JP2013245169A - Pharmaceutical tablet and method for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutical tablet including a medicine of a high content in which leachability is secured while reducing the content of a disintegrating agent more than the conventional one.SOLUTION: A pharmaceutical tablet in which the taking properties of a patient are improved and a method for producing the same are disclosed. The pharmaceutical tablet includes granules including a hygroscopic medicine and a disintegrating agent.The hygroscopic medicine sticks each component composing the granules, the content of the hygroscopic medicine is 30 to 80 mass% to the mass of the whole of the tablet, and the content of the disintegrating agent is 0.01 to 10 mass% to the mass of the whole of the tablet, in the pharmaceutical tablet.

Description

  The present invention relates to a pharmaceutical tablet and a method for producing the same, and more particularly to a pharmaceutical tablet containing a high content of a drug and a method for producing the same.

  In recent years, there has been a demand for pharmaceutical tablets containing a high content of drugs in order to improve patient compliance. For example, a miniaturized preparation containing sarbogrelate hydrochloride is known (Patent Document 1).

  Such needs are the same for pharmaceutical tablets containing other drugs such as imatinib mesylate (Patent Document 2) useful for the treatment of leukemia.

  Here, in order to produce a pharmaceutical tablet containing a high content of drug, a formulation design with a relatively reduced content of additives can be considered. However, with such a simple formulation design, it is difficult to fully exert the original function of the drug. For example, simply reducing the amount of the disintegrant may result in inferior disintegration time and thus dissolution properties of the tablet itself.

JP 2010-120959 A JP 2010-031019 A

  An object of the present invention is to solve the above-mentioned problems, and the object of the present invention is to reduce the content of the disintegrant as compared with the prior art, while containing a high content of drug that ensures dissolution. Is to provide.

  In the granulation of particles containing a high content of drug, the inventors have obtained a particle with a smaller amount of disintegrant by obtaining particles in which the hygroscopic drug itself substitutes for the binder without adding a separate binder. Even so, the inventors have found that tablets with guaranteed dissolution can be produced, and have completed the present invention.

  That is, the present invention is a pharmaceutical tablet containing a granulated product containing a hygroscopic drug and a disintegrant, wherein the hygroscopic drug adheres the components constituting the granulated product, and the hygroscopic The content of the drug is 30% by mass to 80% by mass with respect to the total mass of the tablet, and the content of the disintegrant is 0.01% by mass to 10% by mass with respect to the total mass of the tablet. A pharmaceutical tablet.

  In one embodiment, the hygroscopic drug is at least one drug selected from the group consisting of imatinib, sodium valproate and potassium losartan.

  In a further embodiment, the hygroscopic drug is imatinib mesylate.

The present invention is also a method for producing a pharmaceutical tablet comprising:
A step of granulating a granulated product containing a hygroscopic drug under wet conditions, the step of adhering the components constituting the granulated product with the hygroscopic drug; and the granulated product together with a disintegrant Tableting; and
Here, the content of the hygroscopic drug is 30% by mass to 80% by mass with respect to the mass of the whole tablet, and the content of the disintegrant is 0.01% by mass with respect to the mass of the whole tablet. To 10% by mass.

  In one embodiment, the hygroscopic drug is at least one drug selected from the group consisting of imatinib, sodium valproate and potassium losartan.

  In a further embodiment, the hygroscopic drug is imatinib mesylate.

  ADVANTAGE OF THE INVENTION According to this invention, the pharmaceutical tablet containing the high content drug which ensured the elution property can be provided. Furthermore, according to the present invention, the size of the resulting pharmaceutical tablet can be reduced by not using the binder as an essential component. As a result, the patient's burden can be reduced.

(Medicine tablets)
The pharmaceutical tablet of the present invention is one type of pharmaceutical tablet or drug tablet containing a pharmaceutically useful ingredient. The pharmaceutical tablet of the present invention contains a granulated product containing a hygroscopic drug and a disintegrant.

  A hygroscopic drug is a pharmaceutically effective ingredient having the property of absorbing or adsorbing moisture under wet conditions, that is, when it comes into contact with water or an aqueous solution. Here, the aqueous solution is an aqueous solution containing a pharmaceutically acceptable solute, and includes, for example, hydrous alcohol, more preferably hydrous ethanol. The concentration of the hydrous alcohol is not particularly limited, but is, for example, 10% (v / v) to 99% (v / v), preferably 60% (v / v) to 95% (v / v). Due to this property, in the present invention, the hygroscopic drug itself also has a function as a binder.

