JPH09268126A - Preparation for treating digestive ulcer - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject preparation comprising tretinoin tocoferil, a carboxyvinyl polymer and a low substituted hydroxypropylcellulose having a specific particle diameter and enabling the effective absorption of the active ingredient to the walls of digestive tracts. SOLUTION: This preparation comprises tretinoin tocoferil (0.1-20.0wt.%), a carboxyvinyl polymer (3.0-20.0wt.%) and a low substituted hydroxypropylcellulose having particle diameters whose 90% or more are <=80μm, especially <=74μm (60.0-97.0wt.%). The low substituted hydrouypropylcellulose is preferably a cellulose derivative which is produced by substituting the OH groups of glucose units constituting the cellulose by hydroxypropoxy groups and which has the substituted hydroxypropyl groups in an amount of 0.11-0.07 mole per mole of the glucose residue. Methyl cellulose is preferably further added in an amount of 1.0-20.0wt.% to the preparation. The preparation can effectively treat digestive ulcer through the wall surface of digestive tracts. The preparation can easily be prepared.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to the effective adsorption of tretinoin tocopheryl to the gastrointestinal wall,
Used to treat peptic ulcer through the digestive tract wall,
The present invention relates to a preparation for treating peptic ulcer containing tretinoin tocopheryl as an active ingredient.

[0002]

2. Description of the Related Art Tretinoin tocopheryl, which is an ester of α-tocopherol and retinoic acid, that is, vitamin A acid, is disclosed in Japanese Patent Publication No. Sho 49-2663.
It is a known compound described in Japanese Patent Publication No. 2 and has a therapeutic action on digestive tract ulcer based on the action of promoting submucosa and mucosal repair, and therefore, a therapeutic agent for digestive tract ulcer containing this compound as an active ingredient. The invention of is also disclosed in Japanese Patent Publication No. 60-26770, which is an application of the present applicant, and is publicly known. This tretinoin tocopheryl is a compound having an excellent action for treating peptic ulcer as described above, but it exhibits a semi-solid state or resinous state at room temperature, has very low solubility in water, and has poor dispersibility in water. However, its handling is difficult.

Therefore, various studies have been made to overcome such difficulties and formulate tretinoin tocopheryl. For example, Japanese Unexamined Patent Application Publication No. 2-48 filed by the present applicant
Japanese Patent Application Laid-Open No. 2-300123 relating to the application of the applicant of the present invention, in which 2-50% of high-viscosity hydroxypropyl cellulose is contained together with tretinoin tocopheryl based on the total weight of the preparation disclosed in Japanese Patent No. A preparation which is a therapeutic agent for peptic ulcer comprising a powdery composition of tretinoin tocopheryl adsorbed on light anhydrous silicic acid, low-substituted hydroxypropylcellulose, and polyvinylpyrrolidone disclosed in the publication is proposed.

[0004]

However, in the method described in Japanese Patent Application Laid-Open No. 2-48525, both components to be mixed are highly viscous substances, so many steps are required to prepare a uniform mixture. There are problems, and JP-A-2
In the formulation described in JP-A-300123, tretinoin tocopheryl is taken into the inside of silicic acid anhydride due to the stimulating action of silicic acid anhydride on the gastric mucosa and the adsorptivity of silicic acid anhydride, and the therapeutic effect is not sufficiently exerted. There was a problem.

It is known that, when tretinoin tocopheryl is administered to the human body via the digestive tract, it does not act by being absorbed into the body through the digestive tract but directly from the surface of the wall of the digestive tract to the ulcer. Therefore, by effectively adsorbing tretinoin tocopheryl to the gastrointestinal wall,
It has been desired to provide a new preparation which is a preparation for effectively treating peptic ulcer from the surface of the wall of the digestive tract and which is easy to prepare.

[0006]

[Means for Solving the Problems] In order to solve the above-mentioned problems, the present inventors have earnestly studied, and as a result, tretinoin tocopheryl, carboxyvinyl polymer, and low-substituted hydroxypropylcellulose having a specific particle size are combined to prepare a formulation. In that case, tretinoin tocopheryl can be satisfactorily adsorbed on carboxyvinyl polymer and low-substituted hydroxypropylcellulose, and further, by using this carboxyvinyl polymer and low-substituted hydroxypropylcellulose, an appropriate water absorption and Good adsorption to the digestive tract wall can be obtained. Therefore, the inventors have completed the present invention by finding that when this formulation is administered, tretinoin tocopheryl can act on the gastrointestinal wall for a long time, and that this formulation is extremely easy to formulate. is there.

That is, the present invention relates to a peptic ulcer treatment preparation containing tretinoin tocopheryl, a carboxyvinyl polymer and a low-substituted hydroxypropylcellulose having a particle size of 90% or more and 80 μm or less.

