JP5065519B1 - Method for producing crystalline atorvastatin calcium-containing tablet - Google Patents

Abstract

[PROBLEMS] To provide a pharmaceutical composition capable of increasing the storage stability of atorvastatin calcium without using a basic compound such as calcium carbonate, a metal salt additive or ammonium hydroxide, and a tablet using the same. .
The pharmaceutical composition showing good storage stability of the present invention is characterized by containing at least crystalline atorvastatin calcium and an organic amine as active ingredients. As the organic amine, meglumine and aminoalkyl methacrylate copolymer E are preferable, and the amount is preferably 0.01 to 30 parts by weight with respect to 100 parts by weight of the composition.
[Selection] Figure 1

Description

The present invention relates to a method for producing a tablet containing crystalline atorvastatin calcium and having excellent storage stability .

  Atorvastatin calcium is a pharmaceutical ingredient having an HMG-CoA reductase inhibitory action, and has the effect of lowering serum total cholesterol and LDL-cholesterol, and has excellent utility for hypercholesterolemia and familial hypercholesterolemia. It recognized.

  However, atorvastatin calcium is unstable to heat, moisture, acidic environment, and light. In particular, atorvastatin calcium is an unstable drug such as changing to a lactone form under an acidic environment. Also, in the process of producing preparations such as granules, tablets, capsules, etc., it is destabilized by contact with other additives such as binders, disintegrants, excipients, or by wet granulation processes. Therefore, a means for increasing the stability is required.

  As a commercially available preparation atorvastatin calcium-containing preparation, there are tablets, and those containing precipitated calcium carbonate as a stabilizer are on the market. Patent Document 1 discloses a pharmaceutical composition containing a stabilized metal salt additive and having improved stability.

  However, it is not preferable to use a large amount of a basic compound such as calcium carbonate in oral preparations, particularly when administered to patients with low gastric acid, which may impair the digestive function in the stomach. In general, alkali metal salts and alkaline earth metal salts have deliquescence and hygroscopicity, and therefore, there is a case where they are problematic in handling in the formulation process especially on an industrial production scale.

  Patent Document 2 describes a method of stabilizing by adding ammonium hydroxide in addition to alkali metals and alkaline earth metals. However, it is considered that ammonium hydroxide volatilizes from the preparation during the preparation process or during storage of the preparation, and it is difficult to ensure long-term stability. Furthermore, ammonium hydroxide is difficult to handle in production on an industrial scale due to its volatility and toxicity.

Japanese Patent No. 3254219 Japanese Patent No. 2935220

Therefore, there has been a problem of developing a method for producing an atorvastatin calcium- containing tablet exhibiting good storage stability without using a basic compound such as calcium carbonate, a metal salt additive or ammonium hydroxide.

In order to solve the above problems, the present inventors have made extensive studies and as a result, it is possible to increase stability by using crystalline atorvastatin calcium and further using meglumine , which is a kind of organic amine , as an additive. We found what we could do and completed the present invention.

  That is, the present invention intends to solve the above problems by the following configuration.

[1] At least crystalline atorvastatin calcium as an active ingredient and an excipient are mixed, and granulation containing 0.5 to 3 parts by weight of meglumine per 100 parts by weight of the tableting composition is mixed with this mixture A crystalline atorvastatin calcium-containing tablet showing storage stability, characterized in that a tableting composition is granulated by a general granulation method while adding a solution, and then the tableting composition is tableted. Manufacturing method.

[2] [1] the production method of the tablet to be facilities film coating crystalline atorvastatin calcium containing film-coated tablet according to.

A tablet containing atorvastatin calcium produced by the present invention as an active ingredient is an excellent preparation exhibiting good stability capable of preventing the problem of content reduction and increase in impurities during storage.