  Examples of such hygroscopic drugs include imatinib, sodium valproate, and potassium losartan. “Imatinib” has the chemical name 4- (4-methylpiperazin-1-ylmethyl) -N- [4-methyl-3- (4-pyridin-3-yl) pyrimidin-2-ylamino) phenyl] -benzamide. Called. In the present invention, imatinib mesylate, a compound formulated for leukemia, for example, is particularly useful as a hygroscopic drug. Imatinib in the present invention may be a derivative thereof or a salt thereof.

  In the granulated product, the content of the hygroscopic drug is finally 30% by mass to 80% by mass, preferably 40% by mass to 80% by mass, and more preferably 50% by mass to 70% by mass based on the total mass of the tablet. % By mass. By having such a content, the granulated product according to the present invention can be used in a wet condition or when it comes into contact with water or an aqueous solution, without requiring the addition of a separate binder. Thus, the components constituting the granulated product can be adhered to each other and granulated to a desired particle form.

  The granulated product may further contain an optional additive. Although it does not specifically limit as an additive which can be contained in a granulated material, For example, an excipient | filler and a fluidizing agent are mentioned.

  The excipient is not particularly limited as long as it is a general pharmaceutically acceptable excipient and can be used as a conventional binder, and specific examples include mannitol. Sugar sugars such as xylitol, sorbitol, erythritol; sugars such as glucose, lactose, sucrose (including refined sucrose), powdered sugar, trehalose, dextran; glycerin fatty acid esters; and magnesium aluminate metasilicate, synthetic hydrotalcite, etc. Inorganic powders; and combinations thereof.

  The fluidizing agent is not particularly limited as long as it is a general pharmaceutically acceptable fluidizing agent. Specific examples include silicic anhydride, hydrous silicon dioxide, talc, synthetic aluminum silicate, titanium oxide, Stearic acid, magnesium stearate, calcium stearate, and magnesium aluminate metasilicate, and combinations thereof.

  In the present invention, the contents of the excipient and the fluidizing agent in the granulated product are not particularly limited and can be arbitrarily set by those skilled in the art.

  The granulated product is a particle obtained by adhering the components constituting the granulated product to each other with the hygroscopic drug. This particle essentially does not contain any binder as commonly used in the field, or even if it contains it, it constitutes the granulated product by the hygroscopic action of the hygroscopic drug itself. The content is limited to a minute amount that allows substantial adhesion between components.

  Examples of such binders that are not originally contained or whose content should be limited include methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, gelatin, agar, alginic acid, sodium alginate, dextrin, chitansan gum, gum arabic Powders, polyvinylpyrrolidone, partially saponified polyvinyl alcohol, pullulan, and partially pregelatinized starch and combinations thereof. If such a binder is contained, the content of the binder acceptable in the pharmaceutical tablet of the present invention is, for example, less than 4% by mass, preferably 3% by mass relative to the total mass of the tablet. %, More preferably less than 2% by mass. The lower the binder content, the better. By limiting the content of the binder, in the production of the pharmaceutical tablet of the present invention, the hygroscopic property of the hygroscopic drug itself allows the components in the granulated material to adhere to each other and granulate, as described later. Even in a state where the content of the disintegrant is kept low, the dissolution properties of the resulting pharmaceutical tablet can be sufficiently retained.

  The disintegrating agent is not particularly limited as long as it is a general pharmaceutically acceptable disintegrating agent except for those that also function as a conventional binder. For example, crospovidone, carboxymethylcellulose (carmellose) Croscarmellose sodium, carboxymethylcellulose calcium, low substituted hydroxypropylcellulose, sodium starch glycolate, hydroxypropyl starch, calcium carbonate, precipitated calcium carbonate, calcium citrate, light anhydrous silicic acid, and synthetic aluminum silicate, and these The combination of is mentioned. Crospovidone, carboxymethylcellulose (carmellose) and combinations thereof are preferred.

  Content of a disintegrant is 0.01 mass%-10 mass% with respect to the mass of the whole tablet, Preferably it is 0.1 mass%-9.9 mass%, More preferably, it is 1 mass%-9.5 mass%. Even more preferably, it is 5 mass% to 9.3 mass%. By setting the content of the disintegrant in the above range, the pharmaceutical tablet of the present invention ensures the elution of the hygroscopic drug even if it contains a granulated product that does not substantially require the binder. be able to.

