JPS6136217A - Long-acting drug preparation for oral administration - Google Patents

Abstract

PURPOSE:To obtain the titled drug preparation having excellent bioavailability and keeping the effective blood concentration for a long period, by suspending a thiol group-containing drug in combination with an additive such as ascorbic acid, erythorbic acid, etc. in an oleophilic base which is semisolid in the body. CONSTITUTION:The titled preparation can be produced by suspending (A) a thiol group-containing drug (e.g. captopril, D-penicillamine, etc.) together with (B) an additive selected from ascorbic acid, sodium ascorbate, erythorbic acid, sodium erythorbate, etc. in (C) an oleophilic base which is semisolid in the body, preferably a semisolid base prepared by adding a viscosity modifier (e.g. palmitic acid, cetyl alcohol, etc.) to a fluid oil (e.g. olive oil, sesame oil, etc.). The obtained preparation has nearly comparable bioavailability to the ordinary rapid- dissolving preparation, and nevertheless, exhibits excellent effects, i.e. low blood concentration peak and long duration of the blood concentration.

Description

DETAILED DESCRIPTION OF THE INVENTION An object of the present invention is to provide an orally administrable sustained-release preparation containing 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. Hitherto, a wide variety of methods have been proposed and put into practical use as manufacturing techniques for obtaining these sustained-release preparations. Part 1
Examples are as follows.

1) Coated Slow-Release agents that provide sustained release in body fluids by coating grains with water-insoluble or poorly water-soluble substances and/or non-digestible substances.
2) Double-layered tablets (Tablet with S
low Release Core) 3) Two-step release formulation using a fast-dissolving part in the outer layer of a window tablet coated with an enteric substance (Repeat Action Tablets) 4) Rapid-dissolving formulation with a granule coated with a water-insoluble or poorly water-soluble and/or non-digestible substance Tablets made by mixing and molding grains (
Tableted Mixed-ReleaseGra
Nules) 5) Multi-layer tablet with two or more layers, each layer exhibiting anisotropic release properties (Multiple-LayerTa)
(blets) 6) Sustained release agents with drug dispersed in an insoluble solid continuous matrix (Porous Inert Carriers)
) 7) Preparations using ion exchange resin complexes 8) Preparations forming insoluble or poorly soluble salts or complexes 9) Preparations comprising a drug suspended in a semi-solid oily base (
D., FranFois et al., Pharm, Ind.
, 44 volumes.

(pp. 86-89 (1982)) All of these known formulations involve gradual release and dissolution of the drug in the gastrointestinal tract or stepwise elution.

Therefore, the local concentration of the drug in solution in the gastrointestinal tract is lower than when administering a fast-dissolving conventional formulation. In the case of drugs that are susceptible to interactions with gastrointestinal fluids or dietary components and/or ingested products, they may be susceptible to interactions within the gastrointestinal tract when released from preparations obtained by these known methods. Stability is inhibited and thus bioavailability is reduced.

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 bisulfite, sodium sulfite, and metabisulfite to form a semi-solid substance in the body. It is a special formulation for oral administration, which is characterized by being suspended in a lipophilic base and administered orally, and has almost the same bioavailability as a quick-dissolving ordinary formulation. Moreover, it exhibits excellent effects such as a low maximum blood concentration and a long blood concentration duration.

Examples of drugs having a thiol group in the present invention include captopril, (2R,4R)-2-(2-hydroxyphenyl)-3-(3-mercaptoglobionyl)-4
-thiazolidincal? acid [(2R,4R)-2-(2
-Hydroxyphenyl)-3-(3-mer
captopropionyl) -4-thiaz
olidinecarboxylic acid),
Examples of thiophosphoryl acids include thiouracil, glutathione, N-acetyl-L-cysteine, D-penicillamine, and mercazotopropionylglycine, but preferably captolyl, (2R,4R)-2-(2-hydroxyphenyl) )-3-(3-mercactopropionyl)
-4-thiazolidine acid and D-penicillamine.

Further, among the 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, erythorbine acid, sodium erythorbate.

For example, when ascorbic acid is used, it can be used in an amount of 0.5 to 20 parts by weight, preferably 2 to 10 parts by weight, per 1 part by weight of the drug having a thiol group.

