DE102008045854A1 - Particles of ziprasidone and a disintegrant containing pharmaceutical composition - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for oral administration which comprises particles prepared by compacting and granulating a mixture containing ziprasidone or a pharmaceutically acceptable salt thereof as an active ingredient and a disintegrant, so that intimate contact of the drug particles with the drug Blasting agent is given. Furthermore, the present invention relates to a process for the preparation of the pharmaceutical composition according to the invention, which allows the use of drug particles having an average particle size within a wide range without adverse effects on the solubility of the active ingredient in water.

Description

The The present invention relates to a pharmaceutical composition for oral administration, the ziprasidone or a pharmaceutical acceptable salt thereof, preferably the anhydrous one Hydrochloride salt of ziprasidone.

Ziprasidone is used in psychiatry as an antipsychotic in schizophrenia, as well as in bipolar disorders for the treatment of manic and mixed episodes. Ziprasidone is marketed as capsules under the trade name Zeldox ^® as its Hydrochloridmonohydratsalzes.

• 1. die Mikronisierung des Wirkstoffs
• 2. die Verwendung spezieller pharmazeutisch verträglicher Hilfsstoffe, zum Beispiel die Verwendung von Lösungsvermittlern für den Wirkstoff
• 3. die Verwendung spezieller Herstellungsverfahren.

It is known that the hydrochloride salt of ziprasidone has poor solubility in an aqueous medium, which adversely affects its bioavailability. To overcome the problem of the poor solubility of ziprasidone, in particular its hydrochloride salt in an aqueous medium, essentially three measures are described in the prior art:

• 1. the micronization of the active substance
• 2. the use of special pharmaceutically acceptable excipients, for example the use of solubilizers for the active substance
• 3. the use of special manufacturing processes.

• a) Lösen der freien Base von Ziprasidon in einem Lösungsmittel, welches Tetrahydrofuran (THF) und Wasser umfasst,
• b) Erwärmen der Lösung,
• c) Zugabe von Salzsäure, und
• d) Kühlen der resultierenden Lösung und Isolieren des ausgefallenen kristallinen Ziprasidonhydrochlorids.

EP 0 965 343 discloses ziprasidone-containing pharmaceutical compositions, in particular capsule formulations. In the compositions described, ziprasidone is present as the free base or hydrochloride salt and in crystalline form. The compositions are characterized in that the active ingredient has an average particle size (D ₅₀ ) of equal to or less than 85 μm, it being found that ziprasidone particles having an average particle size of equal to or less than 85 μm are bioequivalent, ie the bioavailability of the Substance below this limit is substantially independent of the particle size. In addition revealed EP 0 965 343 a method of producing ziprasidone hydrochloride comprising the steps of:

• a) dissolving the free base of ziprasidone in a solvent comprising tetrahydrofuran (THF) and water,
• b) heating the solution,
• c) addition of hydrochloric acid, and
• d) cooling the resulting solution and isolating the precipitated crystalline ziprasidone hydrochloride.

By Setting the THF / water volume ratio can be the average particle size of the crystalline ziprasidone hydrochloride be set, being found that with an increase of the THF content in the solvent, the mean particle size increases.

WO 2006/085168 discloses a solid pharmaceutical composition for oral administration, wherein the ziprasidone particles containing have a particle size D ₉₀ of equal to or less than 10 microns and wherein the formation of agglomerates of the Ziprasidonpartikeln is prevented by the addition of colloidal silica. It is described that colloidal silica functions as a carrier material for the active ingredient and has the property of disagglomerating agglomerates of ziprasidone particles by neutralizing the surface charge of the individual particles.

WO 2007/027273 describes pharmaceutical compositions comprising ziprasidone-containing particles, wherein the average particle size of the drug particles is less than 2 microns, which is achieved by the use of surface-active agents as surface stabilizers.

WO 2005/065660 discloses a pharmaceutical composition containing ziprasidone or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the active ingredient has an average particle size greater than 85 microns. WO 2005/065660 essentially describes pharmaceutical compositions for a controlled, e.g. B. sustained release of the active ingredient.

WO 2005/107719 discloses ziprasidone-containing pharmaceutical compositions, wherein in a preferred embodiment the mean particle size of the active ingredient is greater than 85 microns. Increasing the solubility of the active ingredient while avoiding the usual micronization of the active ingredient has been achieved by adding to the pharmaceutical composition a compound having at least one carboxy group. Preferred compounds having at least one carboxy group include monocarboxylic acids, dicarboxylic acids, tricarboxylic acids, polymers having at least one carboxy group, and the like, with citric acid being the most preferred compound. Thieves described pharmaceutical compositions can be obtained by wet and dry granulation, wherein the resulting granules containing both the active ingredient and the compound having at least one carboxy group.