  The pharmaceutical tablet of the present invention may contain other additives in addition to the granulated product and the disintegrant. Other additives are not particularly limited as long as they do not inhibit the pharmaceutical effect of the hygroscopic drug and the dissolution property of the pharmaceutical tablet itself, and examples thereof include excipients and lubricants.

  Examples of excipients are the same as those that can be contained in the granulated product. It may be the same type as that used in the granulated product, or may be different.

  The lubricant is not particularly limited as long as it is a general pharmaceutically acceptable lubricant. For example, stearic acid, sodium stearyl fumarate, magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol , Light silicic anhydride, hydrogenated oil, glycerin fatty acid ester, and talc, and combinations thereof.

  The pharmaceutical tablet of the present invention can be various tablets such as a 100 mg tablet, a 200 mg tablet, and a 400 mg tablet. Furthermore, an arbitrary dose can be set and administered to the patient based on the patient's age, mode of administration, hygroscopic drug type, and the like.

(Method for producing pharmaceutical tablets)
Next, the manufacturing method of the pharmaceutical tablet of this invention is demonstrated.

  In the production method of the present invention, the granulated product is first granulated under wet conditions.

  In this granulation, for example, the hygroscopic drug and an optional additive are mixed with a predetermined amount of water or an aqueous solution and adjusted to a predetermined size by a granulator. Thereby, even if no binder is added, the components in the granulated product due to the hygroscopic action of the hygroscopic drug adhere to each other and particles are formed in the granulator. The obtained particles can be appropriately dried, and then sieved with a desired mesh to obtain particles having a uniform particle size.

  The particles are then tableted with a disintegrant.

  Specifically, for example, the particles, the disintegrant and other additives are once mixed to form a uniform pharmaceutical composition, and then subjected to a tableting machine well known in the art. In tableting, conditions such as the diameter of the tablet to be obtained and its thickness can be appropriately selected by those skilled in the art.

  The obtained tablet may be made into a product as an uncoated tablet, but it can also take the form of a coated tablet coated to remove bitterness and maintain quality, if necessary. The coating method employed in the present invention is not particularly limited. For example, a coating solution is prepared by dissolving or dispersing a coating agent known in the art in a solvent such as water, and the coating solution is sprayed onto the obtained tablets. You may coat. In addition, a pan coating method, a fluid coating method, a rolling coating method, or the like may be employed. The thickness of the coating layer obtained by coating is not particularly limited, and can be arbitrarily set by those skilled in the art.

  In this way, the pharmaceutical tablet of the present invention can be produced.

  EXAMPLES Hereinafter, although an Example demonstrates this invention more concretely, this invention is not limited by these Examples.

Example 1
A tablet having a total mass of 400 mg containing 239 mg (59.8% by mass) of imatinib mesylate as a hygroscopic drug, 36 mg in total of carmellose and crospovidone as disintegrant (9.0% by mass as a whole of the disintegrant) According to the formulation shown in Table 1, it was produced as follows.

  First, 286.8 g of imatinib mesylate as a hygroscopic drug, 58.8 g of D-mannitol as an excipient, and 3.0 g of light anhydrous silicic acid as a fluidizing agent were mixed. To this mixture, 70 g of a 90% (v / v) aqueous ethanol solution was added, and the mixture was stirred and granulated with a stirring granulator (manufactured by POWREC Co., Ltd .: VG-5 type). This was dried at 60 ° C. for 40 minutes, and then passed through a 850 μm sieve to obtain a granulated product that had been sized.

  Next, to 60 g of this granulated product, 4.1 g of carmellose, 3.3 g of crospovidone and 13.9 g of D-mannitol were added, mixed, and 0.62 g of magnesium stearate and 0.62 g of sodium stearyl fumarate were added, respectively. Addition and further mixing gave a pharmaceutical mixture. Using this pharmaceutical mixture, a tablet of imatinib mesylate (400 mg tablet) having a tablet diameter of about 10 mm, a thickness of about 5.8 mm, a mass of about 400 mg, and a hardness of 50 N or more is produced using a rotary tableting machine (manufactured by Kikusui Seisakusho: VIRG0512SS2AZ). did.

