JPH0317809B2 - - Google Patents

Description

[Detailed description of the invention]

<Industrial Application Field> The present invention relates to sustained-release pharmaceutical compositions using chitosans. More specifically, the present invention is a composition comprising chitin and/or chitosan, a carboxyvinyl polymer, and a drug, and the dissolution of the drug is controlled regardless of the acidity (PH) of the site of the body to which the composition is applied. The present invention relates to a sustained release pharmaceutical composition. <Prior Art> Chitin, which is widely distributed in nature as a tissue support for shellfish and insects, and chitosan, which is a deacetylated product thereof, have conventionally been mostly discarded. 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 there are almost no examples of them being put to practical use. On the other hand, sustained-release formulation technology, which controls the elution and absorption of pharmaceuticals in vivo when administered to a living body, has been studied for some time. For example, methods of coating drugs with various films or methods of incorporating drugs in wax or polymer matrices are known, 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 chitosan is a method in which chitosan and a drug are dissolved in acetic acid and then the solvent is distilled off to prepare a dry chitosan gel (S. Miyazaki et al., Chem.Phem.Bull.,
29 (10), 3067-3069 (1981)) are known, but
This method has drawbacks such as requiring a long time for drying and not being applicable to drugs that are sensitive to acetic acid. On the other hand, there is a method of preparing sustained-release preparations by making chitosan powder into tablets with lactose (Y. Sawayanagi et al.
Chem.Pharm.Bull., 30(11), 4213-4215 (1982))
is also known. However, in the above-mentioned mixture of chitosan and lactose, in an acidic solution, the chitosan gels and the encapsulated drug is sustainedly released, but in a neutral or alkaline solution, the chitosan acts as a disintegrant and the tablet disintegrates immediately. , 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 rapidly disintegrating and dissolving 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 not only in acidic conditions but also in 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 determined that a mixture of chitin and/or chitosan and a carboxyvinyl polymer is doped with a drug. It has been found that when mixed to form a mixed composition, the elution of the drug from the mixed composition is delayed regardless of the acidity (PH) of the solvent in which the mixed composition is placed. Although there are no known examples of the use of mixtures of chitin and/or chitosan with other polymeric substances as pharmaceutical compositions, polyionic complexes of chitosan and acidic polysaccharides are known in the food industry. . (USP No. 3833744) However,
USP 3,833,744 lists alginic acid, pectin, carrageenan, carboxymethyl cellulose, etc. as acidic polysaccharides, but does not mention carboxyvinyl polymers. The present inventors have discovered that chitin and/or chitosan,
A mixed composition is prepared by mixing a drug with a mixture of alginic acid or pectin, and the elution of the drug from the mixed composition is controlled by mixing the drug with a mixture of chitin and/or chitosan and carboxyvinyl polymer. As a result of the comparison, it was found that the elution of the drug was significantly delayed in the case of the mixed composition using carboxyvinyl polymer. Therefore, by preparing a formulation from a mixed composition of chitin and/or chitosan, a carboxyvinyl polymer, and a drug, it is possible to obtain a formulation in which the dissolution of the drug is not dependent on the acidity (PH) of the solvent and is sufficiently delayed. This is the heading that led to 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, a carboxyvinyl polymer, and a drug. The chitin used in the present invention is (1→4)-2-
It is acetamido-2-deoxy-β-D-glucan and is represented by the following formula. Chitin is widely distributed in nature, and exists as a tissue support for shellfish and insects, and also exists 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 chitosan, chitosan is particularly preferred for sustained drug release. The carboxyvinyl polymer used in the present invention is an acrylic acid polymer, and a 0.2% aqueous solution of 25%
