JP7200408B2 - Solid pharmaceutical composition containing pregabalin and method for producing the same - Google Patents

Description

TECHNICAL FIELD The present invention relates to a pregabalin-containing solid pharmaceutical composition exhibiting high stability and a method for producing the same.

Pregabalin is a novel calcium channel modulator that blocks voltage-gated calcium channels to reduce neurotransmitter release and is clinically used primarily for the treatment of peripheral neuropathic pain and adjunctive treatment of partial-onset seizures. (non-γ-butanoic acid (GABA) receptor agonists or antagonists).

Patent Document 1 describes that a GABA derivative containing pregabalin produces a lactam that is a degradation product of pregabalin during formulation and storage, and isomalt is used to suppress the production of the lactam. It is stated that

Moreover, Patent Document 2 describes that lactam production can be suppressed by using ethylene glycol, propylene glycol, butylene glycol, triacetin, or decaglyceryl monolaurate as a water retention agent.

Furthermore, Patent Document 3 describes that lactam production can be suppressed by using an α-amino acid.

However, none of these patent documents describes or suggests that glyceryl monostearate suppresses lactam body formation from pregabalin.

U.S. Pat. No. 8,968,780 Japanese Patent No. 4564607 Japanese Patent No. 4612923

An object of the present invention is to provide a new means for suppressing the formation of lactam bodies in solid pharmaceutical compositions containing pregabalin.

The inventors of the present invention conducted intensive studies to solve the above problems, and surprisingly found that glyceryl monostearate significantly inhibits the formation of lactam bodies in solid pharmaceutical compositions containing pregabalin, and completed the present invention. bottom.

Accordingly, the present invention provides a solid pharmaceutical composition containing pregabalin and glyceryl monostearate.

Also provided is a solid pharmaceutical composition containing pregabalin and glyceryl monostearate, wherein the content of pregabalin is 10 to 60% by weight per solid pharmaceutical composition.

Also provided is a solid pharmaceutical composition containing pregabalin and glyceryl monostearate, wherein the content of glyceryl monostearate is 1 to 20% by weight per solid pharmaceutical composition.

Also provided is a solid pharmaceutical composition containing pregabalin and glyceryl monostearate, wherein the content of glyceryl monostearate is 0.01 to 20% by weight relative to the content of pregabalin.

Also provided is a solid pharmaceutical composition containing pregabalin and glyceryl monostearate, which also contains additives other than glyceryl monostearate.

Also provided is a solid pharmaceutical composition comprising crospovidone, pregabalin and glyceryl monostearate.

Also provided is a solid pharmaceutical composition containing crospovidone, pregabalin and glyceryl monostearate, wherein the content of crospovidone is 1 to 20% by weight per solid pharmaceutical composition.

Also provided are tablets, capsules, powders, granules and fine granules containing pregabalin and glyceryl monostearate.

Also provided is an orally disintegrating tablet containing pregabalin and glyceryl monostearate.

Also provided is a method for producing a solid pharmaceutical composition comprising the step of melt granulating pregabalin and glyceryl monostearate.

INDUSTRIAL APPLICABILITY The pregabalin-containing solid pharmaceutical composition of the present invention is useful as a medicament with good stability of pregabalin because the formation of the lactam form of pregabalin, which is an active ingredient, is suppressed.

FIG. 4 shows the ratio of lactam bodies measured in a stress test (heat conditions).

In the present invention, pregabalin ((3S)-3-(Aminomethyl)-5-methylhexanoic acid) is a compound represented by the following chemical formula. Pregabalin can be produced, for example, by the method described in JP-A-7-508288. The content of pregabalin is preferably 10 to 60% by weight, more preferably 20 to 50% by weight, particularly preferably 30 to 40% by weight, per one solid pharmaceutical composition.

In the present invention, glyceryl monostearate may be any one used in the technical field. The content of glyceryl monostearate is preferably 1 to 20% by weight, more preferably 2 to 10% by weight, per solid pharmaceutical composition.
Also, the glyceryl monostearate content is preferably 0.01 to 20% by weight, more preferably 0.1 to 10% by weight, based on the pregabalin content.