It is a figure which shows the powder X-ray-diffraction pattern of D2 type crystal | crystallization atorvastatin calcium as described in Japanese Patent Application No. 2009-552583 gazette used in Examples 1, 2, and 4. FIG. 4 is a diagram showing a powder X-ray diffraction pattern of α-form crystalline atorvastatin calcium described in Japanese Patent Application No. 2010-202286 used in Example 3. FIG. 6 is a diagram showing a powder X-ray diffraction pattern of Form I crystalline atorvastatin calcium described in Japanese Patent No. 3296564 used in Example 5. 4 is a diagram showing a powder X-ray diffraction pattern of amorphous atorvastatin calcium used in Comparative Example 2. FIG.

  The present invention is described in detail below.

  The following embodiment is an example for explaining the present invention, and is not intended to limit the present invention only to this embodiment. The present invention can be implemented in various forms without departing from the gist thereof.

In the production method of the present invention, atorvastatin calcium to use as the active ingredient of the tablet is unstable as described above, an increase of related substances was observed during storage.

The atorvastatin calcium used in the production method of the present invention is crystalline, for example, crystals I, II, IV (described in Japanese Patent No. 3296564), crystal III (described in Japanese Patent 3656563), VII Type crystal (described in Japanese Patent No. 3965155), V type crystal (described in Japanese Patent Application No. 2001-538875), D1, D2 type crystal (described in Japanese Patent Application No. 2009-552583), X, A, B1, B2, C, D , E-type crystals (described in Japanese Patent Application No. 2009-127757), α-type crystals (described in Japanese Patent Application No. 2010-202286), and other novel crystal forms.

The amount of atorvastatin calcium, as long as can be administered an effective amount as an active ingredient of the tablet is not particularly limited, in tableting composition 100 parts by weight described later is 0.1 to 30 parts by weight, preferably Is 1 to 25 parts by weight, more preferably 5 to 20 parts by weight.

An example of the organic amine used in the production method of the present invention is meglumine .

The content of meglumine is 0.5 to 3 parts by weight of an amount capable of satisfactorily stabilizing the active ingredient and obtaining preferable characteristics of the active ingredient-containing tablet with respect to 100 parts by weight of the tableting composition. It is.

In the production method of the present invention, various commonly used components such as a disintegrant, a binder, a colorant, a lubricant and a coating agent can be arbitrarily used in addition to the excipient .

  Examples of excipients include sugars such as lactose hydrate, anhydrous lactose, lactose G, sucrose, and sucrose; sugar alcohols such as D-mannitol, erythritol, sorbitol, maltose, xylitol, sorbitol, and trehalose; crystal cellulose , Cellulose such as powdered cellulose, low-substituted hydroxypropyl cellulose; corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, sodium carboxymethyl starch, hydroxypropyl starch, etc .; calcium hydrogen phosphate, precipitated Examples thereof include calcium carbonate, and among them, D-mannitol, erythritol, lactose hydrate, and crystalline cellulose are preferable.

  Examples of disintegrants include crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, carmellose calcium, carmellose sodium, carmellose, sodium carboxymethyl starch, partially pregelatinized starch, hydroxypropyl starch, crystalline cellulose, powder Examples thereof include cellulose, corn starch, and potato starch. Among them, low-substituted hydroxypropyl cellulose and powdered cellulose are preferable.

  Examples of the binder include hydroxypropylcellulose, hypromellose (substitution type: 1828, 2208, 2906, 2910), polyvinyl alcohol, low-substituted hydroxypropylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylethylcellulose, povidone, carmellose sodium. , Carmellose, sodium carboxymethyl starch, partially pregelatinized starch, crystalline cellulose, dextrin, gum arabic powder, etc. Among them, hydroxypropyl cellulose, polyvinyl alcohol, hypromellose (substitution degree type: 2910) are preferable.

  Examples of the colorant include yellow ferric oxide, ferric oxide, edible yellow No. 4 aluminum lake, edible yellow No. 5 aluminum lake, blue No. 1 aluminum lake, edible red No. 2 aluminum lake, edible red No. 3 aluminum lake, Examples include edible red No. 102 aluminum lake, among which yellow iron sesquioxide and iron sesquioxide are preferable.

