JPH0317810B2 - - Google Patents

Description

[Detailed description of the invention]

<Industrial Application Field> The present invention relates to a sustained release pharmaceutical composition using a methoxyethylene maleic anhydride copolymer hydrolyzate. More specifically, a sustained release pharmaceutical composition comprising a methoxyethylene maleic anhydride copolymer hydrolyzate, at least one cellulose derivative selected from the group consisting of cellulose ethers, chitin, and chitosan, and a drug. Regarding. <Prior Art> Sustained-release formulation technology has been studied for a long time to control the dissolution and absorption of pharmaceuticals in vivo when they are administered to living organisms. 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 and have limited effectiveness. It has the disadvantage that it is not always effective. In particular, if sustained release is not ensured, the drug may be rapidly eluted and absorbed as in conventional formulations, resulting in undesirable side effects, or the drug may not be eluted and absorbed, resulting in no effect. Therefore, it has been desired to develop reliable sustained-release preparations. <Problems to be Solved by the Invention> In view of the above circumstances, the present inventors investigated the conditions for ensuring sustained release of the drug in vivo, and found that (1) the site where the preparation was administered; We have discovered that two conditions are necessary: (2) the formulation must have an affinity for the tissues or organs of the body, and (2) the formulation must be able to easily maintain its shape without being dissolved or digested by body fluids (shape retention). We investigated a sustained-release formulation that meets these two conditions and is easy to prepare. On the other hand, methoxyethylene maleic anhydride copolymers or their hydrolysates have been used as compounds in the cosmetics and pharmaceutical industries, and there are many examples of applications of these compounds to pharmaceuticals. In fact, it has been reported that efuedrin hydrochloride dissolution from tablets containing methoxyethylene maleic anhydride copolymer is delayed (E.
Chalhoub et al., Pharm.Ind.1976, 38 (9), 844−
7). However, since methoxyethylene maleic anhydride copolymer is easily soluble in water, when a tablet containing methoxyethylene maleic anhydride copolymer is actually administered to a living body, the tablet dissolves and the drug is released in a sustained manner. Not done. In addition, methoxyethylene maleic anhydride copolymer hydrolyzate has excellent adhesion to biological components such as gastrointestinal mucosa, muscle, adipose tissue, etc., and preparations containing it have excellent adhesion to tissues or organs at the site of administration. Although it has high relaxation properties, it also has poor shape retention due to its water solubility, making it unsuitable for sustained release of coexisting drugs. In addition, certain cellulose derivatives, such as hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, chitin, and chitosan, all gel with water and have great shape retention, which delays the elution of coexisting drugs. It is expected that
US Pat. No. 4,126,672 discloses a method for producing sustained release formulations using hydroxypropyl methylcellulose. However, since these gel-forming polymers form a gel, they dissolve rapidly in body fluids, are difficult to digest, and have good shape retention, and although they are preferable for sustained release of coexisting drugs, they do not adhere well to living organisms. For example, when these gel-forming polymers are filled with drugs into hard capsules and orally administered to living organisms, they quickly move through the gastrointestinal tract, resulting in insufficient absorption. Something often happens. On the other hand, no example has yet been reported in which a mixture of a methoxyethylene maleic anhydride copolymer hydrolyzate and a cellulose derivative is used in a sustained release preparation.
U.S. Pat. No. 4,172,055 describes hydroxypropylcellulose and poly(maleic anhydride/alkene-
1) are disclosed to be useful as gelling agents, including methoxyethylene maleic anhydride copolymers within the poly(maleic anhydride/alkene-1). However, the above-mentioned US patent provides an aqueous solution of the above-mentioned mixture as a hydraulic fluid for use in drills for exploration of mineral resources such as petroleum, and does not consider any application to pharmaceutical preparations. <Means for Solving the Problems> In view of the above circumstances, the present inventors used a mixture of a methoxyethylene maleic anhydride copolymer hydrolyzate and a cellulose derivative to improve the sustained release properties of such a mixture. When we examined the application to pharmaceutical preparations, we found that when a drug is coexisted in the mixture and formulated,