In the present invention, additives refer to excipients, binders, disintegrants and lubricants, but are not particularly limited to these. In addition to the additives, colorants, antioxidants, thickeners, buffering agents, sweetening agents, flavoring agents, perfume agents, and the like used in the art may be incorporated into the tablet of the present invention. . Sweetening agents include aspartame, acesulfame potassium, sucralose, stevia, maltitol, glycerin, lactitol, galactitol and the like. Examples of coloring agents include titanium dioxide and ferric oxide.

In the present invention, examples of excipients include D-mannitol, lactose (lactose hydrate, spray-dried lactose, fluid bed granulated lactose, isomerized lactose, reduced lactose, etc.), sucrose, erythritol, sorbitol, xylitol, and the like. mentioned. In the present invention, D-mannitol is preferred from the viewpoint of suppression of lactam production.

In the present invention, binders include, for example, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone, polyvinylpyrrolidone, methyl cellulose, polyvinyl alcohol, carboxymethyl cellulose and the like, and one or more of these may be appropriately blended and used. .

In the present invention, disintegrants include, for example, crospovidone, low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, croscarmellose sodium, carboxypropyl starch sodium, partially pregelatinized starch, corn starch and the like. In the present invention, crospovidone, low-substituted hydroxypropyl cellulose, corn starch, and partially pregelatinized starch are preferred from the viewpoint of suppressing the formation of impurities such as lactone bodies. The content of the disintegrant is preferably 1-20% by weight, more preferably 5-10% by weight, per solid pharmaceutical composition.

Examples of lubricants used in the present invention include magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, and talc.

In the present invention, the tablet may be film-coated, for example, an orally disintegrating tablet may be film-coated.

The tablet of the present invention can be produced by a conventional tablet production method, but from the viewpoint of suppressing the formation of impurities such as lactone bodies, pregabalin granules obtained by melt granulation are added with additives and mixed. Afterwards, it is preferable to prepare a formulation by tableting.
More specifically, the pregabalin-containing tablet of the present invention can be produced, for example, by mixing pregabalin with a low-melting-point substance such as glyceryl monostearate and then heating to about 40 to 80° C. to give glyceryl monostearate and the like. In some cases, the low melting point substance is melted, an anti-adhesion agent is added, mixed and granulated, cooled and granulated to prepare a molten granule, then a lubricant, disintegrant, excipient Tablets can be produced by tableting after mixing with agents and the like. Among these operations, the melt granulation operation may be performed using a fluidized bed granulator, a tumbling fluidized bed granulator, a high speed stirring granulator, an extrusion granulator, or the like. Moreover, tableting can be performed using a commercially available tableting machine.

Coating may then be applied by spray coating with an aqueous film coating preparation. Aqueous film coating formulations may also include, for example, polyvinyl alcohol, hydroxypropyl methylcellulose, polyvinyl polyethylene glycol graft copolymers, macrogol, titanium dioxide, ferric oxide. The coating content is, for example, preferably 0.5 to 10% by weight, more preferably 1 to 6% by weight, particularly preferably 2 to 3% by weight of the tablet composition.

EXAMPLES The present invention will be described in more detail with reference to Examples and the like below, but the present invention is not limited to the following Examples and the like.

300 g of pregabalin (manufactured by Sumitomo Chemical Co., Ltd.), 24 g of glycerin monostearate (manufactured by Riken Vitamin; Rikemal P-100) and talc (manufactured by Matsumura Sangyo; 6 g of crown talc) was added, heated while flowing at an air supply temperature of 100°C to melt glyceryl monostearate at 70 to 80°C, and flowed for about 5 minutes after reaching the melting point of glyceryl monostearate. Granulate. Thereafter, the mixture is cooled to below the melting point of glyceryl monostearate to obtain granules. The resulting granules were put into a fluid bed granulator dryer (manufactured by Powrex; FD-MP-01), and 15.96 g of D-mannitol (manufactured by Mitsubishi Shoji Foodtech; Mannitol P) and maltitol (Mitsubishi A solution of 8.04 g of Amalty, manufactured by Shoji Foodtech Co., Ltd. dissolved in 216 g of purified water was sprayed and dried to obtain pregabalin granules.
After sieving the obtained pregabalin granules with a 500 μm sieve, 550.8 g of D-mannitol (manufactured by Freund Corporation, Granutol S), 48 g of crospovidone (manufactured by BASF; Kollidon CF-L) and magnesium stearate (Taihei Kagaku Industrial product; vegetable) (7.2 g) to prepare a powder for tableting, which was then tableted using a rotary tableting machine to obtain tablets with a mass of 80 mg and a diameter of 6 mm.

