JP2019147782A - Pregabalin-containing solid pharmaceutical composition and method for producing the same - Google Patents

Abstract

To provide new means that inhibits lactam production of a pregabalin-containing solid pharmaceutical composition.SOLUTION: The present invention provides a solid pharmaceutical composition containing pregabalin and glyceryl monostearate.SELECTED DRAWING: Figure 1

Description

  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 in the treatment of peripheral neuropathic pain and adjunct treatment of partial seizures (Non-γ-butanoic acid (GABA) receptor agonist or antagonist).

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

  Patent Document 2 describes that lactam formation 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 the production of a lactam body can be suppressed by using an α-amino acid.

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

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

  An object of this invention is to provide the new means which suppresses the lactam body production | generation of a pregabalin containing solid pharmaceutical composition.

  The present inventors have intensively studied to solve the above problems, and surprisingly, found that glyceryl monostearate remarkably suppresses the formation of lactam bodies of pregabalin-containing solid pharmaceutical compositions, and completed the present invention. did.

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

  Moreover, the solid pharmaceutical composition containing the pregabalin whose content of pregabalin is 10 to 60 weight% per solid pharmaceutical composition and glyceryl monostearate is provided.

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

  Moreover, the solid pharmaceutical composition containing pregabalin whose glyceryl monostearate content is 0.01 to 20 weight% with respect to pregabalin content and glyceryl monostearate is provided.

  Moreover, the solid pharmaceutical composition containing the pregabalin containing additives other than glyceryl monostearate and glyceryl monostearate is provided.

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

  Also provided is a solid pharmaceutical composition containing crospopidone, 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.

  An orally disintegrating tablet containing pregabalin and glyceryl monostearate is also provided.

  Moreover, the manufacturing method of a solid pharmaceutical composition including the process of melt-granulating pregabalin and glyceryl monostearate is provided.

  The pregabalin-containing solid pharmaceutical composition of the present invention is useful as a pharmaceutical having good pregabalin stability because the production of lactam bodies of pregabalin, which is an active ingredient, is suppressed.

It is a figure which shows the ratio of the lactam body measured in the severe test (thermal condition).

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-T-7-508288. The content of pregabalin is preferably 10 to 60% by weight, more preferably 20 to 50% by weight, and particularly preferably 30 to 40% by weight per solid pharmaceutical composition.

In the present invention, glyceryl monostearate may be anything as long as it is used in the art. The content of glyceryl monostearate is preferably 1 to 20% by weight, more preferably 2 to 10% by weight, per solid pharmaceutical composition.
Moreover, it is preferable that glyceryl monostearate content is 0.01 to 20 weight% with respect to pregabalin content, and 0.1 to 10 weight% is more preferable.

  In the present invention, the additive refers to an excipient, a binder, a disintegrant, and a lubricant, but is not particularly limited thereto. 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. . Examples of the sweetening agent include aspartame, acesulfame potassium, sucralose, stevia, maltitol, glycerin, lactitol, galactitol and the like. Examples of the colorant include titanium dioxide and ferric oxide.

  In the present invention, examples of excipients include D-mannitol, lactose (lactose hydrate, spray-dried lactose, fluidized bed granulated lactose, isomerized lactose, reduced lactose, etc.), sucrose, erythritol, sorbitol, xylitol and the like. Can be mentioned. In the present invention, D-mannitol is preferable from the viewpoint of suppressing lactam formation.

  In the present invention, examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, polyvinylpyrrolidone, methylcellulose, polyvinyl alcohol, carboxymethylcellulose, and the like, and one or more of these may be appropriately blended and used. .

  In the present invention, examples of the disintegrant include crospovidone, low-substituted hydroxypropylcellulose, carmellose, carmellose calcium, croscarmellose sodium, carboxypropyl starch sodium, partially pregelatinized starch, and corn starch. In the present invention, crospovidone, low-substituted hydroxypropylcellulose, corn starch, and partially pregelatinized starch are preferable from the viewpoint of suppressing the production of impurities such as lactones. Further, the content of the disintegrant is preferably 1 to 20% by weight, more preferably 5 to 10% by weight, per solid pharmaceutical composition.

