JPH02121919A - Tablet having flexibility - Google Patents

Abstract

PURPOSE:To obtain a sustained release tablet, consisting of a mixture containing gelatin, glycerol, polyacrylic acid or salt thereof and drug, having flexibility and capable of being applied to mucous membranes in the oral cavity, etc., or orally administered. CONSTITUTION:A tablet, obtained by blending 10-50wt.% gelatin with 5-20wt.% glycerol, 5-40wt.% polyacrylic acid or salt thereof and 0.03-60wt.% drug, compression forming the resultant blend according to a conventional method and then heating the resultant tablet at 40-150 deg.C for 1min-2hr and having flexibility. Since the objective table is a tablet having flexibility, feeling of administration is soft as an oral agent and readily sticks onto mucous membranes in administration thereto in the oral cavity. Thereby, holding properties in the mouth is excellent with good feelnging of application and good sustained release properties are exhibited in digestive tracts.

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to sustained release preparations. More specifically, the formulation relates to a flexible sustained-release tablet that can be applied to mucous membranes such as the oral cavity or used for oral administration. (Prior Art) Various kinds of oral preparations for mucosal administration 1 having sustained release properties have been known. For example, buccal preparations, troches, sublingual tablets, liquid preparations, ointments, and the like are known as agents for administering PA to mucous membranes, such as in the oral cavity. However, since these conventional preparations are hard, they have a strong foreign body sensation, and the person using them tends to have an urge to chew or swallow, making it difficult to keep them in the oral cavity for a long time. Furthermore, liquids and ointments have the disadvantage that the administered drug is easily swallowed by saliva and that it is difficult to control the dosage. In recent years, oral mucosal-adhesive sustained-release preparations made of water-soluble polymers have become known. However, these formulations. Until it is swollen by saliva in the oral cavity, it has a strong foreign body sensation similar to the above-mentioned conventional buccal tablets, and cannot be said to be particularly comfortable in use. On the other hand, various similar sustained-release oral preparations have been tried, but they are not necessarily satisfactory in terms of the feeling of taking one dose and the expression and sustainability of the sustained-release effect. The problems to be solved in conventional sustained release tablets are as described above. (Structure of the Invention) As a result of extensive research to obtain a new formulation that improves the above problems, the present inventors have found that it has an excellent feeling of use (taking), sustained release properties, etc. when administered orally or intrabuccally. They succeeded in obtaining flexible tablets and completed the present invention. Specifically, the present invention relates to a flexible sustained-release tablet comprising a mixture containing gelatin, glycerin, polyacrylic acid or a pharmaceutically acceptable salt thereof, and a drug. Furthermore, the present invention also relates to a method for producing flexible sustained-release tablets, which is characterized in that the compound is formed into three tablets and then heated if necessary. As the above-mentioned gelatin, one having an effect of promoting absorption of the drug to be mixed is preferably used. Their molecular weight ranges from tens of thousands to several seventy thousand, and they are obtained by hydrolyzing proteins contained in animal bones, skins, ligaments, and bones. Examples of such gelatin include acid-treated gelatin, alkali-treated gelatin, and various known gelatin derivatives such as succinic acid gelatin. Among them, powdered alkali-treated gelatin is preferred. Use 1 of the gelatin includes: -Finally, use 1 of the entire preparation of the present invention
The amount is 0 to 50% by weight, preferably about 30±10% by weight. The above glycerin is used to adjust and maintain the flexibility of the tablet of the present invention, and also to adjust the release rate. Either pure glycerin or hydrous glycerin can be used as the glycerin. However, among them, those with a low water content are preferred, particularly 1 glycerin (Japanese Pharmacopoeia, 11th edition), which has a water content of 2% or less. ~2
0% by weight, preferably about 10±5% by weight of concentrated glycerin. The above-mentioned polyacrylic acid or a pharmaceutically acceptable salt thereof is mainly used for the purpose of imparting flexibility, adhesion, and sustained release properties to the formulation of the present invention. As a specific example of the polyacrylic acid, a polyacrylic acid homopolymer is usually used, but in addition, a copolymer obtained by copolymerizing acrylic acid with methacrylic acid, styrene, a vinyl type ether monomer, etc. may also be used. Pharmaceutically acceptable salts include:
Representative examples include alkali metal salts such as 1-lium salts and potassium salts, alkaline earth metal salts such as calcium salts, and ammonium salts. In addition to polyacrylic acid itself, for example, commercially available polyacrylic acid containing a small amount (usually 20% by weight or less) of a water-soluble polymer may be used. Specific examples of this polyacrylic acid or its pharmaceutically acceptable salt include Hibis Wako (trade name, manufactured by Wako Tsumugi Co., Ltd.), Carbobol (trade name, manufactured by Gutudrich Chemical Co., Ltd.), ), Rubiscoll (product name, B^
, S, F), etc. can be conveniently used. In this case, acrylic acid polymers and their alkali metal salts are particularly desirable.
