JP2002128670A - Medicinal composition for tablet - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicinal composition which is used for tablets, does not have a bitter taste when administered, and finishes the elusion of a clathrate compound comprising β-cyclodextrin and the O-benyloxycarbonylphenyl ester hydrochloride of guanidinomethylcyclohexanecarboxylic acid as a main medicine within 30 minutes. SOLUTION: This tablet is characterized by containing additives and a clathrate compound comprising the β-cyclodextrin and the O- benyloxycarbonylphenyl ester hydrochloride of guanidinomethylcyclohexanecarboxylic acid.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a composition suitable for tablet formation, and more particularly, to a composition containing a specific compound as an active ingredient, which has a bitter taste in the oral cavity when taken. The present invention relates to a composition suitable for producing a tablet in which the dissolution rate of the active ingredient is controlled as soon as it reaches the stomach. Therefore, the present invention is used in the field of manufacturing pharmaceuticals.

[0002]

2. Description of the Related Art A specific compound contained as an active ingredient in a composition according to the present invention is an inclusion compound of O-benzyloxycarbonylphenyl ester hydrochloride of guanidinomethylcyclohexanecarboxylic acid and β-cyclodextrin. Actually, it is actually used as a capsule in the field of medical treatment as an agent for treating ulcer and gastritis with an enhanced protective factor. However, O-benzyloxycarbonylphenylester hydrochloride of guanidinomethylcyclohexanecarboxylic acid and β- Since the inclusion compound with cyclodextrin has an extremely strong bitter taste, the bitter taste is constantly used as a capsule to prevent the bitter taste from appearing in the oral cavity upon taking the drug. Here, what is used as the capsule filling material is one in which an inclusion compound of O-benzyloxycarbonylphenyl ester hydrochloride of guanidinomethylcyclohexanecarboxylic acid and β-cyclodextrin is dispersed in an excipient. Kaihei 4-217913).

[0003] However, since capsules are filled in a shell molded from gelatin using a drug as a raw material, it is good when there is sufficient moisture in the oral cavity when taking a drug, but sometimes the capsule adheres to the oral cavity. In addition, since it is difficult to pass through the throat due to its large size, it is always under study to change to a dosage form that is easier to take.

[0004] By the way, when changing the dosage form,
Depending on the extent of the change, the materials required for proper permission and other disposal under the provisions of the law for the purpose of ensuring safety, etc. may be changed depending on the extent of the change. The content will be significantly different, and it will be inevitable that the content will be complicated and diverse.

[0005] Therefore, there is a need to change the dosage form in order to obtain a dosage form that is easier to take without changing the dosage and administration as much as possible. For that purpose, it is first required that the elution of the active ingredient in the newly provided preparation is within about 60 minutes, preferably about 10 to 30 minutes, and more preferably the same as that of the previous preparation.

[0006]

DISCLOSURE OF THE INVENTION The present invention relates to an O-form of guanidinomethylcyclohexanecarboxylic acid, which is already used in medical practice as a medicinal drug, especially as a therapeutic agent for gastrointestinal tract.
Includes an inclusion compound of benzyloxycarbonylphenyl ester hydrochloride (hereinafter may be abbreviated as benexate hydrochloride) and β-cyclodextrin (hereinafter may be abbreviated as benexate hydrochloride / β-CyD) as an active ingredient. For the purpose of changing the shape of the capsule into a tablet, preferably without changing the usage and dosage, a tablet is provided which preferably exhibits the same dissolution as the active ingredient of the capsule.

[0007]

