JP2013121951A - Stable solid preparation and method for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a tablet that can retain a principal ingredient even after being formulated for a long period of time by reducing unstabilization to such as pressure, impact, friction and heating applied when formulating candesartan cilexetil containing solid preparation which causes the reduction in storage stability of the principal ingredient after formulation by the influence of such as the impact, the friction and the heating.SOLUTION: In the solid preparation produced by using the candesartan cilexetil and an additive generally used, water equivalent to 2-10 wt.% of the total weight of a composition for formulating the solid preparation is contained for the formulation.

Description

  The present invention relates to a stable solid preparation containing candesartan cilexetil (generic drug name).

Candesartan cilexetil, an angiotensin II receptor antagonist, has attracted attention as a drug that exhibits higher efficacy than angiotensin I converting enzyme inhibitors in the treatment of hypertension.
According to Patent Document 1 described later, benzimidazole-7-carboxylic acid or a derivative thereof including candesartan cilexetil is stable with respect to temperature, humidity, and the like in a stationary state of a solid alone. The crystals are distorted by impact, friction, heating, pressurization, etc. due to crushing, mixing, stirring, drying, heating, compression, etc., and the content decreases with time during storage, but a low melting point oily substance is added. In other words, it is described that degradation over time can be suppressed even during storage after formulation.
In addition, since candesartan cilexetil is sparingly soluble in water, it is essential to improve solubility by pulverization to a certain particle size or less (for example, an average particle size of about 4 μm or less). It is necessary to facilitate absorption in the body by uniformly dispersing and finely powdering without agglomerates. However, as described above, candesartan cilexetil has a lower storage stability due to the effects of pressure, impact, friction, heating, etc. during formulation. There is a possibility of causing a significant decrease in content.

Japanese Patent No. 2682353

  An object of the present invention is to suppress the distortion of crystals caused by friction, impact, heating, pressurization, etc. in the preparation process of a candesartan cilexetil-containing preparation, and candesartan cilexetil that can be stably maintained for a long time after preparation It is to provide a containing solid preparation.

  The present inventors diligently studied to solve the above problems. As a result, by incorporating 2 to 10% by weight of water into the formulation composition containing candesartan cilexetil, the stability over time of the main component after the formulation process, especially after pulverization and compression molding, is dramatically improved. I found that it can be improved. The present inventors have further studied based on the knowledge, and have completed the present invention.

That is, according to this invention, the following solid formulation and its manufacturing method can be provided.
(1) A solid preparation obtained by formulating candesartan cilexetil, an additive on the preparation, and a composition for preparation containing 2 to 10% by weight of water based on the total weight of the composition.
(2) The solid preparation according to (1), wherein the additive on the preparation is at least one of a binder and a plasticizer.
(3) The solid preparation according to (1) or 2, wherein the binder is hydroxypropylcellulose or polyvinylpyrrolidone, and the plasticizer is triethyl citrate, tributyl citrate, triacetin, or glycerin.
(4) The solid preparation according to any one of (1) to (3), wherein the solid preparation is a compressed tablet.
(5) The solid preparation according to any one of (1) to (4), wherein the solid preparation is an orally disintegrating tablet.
(6) The solid preparation according to any one of (1) to (5), wherein the content of candesartan cilexetil in the solid preparation is 0.3 to 20% by weight.
(7) A method for producing a solid preparation for preparing a pharmaceutical composition containing 2 to 10% by weight of water relative to the total weight of candesartan cilexetil, an additive on the preparation, and the composition.
(8) The method for producing a solid preparation according to (7), wherein the additive on the preparation is at least one of a binder and a plasticizer.
(9) The method for producing a solid preparation according to (7) or (8), wherein the preparation is a compressed tablet.
(10) The method for producing a solid preparation according to any one of (7) to (9), wherein the content of candesartan cilexetil in the solid preparation is 0.3 to 20% by weight.