More specifically, the present invention has a tretinoin tocopheryl content of 0.1 to 20.0% by weight, a carboxyvinyl polymer content of 3.0 to 20.0% by weight and a particle size of 90%. The above relates to a formulation for treating peptic ulcer having a content of low-substituted hydroxypropylcellulose of 80 μm or less and 60.0 to 97.0% by weight. The above-mentioned preparation for treating peptic ulcer of the present invention may further contain methylcellulose if necessary, and 1.0 to 20.
Used at a content of 0% by weight.

The carboxyvinyl polymer used in the preparation of the present invention is an acrylic acid polymer having a regular side chain of a carboxyl group in the main chain of hydrocarbon, and when the dried one is quantified, the carboxyl group is 58. It contains 0 to 63.0%. Then, those having a viscosity of an aqueous solution of a carboxyvinyl polymer neutralized with 0.2% sodium hydroxide at 20 ° C. of 1500 to 50000 cP are preferably used. Examples of these carboxyvinyl polymers include "carboxyvinyl polymers" listed in "Pharmaceutical Additives Standard 1993", specifically, "Hibiswako 103 ^(R) " (0.2% water produced by Wako Pure Chemical Industries, Ltd. ^). Viscosity of sodium oxide neutralization solution is 9000-22000c
In P, 90% or more of the particles have a particle size of 297 μm or less and 66% or less of the particles have a particle size of 149 μm or more)
Or "Hibiswako 105 ^(R) " manufactured by Wako Pure Chemical Industries, Ltd. (0.
The viscosity of 2% sodium hydroxide neutralized solution is 3000-100
At 100 cP, 90% or more of the particles have a particle size of 297 μm or less and 66% or less of the particles have a particle size of 149 μm or more).

The low-substituted hydroxypropyl cellulose used in the preparation of the present invention is a low-substituted hydroxypropyl ether of cellulose, and the number of moles of hydroxypropoxyl groups substituted per glucose residue in the cellulose is 0.
11 to 0.39, that is, when the dried product is quantified, it contains 5.0 to 16.0% of hydroxypropoxyl groups. 90% or more of the particles have a particle size of 80
Those having a size of not more than μm, preferably 74 μm or less are used. Examples of these low-substituted hydroxypropyl cellulose include "low-substituted hydroxypropyl cellulose" listed in "Twelfth Revised Japanese Pharmacopoeia", specifically, "L-HPC: LH-" manufactured by Shin-Etsu Chemical Co., Ltd. 21 ^(R) "
(Containing 10.0 to 13.0% of hydroxypropoxy group,
90% or more of the particles have a particle size of 74 μm or less and 1% or less of the particles have a particle size of 105 μm or more) or “L-HPC: LH-31 ^(R) ” manufactured by Shin-Etsu Chemical Co., Ltd. (a hydroxypropoxy group is 10. 0 to 13.0%, 50% or more of particles have a particle size of 44 μm or less and 95% or more of particles have a particle size of 74 μm
m or less) or the like is used.

This low-substituted hydroxypropyl cellulose is a substance different from the highly viscous hydroxypropyl cellulose described in JP-A-2-48525.
That is, this high-viscosity hydroxypropyl cellulose has an average substitution mole number of hydroxypropoxyl groups of 2.0 to 4.2 per glucose residue in the cellulose, that is, when the dried one is quantified, it is hydroxy. It contains 53.4 to 77.5% of propoxyl groups, and when water is added to this, it becomes a viscous liquid. On the other hand, when water is added to the low-substituted hydroxypropylcellulose used in the present invention, it swells but does not dissolve (the amount of water required to dissolve 1 g at 20 ± 5 ° C. is 1
0000 ml or more is required) (Refer to the 12th Revised Japanese Pharmacopoeia Manual, Hirokawa Shoten, 1991).

That is, the low-substituted hydroxypropyl cellulose used in the preparation of the present invention is disclosed in Japanese Patent Application No. 2-485.
Since it is not possible to even make the "2% aqueous solution" described in JP-A No. 25, it is clear that it is a substance that is clearly different from the highly viscous hydroxypropyl cellulose.

Methylcellulose optionally used in the preparation of the present invention is a methyl ether of cellulose and has a substitution number of methoxyl groups of 1.7 to 2.2 per one glucose residue in cellulose, that is, When quantifying the dried product, the methoxyl group content is 26.0-33.0%.
Including. As these methyl cellulose,
"Methylcellulose" in the "Twelfth Amended Japanese Pharmacopoeia"
Specifically, "Metroze SM-100 ^(R) " manufactured by Shin-Etsu Chemical Co., Ltd. or "Metroze SM-400 ^(R) " manufactured by Shin-Etsu Chemical Co., Ltd. is used.

