JP2013112675A - Stabilized candesartan-containing drug composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To solve problems of a candesartan cilexetil formulation that a steric structure of a crystal breaks in a production step such as tableting to decrease the stability of an active ingredient, that the decrease in the stability of the active ingredient causes generation of an analogue, resulting in decrease in the content of the active ingredient, and that a stable therapeutic effect may not be obtained after the formulation is stored for a long time, and therefore, to stabilize an active ingredient in a candesartan cilexetil formulation.SOLUTION: A drug composition having excellent storage stability in which the content of an active ingredient is stabilized for a long time can be obtained by incorporating a lower alcohol into a candesartan cilexetil formulation.

Description

The present invention relates to a candesartan-containing drug composition with improved storage stability, and more particularly to a candesartan-containing drug composition containing candesartan cilexetil and a lower alcohol.

  Candesartan cilexetil is known as a benzimidazole derivative showing an angiotensin II receptor antagonistic action and is used as a therapeutic agent for hypertension.

  It is known that tablets containing candesartan cilexetil are distorted in the crystal structure of candesartan cilexetil in the tableting process during production. This distortion of the crystal structure reduces the stability of candesartan cilexetil, and causes an increase in the degradation product of candesartan cilexetil (hereinafter sometimes referred to as “related substances”). For this reason, various devices have been made for formulation. For example, Japanese Patent No. 2682353 discloses that an increase in related substances is suppressed in a preparation in which a higher alcohol is added to candesartan cilexetil.

Japanese Patent No. 2682353

  As described above, since the candesartan cilexetil preparation has low storage stability, there is a concern that a stable therapeutic effect cannot be obtained as a result of the active ingredient being decomposed by long-term storage. Therefore, a candesartan cilexetil formulation with higher storage stability has been demanded.

  As a result of intensive studies, the present inventors have found that the addition of a lower alcohol to a candesartan cilexetil preparation suppresses the decomposition of the active ingredient over a long period of time, and the present invention has been completed. That is, the present invention provides a drug composition containing candesartan cilexetil and a lower alcohol.

  The content of the lower alcohol in the present invention is 3% to 10% by weight of the composition.

  As a lower alcohol in this invention, C1-C3 alcohol is preferable, For example, glycerol, propylene glycol, propanol, etc. are mentioned. The alcohol in the present invention is particularly preferably an alcohol selected from one or more of glycerin, propylene glycol, and propanol.

  According to the present invention, decomposition of an active ingredient accompanying long-term storage of a candesartan cilexetil formulation is suppressed. That is, it is possible to provide a candesartan cilexetil preparation with high storage stability.

  The present invention is a drug composition comprising candesartan cilexetil and comprising a lower alcohol.

  As used herein, the term “lower alcohol” is a linear alcohol having 1 to 3 carbon atoms. Therefore, the branched chain alcohol is not included in the lower alcohol in the present specification. Moreover, the alcohol valence of this lower alcohol is 1-3. Examples of the lower alcohol include monohydric alcohols such as propanol and butanol, dihydric alcohols such as ethylene glycol and propylene glycol (IUPAC name; 1,2-propanediol), and trivalents such as propanetriol and glycerin. Examples include alcohol. The lower alcohol used in the present invention is preferably propylene glycol, glycerin or 2-propanol, more preferably propylene glycol.

  According to the present invention, the storage stability of candesartan cilexetil is increased. That is, the lower alcohol suppresses the formation of a related substance of candesartan cilexetil.

  Hereinafter, the drug composition of the present invention, which is usually a solid preparation, will be described.

  The content of the lower alcohol in the drug composition is preferably 2% by weight to 20% by weight, particularly preferably 3% by weight to 10% by weight, based on the weight of the composition. When the content of the lower alcohol is less than 2% by weight, the storage stabilization effect is insufficient, and the total amount of related substances after long-term storage compared to the case where the lower alcohol is added at a ratio of 2% by weight or more. Will increase. Even when the lower alcohol is added in an amount of more than 20% by weight, the effect of stabilizing the storage can be obtained, but considering the handleability as a solid preparation, the lower alcohol content is preferably within the above range.