According to the present invention, there is provided (1) an inclusion compound comprising O-benzyloxycarbonylphenylester hydrochloride of guanidinomethylcyclohexanecarboxylic acid and β-cyclodextrin, and an additive. (2) substantially no bitterness in the mouth at the time of ingestion, and dissolution of the main drug in accordance with the dissolution test method 2 (paddle method, rotation speed: 50 rpm) prescribed in the 13th revised Japanese Pharmacopoeia Tablets described in (1), which are completed within 30 minutes, (3) Granulation of clathrates obtained by compressing and crushing only clathrates as clathrates (1) or (2) above,
(4) Pharmaceutical composition for tablets comprising the granules according to (3) and an additive, (5) The additive is crystalline cellulose, D-mannitol , One or more selected from the group consisting of higher fatty acids and hydrogenated vegetable oils, tablets described in any of the above (1) to (3), (6) additives are crystalline cellulose, D-mannitol And (7) the tablet described in any one of (1) to (3) above, which is a higher fatty acid or a hydrogenated vegetable oil; and (7) the agent for treating ulcer and gastritis, wherein the outer layer of the tablet is film-coated. (1)-
The tablet according to any one of (3) and (5) to (6), and (8) the therapeutic agent for ulcer and gastritis, wherein the outer layer of the tablet is film-coated using D-mannitol. The tablet according to any one of (1) to (3) and (5) to (7), (9) a package comprising O-benzyloxycarbonylphenyl ester hydrochloride of guanidinomethylcyclohexanecarboxylic acid and β-cyclodextrin. The method for producing a tablet according to any one of the above (1) to (3) and (5) to (8), wherein a granulated product of the contact compound and an additive are mixed and tableted. , And (1
0) O- of guanidinomethylcyclohexanecarboxylic acid
Benzyloxycarbonylphenyl ester hydrochloride and β
(1) to (1) to (3), wherein D-mannitol is mixed with a granulated product of an inclusion compound comprising -cyclodextrin and D-mannitol, and the mixture is mixed with a higher fatty acid or a hydrogenated vegetable oil, followed by tableting. (3) and (5) to (8)
And a method for producing a tablet.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION In order to produce pharmaceutical preparations, apart from liquid preparations, granules suitable for tablets, granules, fine granules, capsules, etc. are molded. Where it is necessary to produce, usually, an active ingredient and an excipient, a disintegrant, a binder, and the like are mixed, kneaded by adding water, passed through a screen, and dried to obtain a granulated product. I have. Then, the obtained granules are processed into a predetermined dosage form.

Since Benexate hydrochloride / β-CyD is an inclusion compound, the inclusion is dissociated in the presence of water and decomposes into Benexate hydrochloride and β-cyclodextrin. Strict limitations, such as the inability to employ a granulation method, will narrow the range of applied technologies. Here is one of the technical difficulties that has long been the long-awaited reason that the tablets of benexate hydrochloride / β-CyD have not appeared.

[0010] Further, as described above, Benexate hydrochloride / β-CyD is decomposed in the presence of water, but when the preparation can be rapidly disintegrated in the course of taking the drug, the active ingredient is eluted in the oral cavity, resulting in Benexate hydrochloride.・ Β-
Strong bitterness, one of the attributes of CyD, spreads in the oral cavity.
Such phenomena are undesirable and must be avoided. Here, conventional Benexate hydrochloride / β-
There is a second reason that CyD tablets did not appear.

The inventor of the present application has reported that Benexate hydrochloride β-C
A device having a pressurizing function (for example, a compressor having at least two rollers, a device capable of sandwiching and pressing the yD powder using two flat plates at a test level is sufficient. What has been issued is what is called a roller compactor), pressurized and compressed to produce a solidified plate or rod, etc., and crush it, preferably further The granulated product of benexate hydrochloride and β-CyD obtained by sieving and sieving is
It was unexpectedly found that it would be a suitable material for providing tablets.

[0012] If an appropriate additive is mixed with the granulated product thus obtained, it is possible to obtain a mixture of Benexate hydrochloride / β-CyD
Was found to be usable as a tabletable state. The above granulated product of benexate hydrochloride and β-CyD is mixed with an additive to obtain the pharmaceutical composition for tablets of the present invention. In addition, tableting was attempted for those without addition of additives, but the adhesion to punches and dies did not lead to satisfactory molded products. Suitable additives used in the present invention are
As described below, it is found by selecting an additive exhibiting good tableting properties and dissolution properties when tableted with Benexate hydrochloride / β-CyD and the amount thereof from additives known per se. The dissolution of the active ingredient is completed within about 60 minutes, preferably about 10 to 30 minutes, and most preferably about 20 minutes.