In the preparation of the present invention, it is preferable to add an antioxidant such as tocopherol or ascorbic acid in order to prevent the oxidation of the active ingredient tretinoin tocopheryl. These antioxidants may be added in any amount capable of exerting an antioxidant effect, but may be in an amount of 0.1 to 20% by weight of the preparation.

As a method for producing the preparation of the present invention, tretinoin tocopheryl and an antioxidant are dissolved in an organic solvent such as acetone or ethanol, and then carboxyvinyl polymer, low-substituted hydroxypropylcellulose, and if necessary, are added. After adding methyl cellulose and mixing well, the organic solvent is distilled off and the residue is pulverized to produce a powdery, granular or granular product, or carboxyvinyl polymer, low-substituted hydroxypropylcellulose, and if necessary, Methyl cellulose is added, granules are prepared according to a conventional method, and tretinoin tocopheryl and an antioxidant dissolved in an organic solvent are adsorbed by a spray or the like and pulverized to produce a powdery, granular or granular product. In addition, other ingredients usually acceptable for formulation preparation, such as coloring agents, flavoring agents,
A flavoring agent, a pH adjusting agent and the like are added, and if necessary, other excipients suitable for an oral administration agent are added to prepare an oral administration preparation such as a powder, powder, granules, tablets and hard capsules. It

The therapeutic agent for peptic ulcer of the present invention is to treat tretinoin tocopheryl in an amount of 5 to 500 m per day for an adult.
g, preferably in an amount in the range of 20 to 100 mg per day. The invention will now be described in more detail by way of examples.

[0017]

Examples Example 1 (Formulation 1) Tretinoin tocopheryl 10.0 g Tocopherol 0.2 g Carboxyvinyl polymer 5.0 g (Wako Pure Chemical Industries, Ltd .: Hibiswako 105) Low-substituted hydroxypropylcellulose 75.0 g (Shin-Etsu Chemical Co., Ltd.) Company: L-HPC LH-31) Total 90.2 g tretinoin tocopheryl 10.0 g acetone 30 ml
0.2 g of tocopherol, 5.0 g of carboxyvinyl polymer and 75.0 g of low-substituted hydroxypropyl cellulose were added and mixed with the whole, then acetone was distilled off, and the obtained residue was pulverized. It was made into powder, and this was made into the prescription 1.

Example 2 (Formulation 2) Tretinoin tocopheryl 10.0 g Tocopherol 0.2 g Carboxyvinyl polymer 10.0 g (Wako Pure Chemical Industries, Ltd .: Hibiswako 103) Low-substituted hydroxypropyl cellulose 70.0 g (Shin-Etsu Chemical Co., Ltd.) Manufactured by: L-HPC LH-31) Total 90.2 g The above components were treated in the same manner as in Example 1 to give a powder, which was designated as Formulation 2.

Example 3 (Formulation 3) Tretinoin tocopheryl 10.0 g Tocopherol 0.2 g Carboxyvinyl polymer 5.0 g (Wako Pure Chemical Industries, Ltd .: Hibiswako 103) Low-substituted hydroxypropylcellulose 65.0 g (Shin-Etsu Chemical Co., Ltd.) Manufactured: L-HPC LH-31) Methylcellulose 10.0 g (Shin-Etsu Chemical Co., Ltd .: Methoze SM100) Total 90.2 g Tretinoin tocopheryl 10.0 g Acetone 30 ml
Dissolved in, and to this was added 0.2 g of tocopherol, 5.0 g of carboxyvinyl polymer, 65.0 g of low-substituted hydroxypropylcellulose and 10.0 g of methylcellulose, and the whole was mixed. Then, acetone was distilled off, and the resulting residue was obtained. The product was crushed into a powder, which was designated as Formulation 3.

Comparative Example 1 (Formulation 4) Tretinoin tocopheryl 50.0 g Light anhydrous silicic acid 55.0 g (Fuji Silysia Chemical Ltd .: Syloid-266) Tocopherol 0.5 g Low-substituted hydroxypropylcellulose 20.0 g (Shin-Etsu Chemical Co., Ltd.) L-HPC LH-31) Corn starch 36.5 g Polyvinylpyrrolidone 7.0 g Magnesium stearate 6.0 g Total 175.0 g Tretinoin tocopheryl 50.0 g acetone 500 m
Tocopherol (0.5 g) and light anhydrous silicic acid (55.0 g) were added to the solution, and the whole was mixed. Then, acetone was distilled off, and the obtained residue was ground to give a powder. Furthermore, low-substituted hydroxypropyl cellulose 20.0
g, corn starch 36.5 g and polyvinylpyrrolidone 7.0 g are added and uniformly mixed, then dry granulated and ground. Next, 21.5 g of corn starch and 6.0 g of magnesium stearate were added and mixed to prepare a formulation 4.

