WO2010115612A2

WO2010115612A2 - Pregabalin compositions

Info

Publication number: WO2010115612A2
Application number: PCT/EP2010/002172
Authority: WO
Inventors: Lisardo ÁLVAREZ FERNÁNDEZ
Original assignee: Synthon B.V.
Priority date: 2009-04-10
Filing date: 2010-04-01
Publication date: 2010-10-14
Also published as: WO2010115612A3

Abstract

The invention relates to a solid pharmaceutical blend which comprises 100 parts of a pregabalin compound and at least 15 parts of a pregelatinized starch, wherein said blend is substantially free of lactose, and to a pharmaceutical capsule filling composition, which comprises a pregabalin compound, pregelatinized starch, and a lubricant; wherein said composition does not contain lactose, mannitol, or microcrystalline cellulose.

Description

PREGABALIN COMPOSITIONS

Background of the Invention

The present invention relates to pharmaceutically acceptable compositions and dosage forms comprising pregabalin.

Pregabalin, S- (+)-4-amino-3- (2-methylpropyl) butanoic acid of the formula (1)

is a structural analogue of gamma-aminobutyric acid (GABA). Pregabalin acts as a modulator of voltage-gated calcium channels in the CNS, having the potential to treat neuropsychiatric disorders and pain. U.S. Pat. No. 6,197,819 discloses pregabalin and processes for its preparation. Pregabalin is an amino acid, i.e., it contains both a basic amino group and an acidic carboxy group, and thus in its free form can exist as a zwitterion (i.e., in a state where the carboxyl group is deprotonated and the primary amine moiety is protonated). Pregabalin may therefore form salts with both acids and bases; e.g., hydrochloride, hydrosulfates, etc., as well as sodium, potassium, etc.

Pregabalin is currently marketed as a capsule for oral administration with brand name LYRIC A® by Pfizer. The capsule is filled by a powder blend comprising free base of pregabalin as the active moiety (25, 50, 75, 100, 150, 200, 225 or 300 mg per capsule), lactose monohydrate, maize starch and talc. It has been reported that pregabalin and lactose can react with each other via a Maillard reaction (see Lovdahl J. L. et al., "Synthesis and Characterisation of Pregabalin Lactose Conjugate Degradation Products," Journal of Pharmaceutical and Biomediacal Analysis 28 (2002), 917-924). Such reactions are between a primary amino-group and a reducible sugar to form a conjugate product. US 7,022,678 confirms that pregabalin undergoes a Maillard reaction with lactose and that the commercial product apparently contained the conjugate products and its degradants. Several of these pregabalin degradation products are taught in US 7,022,678 to be useful as pharmaceuticals themselves. Nonetheless, the regulatory rules generally require the content and variation over time of any degradation products in a marketed composition to be minimal in order to avoid risks in efficacy and safety. The sensitivity of pregabalin to lactose via a Maillard reaction is a disadvantage of the marketed LYRICA® compositions.

Thus, it would be desirable to find a solid pharmaceutically acceptable composition of pregabalin having an improved stability in solid state.

Summary of the Invention

The present invention relates to the discovery that pregelatinized starch is an appropriate excipient for formulating pregabalin. Accordingly, a first aspect of the invention relates to a solid pharmaceutical blend, which comprises 100 parts of a pregabalin compound and at least 15 parts of a pregelatinized starch, wherein said blend is substantially free of lactose. The blend may further contain a lubricant, such as talc, and can be used in making a pharmaceutical unit dose of pregabalin. A second aspect of the invention relates to a pharmaceutical capsule-filling composition, which comprises a pregabalin compound, pregelatinized starch, and a lubricant; wherein said composition does not contain lactose, mannitol, or microcrystalline cellulose. Both the blend and the pharmaceutical composition can be formed into unit doses such as tablets, capsules, etc. Such medicaments can used in treating schizophrenia, epilepsy, neuropathic pain, fibromyalgia, generalised anxiety disorder, panic disorder and social phobia, by administering an effective amount of composition or dosage form of the present invention to a patient in need thereof.

Detailed Description of the Invention

Pregabalin has poor handling properties, particularly concerning flowability, for processing into a pharmaceutical composition, typically a capsule. Therefore, a "dilution" of pregabalin with a suitable solid diluent is a useful tool for making a composition with suitable technological properties. The present invention is based on the discovery that pregelatinized starch is a most suitable excipient for pregabalin, even avoiding the degradation issues mentioned above.