Examples include those with an iE of about 450,000 to 4,000,000, but preferably those with a molecular Ji: JOO of about 1,000,000 (for example, PA, Carboball 934 trade name, manufactured by Gutdrich Chemical Co., Ltd.)
is preferred. The amount used is: -5 to 4 of the total amount of the preparation of the present invention.
The amount is 0% by weight, preferably about 20±10% by weight. The above-mentioned drug may be any drug suitable for oral administration or oral mucosal administration. These drugs include local disease therapeutics that are used to act near the oral mucosa, and systemic disease therapeutics that are absorbed through the gastrointestinal tract or oral mucosa through an oral pitcher. Examples of these drugs include anti-inflammatory analgesics such as indomethacin and ibuprofen:
Oral disinfectants such as chlorhexidine hydrochloride and hexylresorcin; enzymes such as lysozyme chloride, dextranase, and kallikrein; antianginal drugs such as nitroglycerin, insorbitol nitrate, and nifedipine; antiasthmatic drugs such as sodium cromoglycate; penicillin , antibiotics such as erythromycin; transcribing drugs such as sulfathiazole and nitrofurazone; local anesthetics such as benzicaine; digitalis,
Cardiotropes such as digoxin; antitussives such as codeine phosphate;
Gastrointestinal agents such as trimebutine 1-aldioxa; antihypertensive agents such as prazosin; anti-inflammatory agents such as water-soluble azulene; antihistamines such as diphenhydramine hydrochloride and chlorpheniramine maleate; prednisolone, triamcinolone,
In addition to anti-inflammatory steroids such as dexamethacin, hemostatic agents, hormonal agents, antineoplastic agents, vasodilators, vasoconstrictors, and beta blockers. Examples include calcium antagonists and diuretics. Among these drugs, drugs that can be used more effectively due to their sustained release properties. It is effective to use drugs that have a low bioavailability when administered orally, drugs that must be administered by injection, etc. as drugs to be incorporated into the tablets of the present invention. The above drug is used in an amount sufficient to achieve the desired medicinal effect, and in most cases, the amount of the drug is 0.03 to 60% by weight of the entire formulation of the present invention. Within this range, the dosage is appropriately increased or decreased depending on the type of drug and the purpose of treatment.For example, the dosage of each drug is determined depending on whether the medicinal effect is achieved with a small amount of administration or when a larger dose is required. In addition, the characteristics of the tablet of the present invention (
For the purpose of improving the processing/formability, quality, and stability of the preparation, or for the purpose of improving the processing/formability, quality, and stability of the preparation, select desired additives from among the known pharmaceutically acceptable additives. It is possible to further blend ingredients selected depending on the situation. Specific examples of such additives include the following. i.e. white sugar, sorbitol, mannitol. Excipients such as lactose, starch, and crystalline cellulose; absorption enhancers such as isopropyl myristate and diisopropyl adipate, and sucrose fatty acid esters. Lubricants such as magnesium stearate and talc; preservatives such as paraoxybenzoic acid ester; pH regulators such as sulfur and lium citrate; surfactants; 31'! Examples include flavoring agents, sweeteners, coloring agents, and flavoring agents. Next, a method for producing the formulation of the present invention will be described. First, the above mixture is beaten by a commonly used method.