  The water content in the pharmaceutical composition is 2 to 10% by weight, preferably 2.0 to 8.4% by weight, particularly preferably 2.0 to 5.5% by weight. If the content is less than the above, the ratio of the total decomposition products during storage increases and the stability effect is insufficient.If the content exceeds the above content, the strength of the tablet is reduced, so there are problems such as cracking and chipping of the tablet in the distribution process in the market. May occur.

Examples of additives on the preparation used in the present invention include excipients, binders, plasticizers, disintegrants, lubricants, colorants, surfactants, stabilizers, and miso odorants. .
Examples of excipients include lactose, crystalline cellulose, corn starch, potato starch, partially pregelatinized starch, D-mannitol, sucrose, sucrose, glucose, and the like. Usually 5 to 90% by weight, preferably 10 to 80% by weight.

  Examples of the binder used in the present invention include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, pregelatinized starch, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, etc. The amount of the binder used is usually 0.1 to 10% by weight, preferably 0.5 to 6.0% by weight, based on the total weight of the solid agent.

  Preferred examples of the plasticizer used in the present invention include dioctyl adipate, triethyl citrate, tributyl citrate, triacetin or glycerin, diethyl phthalate, dioctyl phthalate, propylene glycol, and the like. preferable. The usage-amount of a plasticizer is 0.1 to 10 weight% normally in the weight of a formulation, Preferably it is 0.2 to 6 weight%.

Examples of the disintegrating agent used in the present invention, particularly the oral disintegrating agent, include carmellose, carmellose calcium, sodium carboxymethyl starch, crospovidone, low-substituted hydroxypropylcellulose, and partially pregelatinized starch. The usage-amount of a disintegrating agent is 0.1 to 10 weight% normally in the weight of a formulation, Preferably it is 0.5 to 6.0 weight%.
As other additives, lubricants, colorants, surfactants, stabilizers, and miso odorants can be blended in appropriate amounts as necessary.

Formulation means making the main agent having a pharmacological effect into a dosage form suitable for administration to the human body, but the solid preparation of the present invention includes tablets, capsules, granules, powders and the like. The preparation process includes pulverization, kneading, spraying, stirring, sizing, sieving, drying, compression tableting and the like of each component and composition. These steps themselves can be performed according to a conventionally known method.
In addition, as a method for producing an orally disintegrating agent, for example, a method in which an aqueous dispersion of saccharides is poured into a mold and dried, and a powder in which saccharides, a binder, etc. are wetted with water or alcohol is formed A method of drying and manufacturing, a method of granulating and drying using saccharides, a binder, etc. after molding at low pressure, then humidifying and drying, a small amount of lubricant on the surface of a mortar for tableting Examples thereof include a method of tableting while coating, a method of blending a highly moldable excipient and a highly disintegrating disintegrant, and tableting and manufacturing.

  According to the present invention, it is possible to provide a solid preparation, particularly a tablet, containing candesartan cilexetil that can guarantee long-term quality and ensure absorption in the body.

(1) A solution in which 30.0 g of hydroxypropyl cellulose and 6 g of triethyl citrate are dissolved in 570.0 g of purified water, and 12.0 g of candesartan cilexetil having an average particle size of 11.96 μm is added and uniformly dispersed. Using a high-pressure shearing homogenizer (manufactured by Paulec, Inc .: MICROFLUIDIZER M-110P type), the mixture was uniformly dispersed and wet-pulverized at a pressure of 207 MPa.
(2) 552.0 g of lactose, 120.0 g of corn starch, and 24.0 g of carmellose calcium were put into a fluidized bed granulator (manufactured by Paulek, Inc .: MP-01 type), fluidized, and obtained in (1). The wet pulverized chemical solution was sprayed and granulated. After the chemical solution spraying was finished, it was dried with a fluidized bed dryer until the water content in the granulated product became 2.0% by weight, and then sized with a 24 mesh sieve. 1.0 g of magnesium stearate was added to 129.0 g, which is a part of the obtained sized product, and mixed in a polyethylene bag. Next, this mixture was compression-molded to a diameter of 7 mm at a tableting pressure of 8 kN using a rotary tableting machine (manufactured by Kikusui Seisakusho: VIRGO type) to obtain tablets having the following composition. In addition, the content rate of the water in a granulated material was measured using the infrared moisture meter.

