplane, diameter 18 mm, height 5.5 mm).

The mass proved to be well tablettable, there were no adhesives or lids, the results of the in-process controls were in the desired range. For example, in formulation according to Example 4.3, a hardness at 90-145 Newton and a disintegration time of 3-5 min. in 200 ml of room temperature water.

Examples 5.1 and 4.2: Chewable tablets

The following chewable tablets were prepared according to the method of the invention.

A mixture of sevelamer hydrochloride and mannitol (1) was made with a high speed mixer. Subsequently, fumed silica (1) and adipic acid (1) were mixed in a free-fall mixer after sieving and the mixture was compacted on a roller compactor suitable for pharmaceuticals. After passage over a crushing sieve with a mesh size of 1.0 mm, the resulting broken compactate was mixed with fumed silica (2), pregelatinized starch, mannitol (2), saccharin Na, aspartame and flavor after sieving, end mixed with adipic acid (2) and then compressed on a high-performance rotary tablet press into tablets of predetermined size (for formulation 5.1 round, biplane, diameter 20 mm, height 5.4 mm).

The mass proved to be well tablettable the results of the in-process controls were in the desired range. For example, in Formulation 5.1, the hardness of 70-105 N was in the easily chewable range, the abrasion was 0.37%.

Examples 6.1 and 6.2: Granules for filling into sachets

The following granules were prepared according to the process of the invention.

Sevelamer HCl, maltitol (1) and pregelatinized starch were blended with a high speed mixer. Subsequently, fumed silica (1) and polyethylene glycol 6000 (in powder form) were mixed in a free-fall mixer after sieving and the mixture was compacted on a roll cage factor suitable for pharmaceutical use. After passage through a 0.8 mm mesh screen, the resulting crushed compactate was mixed with maltitol (2), fumed silica (2), saccharine Na, aspartame and flavor after sieving and packed in sachets.

The mass proved to be well fillable, the relative standard deviation of the fillers was 6.1 srel = 4.2 to 4.6% in formulation.

Claims

claims

A process for producing tablets comprising a polyallylamine polymer comprising the steps

(i) providing a polyallylamine polymer or pharmaceutically acceptable salts thereof, optionally in admixture with one or more pharmaceutical excipients;

(ii) compaction into a slug;

(iii) granulation of the slug; and

(iv) compression of the resulting granules into tablets.

2. The method of claim 1, wherein the compaction conditions in step (ii) are selected such that the slug has a density of 1.18 to 1.50 g / cm ³ , preferably 1.20 to 1.30 g / cm ³ , having.

3. The method according to claim 1 or 2, characterized in that the compaction is carried out in a roll granulator.

4. The method of claim 3, wherein the gap width of the roll granulator is 1 to 3 mm.

5. The method according to claim 3 or 4, wherein the rolling force is 2 to 20 kN / cm, preferably 3 to 15 kN / cm.

6. The method according to any one of claims 1 to 5, wherein the granulation conditions in step (iii) are selected so that the resulting particles have a weight-average particle size of 50 microns to 500 microns.

7. The method according to any one of claims 1 to 6, wherein the granulation is carried out in a sieve mill with a mesh size of the sieve insert from 0.75 mm to 2 mm.

8. The method according to any one of claims 1 to 7, characterized in that in step (i)

(A) 65 to 99 wt .-% polyallylamine polymer or its pharmaceutically acceptable salts and

(B) 1 to 30 wt .-% pharmaceutically acceptable excipients are mixed.

9. The method according to any one of claims 1 to 8, wherein process step (iv) is selected so that the tablets produced contain at least 800 mg of a polyallylamine polymer or its pharmaceutically acceptable salts.

10. The method according to any one of claims 1 to 9, wherein the tablet is additionally coated in a step (v).

11. The method according to any one of claims 1 to 10, characterized in that it is the polyallylamine polymer sevelamer, colesevelam or their pharmaceutically acceptable salts.

12. The method according to claim 11, characterized in that it is the polyallylamine polymer to sevelamer hydrochloride and / or sevelamer carbonate.

13. The method according to claim 12, characterized in that a Mehrfachkompaktierung takes place, wherein the from step (iii) resulting granules is recycled one or more times for compaction (ii).

14. Tablets containing a polyallylamine polymer or pharmaceutically acceptable salts thereof, obtainable by a process according to any one of claims 1 to 13.

15. A tablet comprising a polyallylamine polymer, the tablet having a bimodal pore size distribution.

16. A tablet according to claim 14 or 15, which is a tablet which is swallowed whole, a chewable tablet or a disperse tablet.

17. A slug containing a polyallylamine polymer obtainable by a process comprising the steps

(ii) compaction into a slug.

18. Granules, in particular for filling sachets, containing a polyallylamine polymer obtainable by a process comprising the steps

(ii) compaction into a slug; and granulation of the slug.

19. The method according to any one of claims 1 to 13, wherein a polyallylamine

Polymer having a density of greater than 1, 24 g / cm ³ , preferably with a density of 1, 25 to 1, 30 g / cm ³ , is used.