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. This makes it possible to uniformly suspend particles of a drug having a thiol group in the base together with the additive. Fats and oils that are semi-solid in the body include fats and oils derived from animals and plants, such as cacao butter, tsukoum oil, coconut oil, beef tallow, and lard; mineral oils that are acceptable for safety in preparations such as roe and rough-in; petrolatum, Waxes such as lanolin; fatty acids such as lauric acid; higher alcohols such as myristyl alcohol; fatty acid glycerin esters (Witspsol■, Pharmasol@, etc.)
;Polyoxyethylene stearyl ether, 6? Examples include nonionic surfactants such as lyoxyethylene sorbitan ester ethyl, polyoxyethylene glyceryl stearyl ether, and hydrogenated oils such as polyoxyethylene hydrogenated castor oil.

Furthermore, in the present invention, one or more substances selected from the 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 vegetable oils such as olive oil, sesame oil, soybean oil, peanut oil, corn oil, safflower oil, rapeseed oil, menjitsu oil, and bran oil;
Mineral oils such as liquid paraffin; fatty acid esters such as isopropyl myristate and isopropyl rumitate can be used.

In addition, fatty acids such as myristic acid, palmitic acid, and stearic acid; cetyl alcohol,
Higher alcohols such as stearyl alcohol; fatty acid glycerin esters such as triglycerin laurate air ester, triglycerin palmitate ester, triglycerin stearate ester, monoglycerin stearate ester, monoglycerin oleate ester; sucrose fatty acid ester: stearic acid Polyoxyl; Propylene glycol fatty acid ester; Polyoxyethylene castor oil; Polyoxyethylene hydrogenated castor oil; Polyvinylpyrrolidone; Methyl cellulose; Hydroxypropyl methyl cellulose;
Cal? Examples include oxymethylcellulose; 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, 7 palmitic acid, stearic acid, cetyl alcohol, stearyl alcohol, triglyceryl laurate, triglyceryl rumitate, triglyceryl stearate are preferably added to the fluid oil as a viscosity-imparting agent. Lipophilic group obtained by adding one or more selected esters, stearic acid monoglycerol ester, oleic acid monoglycerol ester, polyoxyethylene hydrogenated castor oil, hydrogenated castor oil, light anhydrous silicic acid. It is a drug.

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゜1 oor of stearic acid monoglycerol ester was added to 350 tons of soybean oil and melted uniformly at 70°C. To the base, Cutpril 50SF and 250 tons of ascorbic acid were added.
was added and suspended uniformly. The above composition was filled into hard capsules at 60° C. to a density of 250 η per capsule, and the capsules were autothermally cooled to room temperature to obtain a captopril specific formulation.

Example 2 In Example 1, captopril 50? The same procedure was repeated using Captopril 251 instead.

Example 3 30f of stearic acid monoglycerin ester was cured in 300v of fluidized rough-in and melted uniformly at 70°C, and then Captogril 251 and ascorbic acid 1 were added to the base.
252 was added and suspended uniformly. 1 at 50°C.
The mixture was filled into hard capsules with a weight of 9,240 square meters per capsule and naturally cooled to room temperature to obtain a captogril-specific preparation.

Example 4゜Stearyl alcohol 601 was added to 70 f soybean oil and 70
251 tons of captopril and 125 tons of ascorbic acid were added to the base that was homogenized and melted at ℃, and suspended uniformly. The above composition was filled into hard capsules at 60° C. to a Jt28 (lv) per capsule, and the capsules were naturally cooled to room temperature to obtain a long-acting preparation of Captogril.

Example 5) Stearyl alcohol 50 t to 60 t corn and cod oil
2 was added to the base K p - which was melted uniformly at 70°C.
Penicillamine 509 and ascorbic acid 120f were added and homogeneously suspended. The above composition was filled into hard capsules at 60 DEG C. so as to yield 1 capsule a 2801"lf, and was naturally cooled to room temperature to obtain a D-penicillamine effective preparation.

Example 6゜ 20S' hydrogenated castor oil and 10r sorbitan triolate were added to 110t of soybean oil and melted uniformly at 70°C. To the base, N-acetyl-L~cysteine 50P and 150f ascorbic acid were added and uniformly suspended. . The above composition was filled into hard capsules at 60 DEG C. so that each capsule weighed 340 cm, and the capsules were naturally cooled to room temperature to obtain a specific N-acetyl-L-cysteine preparation.

