JPS61161216A - Sustained release drug composition using chitosan - Google Patents

Abstract

PURPOSE:The titled composition capable of controlling sufficiently elusion properties of drug independently of acidity (pH) of site of organism, obtained by blending a drug with a chitosan and a carboxyvinyl polymer. CONSTITUTION:A drug is blended with a chitosan shown by the formula I and/or chitosan shown by the formula II and a carboxyvinyl polymer. Any drug can be used as the drug so long as it require frequent administration in order to maintain common effective blood concentration or effective local concentration. A carboxyvinyl polymer [e.g., HAIBISUWAKO (manufactured by WAKO JYUNYAKU KK), etc.] having 1,000-100,000cps viscosity at 0.2wt% aqueous solution at 25 deg.C measured by Brookfield rotational viscometer of B8H type (20rpm) is preferable as the carboxyvinyl polymer. A blending ratio of the chitosan to the carboxyvinyl polymer is preferably 30:70-70:30. The blending of the chitosan with the carboxyvinyl polymer can retard elusion of drug signifi cantly.

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a sustained release pharmaceutical composition using chitosans.

More specifically, the present invention is a composition comprising chitin and/or chitosan, carboxyvinyl polymer, and a drug,
The present invention relates to a sustained release pharmaceutical composition in which the dissolution of a drug is controlled regardless of the acidity (pH) of the site of the living body to which the composition is applied.

<Prior Art> Chitin, which is widely distributed in nature as a tissue support for crustaceans and insects, and chitosan, which is a de7cetylated product thereof, have been largely discarded in the past.

However, in recent years, their properties have been gradually clarified, and since they are non-toxic natural polymers, they are expected to be applied in various fields. However, chitin and chitosan have drawbacks such as not being soluble in common solvents or being difficult to be mechanically crushed, making them difficult to use and very few examples of them being put to practical use.

On the other hand, sustained-release formulation technology has been studied for a long time to control the elution and absorption of pharmaceuticals within the body, in the context of administering pharmaceuticals to living organisms. For example, methods are known in which drugs are coated with various coatings or encapsulated in wax or polymer matrices, but these methods require complicated preparation methods.

<Problems to be Solved by the Invention> In view of the above circumstances, we investigated sustained release preparations using chitosans. An example of a sustained-release preparation using chitosans is a method for preparing dried chitonangal by dissolving chitosan and drug in acetic acid and then distilling off the solvent [7].
iya, zaki, etc., Chem, Phem, Bull
, 29(fO), 3067-3069 (1981))
is known, but this method has drawbacks such as requiring a long time for drying and being inapplicable to drugs that are sensitive to acetic acid.

On the other hand, a method of preparing a sustained-release preparation by binding chitosan powder into tablets with lactose (Y, Sawayanagl et al., Che
m, Pharm, Bull, 30 (11), 42
13-4215 (1982)) is also known. However, in the above-mentioned mixture of chitosan and lactose, the chitosan gels in an acidic solution and the drug contained therein is sustainedly released, but in a neutral or alkaline solution, the lactose acts as a disintegrant and the tablets are It disintegrates instantly and the drug dissolves rapidly.

Therefore, it has the disadvantage that it does not become a sustained release preparation in neutral or alkaline areas in the body, but instead becomes a rapid disintegration and dissolution preparation.

Therefore, it has been desired to develop a sustained release preparation made of chitosans that is easy to manufacture and allows sustained release of drugs even in acidic, neutral, and alkaline sites.

<Means for Solving the Problems> As a result of extensive research into the properties of mixtures of chitin and/or chitosan and other substances, the present inventors have found that a mixture of chitin and/or chitosan and carboxyvinyl polymer contains a drug. When a mixed composition is prepared by mixing the mixed composition, the elution of the drug from the mixed composition depends on the acidity (p) of the solvent in which the mixed composition is placed.
H) It was found that there is a delay regardless of the

Although there are no known examples of using a mixture of chitin and/or -1)san with other polymeric substances as a pharmaceutical composition, polyion complexes of chitosan and acidic polysaccharides are known in the food industry. It is. (U,S
,P.

No. 3,833,744) but the USP3, 833
, No. 744 lists alginic acid, pectin, carrageenan, carboxymethylcellulose, etc. as acidic polysaccharides, but there is no mention of carboxyvinyl polymer.

