JP2012036129A - Design of stable atorvastatin preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an atorvastatin-containing preparation ensuring stability while suppressing a pH of the preparation.SOLUTION: A desiccant is enclosed in a container where an atorvastatin-containing preparation with a reduced pH is contained, so that decomposition of atorvastatin can be suppressed to contribute to stabilization.

Description

  The present invention relates to a preparation containing an unstable atorvastatin or a salt thereof for ensuring stabilization without increasing the pH of the preparation.

  Atorvastatin or a salt thereof (hereinafter sometimes referred to as atorvastatin) is used as a HMG-CoA reductase inhibitor for the treatment of hypercholesterolemia. And many pharmaceutical preparations containing this substance are currently used.

  In atorvastatin, it is also known that the solubility of calcium salt changes depending on pH. It is also known to cause degradation over time. In particular, the degradation over time is a serious problem in terms of storage of pharmaceutical products.

Then, in order to suppress degradation of atorvastatin, an atorvastatin preparation containing calcium carbonate in the preparation has been proposed (Patent Document 1).

Calcium carbonate is also used as an antacid. That is, calcium carbonate is a substance that can change the pH in the stomach. And the lipitol formulation which is a commercial product of atorvastatin is suspended in 100 mL of purified water, and the pH is measured to show a value of about 9.5. That is, it is conceivable to change the pH in the digestive tract, whether locally. As described above, atorvastatin has different solubility depending on pH. Therefore, the solubility of atorvastatin varies depending on the conditions of the gastrointestinal tract, and as a result, individual differences may occur in the blood concentration of atorvastatin.

The pH in the stomach is about 1 to 3, the duodenum is about 5, and the small intestine is about 6.5. Therefore, it was thought that by designing the preparations close to these pHs, it is possible to design preparations that further suppress variation in individual differences.
Japanese National Patent Publication No. 8-505640

  However, it is known that atorvastatin degrades over time when a formulation containing atorvastatin close to the pH in the digestive tract is designed. In fact, it has been confirmed that impurities such as lactones increase with time when calcium carbonate is excluded or the formulation is designed such that the pH of the suspension of the formulation is 9 or less. Therefore, a new formulation design that suppresses the increase in these impurities is required.

  As a result of various studies, the inventors have found that an increase in impurities of atorvastatin can be suppressed by packaging a preparation containing atorvastatin together with a desiccant, thereby completing the present invention. Conventionally, the present inventors have invented a formulation that can ensure stability even in a formulation containing a weak alkaline substance that cannot ensure stability.

That is, the present invention is as follows.
(1) Atorvastatin packaged with desiccant or a salt-containing preparation thereof (2) Atorvastatin is a calcium salt (1) preparation (3) The desiccant is silica gel or zeolite (1) to (2) preparation (4 (1) The atorvastatin-containing preparation has a pH of 9 or less (1) to (3) preparation (5) The atorvastatin-containing preparation has a pH of 8.5 or less (1) to (4) preparation (6) Atorvastatin-containing preparation (1) to (5), which contain sodium hydrogen carbonate.

  This invention is the design of the formulation which can ensure the stability of atorvastatin, making the formulation pH of an atorvastatin containing formulation approximate the pH of a normal digestive tract.

  If the desiccant used for this invention is generally used, there will be no problem in particular. Specifically, the water adsorption amount may be 10 wt% or more at a water vapor pressure of 10 mmHg and 25 ° C. Specific examples of the material include activated alumina, silica gel, zeolite, and the like. Silica gel or zeolite is preferable, and zeolite is more preferable.

  Moreover, there is no special regulation about the amount of these used if the effect of the invention can be exhibited. Preferably, it is 1 g or more, more preferably 2 g or more in a container containing 100 tablets containing atorvastatin.

  As a container for containing the atorvastatin-containing tablet together with the desiccant, any material can be used as long as it does not impair the effect of the desiccant. Specific examples include glass, aluminum, and a highly moisture-proof plastic.

  The atorvastatin-containing preparation is preferably such that its pH is 9 or less when suspended in purified water. As a method for measuring pH, a preparation or the like was collected so as to correspond to 10 mg as atorvastatin and suspended in 100 mL of purified water. A method of measuring the pH of this suspension was adopted. In the present invention, the pH measured by this method is preferably 9 or less, and more preferably 8.5 or less (hereinafter also referred to as a low alkali region).

  Thus, in the atorvastatin-containing preparation of the present invention, the effects of the invention can be exerted by containing an additive that can be made into a low alkali region. Such additives include, but are not limited to, alkali metal salts or alkaline earth metal salts. Preferably, it is a sodium salt, More preferably, sodium hydrogencarbonate is mentioned.

  In addition to these additives, as long as the effects of the present invention are not impaired, various conventionally known lubricants, solubilizers, buffers, adsorbents, binders, suspending agents, antioxidants, A filler, a pH adjuster, an excipient, a dispersant, a disintegrant, a disintegration aid, a moisture proofing agent, a preservative, a solvent, a solubilizing agent, a fluidizing agent, and the like can be used.

