JPS597117A - Pharmaceutical containing chitosan - Google Patents

Abstract

PURPOSE:The titled pharmaceutical, consisting of a mixed pulverized material of chitin and/or chitosan and a slightly soluble drug, and having remarkably improved solubility of the drug. CONSTITUTION:A pharmaceutical prepared by mixing chitin of formula I and/or chitosan of formula II fully with a slightly soluble drug, e.g. an antibiotic substance such as griseofulvin or chloramphenicol, an antiepileptic agent, fat-soluble vitamin such as vitamin D3, steroid such as beclomethasone propionate or prostaglandin such as prostaglandin E1, etc. to give a mixed pulverized material thereof having remarkably improved noncrystallization of the drug and enhanced solubility of the slightly soluble drug. The amounts of the respective components based on the chitin and/or chitosan are as follows: 50wt% or less above-mentioned antibiotic substance or antiepileptic agent and 10wt% or less another slightly soluble drug. EFFECT:The fluidity, hardness and disintegrating property in preparing the pharmaceutical are remarkably improved.

Description

[Detailed description of the invention] The present invention relates to a formulation using L chitosan.

More specifically, the present invention relates to a preparation comprising a co-pulverized mixture of chitin and/or chitosan and a dissolvable drug, which has significantly improved drug dissolution.

Generally, when a poorly soluble drug is orally administered, it is known that the bioavailability, that is, the absorption rate and amount of the drug, mainly depends on the dissolution rate in the gastrointestinal fluid. Therefore, if the bioavailability of a poorly soluble drug is increased by increasing its dissolution, the dose of the drug can be reduced, and as a result, the side effects of the drug can also be reduced.

As a method for increasing the dissolution of poorly soluble drugs, it is known to increase the dissolution by mixing and co-pulverizing crystalline cellulose with, for example, TTF griseofulvin or phenytoin (Japanese Patent Laid-Open No. 51-327194). However, it cannot be said that the method using such crystalline cellulose can sufficiently improve drug dissolution.

On the other hand, tablets using chitin as a disintegrant, which is widely distributed in nature as a tissue support for crustaceans and insects, have been reported (IJ, 8. Patent 4086335
).

However, in the relationship between chitin or chitosan, which is a derivative thereof, and poorly soluble drugs, there has been no detailed study on how chitin or chitosan affects the dissolution properties of drugs.

The present inventor conducted a detailed study on the relationship between chitin or chitosan and poorly soluble drugs, and found that it is not possible to simply physically mix chitin or chitosan and poorly soluble drugs.
It has been found that, in particular, by thoroughly mixing the two to form a so-called mixed co-pulverized product, the amorphousness of the drug is significantly increased and its dissolution property is significantly enhanced.

Therefore, we have found that by preparing a co-pulverized mixture of chitin or chitosan and a poorly soluble drug, a formulation in which the dissolution of the poorly soluble drug is significantly improved can be obtained, and we have arrived at the present invention.

That is, the present invention is a preparation using chitosan, which is a mixture and co-pulverized product of chitin and/or chitosan and a poorly soluble drug.

Chin 6 used in the present invention is (1→4)-2-acetamido-2-deoxy-β-D-glucan and is represented by the following formula.

Chitin is widely distributed in nature, existing as a tissue support in crustaceans and insects, and also in the cells of fungi and microorganisms.

Chitosan is jt→4)-2-amino-2-deoxy-β
It can be obtained by deacetylating chitin with -D-glucan and is represented by the following formula.

Among chitin and chitosan, chitosan is particularly preferred because it strongly enhances the dissolution properties of drugs.

The poorly soluble drug used in the present invention can be administered orally,
And water-insoluble or water-releasable drugs are preferred. Such drugs include, for example, griseofulvin, chloramphenicol, chloriphenicol norirumitate, a/
Picillin.

Antibiotics such as amoxitallin, erythromycin stearate, josamycin, doria heptyloleandomycin, erys tetramycin, rifampicin; antiepileptic drugs such as diphenylhydantoin, nokuramethadione, acetylphenetride; vitamin D3,1α-human tetraxylene Fat-soluble vitamins such as hydroxyvitamin D, 1α, 25-dihydroxyvitamin D, 1α, 24-dihydroxyvitamin DS+vitamin, vitamin E, vitamin Bi+vitamin B; Peclomethasone dipionate, nortestosterone .