The present inventors have discovered that a sustained-release preparation can be obtained that has both the bioadhesiveness and biocompatibility of a hydrolyzed methoxyethylene maleic anhydride copolymer and the shape retention properties of a certain type of cellulose derivative, and have thus arrived at the present invention. It is something. That is, the present invention provides a sustained-release pharmaceutical comprising a methoxyethylene maleic anhydride copolymer hydrolyzate, at least one cellulose derivative selected from the group consisting of cellulose ethers, chitin, and chitosan, and a drug. It is a composition. The methoxyethylene maleic anhydride copolymer hydrolyzate used in the present invention is a compound obtained by hydrolyzing a methoxyethylene maleic anhydride copolymer, and is represented by the following formula []. These copolymer hydrolysates can also be obtained by hydrolyzing the corresponding copolymers (formula [] below). It is preferable that at least 50% or more of the maleic anhydride moiety is converted to carboxylic acid by hydrolysis, and more preferably 75% or more. The cellulose derivative used in the present invention is at least one selected from the group consisting of cellulose ethers, chitin, and chitosan. Examples of cellulose ethers include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, and ethylcellulose. Among these, hydroxypropylcellulose, hydroxypropylmethylcellulose, chitin, and chitosan are preferred. The ratio of the methoxyethylene maleic anhydride copolymer hydrolyzate to the cellulose derivative in the composition of the present invention (methoxyethylene maleic anhydride copolymer hydrolyzate: cellulose derivative)
usually has a weight ratio of 95:5 to 10:90, preferably
80:20-20:80, more preferably 70:30-30:70
It is. The drug used in the present invention may be any additional drug that normally requires frequent administration in order to maintain an effective blood concentration or 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, flurprofen, mepirizole; acebutolol hydrochloride, alprenolol hydrochloride,
Indenolol hydrochloride, oxprenolol hydrochloride,
Antiarrhythmic agents such as carteolol hydrochloride, propranolol hydrochloride, pindolol, disopyramide; clonidine hydrochloride, buntrol hydrochloride, prazosin hydrochloride, captryl, metoprolol tartrate,
Antihypertensive agents such as methyldopa and betanidine sulfate; ethaphenone hydrochloride, oxyphedrine hydrochloride, carbomeclone hydrochloride, dilazep 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 chlorofibrate, ginfibrate, elastase, soysterol, nicomol; Nicardipine hydrochloride, hydrochloric acid Cardiovascular agents such as nimodipine, meclofenoxate hydrochloride, cytochrome C, ifenprodil tartrate, tocopherol nicotinate, pentoxifylline; chlorprenaline hydrochloride, pyrubutyrol hydrochloride,
bitolterol nasylate, salbutamol sulfate,
Terbutaline sulfate, hexoprenaline sulfate, dimemorphan phosphate, mambroxol hydrochloride, L-ethylcysteine hydrochloride, trimethoquinol hydrochloride,
Antitussive sputum agents such as bromhexine hydrochloride, theophylline, tranilast; aceglutamide aluminum, ledartamine, p-(trans-4-aminomethylcyclohexanecarbonyl)-phenylpropionic acid hydrochloride, cetraxate hydrochloride, pirenzepine hydrochloride, gefalnate, cimetidine, Glycopyrronium bromide, 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 content of these drugs in the composition of the present invention is appropriately determined depending on the strength of the pharmacological action of the drug. The composition of the present invention is obtained by mixing the drug, the methoxyethylene maleic anhydride copolymer hydrolyzate, and the cellulose derivative. Preferably, the powder is ground, well mixed and has 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 the methoxyethylene maleic anhydride copolymer hydrolyzate, cellulose derivative, and drug varies depending on the drug used, but is usually appropriately determined depending on the strength of the pharmacological action of the drug. The mixing ratio of the portion other than the drug, that is, the methoxyethylene maleic anhydride copolymer hydrolyzate and the cellulose derivative, is as described above. The thus obtained mixture of methoxyethylene maleic anhydride copolymer hydrolyzate, cellulose derivative, and drug is suitable for formulation for oral administration, intraoral or intranasal topical administration, or direct intratissue administration, and is suitable for tablets. It is preferably formulated into a formulation. The following methods can be used to obtain the preparation. That is, the resulting mixture can be made into tablets by directly compressing it as it is, or by adding one or more of desired lubricants, binders, colorants, and flavorings as necessary. 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, and polyvinyl alcohol. Examples of the coloring agent include tar-based pigments such as sunset yellow. 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 administered locally 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 Methoxyethylene maleic anhydride copolymer hydrolyzate [95% hydrolyzate:
GAF Gantrez S-95〕42.25
parts by weight, 42.25 parts by weight of hydroxypropylcellulose, 15.0 parts by weight of nifedipine, and 0.5 parts by weight of magnesium stearate were thoroughly mixed to obtain a powder composition, and tablets were made from this composition by a conventional method (the weight of 1 tablet was = 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 collected over time, the amount of dissolved nifedipine was measured using a spectrophotometer, and the dissolution rate was calculated from the concentration. At the same time, as a control, microcrystalline cellulose 42.25
Parts by weight, tablets consisting of 42.25 parts by weight of lactose, 15.0 parts by weight of nifedipine, and 0.5 parts by weight of magnesium stearate (control (1)); 84.5 parts by weight of methoxyethylene maleic anhydride copolymer hydrolyzate, 15.0 parts by weight of nifedipine, and Tablet consisting of 0.5 parts by weight of magnesium stearate (control (2)); 84.5 parts by weight of hydroxypropylcellulose, nifedipine
A dissolution test was similarly conducted on a tablet (control (3)) consisting of 15.0 parts by weight and 0.5 parts by weight of magnesium stearate. The results are shown in Table-1.