  The drug composition can be processed into various dosage forms by subjecting it to processes such as granulation and compression. However, a mixture of candesartan cilexetil and a lower alcohol, which is not subjected to such processing, is also a category of the drug composition of the present invention.

  In addition to candesartan cilexetil and lower alcohol, the drug composition of the present invention can also contain other additives generally used in pharmaceutical production. Such other additives include excipients, binders, disintegrants, lubricants and the like. One of these additives may be used, or two or more thereof may be used.

  As the excipient, saccharides such as lactose hydrate, celluloses such as hydroxypropylcellulose, and starches such as corn starch can be used.

  When a binder is added, hydroxypropylcellulose, hypromellose, povidone, carmellose sodium and the like can be used. Hydroxypropyl cellulose is preferable.

  When a disintegrant is added, carmellose calcium, low-substituted hydroxyxypropyl cellulose, croscarmellose calcium, or the like can be used. Carmellose calcium is preferable.

  When a lubricant is added, magnesium stearate, talc, sodium stearyl fumarate, or the like can be used. Magnesium stearate is preferable.

  The form in the case of using another additive is not specifically limited, For example, it can be set as the mixture which mixed candesartan cilexetil and the other additive. Alternatively, candesartan cilexetil and lower alcohol may be mixed homogeneously, and the granulated product obtained by granulation may be sized as necessary to form granules or fine granules.

  The lower alcohol may be dissolved in a solvent and added. As the solvent, an appropriate solvent may be selected according to the lower alcohol to be used, and examples thereof include purified water.

  The granulation method is classified into a dry granulation method and a wet granulation method. In the present invention, wet granulation in which a solvent or a binder is added for granulation is preferable. Examples of the wet granulation method include a method in which a binder solution is added to a mixture of an active ingredient and an excipient and the mixture is stirred and mixed to granulate. As another example, a method of spraying a mixture of an active ingredient and an excipient in the air and spraying a binding solution to granulate can be used. The granulation method used in the present invention is not particularly limited.

  In the present invention, as a method for adding the lower alcohol to the granulated product, when the wet granulation method described above is used, a method in which a solution obtained by dissolving a binder and a lower alcohol in a solvent is added as the binding solution.

  A granulated mixture obtained by adding other additives (excipient, binder, lubricant, disintegrant, stabilizer, etc.) to the obtained granulated product is also an embodiment of the pharmaceutical composition of the present invention.

  The above granulated product or granulated mixture may be filled into capsules or the like to form capsules.

  A preferred form of the pharmaceutical composition of the present invention is a tablet. Tablets can be produced, for example, by the following method.

  Candesartan cilexetil and excipients are mixed to obtain a drug-containing mixture. As a mixing method, a stirring method using a glass rod or the like in a container such as a beaker or a method using a mixer can be employed. Examples of the mixer include a tumbler type mixer.

  The obtained drug-containing mixture and lower alcohol are mixed to obtain the drug composition of the present invention. The obtained drug composition can be compressed as it is (direct compression) to obtain a tablet, but in the present invention, the wet granule compression method can be more preferably employed.

  When the wet granule compression method is employed, the granulated product obtained by the wet granulation method described above is compressed into tablets. Under the present circumstances, after adding a disintegrating agent to the granulated material obtained by the wet granulation method, it can also compress.

EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not limited to these.