  In the present invention, examples of the lubricant 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 usual tablet production method, but from the viewpoint of suppressing the production of impurities such as lactone bodies, additives are added to the pregabalin granules obtained by the melt granulation method and mixed. Thereafter, it is preferable to formulate by tableting.
More specifically, the pregabalin-containing tablet of the present invention is prepared by mixing pregabalin and a low-melting-point substance such as glyceryl monostearate, and then usually heating to about 40 to 80 ° C. to obtain glyceryl monostearate or the like. The low melting point material is melted, and in some cases, an anti-adhesive agent is added, mixed and granulated, then cooled and sized, to prepare a molten granulated product, and then a lubricant, disintegrant, and shaping Tablets can be produced by tableting after mixing with an agent or the like. Among these operations, the melt granulation operation may be performed using an apparatus such as a fluidized bed granulator, a rolling fluidized bed granulator, a high-speed stirring granulator, an extrusion granulator, or the like. Tableting can be performed using a commercially available tableting machine.

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

  Hereinafter, the present invention will be described more specifically with reference to examples and the like. However, the present invention is not limited to the following examples.

In a fluidized bed granulator / dryer (manufactured by Paulec; FD-MP-01), 300 g of pregabalin (manufactured by Sumitomo Chemical), 24 g of glyceryl monostearate (manufactured by Riken Vitamin; Riquemar P-100) and talc (manufactured by Matsumura Sangyo; (Crown talc) 6 g is charged, heated while flowing at a setting of 100 ° C., melted glyceryl monostearate at 70-80 ° C., and allowed to flow for about 5 minutes after reaching the melting point of glyceryl monostearate. Granulate. Then, it cools below to melting | fusing point of glyceryl monostearate, and obtains a granulated material. The obtained granulated product was put into a fluidized bed granulator / dryer (manufactured by Paulec; FD-MP-01), 15.96 g of D-mannitol (manufactured by Mitsubishi Corporation Foodtech; Mannit P) and maltitol (Mitsubishi). A solution obtained by dissolving 8.04 g (manufactured by Shoji Foodtech Co., Ltd., Amalty) in 216 g of purified water was sprayed and dried to obtain pregabalin granules.
The obtained pregabalin granules were sized with a 500 μm sieve, and then D-mannitol (Freund Sangyo, Granitol S) 550.8 g, Crospovidone (BASF; Kollidon CF-L) 48 g and magnesium stearate (Taihei Chemical) After being mixed with 7.2 g of tableting by industrial use; plant type), the mixture was tableted using a rotary tableting machine to obtain tablets with a mass of 80 mg and φ6 mm.

  In addition, as a comparative example, a severe test was carried out on a commercially available Lyrica OD tablet 25 mg (pregabalin-containing orally disintegrating tablet, Pfizer Inc., hereinafter referred to as “Comparative Example 1”) in a sealed state for 14 days at 50 ° C. After that, the proportion of related substances was measured. The composition of Comparative Example 1 is as 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 for 14 days at 50 ° C. for 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>
As a purity measurement, the peak area of pregabalin was measured under the following measurement conditions using HPLC, and the peak area ratio (%) of the lactam body 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 solution is centrifuged as necessary, and the supernatant solution 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: Column packed with octadecylsilylated silica gel for liquid chromatography Column temperature: around 35 ° C. Mobile phase A: Dissolve 5.28 g of hydrogen diammonium phosphate in 1000 mL of water and add phosphoric acid to adjust to pH 6.5. Add 200 mL of methanol to 800 mL of this solution.
Mobile phase B: acetonitrile / methanol mixture (9: 1)
Mobile phase liquid feeding: 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 2, in Comparative Example 1, a significant increase in the lactam form was observed from the start at 50 ° C. for 7 days and 14 days, but in Example 1, the production of the lactam form was suppressed.

Claims (10)

  A solid pharmaceutical composition comprising pregabalin and glyceryl monostearate.   The solid pharmaceutical composition according to claim 1, wherein the content of pregabalin is 10 to 60% by weight per solid pharmaceutical composition.   The solid pharmaceutical composition according to claim 1 or 2, wherein the content of glyceryl monostearate is 1 to 20% by weight per solid pharmaceutical composition.   The solid pharmaceutical composition according to claims 1 to 3, wherein the glyceryl monostearate content is 0.01 to 20% by weight based on the pregabalin content.   The solid pharmaceutical composition according to claims 1 to 4, which also contains additives other than glyceryl monostearate.   The solid pharmaceutical composition according to claim 5, wherein the additive other than glyceryl monostearate is crospovidone.   The solid pharmaceutical composition according to claim 6, wherein the content of crospovidone is 1 to 20% by weight per solid pharmaceutical composition.   The solid pharmaceutical composition according to any one of claims 1 to 7, wherein the dosage form of the solid pharmaceutical composition is any one of tablets, capsules, powders, granules and fine granules.   The solid pharmaceutical composition according to claim 8, wherein the tablet is an orally disintegrating tablet.   The method for producing a solid pharmaceutical composition according to claim 1, comprising a step of melt granulating pregabalin and glyceryl monostearate.

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