Viscosity at °C is measured using a B8H type rotational viscometer (20 rpm)
1000 to 100000cps is desirable. Specifically, such carboxyvinyl polymers include Carbopol 934 manufactured by BFGoodrich;
940, 941, Hivis Wako 103 manufactured by Wako Pure Chemical Industries, Ltd.
104, 105, Jyunron Pw110 manufactured by Nippon Pure Chemical Industries, Ltd.
111th grade can be given. In the present invention, one type of these carboxyvinyl polymers may be used alone or two or more types may be used in combination. The drug used in the present invention may be any drug that normally requires frequent administration in order to maintain an effective blood concentration or an effective local concentration. Specifically, the following drugs may be mentioned as examples. Antipyretic, analgesic and anti-inflammatory agents such as mefenamic acid, acemethacin, indomethacin, alclofenac, ibuprofen, tiaramide hydrochloride, ketoprofen, diclofenac sodium, sulindac, naproxen, fenbuene, flurbiproquen, mepirizole; acebutolol hydrochloride, aceprenolol hydrochloride,
Antiarrhythmic agents such as indenolol hydrochloride, oxprenol hydrochloride, carteolol hydrochloride, propranolol hydrochloride, pindolol, disopyramide; clonidine hydrochloride, buntrol hydrochloride, prazosin hydrochloride, captryl, metoprolol tartrate,
Antihypertensive agents such as methyldopa, betanidine sulfate, ethaphenone hydrochloride, oxyphedrine hydrochloride, carbomeclone hydrochloride, dilazeb hydrochloride, diltiazem hydrochloride, trimetazidine hydrochloride, verapamil hydrochloride, dipyridamole, isosorbide nitrate, trapidil,
Vasodilators such as nicorandil, nifedipine, inositol hexanicotinate, isoxsuprine hydrochloride, nimethate citrate, cilalanderate, cinnarizine; Arteriosclerotic agents such as clofibrate, cinfibrate, elastase, soisterol, nicomol; hydrochloric acid Cardiovascular agents such as nicardipine, nimodipine hydrochloride, meclofenoxate hydrochloride, cytochrome C, isofenprodil tartrate, tocopherol nicotinate, pentochimifiline; chlorprenaline hydrochloride, pirbutyrol hydrochloride,
bitolterol nasylate, salbutamol sulfate,
Terbutaline sulfate, hexoprenaline sulfate, dimemorphan phosphate, mambroxol hydrochloride, le-ethylcysteine hydrochloride, trimethoquinol hydrochloride,
Antitussives such as bromhexine hydrochloride, laofilin, tranilast; aceglutamide aluminum, ledartamine, p-(trans-4-aminomethylcyclohexanecarbonyl)-phenylpropionic hydrochloride, cetraxate hydrochloride, pirenzepine hydrochloride, gefalnate, cimetidine, True glycopyrronium, sulpiride, 17,20-dimethyl-6-oxoprostaglandin E ₁ methyl ester, 6-oxoprostaglandin E ₁ ,15-methyl-prostaglandin E ₂ ,16-methyl-16- Hydroxy-15-dehydroxyprostaglandin E ₁ methyl ester, 7-thiaprostaglandin E ₁
Anti-ulcer agents such as prostaglandins such as methyl ester, 17,20-dimethyl-7-thiaprostaglandin E ₁ methyl ester; chymotrypsin, streptokinase, lysozyme chloride, seaprose, serrapeptase, pronase, promelain, montease, etc. enzyme preparations; antineoplastic agents such as methotrexate, carbocone, carmofur, tegafur, and fluorouracil; chemotherapeutic agents such as oxacillin, phenecillin potassium, amoxicillin, ampicillin, cephalexin, and cefrazine; hydrocortisone, prednisolone, triamcinolone, dexamethasone, betamethasone, etc. anti-inflammatory steroids; antihistamines such as diphenhydramine hydrochloride and chlorpheniramine maleate; local anesthetics such as benzocaine; chlorhexidine hydrochloride, hexylresorcinol,
Examples include oral disinfectants such as ethacridine. The composition of the present invention can be obtained by mixing such a drug, the chitin and/or chitosan, and the carboxyvinyl polymer, and each component is preferably sufficiently ground and mixed to form a powder with a small particle size. . Specifically, the particle diameter is preferably about 500 μm to 5 μm, more preferably about 200 μm to 10 μm. When pulverization is required, it may be pulverized using a conventional pulverizer, such as a centrifugal pulverizer. In that case, the three components may be mixed in advance and then the mixed powder may be pulverized. The mixing ratio of chitin and/or chitosan, carboxyvinyl polymer, and drug varies depending on the drug used, but the amount of drug is usually 0.01% to 50% of the total. The mixing ratio of the part other than the drug, that is, chitin and/or chitosan, and the carboxyvinyl polymer is usually 95:5 to 10:90 by weight, more preferably 80:20 to 20:80, and even more preferably teeth