Example 1
After mixing 2.0 g of candesartan cilexetil (manufactured by Ouchi Shinsei Chemical Co., Ltd.) and 10.0 g of corn starch (manufactured by Nippon Shokuken Co., Ltd.), the mixture was sieved with 30 Mesh to obtain a powdered powder. In the above powdered powder, 10.0 g of corn starch (manufactured by Nippon Shokuken Co., Ltd.), 91.50 g of lactose hydrate (manufactured by DMV), and 3.0 g of hydroxypropylcellulose (manufactured by Nippon Soda Co., Ltd.) are mixed in a beaker. Obtained. To the above mixture was added a binding solution in which 1.0 g of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd.) and 6.50 g of propylene glycol (manufactured by Kaneda Corp.) were dissolved in 16.0 ml of purified water, and granulated in a beaker. The obtained granulated product was dried at 50 ° C. for 12 hours with a shelf dryer (manufactured by Yamato Kagaku Co., Ltd.). The dried granulated product was sized using a power mill (manufactured by Showa Chemical Machinery Co., Ltd.), and 5.60 g of carmellose calcium (manufactured by Gotoku Pharmaceutical Co., Ltd.) was added and mixed. The obtained drug-containing mixture was tableted with a tableting machine (manufactured by Kikusui Seisakusho) at a tableting pressure of 1,100 kg, and propylene glycol-containing candesartan cilexetil tablets (1 tablet 130 g, diameter 7.0 mm, Sumi angle plane) was obtained.

(Example 2)
A glycerin-containing tablet was obtained in the same manner as in Example 1 except that glycerin was used instead of propylene glycol.

(Example 3)
A 2-propanol-containing tablet was obtained in the same manner as in Example 1 except that 2-propanol was used instead of propylene glycol.

(Comparative Example 1)
The lactose hydrate content was changed from 91.5 g to 98.0 g, and a lower alcohol-free preparation was obtained in the same manner as in Example 1 except that no lower alcohol was added.

  Table 1 shows the formulations of the above Examples and Comparative Examples.

(Test Example 1)
The tablets obtained in Example 1, Example 2, Example 3, and Comparative Example 1 were stored at 50 ° C. under sealed conditions (hereinafter sometimes referred to as “preservation test”). The total amount of related substances of candesartan cilexetil at the start of the storage test and one week after the start of the storage test was measured by the HPLC method. The results are shown in Table 2.

  As described above, preparations containing lower alcohol (Examples 1 to 3) showed a significant increase in the amount of candesartan cilexetil related substances in one week of storage test compared to preparations containing no lower alcohol (Comparative Example 1). Was suppressed.

(Examples 4 to 7)
The addition amount was changed so that the propylene glycol content was 1% by weight (Example 4), 3% by weight (Example 5), 5% by weight (Example 6), 10% by weight (Example 7), Propylene glycol-containing tablets were produced in the same manner as in Example 1 except that each tablet was adjusted with lactose hydrate so that the total weight was 130 mg.

(Comparative Examples 2 to 5)
Instead of propylene glycol, PEG 6000 (manufactured by Nippon Oil & Fats Co., Ltd.), a content of 1% by weight (Comparative Example 2), 3% by weight (Comparative Example 3), 5% by weight (Comparative Example 4), 10 A PEG6000-containing tablet was produced in the same manner as in Example 1 except that the amount added was changed to be wt% (Comparative Example 5), and each was adjusted with lactose hydrate so that the total weight of the preparation was 130 mg.

(Test Examples 2 and 3)
The preparations obtained in Examples 4 to 7 and Comparative Examples 2 to 5 were stored under 55 ° C. sealing conditions (hereinafter, sometimes referred to as “severe test”). The total amount of candesartan cilexetil related substances at the start of the severe test and 4 weeks after the start of the severe test was measured by the HPLC method. The results are shown in Tables 3 and 4.

  In the higher alcohol-containing preparations (Comparative Examples 2 to 5), as the stabilizer content increased, the amount of candesartan cilexetil related substance also increased. On the other hand, in the preparation containing a lower alcohol, the increase in the amount of candesartan cilexetil related substances was suppressed with the increase in the content of the stabilizer.

  According to the present invention, it is possible to produce a drug composition containing candesartan cilexetil which has excellent storage stability and has a stable active ingredient content over a long period of time.

Claims (3)

  A drug composition comprising candesartan cilexetil and a lower alcohol.   The drug composition according to claim 1, wherein the content of the lower alcohol is from 3% to 10% by weight of the composition. The drug composition of claim 2, wherein the alcohol is selected from one or more of glycerin, propylene glycol, and 2-propanol.