Test Example (Effect of ulcer treatment) Acetic acid was administered to rats to prepare a gastric ulcer model, and the ulcer treatment effect of the therapeutic agent for peptic ulcer of the present invention was examined. Takagi et al. (Japan J. Pharmac
ol. 18, 9, 1968). That is, SD rats were laparotomized under anesthesia, and 0.1% acetic acid was added to the stomach under the serosa.
Injected 05 ml. Thereafter, the abdomen was sewn up, and the prescriptions 1 to 4 obtained in Examples 1 to 3 and Comparative Example 1 as tretinoin tocopheryl 50 mg once a day from day 1 to day 13 with the suture operation day as 0 day. Oral administration was carried out at a dose of / kg / day, which was used as experimental groups 1 to 4. For comparison with Experimental Groups 1 to 4, drug-free group (Experimental Group 6) and alsalmine (Chugai Pharmaceutical Co., Ltd., trade name: sucralfate) were orally administered at a dose of 2000 mg / kg / day as a positive control. This was designated as Experimental Group 5. A laparotomy was performed on the 14th day, and the area (long diameter x short diameter) of the ulcer surface of each experimental group was measured. When the average area of the ulcer surface of the drug-non-administered group (experimental group 6) was set to 100, The inhibition rate was calculated. In addition, experimental group 1
Each of 6 used 20 mice per group.

[0022]

[Equation 1]

Next, when the ulcer inhibition rate of the alsarmine administration group (experimental group 5) was set to 100, the ulcer inhibition rate of the experimental groups 1 to 4 was calculated and used as the relative ulcer inhibition rate. The ulcer treatment effect of each prescription was evaluated by comparing this relative ulcer inhibition rate. The cure rate for each formulation is shown in Table 1.

[0024]

[Table 1]

From the above results, the prescriptions 1 to 3 obtained in Examples 1 to 3 have a significantly higher relative ulcer inhibitory rate than the prescription 4 obtained in Comparative Example 1, and the digestibility of the present invention is improved. It can be seen that the ulcer therapeutic agent is superior to the conventional prescription. Next, formulation examples of the therapeutic agent for peptic ulcer of the present invention will be given.

Formulation Example 1: Capsule Formulation 1 powder 135.3 g Carboxyvinyl polymer 9.0 g (Wako Pure Chemical Industries, Ltd .: Hibiswako 103) Low-substituted hydroxypropyl cellulose 16.0 g (Shin-Etsu Chemical Co., Ltd .: L- HPC LH-31) Magnesium stearate 1.5 g The above ingredients were mixed and the mixture was encapsulated in a hard capsule such that tretinoin tocopheryl was contained in 0.015 g in one capsule.

Formulation Example 2: Tablet Formulation 1 powder 135.3 g Hydroxypropyl cellulose 11.5 g (Nippon Soda Co., Ltd .: HPC-SSL When a dried product is quantified, it contains 53.4 to 77.5% hydroxypropoxyl groups). Acetyl glycerin fatty acid ester 2.0 g (Eastman Co .: Mybasetto 9-45) Lactose 43.2 g Crystalline cellulose 43.2 g (Asahi Kasei Co .: Avicel PH301) Carboxymethyl cellulose 12.5 g (Gotoku Yakuhin Co., Ltd .: NS- 300) Magnesium stearate 2.5 g The above components were mixed and the mixture was tabletted with a tableting machine to give tablets each containing 0.015 g of tretinoin tocopheryl.

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Claims (5)

[Claims] 1. A formulation for treating peptic ulcer containing tretinoin tocopheryl, a carboxyvinyl polymer, and a low-substituted hydroxypropyl cellulose having 90% or more of particle diameters of 80 μm or less. 2. The low-substituted hydroxypropylcellulose has the hydroxyl groups of glucose constituting cellulose substituted with hydroxypropoxyl groups, and the number of moles of hydroxypropoxyl groups substituted per glucose residue is from 0.11 to 11. The formulation for treating peptic ulcer according to claim 1, which is 0.39. 3. The content of tretinoin tocopheryl is 0.1 to 20.0% by weight, the content of carboxyvinyl polymer is 3.0 to 20.0% by weight, and 90% or more of the particle size is 8%.
The formulation for treating peptic ulcer according to claim 1 or 2, wherein the content of low-substituted hydroxypropylcellulose having a size of 0 µm or less is 60.0 to 97.0% by weight. 4. The preparation for treating peptic ulcer according to claim 1, which further contains methyl cellulose. 5. The content of methyl cellulose is 1.0-2.
The formulation for treating peptic ulcer according to claim 4, which is 0.0% by weight.