11-Example 7 Stearic acid monoglycerin ester 259 was added to 250 tons of soybean oil and melted uniformly at 70°C. To the base, captopril 259 and erythorbic acid 2009 were added and uniformly suspended.

A cabtopril specific formulation was obtained by filling the above composition into soft capsules at room temperature in an amount of 250 q/capsule.

Example 8゜Fatty acid glycerin ester (Witapsc+1■E-
85) 60f was heated to 50°C, and 10f of captogril and 50f of ascorbic acid were added and uniformly suspended. The above composition was filled into hard capsules at a density of 300 μm per capsule, and the capsules were naturally cooled to room temperature to obtain a Captogril time-release preparation.

Example 9゜Fatty acid glycerin ester (W1tepsol■W-3
5) On the 80th floor, the same (Witapgol E-85) 4
0 t, add sorbitan triolate 1 (1') and 70°C.
10 g of captopril and 100 t of ascorbic acid were added to the base that was melted and homogeneous in 1, and uniformly suspended. The above composition was filled into hard capsules at 60[deg.] C. so that the weight per capsule was 240~ and then naturally cooled at room temperature to obtain a long-acting preparation of Captogril.

Test Example The effects of various specific formulations with and without additives were tested.

1) Experimental method 3-6 male peagle dogs (weight 9.8-12.1kl)
? ) was used. Dogs were fed 100 f Gains meal and drinking water and 20 minutes later each formulation was administered orally with 15 td water. The dose of captopril was 50 μ/mouse in all cases, and the administration of Sufu4nsul granules and enteric-coated granules was carried out by filling the required amount of the granules into hard capsules. Venous blood was collected 40 minutes, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours after administration, and free captogril in the plasma was quantified and the area under the blood concentration curve ([ALJ
C:]1o') was calculated. The method for quantifying free cabtopril in the blood is the method of Y. KAWAHARA et al. [Chemical Pharmaceutical Bulletin (Chem,
Pharm, Bull, ) Volume 129, 150-
157 (1981)].

The manufacturing method of the formulation used in the test example is described below.

Formulation example 1) Regular tablet Captopril 50f contains 601 parts of crystalline cellulose and 39 parts of lactose.
? Mix evenly with 1 ton of magnesium stearate and get 1 tablet! The tablets were compressed to a volume of 1 liter and 150 ml to obtain Captonoril 50q ordinary tablets.

Formulation Example 2) Spansul granules Captopril 100F were uniformly mixed with crystalline cellulose 5402 and 500 g of lactose. Then 10% (W/W
) Hydroxypropyl cellulose dissolved in ethanol g6o
After adding or and kneading, the mixture was made into granules using an extrusion granulator, and then immediately treated with a spherical granulator and dried to obtain divil. The resulting bill passed through a 12-mesh sieve, and what remained on a 24-mesh sieve was 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. Coat the building using a coaching gun until the weight increase due to the coating film is 15 inches. Insul granules were obtained.

Formulation Example 3) Double-acting tablet Captopril Crystal 401 was mixed uniformly with 30 g of crystalline cellulose, 91 g of lactose, and 1 f of magnesium stearate, and the mixture was compressed into 980 cm tablets to obtain window tablets with a diameter of 6 mm. It was done. Next, 9 parts by weight of hydroxypropyl methylcellulose phthalate (I (P-55) manufactured by Shin-Etsu Kaimo Kogyo Co., Ltd.) and 1x 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, and coating was performed. It was made into a liquid.

Coating was carried out using a coating pan until the weight increase due to the coating film on the window tablet was J) 12711f per tablet. Next, 52 f of captopril, 60 f of crystalline cellulose, 38 f of lactose, and 1 t of magnesium stearate were uniformly mixed to form a fast-melting zone mixed bed. 20
The coated window tablet was buried in the center of the 8-inch fast-dissolving zone mixing bed and was then compressed to obtain Captopril 50η double-acting tablets with a diameter of 10 mm.

Formulation example 4) Multilayer tablet Captogril crystal 5v, hydroxypropyl cellulose 10t1 lactose 83f and magnesium stearate 2
1 to obtain a first layer mixed powder. Furthermore, captopril crystals 209 were uniformly mixed with 50 g of hydroxypropyl cellulose, 28 r of lactose, and 2 tons of magnesium stearate to obtain a second layer mixed powder. By sequentially filling and tableting within the same day using 100 ml of each of the first and second layer mixed powders, Captogril 5042-layer tablets with a weight of 200 η were obtained.