  Examples of excipients include crystalline cellulose, corn starch, potato starch, and inorganic salts. Examples of the disintegrant include starches such as corn starch and potato starch, partially pregelatinized starch, sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropyl methylcellulose, crystalline cellulose, hydroxypropyl starch Etc. Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, gum arabic, pregelatinized starch, sodium alginate, carboxyvinyl polymer, agar, honey and the like.

Examples of the lubricant include magnesium stearate, calcium stearate, stearic acid, talc, and sucrose fatty acid ester. Examples of the coating agent include hydroxypropyl methylcellulose, ethyl acrylate / methyl methacrylate copolymer, aminoacryl methacrylate copolymer E, aminoacryl methacrylate copolymer RS, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid. Copolymer S etc. are mentioned. Furthermore, examples of the taste masking component include citric acid, tartaric acid, malic acid and the like. Examples of the foaming agent include sodium bicarbonate. Examples of artificial sweeteners include saccharin sodium, dipotassium glycyrrhizin, aspartame, stevia, thaumatin and the like. Examples of the masking agent include water-insoluble polymers such as ethyl cellulose and gastric polymers such as methyl methacrylate / butyl methacrylate / diethylaminoethyl methacrylate copolymer.

  An atorvastatin-containing preparation may be produced by any production method as long as it contains these additives. Specifically, fluidized bed granulation, stirring granulation, tumbling granulation, dry granulation, or a combination of these may be used as a method for producing the granules. Moreover, it is also possible to market these as granules using these granules. However, it is also possible to encapsulate or compression mold to improve the dosage. These methods can be performed by a generally known method.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not restrict | limited at all by these Examples.

Example 1
Atorvastatin calcium 27.05g, lactose (lactose DMV200M manufactured by DMV) 81.8g, sodium hydrogen carbonate (sodium hydrogen carbonate manufactured by Asahi Glass Co., Ltd.) 70g, crystalline cellulose (Ceolus PH-101 manufactured by Asahi Kasei Chemicals) 140g and cross Granules were produced using 10.5 g of carmellose sodium (manufactured by Actisol FMC Co., Ltd.) with a stirrer and granulator using the binders described below.

  The binding solution was 7 g of hydroxypropyl cellulose (HPC-L Nippon Soda Co., Ltd.), 0.07 g of butylhydroxyanisole (Susten 1-F JGC Universal Co., Ltd.) and polysorbate 80 (TO-10M Nikko Chemicals Co., Ltd.). This is a solution obtained by dissolving 1.4 g in 60 mL purified water and 60 mL ethanol.

  10.5 g of croscarmellose sodium (manufactured by Actisol FMC Co., Ltd.) and 1.75 g of magnesium stearate (manufactured by Taihei Chemical Industrial Co., Ltd.) were added to 337.82 g of the granules, and mixed in a V-type mixer. The granules were tableted with a compression molding machine.

  Using this tableted product, coating was performed with a film coating solution produced by the following method. The coating used a doria coater.

  The composition of the coating solution is 7 g of hypromellose (TC-5R manufactured by Shin-Etsu Chemical Co., Ltd.), 1 g of Macrogol 6000 (manufactured by Sanyo Chemical Industries, Ltd.) and titanium oxide (Titanium oxide A-110 Sakai Chemical Industry Co., Ltd.) 2) 2g dissolved in 100g purified water.

  The stability test was carried out under the following conditions using the thus prepared tablets. In addition, as a comparison, 5 mg of Lipitor tablets (manufactured by Astellas Pharma Inc.) already sold was used.

The stability test was conducted under the following conditions.
Temperature: 70 ° C
Period: 4 days Packaging container: Aluminum bag (100 tablets / bag)
Presence or absence of zeolite: When using zeolite (manufactured by MS Shin-Etsu Kasei Kogyo Co., Ltd.), 2.5 g per bag is used. Evaluation item: Total related substances Test method: Extract 5 tablets by the disintegration method, according to USP Measured by reversed phase UPLC method

As a result of the above, the results shown in Table 1 below were obtained.

  In addition, about the pH of a formulation, it measured as follows and resulted in Table 2.

Measurement method Preparations and the like were collected so as to be equivalent to 10 mg of atorvastatin (two tablets of Example 1 above) and suspended in 100 mL of purified water. Using this suspension, pH was measured according to the Japanese Pharmacopoeia pH measurement method.

  As shown in Table 1 and Table 2, even when the pH of the preparation was low, the stability of atorvastatin could be ensured by placing zeolite as a desiccant in the packaging container.

The present invention is useful because it can suppress the generation of impurities, that is, contribute to stabilization, despite the preparation close to the pH of the digestive tract.

Claims (6)

Atorvastatin or its salt-containing preparation packaged with desiccant The formulation of claim 1, wherein atorvastatin is a calcium salt. The preparation according to claim 1 or 2, wherein the desiccant is silica gel or zeolite. 4. The preparation according to claim 1, wherein the atorvastatin-containing preparation has a pH of 9 or less. The preparation according to claims 1 to 4, wherein the atorvastatin-containing preparation has a pH of 8.5 or less. 6. The preparation according to claim 1, wherein sodium hydrogen carbonate is contained in the atorvastatin-containing preparation.