WO 2005/123086 discloses pharmaceutical compositions containing ziprasidone or a pharmaceutically acceptable salt thereof having an average particle size of at least 90 microns and a hydrophilic excipient. Preferably, as a hydrophilic excipient surfactants are used as solubilizers for the active ingredient, in particular polysorbates.

US 2003/0219489 describes a pharmaceutical composition comprising a spray-dried solid dispersion wherein the dispersion comprises a poorly water-soluble active agent, e.g. Ziprasidone, and hydroxypropyl methylcellulose acetate succinate (HPMCAS) as a solubilizer for the active ingredient.

WO 2007/126322 discloses a process for the preparation of a pharmaceutical composition comprising ziprasidone or a pharmaceutically acceptable salt thereof, which is characterized in that the active ingredient is compacted with one or more pharmaceutically acceptable excipients. In a preferred embodiment, the active ingredient is compacted with a solubilizer and optionally with fillers and / or lubricants, with poly (oxyethylene) derivatives, glyceryl derivatives, alkylcellulose derivatives, polyvinyl derivatives and starch derivatives being mentioned as preferred solubilizers. Hydroxypropylcellulose, cyclodextrin, poloxamer and polyvinylpyrrolidone (povidone) are mentioned as particularly preferred solubilizers.

WO 2007/102038 discloses pharmaceutical compositions for the hydrate of ziprasidone hydrochloride, wherein the composition is prepared using a dry granulation process. In particular disclosed WO 2007/102038 a pharmaceutical composition containing the hydrochloride salt of ziprasidone as a hydrate having an average particle size of 100 to 300 microns. WO 2007/102038 Essentially relates to hydrates of ziprasidone hydrochloride which can be dry-granulated with suitable pharmaceutically acceptable excipients and further processed into the final product.

in view of of the prior art described above was the present Invention as an object, a pharmaceutical composition for ziprasidone or a pharmaceutically acceptable Salt of which is sufficient for the active ingredient good solubility in an aqueous medium, e.g. B. in a physiological environment, provides, these sufficiently good solubility for drug particles having a mean particle size within one large area is given. The pharmaceutical composition should thus have a sufficiently good solubility and bioavailability provide for the drug, this solubility essentially independent of the average particle size of the Active ingredient in the composition is.

These The object is achieved by the subject matter specified in the claims solved.

It was found to have sufficiently good solubility of the active ingredient is then given when the drug particles in the intimate Contact with a disintegrant in a pharmaceutical composition. If this intimate contact is given, the solubility and the bioavailability is essentially independent from the mean particle size of the active ingredient within the pharmaceutical composition.

As a result, For example, the present invention relates to a pharmaceutical composition for oral administration, comprising particles obtained by compaction and granulating a mixture containing ziprasidone or a pharmaceutically acceptable salt thereof as an active ingredient and a disintegrant, are made so that intimate contact the drug particles is given with the disintegrant.

Preferably Compaction is a roll compaction.

Furthermore It was completely surprising that it was beneficial is when the mean particle size of the drug relatively large, d. H. equal to or more than 90 μm is.

Starch derivatives, cross-linked polyvinylpyrrolidone (crospovidone), low-substituted sodium carboxymethylcellulose, sodium starch glycolate, microcrystalline cellulose, low-substituted hydroxypropylcellulose and the like, and optionally also mixtures thereof, can be used as disintegrating agents. Be Particularly preferred is low-substituted hydroxypropyl cellulose, which, in contrast to the hydroxypropyl cellulose is insoluble in water and thus can act as a disintegrant. It has been found that a low-substituted hydroxypropyl cellulose of the LH-11 (Shin-Etsu) type, which is fibrous, has a hydroxypropyl content of 11% and an average particle size of 55 μm, is particularly suitable.

The Blasting agent should be based on the total weight of compaction available particles, in an amount of 5 to 50 wt .-%, preferably from 8 to 40% by weight and most preferably from 10 be contained to 20 wt .-%.

The in the pharmaceutical composition according to the invention containing particles preferably contain no solubilizer for ziprasidone or a pharmaceutically acceptable Salt of it. Also, it is not necessary that the pharmaceutical Composition at all a solubilizer for contains the active ingredient.

solubilizers are especially surface-active pharmaceutical excipients, such as anionic, amphoteric and nonionic surfactants. Preferably, neither the particles nor the composition contain the conventionally used solubilizers Sodium lauryl sulfate, an anionic surfactant, or poly (oxyethylene) sorbitan fatty acid ester (Polysorbate), a nonionic surfactant. That is, in a preferred Embodiment of the invention Composition contain the particles or the composition total no solubilizers that are able to the solubility of the active ingredient in water by ingestion of the same in surfactant micelles continue to increase.