  Imatinib having a formulation (Table 2) in which 39.6 g of D-mannitol and 19.2 g of hydroxypropylcellulose as a binder were used instead of 58.8 g of D-mannitol used as an excipient in Example 1 Mesylate tablets were produced in an embodiment (direct compression method) in which imatinib mesylate was not substituted for the binder.

  Specifically, 286.8 g of imatinib mesylate as a main component, 39.6 g of D-mannitol as an excipient, 19.2 g of hydroxypropylcellulose as a binder, 3.0 g of light anhydrous silicic acid as a fluidizing agent, carmellose A pharmaceutical mixture was obtained by mixing 4.1 g, crospovidone 3.3 g and D-mannitol 13.9 g, magnesium stearate 0.62 g and sodium stearyl fumarate 0.62 g. Using this pharmaceutical mixture, a tablet of imatinib mesylate (400 mg tablet) having a tablet diameter of about 10 mm, a thickness of about 5.8 mm, a mass of about 400 mg, and a hardness of 50 N or more is produced using a rotary tableting machine (manufactured by Kikusui Seisakusho: VIRG0512SS2AZ). did.

(Test example: Formulation stability evaluation Dissolution test before and after storage)
The tablets obtained in Example 1 and Comparative Example 1 were subjected to a dissolution test for imatinib mesylate by Japanese Pharmacopoeia Dissolution Test Method 2 (Paddle Method). The test solution was 900 mL, and the elution rate (%) after 30 minutes was measured as follows at a paddle rotation number of 50 rpm.

  First, an imatinib mesylate dissolution test (pH 1.2) was performed on the tablets immediately after production in Example 1 and Comparative Example 1. This test was performed three times each. The obtained results (average value) are shown in Table 3.

  Similarly, the dissolution test (pH 6.8) of imatinib mesylate was performed on the tablets immediately after production of Example 1 and Comparative Example 1. This test was performed three times each. Table 4 shows the obtained results.

  As is clear from Tables 3 and 4, the tablet obtained in Example 1 has a higher dissolution rate at any dissolution time than that of Comparative Example 1, and clearly has excellent dissolution properties. It can be seen that it is a tablet.

  Furthermore, the tablet of Example 1 does not contain a corresponding amount of binder as in Comparative Example 1. Thus, it can be seen that the dissolution properties of the obtained tablets vary greatly depending on whether or not a binder is added separately. That is, by reducing the content of the disintegrant from the amount described in Patent Document 2 (Japanese Patent Laid-Open No. 2010-031019), a pharmaceutical having excellent dissolution properties without adding a binder. Tablets can be manufactured. It was also confirmed that the dissolution property of the tablet obtained in Example 1 was equal to or higher than the dissolution property of the tablet described in Patent Document 2.

  ADVANTAGE OF THE INVENTION According to this invention, the pharmaceutical tablet which has the outstanding dissolution property can be provided, keeping the content of the drug used as an active ingredient high. In addition, by not requiring the prescription of the binder in the tablet, for example, the tablet itself can be reduced in size, and the burden on patients can be reduced.

Claims (6)

A pharmaceutical tablet comprising a granulated product containing a hygroscopic drug and a disintegrant,
The hygroscopic drug adheres the components that make up the granulated product,
The content of the hygroscopic drug is 30% by mass to 80% by mass with respect to the mass of the whole tablet, and the content of the disintegrant is 0.01% by mass to 10% by mass with respect to the mass of the whole tablet. % Pharmaceutical tablets.     The pharmaceutical tablet according to claim 1, wherein the hygroscopic drug is at least one drug selected from the group consisting of imatinib, sodium valproate and potassium losartan.     The pharmaceutical tablet according to claim 2, wherein the hygroscopic drug is imatinib mesylate. A method for producing a pharmaceutical tablet, comprising:
A step of granulating a granulated product containing a hygroscopic drug under wet conditions, the step of adhering the components constituting the granulated product with the hygroscopic drug; and the granulated product together with a disintegrant Tableting; and
Here, the content of the hygroscopic drug is 30% by mass to 80% by mass with respect to the mass of the whole tablet, and the content of the disintegrant is 0.01% by mass with respect to the mass of the whole tablet. To 10% by weight.     5. The method of claim 4, wherein the hygroscopic drug is at least one drug selected from the group consisting of imatinib, sodium valproate and potassium losartan.     6. The method of claim 5, wherein the hygroscopic drug is imatinib mesylate.