  Examples of lubricants include magnesium stearate, calcium stearate, stearic acid, stearyl alcohol, talc, hydrogenated oil, sucrose fatty acid ester, sodium stearyl fumarate, hydrous silicon dioxide, light anhydrous silicic acid, magnesium metasilicate aluminate Among them, magnesium stearate and talc are preferable.

  Examples of the coating agent include gum arabic, ethyl cellulose, carnauba wax, carboxyvinyl polymer, carmellose sodium, triethyl citrate, titanium oxide, magnesium oxide, talc, magnesium carbonate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, propylene glycol, povidone, Polyoxyethylene hydrogenated castor oil, polysorbate, polyvinyl alcohol, macrogol, methacrylic acid copolymer, methylcellulose and the like can be used, and these may be used alone or in combination of two or more, and hydroxypropyl A combination of methylcellulose, titanium oxide and macrogol is preferred.

In the production method of the present invention, a granulating solvent is used when preparing a tableting composition for tableting . The granulating solvent is not particularly limited. For example, water, various organic solvents, and the like, more specifically water; lower alcohols such as methanol and ethanol; ketones such as acetone and methyl ethyl ketone; methylene chloride, or theirs A liquid mixture etc. can be mentioned, Preferably, it is water, ethanol, or a liquid mixture of water and ethanol.

The atorvastatin calcium-containing tablet produced according to the present invention comprises crystalline atorvastatin calcium as an active ingredient, meglumine as an organic amine , and various other ingredients such as excipients . Crystalline atorvastatin calcium, meglumine , Can be obtained by tableting a tableting composition obtained by granulating various optional ingredients by a general granulation method .

Specifically, a mixture containing various optional components such as crystalline atorvastatin calcium and excipient is granulated by adding a granulating solution in which meglumine is dissolved in a granulating solvent such as water, alcohol or water and alcohol, The obtained granulated product is dried and sized. Then the obtained sieved product, excipients optionally, disintegrating agents, by adding a coloring agent and a lubricant and the like are mixed, and tableting composition, the resulting tableting composition, For example, it is compressed into tablets using a single tableting machine or a rotary tableting machine.

The granulation method may be a general-purpose granulation method which is a method used at the time of normal formulation , stirring granulation method, fluidized bed granulation method, rolling fluidized bed granulation method, centrifugal rolling fluidized bed granulation method, Examples thereof include an extrusion granulation method.

The shape of the atorvastatin calcium-containing tablet obtained by the production method of the present invention is not particularly limited, but may be a round shape, a cablet shape, an oblong shape or the like, and a mark or character for distinguishability. Or a dividing line for division.

Atorvastatin calcium-containing tablets were obtained, subjected to film coating, may be provided as a film-coated tablets.

  The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

Example 1
Polyvinyl alcohol (0.9 g) and meglumine (1.8 g) were dissolved in water (11.1 g) to obtain a granulation liquid 1. 2.7 g (1.0 part by weight) of hydroxypropylcellulose was dissolved in 51.3 g of water to obtain granulation liquid 2. Crystalline atorvastatin calcium 16.26 g showing the powder X-ray diffraction pattern shown in FIG. 1, D-mannitol 110.34 g and crystalline cellulose 18 g were mixed in a high-speed stirring granulator (VG-01: manufactured by POWREC Co., Ltd.) Granulation was carried out while adding granulation liquid 1 and 10 g of purified water. This was transferred to a fluidized bed granulator (MP-01: manufactured by Powrec Co., Ltd.) and dried, and the dried product was sieved and sized with a No. 30 sieve (500 μm). Thereafter, the sized product was granulated with the granulating liquid 2 and dried. The dried product is sieved and sized with No. 30 sieve (500 μm), and 18 g of crystalline cellulose, 10.8 g of low-substituted hydroxypropyl cellulose and 1.2 g of magnesium stearate are added to this sized product and mixed to prepare a powder for formulation. Made the body. This powder was tableted with a rotary tableting machine (VEL5: Kikusui Seisakusho Co., Ltd.) with an R punch having a diameter of 5.5 mm and a tablet weight of 60 mg. This tablet was coated with 8% Opadry (OY-7300) solution on a high coater (HC-LABO: Freund Sangyo Co., Ltd.) to obtain a film-coated tablet.