In In a particularly preferred embodiment, the Composition according to the invention Particles containing exclusively from ziprasidone or a pharmaceutical acceptable salt thereof as an active ingredient and a or multiple explosives exist or are made. Possibly In the particle, a lubricant, for. B. sodium stearyl fumarate or magnesium stearate. Furthermore you can the particles optionally contain a binder, for. B. vinylpyrrolidone / vinyl acetate copolymer (Copovidone).

The inventive pharmaceutical composition is preferably a capsule or tablet, optionally one film-coated tablet.

• i) Kompaktieren eines Gemisches, enthaltend Ziprasidon oder ein pharmazeutisch verträgliches Salz davon als einen Wirkstoff und ein Sprengmittel, um ein erstes Komprimat zu erhalten, und
• ii) Granulieren des ersten Komprimats.

Usually, the pharmaceutical composition according to the invention is produced by a dry granulation process, comprising the steps:

• i) compacting a mixture containing ziprasidone or a pharmaceutically acceptable salt thereof as an active ingredient and a disintegrating agent to obtain a first compressed product, and
• ii) granulating the first concentrate.

• iii) Kompaktieren des Granulats aus Schritt (ii), um ein zweites Komprimat zu erhalten,
• iv) Granulieren des zweiten Komprimats, und gegebenenfalls
• v) Wiederholen der Schritte (iii) und (iv).

If appropriate, the following process steps may be followed by the following:

• iii) compacting the granules of step (ii) to obtain a second compressed product,
• iv) granulating the second concentrate, and optionally
• v) repeating steps (iii) and (iv).

The Compacting is preferably a roll compaction, wherein a Comprimat (or Schülpe) is obtained, then ground, d. H. is granulated.

It it was found that the compaction and granulation of a mixture from ziprasidone or a pharmaceutically acceptable Salt thereof and a disintegrating agent may optionally be repeated, to the rate of release of the drug from the pharmaceutical Adjust composition to the desired level. It has also been found that the more frequently the process steps (iii) and (iv) granules containing ziprasidone or a pharmaceutical acceptable salt thereof and a disintegrant applied be, the greater the rate of release, which is observed for the active ingredient.

The granules prepared by the process described above can then be filled either directly, optionally with other pharmaceutically acceptable excipients, into a capsule or further processed into a tablet. For this purpose, the granules are optionally further processed with other pharmaceutically acceptable excipients to a tablet mass, which is then compressed into a tablet. Preferably, after compression of the tablet mass, the integrity of the granules in the resulting Essentially obtained tablet, so that the obtained by the inventive method intimate contact between the drug particles and the disintegrant is maintained.

For the preparation of the capsule formulation and the tablet composition can the usual pharmaceutically acceptable excipients be used.

When Fillers may, for. Cellulose powder, mannitol, Calcium diphosphate, various strengths such. Corn starch, microcrystalline cellulose, silicified microcrystalline cellulose, Calcium carbonate, calcium lactate, sorbitol, dextrose, lactitol, lactose (anhydrous or monohydrate) and the like.

The The tablet according to the invention can also be extragranular contain a disintegrant, for. B. Starch derivatives (pregelatinized Starch), cross-linked polyvinylpyrrolidone (crospovidone), low-substituted sodium carboxymethylcellulose, sodium starch glycolate, microcrystalline cellulose, low-substituted hydroxypropyl cellulose and the same.

Naturally For example, the above-mentioned disintegrants can also be used for the production the granules according to the invention used themselves wherein low-substituted hydroxypropyl cellulose is the preferred disintegrant is.

When a lubricant for improving the flow properties or the flowability of the granules can in particular the tablet mass or capsule formulation magnesium stearate, Calcium stearate, sodium stearyl fumarate, hydrogenated castor oil, Talc and the like may be added.

• i) Kompaktieren eines Gemisches (erste Granuliermischung), das ausschließlich aus Ziprasidon oder einem pharmazeutisch verträglichen Salz davon als einen Wirkstoff, einem oder mehreren Sprengmitteln, und gegebenenfalls einem oder mehreren Gleitmitteln und/oder Bindemitteln besteht, um ein erstes Komprimat zu erhalten,
• ii) Granulieren des ersten Komprimats.