Formulation Example 5) Extended release tablet (insoluble matrix) IJ Luxcaptopril 501 was combined with 50F of stearyl alcohol and 11% of lactose.
9.25F and mixed uniformly.

Next, 200 mg of a 15% (w/w) ethyl cellulose in ethane solution was added and kneaded, and granules were prepared according to a conventional method. Furthermore, 0.5 parts by weight of magnesium stearate is added to 99.5 parts by weight of this granule, mixed uniformly, and then tableted to give 150 Tq per tablet.
Extended release tablets were obtained.

Formulation example 6) Sustained release tablet (water-soluble polymer) Captogril crystal 501 was added to methylcellulose e, of
It was uniformly mixed with 1 B, 5 f of lactose and 1.5 f of magnesium stearate. Captopril 50v when compressed to give 150wg per tablet Formulation example 7) Extended release tablet (constant area elution type) Captopril crystal 502 is lactose 250wg. , hydroxypropylcellulose 682 and magnesium stearate 7t.

The tableting surface is flat so that each tablet weighs 350■
When the tablets were compressed using a certain punch, a window lock with a diameter of 7 mm was obtained. Furthermore, ethyl cellulose 2702 and carnauba wax 30f were uniformly mixed to form a mixed bed for the outer layer. Diameter 9
A 300η mixed bed for the outer layer was placed in a 1 nm mouth, and the above-mentioned partial elution window tablet was placed in the center and tableting was performed to obtain Captopril 25* sustained release tablets.

Formulation Example 8) Enteric coated granules Captogril 502 were uniformly mixed with 1000 g of lactose, Calxymethylcellulose calcium 400f and crystalline cellulose 2501.

Next, 857f of a 7% (W/W) hydroxyglobil cellulose aqueous solution was added and kneaded, and then made into granules using an extrusion granulator, and then immediately treated with a spherical granulator and dried to obtain divil. Ta. The resulting bill passed through a 12-mesh sieve, and what remained on a 24-mesh sieve was taken out and coated with an enteric film. A coating solution was prepared by dissolving 9 parts by weight of hydroxypropyl methylcellulose phthalate (HP[F]-55: manufactured by Shin-Etsu Chemical Co., Ltd.) and 1 part by weight of glycerin fatty acid ester in a mixed solution of 45 parts by weight of acetone and 45 parts by weight of ethanol. Captopril enteric-coated granules were obtained by coating the building with coating tRn until the weight increase due to the coating film became 15%.

Formulation Example 9) (According to the method of Franpois et al.)
Stearic acid monoglycerin ester 1001 was added to soybean oil 3501 and melted uniformly at 70°C to a base.
50 f of cut grill and 250 f of lactose were added and uniformly suspended. 1 capsule of the above composition at 60℃? 25O
The mixture was filled into hard capsules so as to contain N, and allowed to cool naturally to room temperature to obtain an elliptic-acting preparation of cazotopril.

2) Experimental results The experimental results are shown in Table 1 and Figure 1.

Table 1 As is clear from Table 1, in comparison of the areas under the free captogril blood concentration curves, all of the prior art formulations were inferior to the formulations of the present invention, with the exception of the regular tablets.

Next, as is clear from FIG. 1, between the ordinary tablet and the formulation of the present invention, the ordinary tablet had a rapid dissolution, whereas the formulation of the present invention showed remarkable ↑A efficacy.

[Brief explanation of drawings]

In Figure 1, the vertical axis is the plasma free captogril concentration (μ
m/-), and the horizontal axis indicates elapsed time (hours).・・・
・○... indicates Formulation Example 1, --- indicates Example 1, and -Rho indicates Example 3.

Claims (1)

[Claims] 1. A drug having a thiol group together with one or more selected from ascorbic acid, sodium ascorbate, erythorbic acid, sodium erythorbate, sodium bisulfite, sodium sulfite, and metabisulfite, A specific formulation for oral administration characterized by being suspended in a lipophilic base that is semi-solid in the body. 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. It is characterized by the use of a lipophilic base that is semi-solid in the body 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. The preparation according to claim 1, 2, 3, or 4, wherein the drug having a thiol group is captopril. 6. Claims 1, 2, 3, and 4 characterized in that the product is filled into a hard capsule or a soft capsule.
The formulation according to paragraph 5 or paragraph 5.