Hydrococcin, esterin, frednisone, phlogesteone, methyltestosterone, and other steroid drugs; prostaglandin E1゜grostaglandin E3
．． Prostaglandin F! α.

Glostaglandins such as prostaglandin II or their methyl esters and ethyl esters; mefenamic acid, flufenamic acid.

Paraisobutylphenylacetic acid, <2isobutylhydratropic acid, pro7enoic acid, indometacin, anthranilic acid, phenylbutacin.

Non-stettide anti-inflammatory drugs such as azapropacin and methyl salicylate; Phenothiazine tranquilizers such as operazine; penzodiazepine tranquilizers such as chlordiazepoxide and diazepam; sulfisoxazole.

Sulfathiazole, sulfiisomesole.

Examples include sulfa drugs such as sulfdiazine. Among these, antibiotics such as griseofulvin and antiepileptic drugs such as diphenylhydantoin are preferred.

By obtaining a co-pulverized mixture of such a poorly soluble drug and the chitin and/or chitosan, and producing a preparation from the mixed co-pulverized product, a formulation with improved dissolution of the poorly soluble drug can be obtained.

The mixed co-pulverized product referred to in the present invention is not just a physical mixture, but a mixture of a poorly soluble drug and chitin and/or chitosan in coexistence to such an extent that the poorly soluble drug is present in a large amount in an amorphous state. It refers to something that has been thoroughly ground and mixed. Such a mixed and co-pulverized product can usually be obtained by thorough mixing and pulverization in a dry or wet manner using a ball mill, a thermometer mill, a vibrating mill, an A1 machine, or the like.

In this way, by forming a mixed co-pulverized product of chitin and/or chitosan and a poorly soluble drug, the crystalline portion of the soluble drug decreases, the amorphous portion increases, and the mixed co-pulverized product becomes a pharmaceutical preparation. By producing this, the dissolution properties of poorly soluble drugs are significantly improved and nine preparations are obtained.

The amounts of chitin, chitosan, and poorly soluble drug to be used when obtaining a co-pulverized mixture of chitin and/or Φtosan and a poorly soluble drug vary depending on the type of drug used, such as antibiotics such as griseofulvin. Alternatively, in the case of anti-epileptic drugs such as diphenylhydantoin, the drug is 50% by weight or less relative to chitin and chitosan, and in the case of other soluble drugs, it is usually 50% by weight relative to chitin and chitosan.

Less than % by weight of the drug is used.

The following methods for obtaining a paper preparation from the thus obtained mixed co-pulverized product can be mentioned.

That is, the obtained mixed co-pulverized product is mixed as it is or with the addition of one or more of desired excipients, lubricants, binders, colorants, and flavorings to form a powder. be able to. Excipients used here include, for example, starch, crystalline cellulose, texturin, and milk.
, mannitol, sorbitol, calcium anhydride, and the like. Examples of lubricants include talc, stearic acid, and stearic acid salts.

Examples include wax. Examples of binders include starch, dextrin, and tragacanth.

Examples include gelatin, polyvinyl bitetraridone, hydroxypropyl cellulose, polyvinyl alcohol, and the like.

Examples of coloring agents include tar-based pigments such as sunset yellow1.Also, the resulting mixed co-pulverized product is mixed with tt, excipients such as lactose and starch, and a lubricant if necessary. It is possible to make tablets by adding a binder, a coloring agent, etc., and directly compressing the mixture.

It can also be made into granules by granulating it by a normal method, and the granules can be further crushed.
Therefore, it can also be used as a powder.

According to the research of the present inventor, when a powder is made from a co-pulverized mixture of chitin or chitosan and a poorly soluble drug, it is possible to obtain a powder with particularly excellent fluidity11. It was revealed that tablets with excellent hardness and disintegration properties could be obtained. Therefore, by mixing and co-pulverizing a drug using chitin and/or chitosan, the dissolution of the drug is increased, and on the other hand, the fluidity, hardness, and disintegration properties during formulation are also significantly improved.

As detailed above, according to the present invention, there is provided a formulation comprising a co-pulverized mixture of chitin and/or chitosan and a poorly soluble drug, and in such a formulation, the dissolution of the drug is significantly improved. Therefore, a preparation with good drug availability can be obtained.

Hereinafter, the present invention will be explained in more detail with reference to Examples.