A tablet having the desired flexibility can be obtained by obtaining a tablet (2<compression molding) and then heating it. That is, a heating process is added to the conventional tablet manufacturing process (for rIA, the steps of crushing, mixing, granulation, drying, sieving, mixing, and tabletting are the usual means used to manufacture one tablet). The object of the present invention is thereby achieved. That is, the manufacturing method of the present invention is characterized in that by applying heat to a tablet obtained by compression molding the ingredients, a preparation with unexpected flexibility can be obtained. As for the heating method, heating using hot air or hot air is generally used, but heating methods using infrared rays or high frequency waves may also be employed. The heating temperature is −
It is preferable to heat the shell at 40-150°C for a heating time of 1 minute to 2 hours, preferably 5 minutes to 1 hour. The form of the obtained preparation is conveniently employed in the thickness and shape known per se, and there is no particular restriction as long as it does not impede the purpose of the present invention.The specific form of the preparation is 1. In the case of a preparation, the thickness is 0.2 to 3. 1 in office lady
Flat (circular) tablets with a width (diameter) of 4 to 10 cm are generally preferred; in the case of oral preparations, the shape may be similar to that of oral preparations; is 0.5~
At 4■. A disc-shaped material with a diameter (longer axis) of 3 to 15 a+m is used. The thus obtained preparation is a highly flexible tablet that is soft enough to be deformed without breaking its shape, compared to ordinary hard tablets. For example, the tablet of the present invention can be easily bent at an angle of about 10 to 90 inches, and can also be easily deformed by applying external force. (Operations and Effects of the Invention) Effects of the Invention Although the effects are clear from the above, the special feature of the preparation of the present invention is that it has flexibility even though it is a single tablet.Such flexibility gives it a soft feeling when taken as an oral preparation. 1. When administered to the oral mucosa, 8. The tablet conforms to the shape of the oral cavity and easily adheres to the mucous membrane, resulting in good retention in the mouth and making it easy to retain the tablet during the day. As a result, there is almost no foreign body sensation, so daily activities are not restricted during application.The tablet of the present invention, which is administered orally, gradually swells in the gastrointestinal tract (stomach, intestines) and adheres to mucous membranes. Coupled with its properties, it remains in the gastrointestinal tract for a long time and releases the drug, so it can exhibit good sustained release properties.Therefore, the present invention provides a medically useful sustained release preparation.Next The present invention will be explained in more detail by describing a more specific manufacturing method and test results of the preparation of the present invention.Implementation IN 1゜Formulation (in 1 tablet) Sodium azulene sulfonate 5.Oll [1 gelatin] hmm
18.0ngmanito
- Le 24.0L
Ogori Glycerin
6.0 mg carboxyvinyl polymer 11.5-g magnesium stearate
0.5tag65.0-Bi''11 sides] L Gelatin (manufactured by Miyagi Chemical Industry Co., Ltd.) 90g, sodium azulene sulfonate 258g, and mannitol 120g
After mixing with Ni-Goo, 30 g of concentrated glycerin (manufactured by Kosakai Pharmaceutical Co., Ltd.) diluted with 10 g of absolute ethanol was added to perform granulation, and after drying at 50°C for 5 hours, 12 m e s h
Carboxyvinyl polymer (Carboball 934, manufactured by Gutdrich Chemical Co., Ltd.) 57.5
g and 2.5 g of magosium stearate,
The tablets were compressed to a thickness of about 1.51 cm using a flat punch with a diameter of 7IIIl. The tablets R & J2 were heated at 70° C. for 1 hour to obtain flexible tablets. 2 products J1 left fly - As a control product, a dissolution test was conducted using Nippon Shinyaku Co., Ltd.'s sustained release insert tablet Azunol ST (trade name) (hereinafter referred to as A tablet) for comparison. The test method is the dissolution test method 2 of the 11th revised Japanese Pharmacopoeia (
The test solution was 100 ml of the second solution (pH 6, 8) of the 11th revised Japanese Pharmacy disintegration test method (paddle method), and the measurement was performed with a spectrophotometer (measurement wavelength: 292 nm). As shown in Figure 1, approximately 90% of the drug was eluted in 90 minutes. Compared to Tablet A, the elution pattern of the drug is about 2 fΔ drug elution that lasts for a longer period of time, making it desirable as a sustained-release preparation. Dimensions in m-1 For flexibility, use rheometer-NRM-2010J-C
ill (manufactured by Fudo Kogyo Co., Ltd.). Fix the sample to the dedicated adapter No. 17 together with a 21-thick acrylic plate with one side cut into a semicircle of 71φ.