The present inventors prepared a mixed composition by mixing a drug with a mixture of chitin and/or chitosan and alginic acid or pectin, and determined the elution of the drug from the mixed composition by combining chitin and/or chitosan with carboxyvinyl. When a mixed composition was prepared by mixing a drug with a mixture with a polymer, a comparison was made and it was found that the elution of the drug was significantly delayed in the case of a mixed composition using carboxyvinyl polymer.

Therefore, by formulating a mixed composition of chitin and/or chitosan, carbo=5-xyvinyl polymer, and drug, the elution of the drug can be controlled by adjusting the acidity (p iI) of the solvent.
The inventors have discovered that a formulation that does not depend on the effects of oxidation and has a sufficient delay can be obtained, and has thus arrived at the VC of the present invention.

That is, the present invention is a sustained-release pharmaceutical composition using chitosan, which is characterized by comprising chitin and/or chitosan, carboxyvinyl polymer, and a drug.

The chitin used in the present invention is (1→4)-2-7cetamido-2-deoxy-β-1)-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.

The chitosan used in the present invention is (1→4)-2-amino-2-deoxy-β-D-glucan, which can be obtained by deacetylating chitin and is represented by the following formula.

Among chitin and yalzan', chitosan is particularly preferred for sustained release of drugs.

The carboxyl vinyl polymer used in the present invention is an acrylic polymer, and the viscosity of a 0.2% water bath solution at 25°C is 1,
0 CIO to 100,000 cps J' - desirable.

Specific examples of such carboxyvinyl polymers include
(, F, Goodrich Carbopol 93
4.940,941. Hibis Wako-10 manufactured by Wako Pure Industries Co., Ltd.
3,104,105, Shun pwl manufactured by Nihon Tsumugi Co., Ltd.
lo, 111 婢 can be given. In the present invention, one of these carboxyvinyl polymers may be used alone or 2ilVI or more may be used in combination.

The drugs used in the present invention usually require frequent administration to maintain effective blood concentrations or effective local concentrations.
Any drug may be used as long as it is The following drugs may be cited as examples.

Menoenamic acid, acemethacin, indomethacin, fulc'jfenac, inobufen.

Thi7ramide hydrochloride, Ri1-wo'nofunin, dikup7ebsokunarium, sulindac, naproxen, noninzen, flurbipurquen.

Antipyretic, analgesic and anti-inflammatory agents such as mehirizole: acenodol cilanate, fluprenol hydrochloride, hydrochloric acid.
fndenop-ru! Hydrochloric acid solution; 4-butsunorol, hydrochloric acid kalao μm, hydrochloric acid butupranolol! Drugs for arrhythmia such as pin 1 μm drug; anti-arrhythmia agents such as phlegm F; anti-hypertensive drugs such as p-hersin hydrochloride, nont-μl norl, prazosin hydrochloride, cabb-1-ril, tartaric acid, metoprol, methyldopa, betanicin sulfate, etc. Agents: ethaphenone hydrochloride, oxypherin hydrochloride.

Lupomecne hydrochloride, dilazep hydrochloride, diltiazem hydrochloride, trimetazidine hydrochloride, verapamil hydrochloride, diviridamol, insorbide nitrate.

(・Ravidil, nicorandil, nifedipine.

Vasodilators such as inositol hexanicotinate, inxubrin hydrochloride, dimethate citrate, cilalandele 1-, cinnarizine; riμ fibrate, cinquiplar 1. Elastase, Nystere, Nicomo
Le.

Agents for arteriosclerosis such as nicardipine hydrochloride, nimodipine hydrochloride, Mekp Fair/Kizate hydrochloride, Titoku p-m C, Ifemp dil tartrate, Tocofyl nicotinate 1 Bentochimifilin 1, etc. Agents for the circulatory system: Luprenaline hydrochloride , pyrubutyrol hydrochloride, bitolterol hydrochloride, salbutamol sulfate, kerbutaline sulfate, hexobunnarin sulfate, dimemorphan phosphate, mangoo hydrochloride 9-pxol, leethyl cysteine hydrochloride, trimethoquinol hydrochloride, bromhexine hydrochloride.

