JP2021066740A - 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 regulator that blocks potential-dependent calcium channels to reduce neurotransmitter release and is clinically used primarily in the treatment of peripheral neuropathic pain and adjunctive treatment of partial epilepsy. (Non-γ-butanoic acid (GABA) receptor agonist or antagonist).

Patent Document 1 describes that a GABA derivative containing pregabalin produces a lactam form, which is a decomposition product of pregabalin, during formulation and storage of the preparation, and isomalt is used to suppress the formation of the lactam form. It is stated that it should be done.

Further, 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.

Further, Patent Document 3 describes that the production of lactams can be suppressed by using α-amino acids.

However, neither of these patent documents describes or suggests that glycerin monostearate suppresses the production of lactams from pregabalin.

U.S. Pat. No. 8968780 Japanese Patent No. 4564607 Japanese Patent No. 4612923

An object of the present invention is to provide a new means for suppressing the production of lactams in a pregabalin-containing solid pharmaceutical composition.

As a result of diligent studies to solve the above problems, the present inventors have surprisingly found that glycerin monostearate significantly suppresses the production of lactam in a pregabalin-containing solid pharmaceutical composition, and completed the present invention. did.

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

Further, a solid pharmaceutical composition containing pregabalin and glycerin monostearate having a pregabalin content of 10 to 60% by weight per solid pharmaceutical composition is provided.

Further, a solid pharmaceutical composition containing pregabalin and glycerin monostearate having a content of glycerin monostearate of 1 to 20% by weight per solid pharmaceutical composition is provided.

Also provided is a solid pharmaceutical composition containing pregabalin and glycerin monostearate having a glycerin monostearate content of 0.01 to 20% by weight based on the pregabalin content.

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

Also provided are solid pharmaceutical compositions containing crospopidone, pregabalin and glycerin monostearate.

Further, a solid pharmaceutical composition containing crospopidone, pregabalin and glycerin monostearate having a content of crospopidone of 1 to 20% by weight per solid pharmaceutical composition is provided.

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

Also provided are orally disintegrating tablets containing pregabalin and glycerin monostearate.

Also provided is a method for producing a solid pharmaceutical composition, which comprises a step of melt-granulating pregabalin and glycerin monostearate.

Since the pregabalin-containing solid pharmaceutical composition of the present invention suppresses the production of lactams of pregabalin, which is an active ingredient, it is useful as a drug having good stability of pregabalin.

It is a figure which shows the ratio of the lactam body measured in a harsh test (heat 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-A-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, the glycerin monostearate may be anything as long as it is used in the art. The content of glycerin monostearate is preferably 1 to 20% by weight, more preferably 2 to 10% by weight, per solid pharmaceutical composition.
The glycerin 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, 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, buffers, sweetening agents, flavoring agents, perfumes and the like used in the art may be blended into the tablets 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 layer 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 the production of lactams.

In the present invention, examples of the binder include 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, examples of the disintegrant include crospovidone, low-degree-of-substitution hydroxypropyl cellulose, carmellose, carmellose calcium, croscarmellose sodium, carboxypropyl starch sodium, partially pregelatinized starch, corn starch and the like. In the present invention, crospovidone, low-degree-of-substitution hydroxypropyl cellulose, corn starch, and partially pregelatinized starch are preferable from the viewpoint of suppressing the formation of impurities such as lactones. The content of the disintegrant is preferably 1 to 20% by weight, more preferably 5 to 10% by weight, per 1 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 formation of impurities such as lactones, an additive is added to the pregabalin granules obtained by the melt granulation method and mixed. After that, it is preferable to formulate by tableting.
More specifically, the pregabalin-containing tablet of the present invention is prepared by, for example, mixing pregavalin with a low melting point substance such as glycerin monostearate and then heating to about 40 to 80 ° C. to glycerin monostearate or the like. Melt the low melting point material, and in some cases, add an anti-adhesion agent, mix and granulate, then cool and sizing to prepare a molten granule, then a lubricant, a disintegrant, and a shaping. Tablets can be produced by mixing with an agent or the like and then tableting. Among these operations, the molten granulation operation may be performed using, for example, an apparatus such as a fluidized bed granulator, a rolling fluidized bed granulator, a high-speed stirring granulator, or an extrusion granulator. Further, the locking can be performed using a commercially available locking machine.