"Pregabalin" as used herein refers to S- (+)-4-amino-3- (2-methylpropyl) butanoic acid. Pregabalin is obtainable by known methods, such as those described in EPB 641 330. In free form, pregabalin is generally a crystalline compound but may be also prepared in an amorphous form (US Patent Application 20080014280). Crystalline forms of pregabalin may also comprise hydrated or solvated forms. The "pregabalin compound "as used herein is a free form of pregabalin or a pharmaceutically acceptable acid addition salt of pregabalin. A "pharmaceutically acceptable" salt is a salt in which the acid anion is not toxic to the human body to such an extent that it would affect the safety of the administration of pregabalin. Advantageously, a suitable pharmaceutically acceptable pregabalin salt may be pregabalin hydrochloride, pregabalin besylate or pregabalin tosylate.

The pregabalin compound, and particularly the free form of pregabalin, is advantageously formulated into the compositions of the present invention in a particulate state. Typically the pregabalin compound particles to be formulated have a median diameter of less then 500 microns, more particularly less than 300 microns.

"Pregelatinized starch" as used herein is a starch that has been chemically and/or mechanically processed to rupture all or part of the starch granules to yield a flowable and compressible powder. In general, the "pregelatinized starch" in the compositions of the present inventions is a starch that corresponds to the respective monograph of Ph.Eur. or US Pharmacopoeia.

Suitable particle size of the pregelatinized starch for making the composition of the present invention is a median diameter of less then 150 microns, preferably of about 50 microns.

In a basic form, the composition of the invention is a solid pharmaceutical blend, which comprises 100 parts of a pregabalin compound and at least 15 parts of a pregelatinized starch. Such an amount of pregelatinized starch is generally sufficient to provide the desired minimum flowability to the blend. Typically, however, the pregelatinized starch is contained in a proportion of 15 to 400 parts, preferably 20 to 200 parts per 100 parts of the pregabalin compound. Often the amount of pregabalin compound and pregelatinized starch in a composition of the invention is within the range of 20-85 weight % of pregabalin compound and 80-15 weight % of pregelatinized starch, based on the total weight of the composition, i.e., the blend, a capsule, etc. The blend is useful in forming pharmaceutical dosage forms such as capsules and tablets. Other excipients are typically combined therewith before the final dosage form is made; e.g., before filling the capsule or compressing a tablet. Accordingly, the blend can include additional excipients such as lubricants, etc., as are known in the art. But for stability concerns, it is preferred that the blend and all other compositions of the invention do not contain lactose, more preferably do not contain a reducible sugar, and in most cases contain no sugar; e.g., no mannitol. For clarity, the term "sugar" as used herein refers to mono- and disaccharides and is not intended to cover polysaccharides. Also the blend and other compositions of the invention preferably do not contain microcrystalline cellulose. As shown in Example 1 below, compositions of the invention that contain pregelatinized starch provide superior stability against the formation of pregabalin compound degradation products in comparison with similar blends comprising lactose, microcrystalline cellulose, or mannitol. Accordingly, preferred embodiments do not substantially contain these sugar or microcrystalline cellulose excipients; that is, such excipients are either not detectable or are present in such low amounts as to not adversely affect stability. As mentioned above, the pregabalin compound and pregelatinized starch blend may be combined with other suitable excipients before making the final form comprising it. In particular, it may be combined with a lubricant. Typical lubricants include magnesium stearate, stearic acid and/or talc. The preferred lubricant is talc. The relative amount of the lubricant may be from 2 to.25 weight %, relative to the total weight of the composition. Additional excipients include starch such as corn/maize starch. Such diluent or filler excipients are typically present from 0 to 50 weight %, more typically from 1 to 30 weight %, including 10-25 weight %, based on the total weight of the composition. The solid blend of the invention can be made by normal pharmaceutical means for blending an active ingredient with an excipient. Typically the blending is achieved by mixing in a suitable mixer and, optionally, milling and sieving the mixture to obtain a relative homogenous and intimate blend. The mixing can be done in one or more steps and can include additional excipients added in various orders; e.g., the pregabalin compound and pregelatinized starch do not have to be mixed first before additional excipients are added, though such is not excluded. Alternatively, the mixture of pregabalin compound and pregelatinized starch components may be granulated, with or without additional excipients, by means of wet or dry granulation, by processes known in the art, to form the blend in a form of a granulate. The granulate may be screened and/or milled to obtain a blend with suitable technological properties/sizes.