[Table] It can be seen that the elution of Example 1 was delayed compared to Control Examples 1 to 3. Example 2 Regarding the tablets produced in Example 1 and the tablets of Control Examples 2 and 3 in Example 1, healthy volunteers were given 50 ml of water.
After administration, samples were taken over time and the concentration of nifedipine in the blood was measured using ECD gas chromatography. The results are shown in Table-2. It can be seen that even when Example 1 is actually taken by humans, the release is more sustained than that of Control Examples 2 and 3.

[Table] Example 3 Methoxyethylene maleic anhydride copolymer hydrolyzate [95% hydrolyzate:
43.5 parts by weight of GAF's Gantrez S-99, 43.5 parts by weight of hydroxypropyl cellulose, 12.5 parts by weight of indomethacin, and 0.5 parts by weight of magnesium stearate were thoroughly mixed to obtain a powder composition, and tablets were prepared by a conventional method. (weight of 1 tablet = 200 mg), and the 1st solution (PH=
1.2) was used to conduct the dissolution test. 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, 43.5 parts by weight of lactose, indomethacin
Tablets consisting of 12.5 parts by weight and 0.5 parts by weight of magnesium stearate (control (4)); 87.0 parts by weight of methoxyethylene maleic anhydride copolymer hydrolyzate;
Tablets consisting of 12.5 parts by weight of indomethacin and 0.5 parts by weight of magnesium stearate (control (5)); Tablets consisting of 87.0 parts by weight of hydroxypropyl cellulose, 12.5 parts by weight of indomethacin and 0.5 parts by weight of magnesium stearate (control (6)); A dissolution test was also conducted in the same manner. The results are shown in Table-3.

[Table] Examples 4 to 6 Indometacin tablets were manufactured using the cellulose derivatives listed in Table 4 instead of the hydroxypropyl cellulose in Example 3, and the dissolution test was conducted in the same manner as in Example 3. The results are shown in Table 4.

[Table] Example 7 Same as Example 1, 42.5 parts by weight of methoxyethylene maleic anhydride copolymer hydrolyzate, 42 parts by weight of hydroxypropyl cellulose, 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 8 One tablet consisting of 50.0 parts by weight of methoxyethylene maleic anhydride copolymer hydrolyzate, 49.5 parts by weight of hydroxypropyl cellulose, 0.01 part by weight of triamcinolone acetonide, and 0.5 parts by weight of magnesium stearate was prepared in the same manner as in Example 1. 40mg tablets were made.

Claims (1)

[Scope of Claims] 1. A sustained release characterized by comprising a methoxyethylene maleic anhydride copolymer hydrolyzate, at least one cellulose derivative selected from the group consisting of cellulose ethers, chitin, and chitosan, and a drug. Sex pharmaceutical composition. 2. A patent in which the methoxyethylene maleic anhydride copolymer hydrolyzate is a methoxyethylene maleic anhydride copolymer hydrolyzate in which at least 50% of the maleic anhydride portion of the methoxyethylene maleic anhydride copolymer has been hydrolyzed. Claim 1
The sustained-release pharmaceutical composition described in Section 1. 3. The sustained-release pharmaceutical composition according to claim 1 or 2, wherein the drug is a drug that normally requires frequent administration in order to maintain an effective blood concentration or an effective local concentration. 4. The sustained release pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition is a composition for tablets.