In the present invention, benexate hydrochloride β-
Although the proportion of CyD and the additive used differs depending on the type of additive, it cannot be unconditionally determined. However, Benexate hydrochloride / β-C
It is about 5 to 100 parts by weight, preferably about 10 to 50 parts by weight, based on 100 parts by weight of yD. Here, as an additive to be used, where it is usually used,
Lactose, corn starch, potato starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch,
Low-substituted hydroxypropyl cellulose, gelatin, crystalline cellulose, partially pregelatinized starch, hydroxypropyl starch, croscarmellose sodium, crospovidone, povidone, agar powder, sucrose fatty acid ester, xylitol, D-sorbitol, D-mannitol, erythritol Where, trehalose, sucrose / starch spherical granules, purified sucrose spherical granules, etc. are considered,
The inventor of the present application examined, on a trial-and-error basis, whether or not these functions effectively for elution of the active ingredient.

Among these additives, crospovidone, hydroxypropyl starch, partially pregelatinized starch, gelatin, crystalline cellulose, and sugar alcohol are the target conditions for dissolution, ie, the dissolution specified in the Japanese Pharmacopoeia 13th Edition. Test method 2 method (paddle method, rotation speed: 50
85% of the active ingredient (inclusion compound consisting of O-benzyloxycarbonylphenyl ester hydrochloride of guanidinomethylcyclohexanecarboxylic acid as the main drug and β-cyclodextrin) in water within 15 minutes in a test conducted in accordance with The above was eluted, and it was found that all of them eluted and completed by 30 minutes.

Further, the present inventors have found that compared with the case where the above-mentioned additive is used alone, it is compared with Benexate hydrochloride / β-CyD
In order to further accelerate the dissolution of, particularly under strongly acidic conditions, the formulation of additives was further studied.

[0016] Microcrystalline cellulose, hydroxypropyl starch, crospovidone, partially pregelatinized starch, and sugar alcohol were selected and formulated. The elution in water was satisfactory even if the elution in water was satisfactory. Will be insufficient. For example, crospovidone, xylitol, erythritol or trehalose in combination with microcrystalline cellulose shows satisfactory elution in a weakly acidic liquid, but poorly eluted in a strongly acidic region,
Keeping in mind that the active ingredient in the formulation of the present invention has a mechanism of action that exerts its effect by directly acting on the stomach wall, the additive of these formulations is the main drug, benexate hydrochloride. The pharmacological effect of β-CyD cannot be sufficiently exerted.

The inventor of the present application has repeated trial and error,
A composition using a mixture of crystalline cellulose and a sugar alcohol, especially D-mannitol or D-sorbitol, as an additive in the granulated product of benexate hydrochloride / β-CyD has a pH of 1.
It was found that the strong acid 2 exhibited the desired elution state. However, since D-sorbitol has a strong hygroscopic property, it has been found that the inclusion of benexate hydrochloride / β-CyD used as an active ingredient in the present invention is impaired under some conditions, and D-mannitol is more preferable than D-sorbitol. It was found to be an additive.

However, Benexate hydrochloride β-C
When a mixture of yD granulated product and crystalline cellulose and D-mannitol is mixed and compression molded to produce a tablet, the fluidity is insufficient, or the molded product is strongly adhered to a die or a punch, and chipping or cracking occurs. It was found that cracking occurred and making a satisfactory tablet was not always satisfactory, and further improvement was desired.

In order to improve this point, as a part of additives, higher fatty acids having a melting point of about 50 ° C. or higher (eg, palmitic acid, stearic acid, nanodecanoic acid, arachidonic acid, behenic acid, serotinic acid, heptagonic acid) , A carboxylic acid such as sodium stearyl fumarate), and hydrogenated vegetable oils (eg, hydrogenated vegetable oils such as hydrogenated castor oil and hydrogenated rapeseed oil). The amount is about 0.3% to 5% of the composition, preferably about 0.5% to 2%,
It has been found that when a tablet is produced by compression molding using the tablet composition thus obtained, the obtained tablet can be used as a formulation which can be substituted for a capsule which is practically used also from the dissolution rate.