Example 2
1 g of polyvinyl alcohol and 2 g (1.1 parts by weight) of meglumine were dissolved in 12.3 g of water to obtain a granulating liquid 1. 2.75 g of hydroxypropylcellulose was dissolved in 53 g of water to obtain granulation liquid 2. 17.1 g of crystalline atorvastatin calcium, 100.9 g of D-mannitol and 18.25 g of crystalline cellulose showing the powder X-ray diffraction pattern shown in FIG. Then, granulation was performed while adding granulation liquid 1 and 8 g of purified water. This was transferred to a fluidized bed granulator (MP-01: manufactured by Powrec Co., Ltd.) and dried, and the dried product was sieved and sized with a No. 30 sieve (500 μm). Thereafter, the sized product was granulated with the granulating liquid 2 and dried. The dried product is sieved and sized with No. 30 sieve (500 μm), and 18.25 g of crystalline cellulose, 11 g of low-substituted hydroxypropyl cellulose and 1.25 g of magnesium stearate are added to this sized product and mixed to prepare a powder for formulation. Made the body. This powder was tableted with a rotary tableting machine (VEL5: Kikusui Seisakusho Co., Ltd.) with an R punch having a diameter of 6.0 mm and a tablet weight of 73 mg. This tablet was coated with 8% Opadry (OY-7300) solution on a high coater (HC-LABO: Freund Sangyo Co., Ltd.) to obtain a film-coated tablet.

Example 3
In the same manner as in Example 2, the crystalline atorvastatin calcium showing the powder X-ray diffraction pattern shown in FIG. 2 was used instead of the crystalline atorvastatin calcium showing the powder X-ray diffraction pattern shown in FIG. Preparation, tableting, and film coating were performed.

Example 4
1.5 g of Tween 80 and 3 g (1.0 part by weight) meglumine were dissolved in 15 g of water to obtain granulation liquid 1. 6 g of hydroxypropyl cellulose and 2.5 g of aminoalkyl methacrylate copolymer E were dissolved in 100 g of ethanol to obtain a granulation liquid 2. Crystalline atorvastatin calcium 27.1 g showing the powder X-ray diffraction pattern shown in FIG. 1, D-mannitol 180.4 g and crystalline cellulose 60 g were mixed in a high-speed stirring granulator (VG-01: manufactured by POWREC Co., Ltd.) Granulation was carried out while adding granulation liquid 1 and 20 g of purified water. This was transferred to a fluidized bed granulator (MP-01: manufactured by Powrec Co., Ltd.) and dried, and the dried product was sieved and sized with a No. 30 sieve (500 μm). Thereafter, the sized product was granulated with granulation liquid 2 and dried. The dried product was sieved and sized with a No. 30 sieve (500 μm), and 18 g of low-substituted hydroxypropylcellulose and 1.5 g of magnesium stearate were added to the sized product and mixed to prepare a powder for preparation. This powder was tableted with a rotary tableting machine (VEL5: Kikusui Seisakusho Co., Ltd.) with an R punch having a diameter of 5.5 mm and a tablet weight of 60 mg. This tablet was coated with 8% Opadry (OY-7300) solution on a high coater (HC-LABO: Freund Sangyo Co., Ltd.) to obtain a film-coated tablet.

Example 5
In the same manner as in Example 2, the crystalline atorvastatin calcium having the powder X-ray diffraction pattern shown in FIG. 3 was used instead of the crystalline atorvastatin calcium showing the powder X-ray diffraction pattern shown in FIG. Preparation, tableting, and film coating were performed.

