JPH0566365B2 - - Google Patents

Description

[Detailed description of the invention]

An object of the present invention is to provide a sustained-release preparation that can be orally administered and contains a drug having a thiol group as an active ingredient. The advantages of extended-release preparations are that they reduce the number of doses per day, which reduces the burden on patients, makes it easier to follow the prescribed dosage, and maintains the blood concentration of the drug at a desired constant value. It is more useful than conventional preparations in that it is possible to avoid unnecessary drug concentrations and reduce side effects. Conventionally, a wide variety of methods have been proposed and put into practical use as manufacturing techniques for obtaining these sustained-release preparations. One example is as follows. (1) Coated slow-release agents that are slow-released in body fluids by coating grains with water-insoluble or poorly water-soluble substances and/or non-digestible substances.
Release Beads) (2) Tablet with Slow Release Core consisting of a core tablet made of a mixture of water-insoluble or poorly water-soluble substances and/or non-digestible substances, and a fast-dissolving part and an outer layer. ) (3) Two-stage release formulation (Repeat Action
Tablets) (4) Tablets formed by mixing granules coated with water-insoluble or poorly water-soluble and/or non-digestible substances with rapidly dissolving granules (Tableted Mixed-Release Tablets)
(5) Multi-layer tablets with two or more layers, each layer having a different release property.
Tablets) (6) Sustained release agents in which the drug is dispersed in an insoluble solid continuous matrix (Porous Inert Carriers) (7) Preparations using ion exchange resin complexes (8) Preparations that form insoluble or sparingly soluble salts or complexes (9) A preparation consisting of a drug suspended in a semi-solid oily base (D.Fran, cois et al., Pharm.Ind. vol. 44, 86
89 (1982)) All of these known formulations are methods in which the drug is gradually released and dissolved in the gastrointestinal tract, or is dissolved in stages. Therefore, the local concentration of the drug present in solution in the gastrointestinal tract is lower than when administering a fast-dissolving conventional preparation. In the case of drugs that are susceptible to interactions with gastrointestinal fluids or dietary components and/or their digested products, when released from preparations obtained by these known methods, they are susceptible to interactions within the gastrointestinal tract and their stability may be impaired. This reduces bioavailability. Drugs with thiol groups are typical compounds that are susceptible to interactions with dietary components. The present inventors investigated sustained-release preparations of drugs having a thiol group using the above-mentioned known representative techniques, and as a result, no preparation with satisfactory bioavailability could be obtained by any of the methods. Therefore, as a result of intensive research into a preparation that exhibits bioavailability equivalent to that of a normal fast-dissolving preparation and maintains a sustained blood concentration even when taken with meals, the present invention was completed. That is, the present invention uses a drug having a thiol group together with one or more selected from ascorbic acid, sodium ascorbate, erythorbic acid, sodium erythorbate, sodium hydrogen sulfite, sodium sulfite, and metabisulfite, and half of it in the body. It is an oral long-acting preparation that is suspended in a solid lipophilic base and administered orally, and has almost the same bioavailability as a quick-dissolving ordinary preparation. Moreover, it exhibits excellent effects in that the maximum blood concentration is low and the blood concentration lasts for a long time. Examples of drugs having a thiol group in the present invention include captopril, (2R,4R)-2-(2-
hydroxyphenyl)-3-(3-mercaptopropionyl)-4-thiazolidinecarboxylic acid [(2R,
4R)-2-(2-Hydroxyphenyl)-3-(3-
mercaptopropionyl)-4-thiazolidine
carboxylic acid], thiomalic acid, thiouracil, glutathione, N-acetyl-L-cysteine, D-penicillamine, and mercaptopropionylglycine, but preferably captopril, (2R,4R)-2-(2-hydroxyl glycine, enyl)-3-(3-mercaptopropionyl)
-4-thiazolidinecarboxylic acid and D-penicillamine. Further, among ascorbic acid, sodium ascorbate, erythorbic acid, sodium erythorbate, sodium bisulfite, sodium sulfite, and metabisulfite (hereinafter referred to as additives) used in the present invention, preferably ascorbic acid, sodium ascorbate, erythorbic acid, It is sodium erythorbate. For example, when using ascorbic acid, the amount to be used is based on 1 part by weight of the drug having a thiol group.
0.5 to 20 parts by weight can be used, preferably 2 to 10 parts by weight. In addition, the lipophilic base in the present invention refers to oils and fats that are semi-solid in the body and/or oils that can be made semi-solid by adding a viscosity enhancer to fluid oil. Thus, particles of a drug having a thiol group can be uniformly suspended together with the additive in the base. Oils and fats that are semi-solid in the body include fats and oils derived from animals and plants such as cacao butter, palm oil, coconut oil, beef tallow, and lard; mineral oils that are acceptable for safety in preparations such as paraffin; petrolatum, lanolin, etc. Wax; Which fatty acid is lauric acid? Higher alcohols such as myristyl alcohol; Fatty acid glycerin esters (Witepsol,
Pharmasol, etc.); nonionic surfactants such as polyoxyethylene stearyl ether, polyoxyethylene sorbitan stearyl ether, and polyoxyethylene glyceryl stearyl ether; and hydrogenated oils such as polyoxyethylene hydrogenated castor oil. Furthermore, in the present invention, one or more substances selected from oils that are fluid in the body and/or the above-mentioned oils and fats that are semi-solid in the body, By adding a consistency filler, a lipophilic base that is semisolid in the body can be obtained. Here, examples of oils that are fluid in the body include olive oil, sesame oil, soybean oil, peanut oil, corn oil, safflower oil, rapeseed oil, menjitsu oil,