[Components] [Weight per tablet (mg)]
Candesartan cilexetil 2.0
Lactose 92.0
Corn starch 20.0
Carmellose calcium 4.0
Hydroxypropyl cellulose 5.0
Triethyl citrate 1.0
(2.5 mg of water is retained for the whole additive)
Magnesium stearate 1.0

  The same operation as in Example 1 was performed to obtain a sized product having a water content of 2.4% by weight in the granulated product. Using the obtained sized product, a tablet was obtained in the same manner as in Example 1 below.

  The same operation as in Example 1 was performed to obtain a sized product having a water content of 2.9% by weight in the granulated product. Using the obtained sized product, a tablet was obtained in the same manner as in Example 1 below.

  The same operation as in Example 1 was performed to obtain a sized product having a water content of 3.3% by weight in the granulated product. Using the obtained sized product, a tablet was obtained in the same manner as in Example 1 below.

  The same operation as in Example 1 was performed to obtain a sized product having a water content of 5.1% by weight in the granulated product. Using the obtained sized product, a tablet was obtained in the same manner as in Example 1 below.

  The same operation as in Example 1 was performed to obtain a sized product having a water content of 8.4% by weight in the granulated product. Using the obtained sized product, a tablet was obtained in the same manner as in Example 1 below.

[Comparative Example]
The same operation as in Example 1 was performed to obtain a sized product having a water content of 1.6% by weight in the granulated product. Using the obtained sized product, a tablet was obtained in the same manner as in Example 1 below.

[Test Example] Determination of Degradation Amount by Tablet Severe Test Each of the tablets of Examples and Comparative Examples was placed in a glass bottle, sealed, and stored at a temperature of 60 ° C. After 7 days and 14 days from the start of storage, degradation products in each tablet were measured by high performance liquid chromatography. From the results, the total amount of decomposed products (area percentage) was calculated, and the results are shown in Table 1.
From Table 1, it was found that the tablets of the examples according to the present invention can stably hold candesartan cilexetil as compared with the comparative example having a low water content.

  ADVANTAGE OF THE INVENTION According to this invention, the candesartan cilexetil containing tablet which can guarantee the long-term quality of a main ingredient can be provided to a medical field.

Claims (10)

A solid preparation obtained by formulating a composition for preparation containing candesartan cilexetil, an additive on the preparation, and water of 2 to 10% by weight relative to the total weight of the composition. The solid preparation according to claim 1, wherein the additive on the preparation is at least one of a binder and a plasticizer. The solid preparation according to claim 1 or 2, wherein the binder is hydroxypropylcellulose or polyvinylpyrrolidone, and the plasticizer is triethyl citrate, tributyl citrate, triacetin or glycerin. The solid preparation according to any one of claims 1 to 3, wherein the solid preparation is a compressed tablet. The solid preparation according to any one of claims 1 to 4, wherein the solid preparation is an orally disintegrating tablet. The solid preparation according to any one of claims 1 to 5, wherein the content of candesartan cilexetil in the solid preparation is 0.3 to 20% by weight. A method for producing a solid preparation, wherein candesartan cilexetil, an additive on the preparation, and a composition for preparation containing 2 to 10% by weight of water based on the total weight of the composition are formulated. The method for producing a solid preparation according to claim 7, wherein the additive on the preparation is at least one of a binder and a plasticizer. The method for producing a solid preparation according to claim 7 or 8, wherein the preparation is a compressed tablet. The method for producing a solid preparation according to any one of claims 7 to 9, wherein the content of candesartan cilexetil in the solid preparation is 0.3 to 20% by weight.