In particular, the pharmaceutical composition according to the invention is characterized in that there is an intimate contact between the active ingredient particles and the disintegrating agent obtained by applying the dry granulation method described above. The granulation mixture used to prepare the first concentrate preferably consists exclusively of ziprasidone or a pharmaceutically acceptable salt thereof, one or more disintegrants, and optionally a lubricant and / or binder (step (i)). In other words, the diluents or fillers customarily used in dry granulation are not used in the production of the first concentrate, so that intimate contact between the active substance and the disintegrant, ie the largest possible contact surface between the active substance surface and the disintegrant surface, is possible consists. The first compressed product thus obtained is then granulated (step (ii)). The composition according to the invention therefore preferably comprises particles prepared by compacting and granulating a mixture containing ziprasidone or a pharmaceutically acceptable salt thereof as an active ingredient, a disintegrant and no filler such that intimate contact of the drug particles with the disintegrant is provided. The resulting first granulate may then optionally again be subjected to compaction (step (iii)), wherein the first granules may be further pharmaceutically acceptable auxiliaries, such as binders and disintegrating agents, which may be the same or different from those used in the preparation of the first granulating mixture were added to obtain a second granulation mixture. If desired, this second granulation mixture can be diluted with fillers which, however, are preferably not present in the first granulation mixture in step (i). Thus, in a particularly preferred embodiment, the process for the preparation of the pharmaceutical composition according to the invention comprises the steps:

• i) compacting a mixture (first granulation mixture) consisting exclusively of ziprasidone or a pharmaceutically acceptable salt thereof as an active ingredient, one or more disintegrants, and optionally one or more lubricants and / or binders to obtain a first compressed product,
• ii) granulating the first concentrate.

• iii) Kompaktieren des ersten Granulats aus Schritt (ii), um ein zweites Komprimat zu erhalten, wobei dem ersten Granulat vor dem Kompaktieren pharmazeutisch verträgliche Hilfsstoffe zugesetzt werden, die aus Sprengmitteln, Bindemitteln und Füllstoffen ausgewählt sind, um eine zweite Granuliermischung zu erhalten,
• iv) Granulieren des zweiten Komprimats, und gegebenenfalls
• v) Wiederholen der Schritte (iii) und (iv), wobei die dritte, vierte, etc. Granuliermischung im Schritt (iii) weitere pharmazeutisch verträgliche Hilfsstoffe enthalten kann oder nicht.

If necessary, the process described above may be followed by the following process steps:

• iii) compacting the first granulate from step (ii) to obtain a second compressed product, wherein pharmaceutically acceptable excipients selected from disintegrants, binders and fillers are added to the first granule prior to compaction to obtain a second granulation mixture,
• iv) granulating the second concentrate, and optionally
• v) repeating steps (iii) and (iv), wherein the third, fourth, etc. granulation mixture in step (iii) may or may not contain further pharmaceutically acceptable excipients.

Without to be bound to a theory, it is believed that the in the pharmaceutical composition according to the invention observed increased release rate for the active ingredient by the intimate contact of the drug particles with given to the disintegrant, so that when the tablet disintegrates in an aqueous medium through the use of disintegrants not only the disintegration of the composition according to the invention itself, but also a crushing of drug particles occurs. This makes it possible, even relatively large particles of active ingredient, the one mean particle size equal to or more than 90 microns for the production of pharmaceutical Use composition as this during the dissolution process the tablet are crushed. It is believed that through this In situ comminution of the drug its solubility in the physiological environment and ultimately increases its bioavailability becomes.

Examples

The capsule formulations described below were prepared by the method according to the invention. example 1 ingredients Mass [mg] granulation Ziprasidone hydrochloride (anhydrous) 87.676 Lactose monohydrate (Tablettose ^® 80) 178.72 Pre-gelatinized starch (Starch 1500 ^® ) 30,000 magnesium stearate 1,200 Final Formulation corn starch 1,200 magnesium stearate 1,200 total weight 300.00

Method:

Ziprasidone hydrochloride, lactose, pregelatinized starch and magnesium stearate were sieved and mixed. The granulation mixture thus obtained was compacted by roll compacting to obtain a compact and subsequently granulated to obtain a granule which was mixed with corn starch and magnesium stearate and filled into a capsule. Examples 2-6 Example 2 [mg] Example 3 [mg] Example 4 [mg] Example 5 [mg] Example 6 [mg] granulation Ziprasidone hydrochloride (anhydrous) 43.838 43.838 43.838 43.838 43.838 Low-substituted hydroxypropyl cellulose (LH 11) 40,000 30,000 20,000 10,000 5,000 sodium stearyl 1,000 1,000 1,000 1,000 1,000 Final Formulation Lactose (anhydrous) (Pharmatose ^® DCL 21) 64.662 74.662 84.662 94.662 99.662 sodium stearyl 0,500 0,500 0,500 0,500 0,500 total weight 150.00 150.00 150.00 150.00 150.00