Vegetable oils such as bran oil; mineral oils such as liquid paraffin; and fatty acid esters such as isopropyl myristate and isopropyl palmitate. Furthermore, as a viscosity enhancer, myristic acid,
Fatty acids such as palmitic acid and stearic acid; Higher alcohols such as cetyl alcohol and stearyl alcohol; Triglyceryl laurate, triglyceryl palmitate, triglyceryl stearate, monoglyceryl stearate, monoglyceryl oleate, etc. Fatty acid glycerin ester;
Sucrose fatty acid ester; polyoxyl stearate; propylene glycol fatty acid ester; polyoxyethylene castor oil; polyoxyethylene hydrogenated castor oil; polyvinylpyrrolidone; methylcellulose; hydroxypropyl methylcellulose;
Examples include carboxymethyl cellulose; hydrogenated castor oil; light anhydrous silicic acid; beeswax; and the like. A suitable viscosity enhancer is selected depending on the type of oil or fat that is semi-solid in the body or fluid in the body to be used. The amount of the viscosity enhancer added is not particularly limited, as long as it becomes semi-solid in the body when the thiol group-containing drug and additives are added. In the present invention, preferably fluid oils are used as viscosity enhancers such as palmitic acid, stearic acid, cetyl alcohol, stearyl alcohol, triglyceryl laurate, triglyceryl palmitate, triglyceryl stearate, stearin. It is a lipophilic base obtained by adding one or more selected from acid monoglycerin ester, oleic acid monoglycerin ester, polyoxyethylene hydrogenated castor oil, hydrogenated castor oil, and light anhydrous silicic acid. The lipophilic base of the present invention may optionally contain a sorbitan fatty acid ester such as sorbitan triolate as a surfactant. Next, the present invention will be illustrated in more detail with reference to Examples. Example 1 100 g of stearic acid monoglycerol ester was added to 350 g of soybean oil and melted uniformly at 70° C. To the base, 50 g of captopril and 250 g of ascorbic acid were added and uniformly suspended. 60% of the above composition
The mixture was filled into hard capsules at 250 mg per capsule at ℃ and allowed to cool naturally to room temperature to obtain a sustained-release preparation of captopril. Example 2 The same procedure as in Example 1 was carried out except that 25 g of captopril was used instead of 50 g of captopril. Example 3 30 g of stearic acid monoglycerol ester was added to 300 g of liquid paraffin and melted uniformly at 70° C. To a base, 25 g of captopril and 125 g of ascorbic acid were added and uniformly suspended. The above composition was filled into hard capsules at 50° C. so that each capsule contained 240 mg, and the capsules were naturally cooled to room temperature to obtain a captopril specific formulation. Example 4 Add 60g of stearyl alcohol to 70g of soybean oil
Captopril is melted uniformly at 70℃ as a base material.
25 g and 125 g of ascorbic acid were added and uniformly suspended. 280% per capsule of the above composition at 60℃
mg of captopril into hard capsules and allowed to cool naturally to room temperature to obtain a sustained-release preparation of captopril. Example 5 60g of corn oil and 50g of stearyl alcohol
D-
50 g of penicillamine and 120 g of ascorbic acid were added and uniformly suspended. The above composition is filled into hard capsules at 60°C so that each capsule contains 280 mg,
After natural cooling to room temperature, a D-penicillamine sustained-release preparation was obtained. Example 6 20 g of hydrogenated castor oil and 10 g of sorbitan triolate were added to 110 g of soybean oil and melted uniformly at 70°C.To the base, 50 g of N-acetyl-L-cysteine and 150 g of ascorbic acid were added and uniformly suspended. The above composition per capsule at 60℃
The mixture was filled into hard capsules to give a total weight of 340 mg, and allowed to cool naturally to room temperature to obtain a sustained-release N-acetyl-L-cysteine preparation. Example 7 25 g of stearic acid monoglycerol ester was added to 250 g of soybean oil and melted uniformly at 70°C. To the base, 25 g of captopril and erythorbic acid were added.
200g was added and suspended uniformly. A sustained-release preparation of captopril was obtained by filling the above composition into soft capsules at room temperature at a concentration of 250 mg per capsule. Example 8 Fatty acid glycerin ester (Witepsol E-
85) 60g was heated to 50°C, 10g of captopril and 50g of ascorbic acid were added, and the mixture was uniformly suspended. The above composition was filled into hard capsules so that each capsule contained 300 mg, and the capsules were naturally cooled to room temperature to obtain a sustained-release preparation of captopril. Example 9 Fatty acid glycerin ester (Witepsol W-
35) To 80 g, 40 g of Witepsol E-85 and 10 g of sorbitan triolate were added and melted uniformly at 70°C. To the base, 10 g of captopril and 100 g of ascorbic acid were added and uniformly suspended. The above composition was filled into hard capsules at 60° C. so that each capsule weighed 240 mg, and the capsules were naturally cooled to room temperature to obtain a sustained-release preparation of captopril. Test Example The effects of various sustained-release preparations with and without additives were tested. (1) Experimental method 3 to 6 male beagle dogs (weight 9.8 to 12.1
Kg) was used. Dogs were given 100 g of Gaines meal and drinking water, and 20 minutes later each formulation was administered orally with 15 ml of water. The dose of captopril was 50 mg per animal in all cases, and the administration of Spansul granules and enteric-coated granules was carried out by filling the required amount of the granules into hard capsules. 40 minutes after administration, 1, 1.5, 2, 3, 4, 6, 8, 10