As a comparative example, 25 mg of commercially available Lyrica OD tablets (pregabalin-containing orally disintegrating tablet, Pfizer Japan Inc., hereinafter referred to as "Comparative Example 1") were subjected to severe tests in a sealed state at 50°C for 7 days and 14 days. After that, the ratio of related substances was measured. The composition of Comparative Example 1 is shown in Table 1.

(Test example 1)
The tablets of Example 1 and Comparative Example 1 were subjected to a severe test in a sealed state at 50°C for 7 days and 14 days, and the amount of lactam in the tablets after the severe test was measured by high performance liquid chromatography (HPLC).
<Purity test method>
To measure the purity, the peak area of pregabalin was measured using HPLC under the following measurement conditions, and the peak area ratio (%) of the lactam form to the peak area of pregabalin was measured.
Take an amount corresponding to 100 mg of pregabalin, add 10 mL of water, and sonicate with occasional shaking. This liquid is centrifuged if necessary, and the supernatant liquid is filtered through a filter having a pore size of 1.0 μm or less to obtain a sample solution.
HPLC measurement conditions Detector: UV absorption photometer (210 nm)
Column: octadecylsilylated silica gel packed column for liquid chromatography Column temperature: around 35° C. Mobile phase A: 5.28 g of diammonium hydrogen phosphate is dissolved in 1000 mL of water, and phosphoric acid is added to adjust the pH to 6.5. 200 mL of methanol is added to 800 mL of this liquid.
Mobile phase B: acetonitrile/methanol mixture (9:1)
Transfer of mobile phase: The concentration gradient is controlled by changing the mixing ratio of mobile phase A and mobile phase B as follows.

As a result, as shown in Table 3, in Comparative Example 1, a significant increase in the lactam form was observed from the start of the period of 7 days and 14 days at 50°C, but in Example 1, the production of the lactam form was suppressed.

Claims (10)

A solid pharmaceutical composition characterized by containing pregabalin and glyceryl monostearate ( consisting of pregabalin, glyceryl monostearate, mannitol, corn starch and magnesium stearate, the weight of one tablet is 200.0 mg, and the content of pregabalin is 75.0 mg tablet, pregabalin, glyceryl monostearate, sucralose, mannitol, corn starch, crystalline cellulose, crospovidone, magnesium stearate, tablet weight 420.0 mg, oral cavity containing 150.0 mg of pregabalin Use of glyceryl monostearate to inhibit the formation of the lactam form of pregabalin in the manufacture of disintegrating tablets and those containing hydrogenated oil. The use of glyceryl monostearate according to claim 1, wherein the content of pregabalin is 10-60% by weight per solid pharmaceutical composition. The use of glyceryl monostearate according to claims 1 and 2, wherein the content of glyceryl monostearate is 1-20% by weight per solid pharmaceutical composition. Use of glyceryl monostearate according to any one of claims 1 to 3, wherein the content of glyceryl monostearate is 0.01 to 20% by weight based on the content of pregabalin. Use of glyceryl monostearate according to claims 1 to 4, wherein the solid pharmaceutical composition also contains additives other than glyceryl monostearate. Use of glyceryl monostearate according to claim 5, wherein the additive other than glyceryl monostearate is crospovidone. The use of glyceryl monostearate according to claim 6, wherein the content of crospovidone is 1-20% by weight per solid pharmaceutical composition. Use of glyceryl monostearate according to any one of claims 1 to 7, wherein the dosage form of the solid pharmaceutical composition is tablet, capsule, powder, granule or fine granule. The use of glyceryl monostearate according to claim 8, wherein the dosage form of the solid pharmaceutical composition is a tablet, and the tablet is an orally disintegrating tablet. Pregabalin-containing solid pharmaceutical composition ( pregabalin, glyceryl monostearate, mannitol, corn starch, magnesium stearate, tablets each weighing 200.0 mg and containing 75.0 mg of pregabalin, pregabalin, glyceryl monostearate , sucralose, mannitol, corn starch, crystalline cellulose, crospovidone, and magnesium stearate, with a tablet mass of 420.0 mg and a pregabalin content of 150.0 mg, and orally disintegrating tablets containing 150.0 mg of pregabalin, and those containing hydrogenated oil ), a method for stabilizing pregabalin by including glyceryl monostearate.

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