Antitussive medicines such as laofillin and tranilast; aceglutamide aluminum, leucultamine +p () lance-4-aminomethylcyclohexanecarbonyl)-
Phenyl pionate hydrochloride, cetraxate hydrochloride,
Pirenzepine hydrochloride, gefarnate, Nmemitjin.

glycopinium bromide, sulpiride, 17.20-dimethyl-6-oxoprostaglandin E, methyl ester, 6-oxoprostaglandin E, 15
-Methyl-prostaglandin heart, 16-methyl-16
-Hydroxy-15-dehydroxyprostaglandin E, methyl ester, 7-thiaprostaglandin E,
Anti-ulcer agents such as prostaglandins such as methyl ester, 17.20-dimethyl-7-thiabrostagerane, methyl ester; chymotrypsin, streptokinase, lysozyme chloride, seabrose, serapebutase, bupnase, Enzyme preparations such as promelain and montase; anti-malignant tumor agents such as methotrexate, carbocone, carmofur, degafur, and fluorouracil; chemotherapeutic agents such as nioxacillin, fuesilisopotassium, amoyasicillin, anbinlin, cefanxin, and senradin; Anti-inflammatory steroids such as chlorine, prednisolone, triamcimerone, dexamethacin, and betamethacin; Antihistamines such as diphenhydramine hydrochloride and chlorpheniramine maleate; Local anesthetics such as benzocaine; pruhexidine hydrochloride, hexylresorcinol, and ethacridine Examples include ``1-internal sedicides,'' etc.

The composition of the present invention can be obtained by mixing such a drug, the chitin and/or chitosan, and the carboxyvinyl polymer, but each component must be sufficiently ground and mixed to form a powder with a small particle size. Preferable cl Specifically, the particle diameter is preferably about 500 ArR to 5 am, more preferably about 200 μm to 1 m@degree. When pulverization is required, it may be pulverized using a conventional pulverizer 1, such as a centrifugal pulverizer. In that case, the three components may be mixed in advance and then the mixed powder may be ground.

The mixing ratio of chitin and/or chitosan, carboxyvinyl polymer, and drug varies depending on the drug used, but the drug content is usually 1% to 50% of the total. Non-drug autopsy.

That is, the mixing ratio of chitin and/or chitosan and carboxyvinyl polymer is usually 95:5 to 10:9 by weight.
0, but more preferably 80:20 to 20:8
0, more preferably 30:70-70:
It is 30.

The tetracompound of chitin and/or chitosan, calhoki divinyl polymer, and drug obtained by the method can be administered orally, intracavitally or nasally. l! 7 Suitable for formulations for topical administration or direct intra-tissue administration, such as powders, powders, etc.
Granules.

It is preferably formulated into tablets and the like. The preparation can be obtained by the "Lido" method.

That is, the resulting mixture can be made into a powder as it is, or by adding one or more of a desired lubricant, binder, coloring agent, and flavoring agent as necessary to form a powder.

Examples of the lubricant used here include talc, stearic acid, salt of stearin powder, and wax. Examples of the binder include De/Bun, Textrin, Tragacanth 9 Gelatin Polyvinyl Biμlidone, Hydroxypropylene Vylcell I:I-S, Polyvinyl Alcohol tx
gb' can be mentioned. Examples of the coloring agent include tar-based pigments such as Zancet Yellow.

Alternatively, the resulting mixture can be made into tablets by directly compressing it as it is, adding a lubricant, a binder, a coloring agent, etc. as necessary.

Furthermore, it can be made into granules by granulating it by a conventional method, and it can also be made into powder or dust by further crushing the granules.

These preparations are administered to living organisms in such a way that the effects of the drugs they contain are fully exhibited. For example, antipyretic, analgesic, anti-inflammatory agents, and antiarrhythmia agents.

Antihypertensive agents, vasodilators, arteriosclerotic agents, circulatory system agents, antitussive and sputum agents, antiulcer agents, anti-ulcer agents, and anti-malignant agents. Medicinal drugs, chemotherapy drugs, anti-inflammatory steroids, antihistamines, etc. are administered lightly.

Also, antiarrhythmic agents, antihypertensive agents, and vasodilators.