Generally the pharmaceutical blend, typically in bulk form, is used to form a pharmaceutical capsule for oral dosing of pregabalin. Such a pharmaceutical capsule- filling composition generally comprises a pregabalin compound, pregelatinized starch, and a lubricant; wherein the composition does not contain lactose, mannitol, or microcrystalline cellulose. Typically the capsule-filling composition comprises, per 100 parts of the pregabalin compound, 15 to 400 parts of the pregelatinized starch, and 5 to 100 parts of the lubricant. Additionally the composition can contain starch or such other excipient(s) as may be useful. Of course, lactose and more preferably all sugars as well as microcrystalline cellulose are preferably not substantially present in the capsule-filling composition. In some embodiments, the capsule-filling composition contains no more than 10% additional excipient(s) beyond the pregabalin compound, pregelatinized starch, lubricant, and optional starch. The use of a simple formulation is generally preferred and hence the presence of additional excipients is often preferred to not exceed 5%, in some cases not greater than 1 % and in many cases, the capsule-filling composition consists of the pregabalin compound, pregelatinized starch, lubricant, and optional starch.

The ready-to-use filling mixture, which again is generally made by conventional mixing techniques of the dry or solid components, can be filled into a capsule, particularly a gelatine capsule, of a proper size. In general, 20 to 1000 mg of the filling mixture is filled per capsule, thus obtaining a single dosage form comprising the therapeutically effective or desirable amount of pregabalin. The capsule may comprise from 10 to 500 mg of pregabalin within the mixture, particularly 25, 50, 75, 100, 150, 200, 225 or 300 mg of pregabalin per capsule.

The pharmaceutical compositions and dosage form of the present invention may be used in treating various diseases and conditions, towards which the pregabalin is active ("pregabalin- treatable diseases"), such as treating epilepsy, schizophrenia, neuropsychiatric disorders (e.g. generalized anxiety disorder, panic disorder, social phobia), and pain incl. neuropathic pain, fibromyalgia and acute herpetic and postherpetic pain. In general, the treatment comprises administering an effective amount (e.g. a pain relieving amount) of the pregabalin composition of the present invention to a patient in need thereof.

The invention will be further described with reference to the following non- limiting examples.

Example 1

A blend comprising 25 % of pregabalin, 20% of starch, 20 % of talc and 35 % of another excipient (the variable excipient) as listed below were prepared and filled into the Size 0 gelatine capsules. The capsules were placed in an open dish at 4OC 1 15 % RH for two months and analysed. Assay and purity was measured at t = 0, t = 1 and t=2 months, using pregabalin as reference material. The content of the known lactam impurity (arisen from pregabalin) was calculated using the known response factor (RRF = 17); the other impurities were calculated as if having the RRF 1.0.

Results:

Example 2

A pregabalin capsule dosage form was prepared as follows:

Composition

Pregabalin 75 %

Pregelatinized starch 16.625 %

Talc 8.375 %

100 % Pregabalin was sieved and blended with pregelatinized starch (Starch 1500) to a homogeneous blend. To the blend, talc (Super 60) was added and the mixture was blended again. The final mixture was filled in a Size 0 capsule in an amount of 400 mg of the blend per capsule (300 mg of pregabalin per capsule).

The invention having been described it will be obvious that the same may be varied in many ways and all such modifications are contemplated as being within the scope of the invention as defined by the following claims.

Claims

1. A solid pharmaceutical blend which comprises 100 parts of a pregabalin compound and at least 15 parts of a pregelatinized starch, wherein said blend is substantially free of lactose.

2. The blend according to claim 1, wherein said pregelatinized starch is contained in an amount within the range of 15 to 400 parts, preferably 20 to 200 parts.

3. The blend according to claim 1 or 2, wherein said pregabalin compound is pregabalin free form.

4. The blend according to claims 1-3, wherein said pregelatinized starch has a median diameter of less then 150 microns, preferably of about 50 microns.

5. The blend according to claims 1-4, wherein said blend is substantially free of a reducible sugar, and preferably said blend is substantially free of sugar.

6. The blend according to claims 1-5, wherein said blend is substantially free of microcrystalline cellulose.

7. The blend according to claims 1-6, which further comprises a lubricant, which lubricant is preferably talc.

8. A pharmaceutical capsule filling composition, which comprises a pregabalin compound, pregelatinized starch, and a lubricant; wherein said composition does not contain lactose, mannitol, or microcrystalline cellulose.

9. The pharmaceutical composition according to claim 8, wherein said composition comprises 100 parts of said pregabalin compound, 15 to 400 parts of said pregelatinized starch, and 5 to 100 parts of said lubricant.

10. The pharmaceutical composition according to claim 8 or 9, which further comprises starch.

11. An oral capsule comprising a therapeutically effective amount of the pharmaceutical composition according to claims 8-10.

12. The capsule according to claim 11 , wherein said capsule contains 10 to 500 mg of pregabalin, particularly, 25, 50, 75, 100, 150, 200, 225 or 300 mg of pregabalin per capsule.

13. Pharmaceutical blend of claims 1-7 or the pharmaceutical composition of claims 8-10, or the oral capsule of claims 11 or 12 for use in treating pregabalin-treatable diseases.