*φ) at a table speed of 5 cm/Min. In the sample immediately after compression (tablet before heat treatment in Example 1),
The breaking strength was 8 g, which was the same as that of conventional tablets, whereas the samples heated at 0°C for 1 hour (tablets in Table 7 of heat treatment in Example 1) did not break. about 9 to
Bends at 0° and has a softness of 4.0cm/Ki1
Met. Example 2゜Prescription (in 1 tablet) Triamcinolone acetonide 0.06mg gelatin
18.00g mannitol
23.94 fake g concentration
6.00mg carboxyvinyl polymer' 11.50mg red sea bream sium stearate 0.50B60.00g ] 1 tachiushi gelatin (Miyagi

[Higaku Kogyo Co., Ltd. 028g and Mannitol 167.58. After mixing in a kneader, 42 g of triamcinolone acetonide Q was dispersed in 42 g of concentrated glycerin (manufactured by Kosakai Pharmaceutical Co., Ltd.) diluted with 14 g of boiled water ethanol, and granulation was performed. After drying, the mixture was granulated for 12 mes.
Carboxyvinyl polymer (Carboball 934, manufactured by Gutdrich Chemical Co., Ltd.) is added to the powder obtained by sieving.
80.5 g and 3.5 g of magnesium stearate were mixed and tableted to a thickness of about 1.5 mm using a flat punch with a diameter of 71 mm. After pressing, the five tablets were heated at 70° C. for 1 hour to obtain flexible tablets. Example 3 Prescription (in 1 tablet) Biloxicum nitrol concentrated glycerin 2.0mg 18, OII [1 24.0mg 8 6.0g 11. 5g carboxyvinyl polymer magnesium stearate 0.5B62.0vg 90g of gelatin (manufactured by Miyagi Chemical Industry Co., Ltd.), 10g of piroxicam and 120g of mannitol were mixed in a kneader, and then mixed with 10g of mature water ethanol. Granulation was carried out by adding 30 g of diluted concentrated glycerin (manufactured by Kosakai Pharmaceutical Co., Ltd.).
57.5 g of carboxyvinyl polymer (Carboball 934, manufactured by Gutdrich Chemical Co., Ltd.) and 2.58 g of magnesium stearate were mixed with the powder obtained by drying at °C for 5 hours and passing through a f&12+*esh sieve. The tablets were compressed to a thickness of 1.5H using a flat punch. After compression, heat one tablet to 70″C
After heating for 1 hour, flexible tablets were obtained. Example 4 Prescription (in 1 tablet) Buprenorphine hydrochloride 0.2mg Zera
Chin
18.0mg mannitol 24.0+
ag concentration glycerin
6.0g carboxyvinyl polymer 11.5B stearic acid mago, sium 0.5mg60.2mg 11 gelatin (manufactured by Miyagi Chemical Industry Co., Ltd.) 90. , 1 g of buprenorphine hydrochloride and 120 g of mannitol were added in a kneader.
After mixing, 30 g of concentrated glycerin (manufactured by Ko S'! I Pharmaceutical Co., Ltd.) diluted with anhydrous ethanol leg was added to granulate the powder, dried at 50°C for 5 hours, and sieved with 7 & 12 mesb to obtain a powder. 57.58 g of Carbo-divinyl polymer (Riki-Bobol 934, manufactured by Gutdrich Chemical Co.) and 2.5 g of magnesium stearate were mixed into the mixture. The tablets were compressed to a thickness of about 1.5 a+m using a flat punch with a diameter of 1. After casting, the 32 tablets were heated at 70° C. for 1 hour to obtain flexible tablets. Examples et al. Prescription (in 1 tablet) Bromocriptine mesylate 2.56 Zera
Chin
18. Ogmannito -
le 24.0m
g thick glycerin
6. (hg carboxyvinyl polymer 11.5IIIg magnesium stearate 0.5B62.5-g) 1 L gelatin (manufactured by Miyagi Chemical Co., Ltd. > 90 g, bromocriptine mesylate 12.5 g and mannitol 1208
After mixing in a kneader, add 10% of absolute ethanol. Granulation was carried out by adding 30 g of concentrated glycerin (manufactured by Kosakai Pharmaceutical Co., Ltd.) diluted with powder, dried at 50°C for 5 hours, and sieved through a 12 mesh mesh. (manufactured by Dorich Chemical Co.) 57.5. and 2.5 g of magnesium stearate, and a diameter of 7.