Example 1
Polyvinyl alcohol ( 0.9 g) and meglumine ( 1.8 g ) (1.0 part by weight) were dissolved in 11.1 g of water to obtain granulation liquid 1. Hydroxypropyl cellulose ( 2.7 g ) was dissolved in water (51.3 g ) to prepare granulation liquid 2. Crystalline atorvastatin calcium 16.26 g showing the powder X-ray diffraction pattern shown in FIG. 1, D-mannitol 110.34 g and crystalline cellulose 18 g were mixed in a high-speed stirring granulator (VG-01: manufactured by POWREC Co., Ltd.) Granulation was carried out while adding granulation liquid 1 and 10 g of purified water. This was transferred to a fluidized bed granulator (MP-01: manufactured by Powrec Co., Ltd.) and dried, and the dried product was sieved and sized with a No. 30 sieve (500 μm). Thereafter, the sized product was granulated with the granulating liquid 2 and dried. The dried product is sieved and sized with No. 30 sieve (500 μm), and 18 g of crystalline cellulose, 10.8 g of low-substituted hydroxypropyl cellulose and 1.2 g of magnesium stearate are added to this sized product and mixed to prepare a powder for formulation. Made the body. This powder was tableted with a rotary tableting machine (VEL5: Kikusui Seisakusho Co., Ltd.) with an R punch having a diameter of 5.5 mm and a tablet weight of 60 mg. This tablet was coated with 8% Opadry (OY-7300) solution on a high coater (HC-LABO: Freund Sangyo Co., Ltd.) to obtain a film-coated tablet.

Comparative Example 2
A powder for formulation was prepared in the same manner as in Example 2, using amorphous atorvastatin calcium showing the powder X-ray diffraction pattern shown in FIG. 4 instead of crystalline atorvastatin calcium showing the powder X-ray diffraction pattern shown in FIG. Then, tableting and film coating were performed.

  The atorvastatin calcium tablets obtained in Examples 1 to 5 and Comparative Examples 1 to 2 were stored for 2 weeks at 40 ° C. and 75% RH and 60 ° C. in an unwrapped state, and then the total affinity in the tablets by high performance liquid chromatography. The amount of substance and the lactone form were measured. Tables 1 and 2 show the results of the increase in the total related substances and the increase in the lactone form determined by area percentage.

  As shown in Tables 1 and 2, the atorvastatin calcium tablets of Examples 1 to 5 were stored under any conditions of 40 ° C. 75% RH and 60 ° C. storage compared to the atorvastatin calcium tablets of Comparative Examples 1-2. However, it was confirmed that the increased amount of decomposition products was small and the stability was ensured even under high temperature and humidification conditions.

  That is, under the storage conditions of 40 ° C. and 75% RH, compared with Examples 1 to 5, both the amount of increase in the total related substances and the amount of increase in the lactone form are large in Comparative Example 1, and the amount of increase in the lactone form in Comparative Example 2 is Although not observed, the increase in total related substances is large. Although the same tendency is shown even under the storage condition of 60 ° C., the increase in the total related substances in Comparative Example 2 is larger than that in Comparative Example 1, and thus, both of the storage conditions under both storage conditions. It is difficult to say that a formulation in which the amount of increase in the amount is not suppressed is stable.

Production method of the present invention, using conventional pharmaceutical and additives thereof are used, further it is not necessary, such as special facilities, easily since it is possible to produce atorvastatin calcium containing tablets, useful in industry is extremely It is expensive.

Moreover, it was shown that the obtained atorvastatin calcium- containing tablet is stable even under high temperature and humidification conditions.

Claims (2)

At least crystalline atorvastatin calcium as an active ingredient and an excipient are mixed, and a granulation solution containing 0.5 to 3 parts by weight of meglumine is added to 100 parts by weight of the tableting composition. A method for producing a crystalline atorvastatin calcium-containing tablet exhibiting storage stability, comprising granulating by a general granulation method to form a tableting composition and then tableting the tableting composition . Method for producing a tablet to facilities the film coating crystalline atorvastatin calcium containing film-coated tablet according to claim 1.