JPH04264021A - Sustained-release tablet - Google Patents

Abstract

PURPOSE:To obtain the subject tablet having a suitable shape by effectively utilizing chitosan. CONSTITUTION:A formulation prepared by forming a coating film mainly composed of chitosan on the surface of a tablet containing the main drug. It is also effective to admix a lubricant with the above-mentioned coating film and the dissolution velocity of the main drug can be controlled by suitably adjusting the mixture ratio between chitosan and the lubricant.

Description

[Detailed description of the invention]

0001

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a long-acting tablet capable of continuously exerting the pharmacological action of a main drug.

0002

BACKGROUND OF THE INVENTION Chitin is a natural basic polysaccharide that is widely present in nature and is included as a component of the exoskeleton of crustaceans such as crabs, shrimp, and krill, as well as insects. Chitin, in which N-acetyl-P-glucosamine is linearly linked, and chitosan obtained by deacetylation of chitin have been left as unused biological resources for a long time. However, in recent years,
Research into the effective use of chitin and chitosan is actively underway, attracting attention for their non-toxicity and physicochemical properties.
It is expected to be used in a wide range of fields such as flocculants, ion exchangers, enzyme fixing agents, raw materials for hair cosmetics, medical materials, food additives, and soil conditioners. In particular, chitosan is easily soluble in dilute hydrochloric acid and organic acid aqueous solutions, and the glucosamine residues that make up the molecular chain are free primary amino groups (-NH2
) It is considered to be promising because it has advantages such as being a polymer electrolyte with

On the other hand, in the field of pharmaceuticals, various techniques have been studied for oral preparations that aim to improve the sustainability of pharmacological action by controlling the release of pharmaceutical drugs in the body (sustained release elution) and adjusting absorption. It's here. Various forms of long-acting preparations have been proposed so far, such as: (1) granules or tablets with a semi-permeable film formed on the surface, (2) formulations with a water-soluble medium and insoluble or poorly soluble substances. Two types of drugs are known: one in which a drug is dispersed in a continuous matrix consisting of (2) a continuous matrix consisting of a soluble substance, and the other in which a drug is dispersed in a continuous matrix consisting of a soluble substance.

0004

[Problems to be Solved by the Invention] However, with conventional long-acting preparations, not only are their preparation methods complicated, but also, especially in matrix preparations, the function of the preparation may vary depending on the physical properties of the drug used. The drawback was that only certain drugs could be used, resulting in poor applicability. Furthermore, with conventional techniques, there has been a problem in that the effects of long-acting preparations are not always effectively exhibited. For example, the sustained release elution of the drug may not be achieved reliably and the drug may elute quickly, which not only results in early absorption and the lack of sustained pharmacological action as with conventional preparations, but also causes undesirable side effects. Sometimes. Alternatively, the drug may be excreted without being eluted or absorbed, resulting in the drug not exerting its pharmacological effects. Drug dissolution can be adjusted by adjusting the thickness of the coating applied to the surface of the solid preparation, but if the coating thickness is too large, the tablets will stick to each other during film coating, which increases the working time. Undesirable situations may also occur. The present invention was made under these circumstances, and its purpose is to effectively utilize chitosan and realize a long-lasting tablet in an optimal form, without causing the problems encountered in the prior art. It is something.

[0005]

[Means for Solving the Problems] The present invention, which has achieved the above object, is a long-acting tablet whose main feature is that a coating mainly composed of chitosan is formed on the surface of a tablet containing a main drug. .

[0006]

[Operation] Based on the viewpoint of effectively utilizing non-toxic chitosan as a material for long-acting preparations, the present inventors investigated the optimal form of long-acting tablets from various angles. As a result, they discovered that by forming a film mainly composed of chitosan on the surface of a tablet, long-lasting tablets could be easily obtained due to the film's ability to control elution, and the present invention was completed.

The chitosan used in the present invention is dissolved in a dilute acid solution and is deacetylated chitin, and if the degree of deacetylation is 60% or more, the origin organism, purification method, deacetylation method, etc. is not limited in any way. In addition, examples of solvents that dissolve chitosan when forming a film mainly composed of chitosan include acetic acid, lactic acid, citric acid, malic acid, tartaric acid, and the like.