After a period of time, venous blood was collected, and free captopril in the plasma was quantified to determine the area under the blood concentration curve ([AUC] ¹⁰ ₀ ). The method for quantifying free captopril in the blood was based on the method of Y. KAWAHARA et al. [Chem.Pharm.Bull., Vol. 29, pp. 150-157 (1981)]. The manufacturing method of the formulation used in the test example is described below. Formulation example (1) Regular tablet Captopril 50g, crystalline cellulose 60g, lactose
39 g and 1 g of magnesium stearate were uniformly mixed and compressed to give 150 mg per tablet to obtain 50 mg captopril regular tablets. Formulation Example (2) Spansul Granules 100 g of captopril was uniformly mixed with 540 g of crystalline cellulose and 500 g of lactose. then 10%
After adding and kneading 600 g of an ethanol solution of (w/w) hydroxypropylcellulose, the mixture was made into granules using an extrusion granulator, and then immediately treated with a spherical granulator and dried to obtain pills. The obtained pills passed through a 12-mesh sieve, and those remaining on a 24-mesh sieve were taken out and coated. A coating solution was prepared by dissolving 5 parts by weight of hydrogenated castor oil, 4.5 parts by weight of stearyl alcohol, and 0.5 parts by weight of sorbitan monostearate in a mixed solution of 70 parts by weight of chloroform and 20 parts by weight of methanol. Captopril Spansul granules were obtained by coating the pill using a coating pan until the weight increase due to the coating film became 15%. Formulation example (3) Double-acting tablet: 40g of captopril crystals, 30g of crystalline cellulose,
The mixture was uniformly mixed with 9 g of lactose and 1 g of magnesium stearate and compressed into 80 mg per tablet to obtain core tablets with a diameter of 6 mm. Next, hydroxypropyl methylcellulose phthalate (HP-55
: manufactured by Shin-Etsu Chemical Co., Ltd.) and 1 part by weight of glycerin fatty acid ester were dissolved in a mixed solution of 45 parts by weight of acetone and 45 parts by weight of ethanol to prepare a coating liquid. Coating was carried out using a coating pan until the weight increase due to the coating film on the core tablet was 12 mg per tablet. Then captopril 5
g, 60 g of crystalline cellulose, 38 g of lactose, and 1 g of magnesium stearate were uniformly mixed to prepare a fast-dissolving mixed powder. Captopril 50 mg double-acting tablets with a diameter of 10 mm were obtained by tableting with the coated core tablet buried in the center of 208 mg of fast-dissolving mixed powder. Formulation Example (4) Multilayer Tablet 5 g of captopril crystals were uniformly mixed with 10 g of hydroxypropyl cellulose, 83 g of lactose and 2 g of magnesium stearate to form a first layer mixed powder. Further, 20 g of captopril crystals were uniformly mixed with 50 g of hydroxypropyl cellulose, 28 g of lactose, and 2 g of magnesium stearate to obtain a second layer mixed powder. 100 each of 1st layer and 2nd layer mixed powder
When sequentially filling and tableting in the same mortar using mg, 1
Captopril 25 mg bilayer tablets of 200 mg were obtained. Formulation example (5) Extended release tablet (insoluble matrix) 50g of captopril and 50g of stearyl alcohol
and 19.25 g of lactose. then 15
% (w/w) ethyl cellulose in ethanol solution
200 mg was added and kneaded to produce granules according to a conventional method.
Furthermore, 0.5 parts by weight of magnesium stearate was added to 99.5 parts by weight of this granule and mixed uniformly.
Captopril 50mg when compressed into 150mg tablets
Extended release tablets were obtained. Formulation example (6) Sustained release tablet (water-soluble polymer) 50g of captopril crystals mixed with 80g of methylcellulose
g, lactose 18.5 g and magnesium stearate
1.5g was mixed uniformly. Captopril 50 mg extended-release tablets were obtained by compressing the tablets to give 150 mg per tablet. Formulation Example (7) Sustained-release tablet (constant area elution type) 50 g of captopril crystals were uniformly mixed with 250 g of lactose, 43 g of hydroxypropylcellulose, and 7 g of magnesium stearate. 350 per tablet
A core tablet with a diameter of 7 mm was obtained by compressing the core tablet using a punch with a flat tableting surface so as to give a tablet size of 7 mm. Further, 270 g of ethyl cellulose and 30 g of carnauba wax were uniformly mixed to obtain a mixed powder for the outer layer. 300 mg of the mixed powder for the outer layer was placed in a mortar with a diameter of 9 mm, the above-mentioned dissolving partial core tablet was placed in the center, and tableting was carried out to obtain 25 mg sustained-release tablets of captopril. Formulation Example (8) Enteric Coated Granules 50 g of captopril was uniformly mixed with 1000 g of lactose, 400 g of carboxymethyl cellulose calcium, and 250 g of crystalline cellulose. followed by 7%
(w/w) Hydroxypropylcellulose aqueous solution
After adding 857 g and kneading, it was made into granules using an extrusion granulator, and then immediately treated with a spherical granulator and dried to obtain pills. The obtained pills were passed through a 12-mesh sieve, and those remaining on a 24-mesh sieve were taken out and coated with an enteric film. 9 parts by weight of hydroxypropyl methylcellulose phthalate (HP-55: manufactured by Shin-Etsu Chemical Co., Ltd.) and 1 part by weight of glycerin fatty acid ester
Part by weight was dissolved in a mixed solution of 45 parts by weight of acetone and 45 parts by weight of ethanol to prepare a coating liquid. Weight increase due to coating film is 15% compared to pill.
Captopril enteric-coated granules were obtained by coating using a coating pan until . Formulation Example (9) (According to the method of Fran, Cois et al.) 100 g of stearic acid monoglycerol ester was added to 350 g of soybean oil and melted homogeneously at 70°C. To this base, 50 g of captopril and 250 g of lactose were added and suspended uniformly. . The above composition was filled into hard capsules at 60° C. so that each capsule contained 250 mg, and the capsules were naturally cooled to room temperature to obtain a sustained-release preparation of captopril. (2) The experimental results are shown in Table 1 and Figure 1.