Agents for arteriosclerosis, cardiovascular agents, anti-inflammatory steroids; 9. Topical blister agents; 2. Oral disinfectants. These drugs are locally administered into the oral cavity or nasal cavity. Also, anti-malignant It! It is also possible to administer the tumor agent directly into the tissue.

<Effects of the Invention> According to the pharmaceutical composition of the present invention, frequent administration is usually required to maintain effective blood concentration or effective local concentration. The present invention has great significance in that it provides a new sustained-release pharmaceutical composition that can control the in-vivo release of drugs and reduce the number of administrations.

<Example> The present invention will be explained in more detail below using examples.

Example 1 By the method of the present invention, 43.5 parts by weight of chitozan, 43.5 parts by weight of carpoquinhinyl polymer, 12 parts by weight of indomesason
．． The weight of one tablet is 200m. i'
), 10th revised Japanese Pharmacopoeia, dissolution test method 2 (paddle method), using the first solution (pH = 1.2) as the test solution, a dissolution test was conducted.

The tablets were compressed for 30 seconds at a compression pressure of 100 kg using a KBr tablet press for measuring infrared absorption spectra and a hydraulic press to form flat tablets with a diameter of 13 mm. The test solution was sampled over time, the amount of dissolved indomethacin was measured using a spectrophotometer, and the dissolution rate was calculated from the concentration. At the same time, as a contrast,
43.5 parts by weight of microcrystalline cell ρ-se, 43.5 parts by weight of lactose. [(
Department, in)! Tablets consisting of 12.511 parts of Mesasif and 0.5 parts by weight of magnesium stearate (for
1) + Tablet consisting of 43.5 parts by weight of chitosan, 43.5 parts by weight of pectin, 12.5 parts by weight of Indomesacif, and 0.5 parts by weight of magnesium stearate (Control + 2)
); 43.5 parts of chitosan, 43 parts of alginic acid.
Tablets consisting of 5 parts by weight, 12.5 parts by weight of Intome→Nosine and magnesium stearate (J, 51 parts (control +3+); and 1 part by weight of chitosan 8 parts, 12.51 parts by weight of indomesacin, and magnesium stearate
A tablet consisting of 1 part of 53mj (Control (4) > VC) was similarly subjected to the dissolution test.

The results are shown in Table IK.

Example 2 For each tablet described in Example 1, the test solution was mixed with a second solution (p
Table 2 shows the results of testing in the same manner except that H = 6.8).

Compositions of the invention from Examples 1 and 2 (Example 10 tablets)
The elution of indomethacin from Control Examples 1 and 2. The elution of indomethacin in Control Example 4 was delayed in both the first and second solutions compared to Example 1 and 3, and the elution of indomethacin in the first solution was the same as in Example 1, but in the second solution. As compared with Example 1, it can be seen that the speed is significantly faster. That is, it can be seen that the elution of indomethacin from the tablets by the composition of the present invention is sustained.

Example 3 In the same manner as in Example 1, chitosan 42.5 was placed on the overlapping part, and poyasi vinyl poly-? -42 parts by weight, 15 parts by weight of platinyl hydrochloride, and 0.5 parts by weight of magnesium stearate.
A tablet with 200 tablets each consisting of intussusception was manufactured.

Example 4 In the same manner as in Example 1, 200 Q tablets containing 47.5 parts by weight of chitosan, 47 parts by weight of carboxyvinyl polymer, 5 parts by weight of nifedibine, and 0.5 parts by weight of magnesium stearate were prepared.

Example 5 Same as Example 1, consisting of 50.0 parts by weight of chitosan, 49.5 parts by weight of carboxyvinyl polymer, 0.01 parts by weight of tri7mucino-7cetonide, and 0.5 parts by weight of magnesium stearate. One tablet of 4089 was manufactured.

Claims (1)

[Scope of Claims] 1. A sustained-release pharmaceutical composition using chitosans, which is characterized by comprising chitin and/or chitosan, a carboxyvinyl polymer, and a drug. 2. A sustained-release pharmaceutical composition using chitosans according to claim 1, wherein the drug is a drug that normally requires frequent administration in order to maintain an effective blood concentration or an effective local concentration. 3. A sustained-release pharmaceutical composition using chitosans according to claim 1 or 2, which is a composition for powder, powder, granule, or tablet.