[0008] It is preferable that the coating mainly composed of chitosan contains a lubricant. That is, by appropriately combining chitosan and a lubricant, the release rate of the main drug in the tablet can be adjusted easily and arbitrarily. Examples of such lubricants include talc, magnesium stearate, aluminum stearate (including mono, di, and tri), calcium stearate, and one or more of these can be used.

When a lubricant is included, the ratio of lubricant to chitosan is preferably about 95:5 to 5:95, more preferably 70:10 to 10:90. If the proportion of the lubricant is too large, the coating becomes brittle and cracks may occur, which is not preferable.

[0010] In order to form a coating mainly composed of chitosan, a plain tablet prepared using a base drug according to a conventional method may be immersed in an aqueous chitosan solution (or an aqueous chitosan solution containing a lubricant). This aqueous solution may contain a plasticizer such as glycerin, polyethylene glycol, propylene glycol, butanediol, etc., if necessary. If a plasticizer is included, the amount added should be up to about 60%; if the amount is too large, it may undesirably seep into the surface of the coating. Further, the thickness of the coating mainly composed of chitosan is preferably about 30 to 300 μm, more preferably about 40 to 150 μm.

[0011] If necessary, a coating made of an enteric polymer compound is formed on the surface of the coating mainly composed of chitosan. That is, although the tablet can be dissolved in the stomach with the above-mentioned structure, by forming a coating made of the enteric polymer compound above on the surface of the coating mainly composed of chitosan, the tablet can be dissolved in the stomach with the above-mentioned structure. Dissolution can be prevented and the drug can be dissolved after reaching the lower gastrointestinal tract. Examples of such enteric polymer compounds include methacrylic acid copolymers (Eudragit L, Eudragit S, both trade names).
, hydroxypropyl methylcellulose phthalate (H
PMCP), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), cellulose acetate phthalate (CAP), hydroxypropyl cellulose (HPC), shellac, and the like.

[0012] In order to form a coating mainly composed of an enteric polymer compound, a tablet having a coating mainly composed of chitosan may be immersed in an aqueous suspension of the enteric polymer compound. This suspension may contain a mixture of an organic solvent and a plasticizer such as castor oil and triethyl citrate, if necessary. When such a plasticizer is included, the appropriate amount is about 10 to 30%. In addition, the thickness of the coating mainly composed of enteric polymer compound is
It is preferably about 30 to 150 μm, more preferably about 40 to 100 μm.

[0013] The main drug used in the present invention is not particularly limited, and there are various types as shown below. Such main drugs include drugs that are effective for lower gastrointestinal diseases such as Crohn's disease, ulcerative colitis, and colon cancer, such as salazosulfapyridine, cortisone acetate, triamcinolone,
Examples include tegafur and fluorouracil. In addition, physiologically active polypeptides such as insulin, calcitonin, angiotensin, vasopressin, desmopressin, luteinizing hormone-releasing hormone (LHRH), somatostatin, glucagon, oxytocin, gastrin, cyclosporine, and derivatives thereof can also be used as the main drug of the present invention. .

[0014] When forming a tablet using the above-mentioned main drug, binders, excipients, disintegrants, or the above-mentioned lubricants may be used if necessary. Examples of the binder include gelatin, hydroxypropylcellulose, polyvinylpyrrolidone, and the like. As excipients, those commonly used in oral preparations, such as lactose, corn starch, potato starch, and crystalline cellulose, can be used. Examples of the disintegrant include carboxymethyl cellulose calcium, low substituted hydroxypropyl methyl cellulose, and the like. Hereinafter, the present invention will be explained in more detail with reference to examples, but the following examples are not intended to limit the present invention, and any design changes in accordance with the spirit described above and below are within the technical scope of the present invention. It is included in

[0015]

[Example] Example 1 According to the tablet composition shown in Table 1 below, lactose, cornstarch and triamcinoline were mixed, an aqueous hydroxypropylcellulose solution was added to form a mixture, which was extruded and granulated to form granules. Magnesium stearate was added to 298.5 g of this granule, and a mixture was compressed using a tablet machine to obtain uncoated tablets with a diameter of 6 mm and a weight of 100 mg.

[0016]

[Table 1] Using the above uncoated tablet, coating was applied using a Hi-Coater using a chitosan-talc suspension prepared according to the coating composition shown in Table 2 to form a coating mainly composed of chitosan with a thickness of 60 μm.