It is from 30:70 to 70:30. The mixture of chitin and/or chitosan, carboxyvinyl polymer, and drug thus obtained is
Suitable for formulation for oral administration, intraoral or intranasal topical administration, or direct intra-tissue administration;
For example, it is preferably formulated into powders, powders, granules, tablets, etc. The following methods can be used to obtain the preparation. That is, the resulting mixture can be made into a powder as it is, or by adding one or more of desired lubricants, binders, coloring agents, and flavoring agents as needed to form a powder. Examples of the lubricant used here include talc, stearic acid, stearic acid salts, and wax. Examples of the binder include starch, dextrin, tragacanth, gelatin, polyvinylpyrrolidone, hydroxypropylcellulose, and polyvinyl alcohol. Examples of the coloring agent include tar-based pigments such as sunset yellow. Further, the resulting mixture can be made into tablets by directly compressing it as it is or by adding a lubricant, binder, 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 powder 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, and antiinflammatory agents, antiarrhythmic agents, antihypertensive agents,
Vasodilators, arteriosclerotic agents, cardiovascular agents, antitussive sputum agents, antiulcer agents, enzyme preparations, antineoplastic agents, chemotherapy agents, anti-inflammatory steroids, antihistamines, etc. are administered orally. In addition, arrhythmia agents, antihypertensive agents, vasodilators, arteriosclerotic agents, cardiovascular agents, anti-inflammatory steroids, local anesthetics, oral disinfectants, and the like are locally administered into the oral cavity or nasal cavity. Moreover, the anti-malignant tumor agent can also be administered directly into the tissue. <Effects of the Invention> According to the pharmaceutical composition of the present invention, the in vivo release of a drug, which normally requires frequent administration to maintain an effective blood concentration or effective local concentration, is controlled and the number of administrations is reduced. The present invention is of great significance as it provides a new sustained-release pharmaceutical composition. <Examples> The present invention will be explained in more detail below using examples. Example 1 43.5 parts by weight of chitosan, 43.5 parts by weight of carboxyvinyl polymer, 12.5 parts by weight of indomethacin and 0.5 parts by weight of magnesium stearate were prepared by the method of the present invention.
Make tablets consisting of parts by weight (weight of 1 tablet = 200
mg), the 10th edition of the Japanese Pharmacopoeia, dissolution test method 2 (paddle method) was conducted using the first solution (PH = 1.2) as the test solution. The tablets were compressed into flat tablets with a diameter of 13 mm using a KBr tablet press for infrared absorption spectroscopy and a hydraulic press at a compression pressure of 100 kg for 30 seconds. A 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 control, microcrystalline cellulose 43.5
Parts by weight, tablets consisting of 43.5 parts by weight of lactose, 12.5 parts by weight of indomethacin, and 0.5 parts by weight of magnesium stearate (control (1)); 43.5 parts by weight of chitosan, 43.5 parts by weight of pectin, 12.5 parts by weight of indomethacin,
and tablets consisting of 0.5 parts by weight of magnesium stearate (control (2)); tablets consisting of 43.5 parts by weight of chitosan, 43.5 parts by weight of alginic acid, 12.5 parts by weight of indomethacin and 0.5 parts by weight of magnesium stearate (control (3)); and chitosan A dissolution test was similarly conducted on a tablet (control (4)) consisting of 87 parts by weight, 12.5 parts by weight of indomethacin, and 0.5 parts by weight of magnesium stearate. The results are shown in Table-1.