Example 1 Chitin and chitosan were ground in a ball mill for 5 days and
Use mesh sieved cellulose, and crystalline cellulose is
The following experiment was conducted using the material that had been passed through a 00 mesh sieve.

That is, griseofulvin is used as a drug, and a mixture of griseofulvin, chitin, chitosan, or crystal cells (MO, O) is prepared at a weight mixing ratio of 1:2.1.
:, the mixture of 9 was ground in a ball mill for 24 hours,
A co-ground mixture (GM) of griseofulvin and chitin, chitosan or crystalline cellulose was prepared.

Using the obtained mixed co-pulverized product, a griseofulvin dissolution test was conducted using a diurnal 1o dissolution test method. In the test method, a physical mixture is prepared by simply mixing the drug and the medium, chitosan, or crystalline cellulose (MOO) lightly in the hole without co-pulverizing the paddle in the first liquid. (PM) was also subjected to a dissolution test at the same time.

The results of the dissolution test of a co-pulverized mixture of drug, chitin, chitosan, and crystalline cellulose (MOO) at a weight mixing ratio of 1:2 are shown in FIG. Weight mixing ratio is l:9
The results of the mixed co-pulverized product are shown in Figure 2.

A mixed co-pulverized product having a weight mixing ratio of chitosan and crystalline cellulose (MOO) of 1:2 was obtained in the same manner as in Example 1,
A dissolution test was conducted. The results are as shown in Figure 3.

Example 3 The mixed co-pulverized product (1:o) of griseofulvintochitosan obtained in Example 1 and lactose were weighed out in various ratios, and this was added to a KBr manufactured by Takashi Seisakusho for infrared absorption spectrum measurement. 100KLI using tablet press and hydraulic press
It was compressed for 30 seconds at a compression pressure of 1.5 mm in diameter and 1.5 mm in thickness.
It was made into a 7s+z flat tablet.

The hardness of this tablet was measured using a bookstore type hardness meter at a relative humidity of 55 to 65% to a hardness of up to 20-. The results are shown in FIG.

From FIG. 4, it can be seen that the tablets obtained from the mixed pulverized product have high hardness and have excellent properties as tablets.

Example 4 The co-pulverized mixture of griseofulvin and chitosan obtained in Example 1 (1:9) and lactose were weighed and mixed in various ratios, and the repose angle of the resulting mixture was determined by Konishi Seisakusho's repose angle. Measurements were made using a goniometer at a relative humidity of 55-65%. The results are shown in Figure 5.

In addition, the minimum orifice diameter was measured at a relative humidity of 55% to 65%. The results are shown in Figure 6.

FIG. 5 and FIG. 6 show that the mixed co-pulverized product of the present invention has excellent fluidity and can be a very useful composition for formulations such as tablets and capsules.

[Brief explanation of drawings]

Figure 1 shows griseofulvin, chitin, chitosan, etc. (1:
Figure 2 shows the results of a griseofulvin dissolution test of a co-pulverized mixture consisting of griseofulvin, chitin, chitosan, etc. (1:9), and the quantitative ratio thereof. Figure 3 shows the results of an elution test for griseofulvin, although the ratios are different. Figure 3 shows the results of an elution test for diphenylhydantoin from a co-pulverized mixture of diphenylhydantoin and chitosan (1:2). Figure 4 shows the hardness test results of tablets made of a co-pulverized mixture of griseofulvin and chitosan and lactose, and Figure 5 shows the results of a hardness test of a tablet made of a co-pulverized mixture of griseofulvin and chitosan and lactose. Figure 6 shows the measurement results of the angle of repose of the mixture, and Figure 6 shows the measurement results of the minimum orifice diameter. Tsumugi）■ ♂ d``

Claims (1)

[Scope of Claims] L. A preparation using chitosans, characterized by comprising a co-pulverized mixture of chitin and/or chitosan and a dissolvable drug. 2. A preparation using chitosans according to claim 1, wherein the 11A soluble lactic acid is an antibiotic or an antiepileptic drug. 1. A preparation using chitosans according to claim 2, wherein the antibiotic is griseofulvin. 4. A preparation using chitosans according to claim 2, wherein the antiepileptic drug is diphenylhydantoin. & A preparation using chitosan according to any one of claims 1 to 4, which is a co-pulverized mixture of chitosan and a poorly soluble drug. (a) A formulation using chitosan according to any one of claims 1 to 5, wherein the formulation is a powder, granule, or tablet.