[0017]

[Table 2] On the film mainly composed of chitosan, an enteric polymer solution prepared according to the enteric film composition shown in Table 3 was coated with a high coater, and the enteric film was coated with 50μ
The tablets of the present invention were obtained.

[0018]

[Table 3]

Example 2 A chitosan-talc suspension prepared according to the coating composition shown in Table 4 was used in place of the coating composition shown in Table 2, and the amount of insulin as a medicinal ingredient was 10 units in one tablet. Tablets of the present invention were obtained in the same manner as in Example 1.

[0020]

[Table 4]

Example 3 Tablets of the present invention were prepared in the same manner as in Example 1, using a chitosan-talc suspension prepared according to the coating composition shown in Table 5, and containing 10 IU of calcitonin as a medicinal ingredient in one tablet. I got it.

[0022]

[Table 5]

Example 4 The thickness of the chitosan-talc coating in Example 3 was 120 μm.
Tablets of the present invention were obtained in the same manner as in Example 3, except for the following.

Example 5 Instead of the coating composition shown in Table 2, a chitosan-talc suspension prepared according to the coating composition shown in Table 6 was used, and the amount of cortisone acetate as a medicinal ingredient was 20 mg in one tablet. , Tablets of the present invention were obtained in the same manner as in Example 1.

[0025]

[Table 6]

Example 6 Instead of the enteric coating composition shown in Table 3, an enteric polymer solution prepared according to the enteric coating composition shown in Table 7 was used.
The tablets of the present invention were obtained in the same manner as in Example 1 in other respects.

[0027]

[Table 7]

Example 7 Instead of the enteric coating composition shown in Table 3, an enteric polymer solution prepared according to the enteric coating composition shown in Table 8 was used.
The tablets of the present invention were otherwise obtained in the same manner as in Example 1.

[0029]

[Table 8]

Example 8 Tablets of the present invention were obtained in the same manner as in Example 1, except that instead of the coating composition shown in Table 2, a chitosan solution prepared according to the coating composition shown in Table 9 was used.

[0031]

[Table 9]

Comparative Example Uncoated tablets with the composition shown in Table 1 were prepared, and an enteric coating with the composition shown in Table 3 was directly formed on the surface of the uncoated tablet without forming a coating mainly composed of chitosan. , got the tablets.

Example 9 In the tablets obtained in Examples 1 to 4, 8 and Comparative Example, food coloring red No. 106 was used instead of the medicinal ingredient, and the 11th revised Japanese Pharmacopoeia dissolution test method 2 (paddle method) was used. A dissolution test was conducted according to the following. The test liquid includes disintegration test second liquid (PH6
．． 8), the elution of Red No. 106 at a temperature of 37°C ± 0.5°C was measured by absorbance at a wavelength of 565 μm. The results are shown in FIG. 1, and it can be seen that the elution rate changes depending on the content ratio of the lubricant.

Example 10 The tablets obtained in Examples 1 to 8 and Comparative Example were subjected to the 11th edition Japanese Pharmacopoeia disintegration test using food coloring red No. 106 instead of the medicinal ingredient. The disintegration test first solution was used as the test solution, and disintegration at a temperature of 37°C ± 0.5°C was investigated. As a result, for all tablets, 2
It did not disintegrate within time, and no dye was observed to elute from the tablet.

[0035]

[Effects of the Invention] The present invention is constructed as described above, and by forming a film mainly composed of chitosan on an ordinary tablet, sustained release dissolution of the tablet can be achieved, and a tablet with improved sustainability can be obtained. Ta. In particular, when a lubricant is added, the dissolution rate of the main drug can be adjusted by appropriately adjusting the ratio of the lubricant and chitosan. It also has the advantage that the process is simpler and does not require complicated operations compared to the case of producing capsules.

[Brief explanation of the drawing]

FIG. 1 is a graph showing the results of the dissolution test shown in Example 9.

Claims (3)

[Claims] 1. A long-acting tablet characterized by having a coating mainly composed of chitosan formed on the surface of the tablet containing the main drug. 2. The long-acting tablet according to claim 1, wherein a coating mainly composed of an enteric polymer compound is formed on a coating mainly composed of chitosan. 3. The long-acting tablet according to claim 1, wherein the coating mainly composed of chitosan contains a lubricant.