Since Benexate hydrochloride / β-CyD used in the present invention has a strong bitter taste, it is necessary to wait until the start of elution of the active ingredient so as not to immediately feel bitter taste in the oral cavity when taking the drug. When it is necessary to provide a lag time of at least about 30 seconds, a film coating is performed using a solution obtained by dissolving D-mannitol or D-sorbitol in a film coating solution using a coating machine. The amount of the film is preferably about 5 to 12 parts by weight per 100 parts by weight of the uncoated tablet. Here, when D-sorbitol was used, the elution of the active ingredient was fast, and a sufficient lag time was not provided compared with D-mannitol, so that D-mannitol was found to be the best.

Thus, crystalline cellulose and D
-A mixture of mannitol (crystalline cellulose and D-
The ratio with mannitol is most preferably about 80 to 130 parts by weight of D-mannitol per 100 parts by weight of crystalline cellulose. When the amount of D-mannitol is small, the disintegration of the tablet is deteriorated, and when the amount of D-mannitol is large, the disintegration of the tablet is deteriorated), and the additive is selected from Benexate hydrochloride / β-CyD100.
Add about 10 to 50 parts by weight to the parts by weight and mix.
Higher fatty acids or hydrogenated vegetable oil is added to the mixture to obtain a tabletable pharmaceutical composition for tablets. The pharmaceutical composition for tablets obtained in this manner is tableted according to a means known per se to produce the tablet according to the present invention.

[0022]

DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, embodiments will be described in order to explain the present invention in detail. In addition,% represents weight%. Example 1 Benexate hydrochloride / β-CyD (30 kg) was supplied to a dry granulator (roller compactor; Turbo Kogyo Co., Ltd.), compressed and crushed to obtain a granulated product. 498 g of crystalline cellulose and 500 g of D-mannitol were added to 4124 g of the granulated product and mixed, and 78 g of stearic acid was further added and mixed. After mixing, 5200 g of the mixture for tableting was added to a tableting machine (Clinpress 24;
(Kikusui Seisakusho Co., Ltd.) and tableted so that the weight of one tablet was 260 mg to obtain a tablet for coating (uncoated tablet). Next, 4.5 kg of uncoated tablets were charged into a coating machine (HCT-48; Freund Corporation) to perform coating, and hydroxypropyl methylcellulose 7.1 was added.
%, Polyethylene glycol 6000 1.4%, D-
20 mg using an aqueous solution consisting of 2.1% mannitol
To give tablets (film tablets) coated with a film.

Comparative Example 1 Benexate Hydrochloride β-Cy
D4124g, lactose 500g, crystalline cellulose 460
g, 78 g of stearic acid and 20 g of light anhydrous silicic acid were weighed and mixed. After mixing, 5182 g of a mixture for tableting
Into a tableting machine (RT-S-9; Kikusui Seisakusho).
A slug tablet weighing 285 mg per tablet was obtained. Next, this slug tablet was placed in a pulverizer (Power Mill; Showa Giken Co., Ltd.) and pulverized, and 5182 g of the obtained pulverized product was mixed with 18 g of light anhydrous silicic acid. After mixing, 5200 g of the mixture for tableting was put into a tableting machine (RT-S-9; Kikusui Seisakusho), and tableting was performed so that the weight of one tablet was 260 mg, and the tablet for coating (uncoated tablet) was obtained. I got next,
A coating machine (HCT-48; Freund Sangyo Co., Ltd.) was charged with 4.5 kg of uncoated tablets to perform coating, from hydroxypropyl methylcellulose 7.1%, polyethylene glycol 6000 1.4%, and D-mannitol 2.1%. Using the resulting aqueous solution, a tablet (film tablet) coated with 20 mg of a film was obtained.

Comparative Example 2 Using the uncoated tablet obtained in the previous step of Example 1, hydroxypropyl methylcellulose 7.1 was used.
%, Polyethylene glycol 6000 1.4%, and D-sorbitol 2.1%, to obtain a film tablet.

[Test Example 1] The dissolution test method (test solution: 900 mL of purified water, paddle) of the film tablets and the commercially available capsules obtained by the coating operation of Example 1 and Comparative Example 1 as specified in the thirteenth revised Japanese Pharmacopoeia Fig. 1 shows the results of a dissolution test of the pharmaceutical ingredient benexate hydrochloride / β-CyD by the method of 50 rpm).
It was shown to.