The tablets were compressed to a thickness of approximately 1.50 mm using a +im flat punch. After tableting, the three tablets were heated at 70° C. for 1 hour to obtain flexible tablets. Example 6゜formulation (in 1 tablet) Trimebutine maleate 50, Ogzera
Chin
30.0mg Mannitol 40, Og Concentrated Glycerin
10.0mg carboxyvinyl polymer 19.0mg magnesium stearate
1.0 mg 150.0 mB'' L Gelatin (manufactured by Miyagi Chemical Co., Ltd.) Bog, trimebutine maleate 100.0 g and mannitol 80 g were mixed in a kneader, then concentrated glycerin diluted with 8 g of absolute ethanol (unnecessary pharmaceuticals) After drying at 50°C for 5 hours and sieving with R&12+++esh, 20g of carboxyvinyl polymer (Bopol 934, manufactured by Gutdrich Chemical Co., Ltd.) was added to the powder, which was then granulated at 38°C. Mix Og and 2.0 g of magnesium stearate. The tablets were compressed to a thickness of about 1.8++* using a flat punch with a diameter of 8I. After tableting, each tablet was heated at 70° C. for 1 hour to obtain a flexible tablet. Example 7 Prescription (in 1 tablet) Aldioxa 50.0mg Gelatin
30.0g mannitol 40.0mg concentrated glycerin
10. Omg carboxyvinyl polymer 19. OB Magnesium Stearate L
, 0 mg 150.0-g" [Ebu L excluded- Gelatin (manufactured by Miyagi Chemical Industry Co., Ltd.) 60. , 100.0 g of aldioxa and 80 g of mannitol were kneaded.
After mixing with concentrated glycerin diluted with 8 g of absolute ethanol (
Carboxyvinyl polymer (Carl Pole 934.Gutudoritsu) was added to the powder obtained by adding 20 g of small PII Pharmaceutical Co., Ltd. for granulation, drying at 250°C for 5 hours, and sieving at 12 mesh. (manufactured by Chemical Co., Ltd.) and 2.0 g of magnesium stearate were mixed, and a diameter of 8 a.
The tablets were compressed to a thickness of about 1.81 mm using a rm flat punch. After tableting, each tablet was heated at 70° C. for 1 hour to obtain a flexible tablet. Test on anti-inflammatory effect Test method Anesthetized male golden hamster (weight 80-120)
A cotton ball weighing 15±1 mg was implanted subcutaneously in the right cheek of a group of 10 animals (g, 10 animals per group), and one tablet obtained in Example 2 was inserted into the right cheek pouch. Starting from the next day, the tablet obtained in Example 2 was inserted under the same anesthesia once a day for 5 days, and on the 6th day after the cotton ball was implanted, the cotton ball and the granulation tissue surrounding it were peeled off and heated at about 80°C. After drying for 5 hours, it was weighed, and the weight obtained by subtracting the cotton ball type 1 (15 mg) from the dry weight was determined as the granuloma dry weight. Results and Discussion As shown in Table 1, the tablet of Example 2 showed a significant inhibition rate of 40.3% compared to the non-administered control group. Table: Anti-inflammatory effect U of triamcinolone acetonide tablets; Significant difference compared to control group (risk rate 1% or less)

[Brief explanation of the drawing]

FIG. 1 shows the dissolution pattern of the dissolution test using the formulation described in Example 1 and Tablet A.

Claims (3)

[Claims] (1) A flexible sustained-release tablet consisting of a mixture containing gelatin, glycerin, polyacrylic acid or a pharmaceutically acceptable salt thereof, and a drug. (2) A method for producing flexible sustained-release tablets by compressing a mixture containing gelatin, glycerin, polyacrylic acid or a pharmaceutically acceptable salt thereof, and a drug. (3) A method for producing flexible sustained-release tablets, which comprises compressing a mixture containing gelatin, glycerin, polyacrylic acid or a pharmaceutically acceptable salt thereof, and a drug, and then heating the mixture.