Method:

The capsules according to Examples 2-6 were prepared as indicated in Example 1. Example 7 ingredients Mass [mg] granulation Ziprasidone hydrochloride (anhydrous) 87.676 Crospovidone (Polyplasdone ^® XL-10) 60,000 Copovidone (Plasdone ^® S-630) 20,000 magnesium stearate 1,000 Final Formulation Lactose monohydrate (Capsulac® ^® 60) 130.324 magnesium stearate 1,000 total weight 300.00

Method:

A mixture of ziprasidone hydrochloride (anhydrous), crospovidone, copovidone and magnesium stearate was provided. This granulation mixture was compacted and then granulated to obtain a first granules. The above-mentioned process steps compacting and granulating were repeated up to four times. The ultimately resulting granules, z. B. the fifth granules were mixed with lactose monohydrate and magnesium stearate and filled into a capsule. Examples 8-11 Example 8 [mg] Example 9 [mg] Example 10 [mg] Example 11 [mg] granulation Ziprasidone hydrochloride (anhydrous) 21.766 43.531 65.297 87.062 Low-substituted hydroxypropyl cellulose 2,500 5,000 7,500 10,000 sodium stearyl 0,500 1,000 1,500 2,000 Final Formulation Lactose (anhydrous) 56.984 113.969 170.953 227.938 sodium stearyl 0,250 0,500 0,750 1,000 total weight 82,000 164000 246000 328000

Method:

Anhydrous Ziprasidone hydrochloride, low-substituted hydroxypropyl cellulose and sodium stearyl fumarate were sieved and mixed. The thus preserved Granulation mixture was compacted using a Roll compaction to obtain a compact, and subsequently granulated to obtain granules containing Lactose (anhydrous) and sodium stearyl fumarate mixed and in one Capsule was filled.

QUOTES INCLUDE IN THE DESCRIPTION

This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

Cited patent literature

• EP 0965343 [0004, 0004]
• WO 2006/085168 [0006]
• - WO 2007/027273 [0007]
• WO 2005/065660 [0008, 0008]
• WO 2005/107719 [0009]
• WO 2005/123086 [0010]
• US 2003/0219489 [0011]
• - WO 2007/126322 [0012]
• - WO 2007/102038 [0013, 0013, 0013]

Claims (12)

Pharmaceutical composition for oral administration, comprising particles obtained by compacting and granulating a A mixture containing ziprasidone or a pharmaceutically acceptable salt of which are manufactured as an active ingredient and a disintegrating agent, so that intimate contact of the drug particles with the disintegrant given is. A composition according to claim 1, wherein the compaction is a Walzenkompaktierung. A composition according to claim 1 or 2, wherein the mean particle size of the active ingredient is equal to or more than 90 microns. Composition according to one of the claims 1 to 3, wherein the disintegrant is low-substituted hydroxypropyl cellulose is, optionally in admixture with other disintegrants. Composition according to one of the claims 1 to 4, wherein the disintegrant is in an amount of 5 to 50 wt .-%, preferably from 8 to 40% by weight and most preferably from 10 to 20 wt .-%, based on the total weight of the particles is. Composition according to one of the claims 1 to 5, wherein the particles no solubilizer for the Contain active substance, in particular not sodium lauryl sulfate (SDS) or a polysorbate. A composition according to claim 6, wherein the composition does not contain a solubilizer for the active substance, especially not sodium lauryl sulfate (SDS) or a polysorbate. Composition according to one of the claims 1 to 7, wherein the particles exclusively from ziprasidone or a pharmaceutically acceptable salt thereof as one Active ingredient, one or more disintegrants, and optionally a lubricant and / or binder are made. Capsule or tablet comprising the pharmaceutical Composition according to one of Claims 1 to 8. Process for the preparation of a pharmaceutical A composition according to any one of claims 1 to 8 comprising the steps: i) compacting a mixture containing ziprasidone or a pharmaceutically acceptable salt thereof as one Drug and a disintegrant to get a first and ii) granulating the first concentrate. The method of claim 10, comprising the additional ones Steps: iii) compacting the granules from step (ii), to get a second copy, iv) granulating the second Compressed, and if necessary v) Repeat the steps (iii) and (iv). A method according to claim 10 or 11, wherein the compacting is a Walzenkompaktierung.