[Table] As is clear from Table 1, in a comparison of the areas under the free captopril blood concentration curves, all of the prior art formulations were inferior to the formulations of the present invention, except for the regular tablets. Next, as is clear from FIG. 1, between the ordinary tablet and the formulation of the present invention, while the ordinary tablet dissolves quickly, the formulation of the present invention exhibits a remarkable long-lasting effect.

[Brief explanation of the drawing]

In FIG. 1, the vertical axis shows the plasma free captopril concentration (μg/ml), and the horizontal axis shows the elapsed time (hours). ... indicates Formulation Example 1, -●- indicates Example 1, and -□- indicates Example 3.

Claims (1)

[Claims] 1. A drug having a thiol group is ascorbic acid,
Suspending it in a lipophilic base that is semisolid in the body together with one or more selected from sodium ascorbate, erythorbic acid, sodium erythorbate, sodium bisulfite, sodium sulfite, and metabisulfite. A sustained-release preparation for oral administration, characterized by: 2. The preparation according to claim 1, characterized in that one or more types of fats and oils that are semi-solid in the body are used as the lipophilic base. 3. A lipophilic base that is semi-solid in the body is used by adding one or more types of viscosity imparting agent to one or more types of oil that is fluid in the body. The formulation according to claim 1. 4. The formulation according to claim 1, 2, or 3, characterized in that ascorbic acid is added. 5. Claims 1 and 2, characterized in that the drug having a thiol group is captopril.
3. The formulation according to item 3 or 4. 6 Claims 1 and 2, characterized in that they are filled into hard capsules or soft capsules.
The formulation according to item 3, 4 or 5.