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

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

In a fluidized layer granulator / dryer (made by Paulec; FD-MP-01), 300 g of pregavalin (manufactured by Sumitomo Chemical Co., Ltd.), 24 g of glycerin monostearate (manufactured by RIKEN Vitamin; Rikemar P-100) and talc (manufactured by Matsumura Sangyo; 6 g of crown talc) is added and heated while flowing at a supply air temperature of 100 ° C. to melt glycerin monostearate at 70 to 80 ° C., and flow for about 5 minutes after reaching the melting point of glycerin monostearate or higher. Granulate. Then, the mixture is cooled to below the melting point of glycerin monostearate to obtain a granulated product. The obtained granules were put into a fluidized layer granulation dryer (manufactured by Paulec Co., Ltd .; FD-MP-01), and D-mannitol (manufactured by Mitsubishi Corporation Food Tech; Mannitol P) 15.96 g and maltitol (Mitsubishi). A solution prepared by dissolving 8.04 g of (Amarty) manufactured by Shoji Food Tech in 216 g of purified water was sprayed, and after drying, pregavalin granules were obtained.
After sizing the obtained pregabalin granules with a sieve of 500 μm, 550.8 g of D-mannitol (manufactured by Freund Sangyo, Granutol S), 48 g of crospovidone (manufactured by BASF; Corridon CF-L) and magnesium stearate (Taipei Kagaku). Industrial; vegetable) After mixing with 7.2 g to prepare a powder for tableting, the tablet was tableted using a rotary tableting machine to obtain a tablet having a mass of 80 mg and a diameter of 6 mm.

In addition, as a comparative example, a rigorous test was also conducted on a commercially available Lyrica OD tablet 25 mg (pregabalin-containing orally disintegrating tablet, Pfizer Corporation, hereinafter referred to as "Comparative Example 1") at 50 ° C. for 7 days and 14 days in a sealed state. 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 harsh test in a sealed state at 50 ° C. for 7 days for 14 days, and the amount of lactam in the tablets after the harsh test was measured by high performance liquid chromatography (HPLC).
<Purity test method>
As a measurement of purity, the peak area of pregabalin was measured under the following measurement conditions using HPLC, and the peak area ratio (%) of the lactam 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. If necessary, this solution is centrifuged, and the finished solution is filtered through a filter having a pore size of 1.0 μm or less to prepare a sample solution.
HPLC measurement conditions Detector: Ultraviolet absorptiometer (210 nm)
Column: Octadecylsilylated silica gel-filled column for liquid chromatography Column temperature: Around 35 ° C Mobile phase A: Dissolve 5.28 g of diammonium hydrogen phosphate in 1000 mL of water and add phosphoric acid to adjust the pH to 6.5. Add 200 mL of methanol to 800 mL of this solution.
Mobile phase B: Acetonitrile / methanol mixed solution (9: 1)
Liquid 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 2, in Comparative Example 1, a remarkable increase in lactam form was observed from the start at 50 ° C. for 7 days and 14 days, but in Example 1, the production of lactam form was suppressed.

Claims (10)

A solid pharmaceutical composition comprising pregabalin, glycerin monostearate and talc. 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 glycerin monostearate is 1 to 20% by weight per solid pharmaceutical composition. The solid pharmaceutical composition according to claims 1 to 3, wherein the glycerin 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 an additive other than glycerin monostearate and talc. The solid pharmaceutical composition according to claim 5, wherein the additive other than glycerin monostearate and talc is crospopidone. The solid pharmaceutical composition according to claim 6, wherein the content of crospopidone is 1 to 20% by weight per solid pharmaceutical composition. The solid pharmaceutical composition according to claim 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 to 9, which comprises a step of melt-granulating pregabalin, glycerin monostearate and talc.

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