Test Example 2 The dissolution test method (test liquid: 900 mL of liquid I, specified in the thirteenth revised Japanese Pharmacopoeia) of the film tablets and the commercially available capsules obtained by the coating operation of Example 1
FIG. 2 shows the results of a dissolution test of the drug component Benexate hydrochloride / β-CyD by the paddle method: 50 rpm. Solution I: Solution 1 (pH 1.2) used in the 13th Revised Japanese Pharmacopoeia Disintegration Test

[Test Example 3] Sensory test Ten subjects were administered the film-coated tablets obtained in Example 1 and Comparative Example 2 to examine the development of bitter taste in the oral cavity. No bitterness was detected until 30 seconds passed, but Comparative Example 2
All tablets felt bitter by 15 seconds.

[0028]

The tablet of the present invention has no bitterness when taken,
Elution of the main drug, an inclusion compound consisting of O-benzyloxycarbonylphenylester hydrochloride of guanidinomethylcyclohexanecarboxylic acid and β-cyclodextrin, is completed within 30 minutes after administration.

[Brief description of the drawings]

BRIEF DESCRIPTION OF DRAWINGS FIG. 1 is an elution curve of purified products from Examples 1, Comparative Example 1, and commercial capsule products.

FIG. 2 is an elution curve of the product of Example 1 and a commercially available capsule in Solution I. In each figure, △ means a commercially available capsule, ○ means Example 1, and × means Comparative Example 1.

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (Reference) A61K 47/26 A61K 47/26 47/38 47/38 47/40 47/40 47/44 47/44 A61P 1/04 A61P 1/04 F term (reference) 4C076 AA37 AA44 BB01 CC16 DD41 DD67T EE31 EE39 FF52 GG14 GG16 4C206 HA31 MA05 MA28 MA55 MA72 ZA66

Claims (10)

[Claims] 1. A tablet comprising: an inclusion compound comprising O-benzyloxycarbonylphenylester hydrochloride of guanidinomethylcyclohexanecarboxylic acid and β-cyclodextrin; and an additive. 2. When taken, there is substantially no bitterness in the mouth,
3. The tablet according to claim 1, wherein the dissolution of the main drug according to the second dissolution test method (paddle method, rotation speed: 50 rpm) specified in the 3rd revised Japanese Pharmacopoeia is completed within 30 minutes. 3. The tablet according to claim 1, wherein the clathrate is a granule of the clathrate obtained by compressing and crushing only the clathrate. 4. A pharmaceutical composition for tablets comprising the granulated product according to claim 3 and an additive. 5. The tablet according to claim 1, wherein the additive is one or more selected from the group consisting of crystalline cellulose, D-mannitol, higher fatty acids, and hydrogenated vegetable oil. 6. The additive according to claim 1, wherein the additive is crystalline cellulose, D-mannitol and higher fatty acids, or hydrogenated vegetable oil.
The tablet according to any one of claims 1 to 3. 7. A method for treating ulcer and gastritis wherein the outer layer of the tablet is film-coated.
6. The tablet according to any one of 6. 8. The tablet according to any one of claims 1-3 and 5-7, wherein the outer layer of the tablet is a therapeutic agent for ulcer and gastritis, the film being coated with D-mannitol. 9. A mixture of a granulated product of an inclusion compound comprising O-benzyloxycarbonylphenyl ester hydrochloride of guanidinomethylcyclohexanecarboxylic acid and β-cyclodextrin and an additive, and tableting. A method for producing a tablet according to any one of claims 1 to 3 and 5 to 8. 10. A granulated product of an inclusion compound consisting of O-benzyloxycarbonylphenyl ester hydrochloride of guanidinomethylcyclohexanecarboxylic acid and β-cyclodextrin and D-mannitol, and the mixture is further mixed with higher fatty acids. Or add hydrogenated vegetable oil and mix,
The tablet manufacturing method according to any one of claims 1 to 3 and 5 to 8, characterized in that tableting is performed.