[Table] Example 2 Table 2 shows the results of testing each tablet described in Example 1 in the same manner except that the second liquid (PH=6.8) was used as the test liquid.

[Table] Compositions of the present invention from Examples 1 and 2 (Example 1
The elution of indomethacin from the tablets of Control Example 4 was delayed in both the first and second liquids compared to Control Examples 1, 2, and 3, and the elution of indomethacin in Control Example 4 was delayed compared to Control Examples 1, 2, and 3. Inside, it is the same as in Example 1, but it can be seen that it is significantly faster in the second liquid than in Example 1. 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 Same as Example 1, 42.5 parts by weight of chitosan, 42 parts by weight of carboxyvinyl polymer, 15 parts by weight of propranolol hydrochloride, and 0.5 parts by weight of magnesium stearate.
Tablets each weighing 200 mg were prepared, consisting of parts by weight. Example 4 In the same manner as in Example 1, 200 mg tablets containing 47.5 parts by weight of chitosan, 47 parts by weight of carboxyvinyl polymer, 5 parts by weight of nifedipine, and 0.5 parts by weight of magnesium stearate were prepared. Example 5 In the same manner as in Example 1, 40 mg tablets containing 50.0 parts by weight of chitosan, 49.5 parts by weight of carboxyvinyl polymer, 0.01 parts by weight of triamcinolone acetonide, and 0.5 parts by weight of magnesium stearate were prepared. Example 6 and Control Example 5 43.5 parts by weight of carboxyvinyl polymer, chitin
43.5 parts by weight, 12.5 parts by weight of indomethacin, and 0.5 parts by weight of magnesium stearate were uniformly mixed to obtain a powdery composition. Next, 200 mg tablets were prepared from this powder in the same manner as in Example 1. Regarding the obtained tablets, the dissolution rate of indomethacin was examined using the first solution with a pH of 1.2 as a test solution. The results are shown in Table-3. At the same time, as a control (Control Example 5), a dissolution test was similarly conducted on a tablet consisting of 87.0 parts by weight of carboxyvinyl polymer, 12.5 parts by weight of indomethacin, and 0.5 parts by weight of magnesium stearate. The results are shown in Table-3.

[Table] Examples 7 to 8 and Control Examples 6 to 7 44.5 parts by weight of chitosan, 40.0 parts by weight of carboxyvinyl polymer, 15.0 parts by weight of nifedipine and 0.5 parts by weight of magnesium stearate were uniformly mixed to obtain a powder, and a powder was obtained, and a normal hard capsule was obtained. It was filled into hard capsules (No. 2) using a filling machine. The capsules thus obtained contain 200 mg of powder per capsule. The obtained capsules were orally administered with 20 ml of water to beagle dogs [male, body weight 10 kg (Example 7), same body weight 9.2 kg (Example 8)] that had been fasted overnight. After that, blood was collected from the forearm vein over time, and the blood nifedipine concentration (ng/
ml) was determined by gas chromatography (ECD type). The results are shown in Table 4. At the same time, as a control, capsules (total amount 200 g/No. 2 hard capsules) consisting of 42.5 parts by weight of crystalline cellulose, 42.0 parts by weight of lactose, 15.0 parts by weight of nifedipine and 0.5 parts by weight of magnesium stearate were prepared in the same manner as in Example 7. The blood concentration was determined in the same manner in male beagle dogs [9.6 kg (control example 6), 9.8 kg (control example 7)] using the same method. The results are shown in Table 4.

[Table] From Table 4, compared to Control Examples 6 and 7, Example 7,
It can be seen that the capsules filled with the powder obtained in 8 had an excellent sustained release effect.

Claims (1)

[Scope of Claims] 1. A sustained-release pharmaceutical composition using chitosans, 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 chitosan according to claim 1 or 2, which is a composition for powder, powder, granule, or tablet.