JP2009073829A - Diphenhydramine-filled capsulated formulation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a capsulated formulation which is good in compliance when taken, hardly causes softening or breaking of a capsule membrane, and is filled with a solution containing diphenhydramine or its salt. <P>SOLUTION: The capsulated formulation is prepared by filling a solution containing diphenhydramine or its salt into a capsule membrane containing macrogol and gelatine. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a capsule filled with a solution containing diphenhydramine or a salt thereof.

Diphenhydramine is an aminoalkyl ether antihistamine and is used as an oral agent for urticaria, allergic rhinitis associated with skin diseases, pruritus, acute rhinitis, and the like, and in recent years, it is widely used as a sleep improving drug.
However, when diphenhydramine is used for allergic rhinitis etc., the dose per dose is 10 mg, whereas when used as a sleep improving drug, the dose per dose is 50 mg, and the number of formulations to be taken In order to reduce this, there was a problem in compliance with the diphenhydramine-containing preparation, as well as an increase in the preparation itself.

On the other hand, tablets such as film-coated tablets and sugar-coated tablets, hard capsules, and soft capsules are known as embodiments of oral pharmaceutical preparations.
However, there is a concern that tablets may have different dissolution properties depending on the environment in the stomach, and there is a problem that the tablets are not necessarily a preferable dosage form in terms of rapid drug efficacy.

As for capsules, the following techniques are already known.
(1) It is known that when a capsule containing a liquid containing water is filled, the capsule film is softened, so that the amount of water in the filling liquid needs to be less than 20% by mass in order to avoid softening (patent) Reference 1).
(2) A capsule containing 12.5 mg (diphenhydramine hydrochloride concentration: 3%) in 400 mg of a filling liquid in a state where diphenhydramine hydrochloride is dissolved in a mixed solution of macrogol 400 and water is already known (patent document) 1). However, if the dose per dose is 50 mg at this concentration, there is a problem in terms of compliance because the capsule becomes large (No. 000 capsule) or the number of capsules to be taken at one time (4 capsules).
Japanese Patent No. 3553562

  Accordingly, an object of the present invention is to provide a capsule filled with a solution containing diphenhydramine or a salt thereof, which is good in compliance at the time of taking and hardly causes softening or cracking of the capsule film.

In order to solve the compliance problem of diphenhydramine-containing capsules, the present inventors tried to fill capsules with a solution containing diphenhydramine or a salt thereof in a high concentration.
First, in order to suppress softening of the capsule, filling was attempted with the amount of water being less than 20% by mass as in the prior art. However, the gelatin capsule cracked only by reducing the amount of water. On the other hand, when the filling liquid not containing diphenhydramine or its salt was filled, the capsule did not crack. Accordingly, it was found that diphenhydramine or a salt thereof had some adverse effect on the gelatin capsule.
Therefore, as a result of further investigation, the capsule film containing macrogol in gelatin was adopted instead of improving the filling liquid, and when this was filled with a solution containing diphenhydramine or a salt thereof, softening or cracking occurred. And found that diphenhydramine or a salt thereof can be blended at a high concentration, thereby completing the present invention.

  That is, the present invention provides a capsule in which a capsule comprising a capsule film containing macrogol and gelatin is filled with a solution containing diphenhydramine or a salt thereof.

  According to the present invention, it is possible to provide a capsule containing diphenhydramine or a salt thereof, which is easy to take and has excellent stability and high commercial value.

  In the present invention, a film containing macrogol and gelatin is used as the capsule film. Here, the content of the macrogol may be appropriately examined in consideration of the mechanical strength of the capsule and the uniformity of the film during molding, but is preferably 0.5 to 15% by mass with respect to the total amount of the capsule film. 1-10 mass% is more preferable.

  The average molecular weight of the macrogol contained in the capsule film used in the present invention is not particularly limited, but is preferably 950 to 25000, more preferably 2500 to 7000, Macrogol 1000, Macrogol 1500, Macrogol. 1540, macrogol 4000, and macrogol 6000 are more preferable, and macrogol 4000 is particularly preferable. One macrogol may be used, or a plurality of mixtures may be used.

The gelatin in the capsule film used in the present invention is not particularly limited. For example, gelatin that changes sol-gel with heat change, gelatin or succinylated gelatin from cattle, pigs, birds, fish, etc. And acylated gelatin.
The gelatin content may be appropriately examined in consideration of the mechanical strength of the capsule and the uniformity of the film during molding, but is preferably 50 to 99.5% by mass with respect to the total amount of the capsule film. 99 mass% is more preferable.

  The capsule film used in the present invention may contain substances other than macrogol and gelatin. Examples of the substances include dyes such as legal dyes, pigments such as titanium oxide, polyvinyl acetal diethylaminoacetate, preservatives, and fragrances. , Disintegrants, plasticizers such as glycerin and sorbitol.

  The capsule of the present invention includes both hard capsules and soft capsules, but hard capsules are preferable from the viewpoint of rapid drug efficacy.

  Further, the color of the capsule film used in the present invention is not particularly limited, but is preferably transparent or translucent so that the capsule filling liquid can be visually observed from the viewpoint of the commercial property of the capsule.

Diphenhydramine or a salt thereof used in the present invention is a known compound, and may be produced by a known method, or a commercially available product may be used.
Examples of the salt of diphenhydramine include acid addition salts such as hydrochloride, citrate, succinate, salicylate, diphenyldisulfonate, tartrate, tannate, lauryl sulfate, sulfate, maleate, etc. In particular, diphenhydramine hydrochloride is preferable.

  The content of diphenhydramine or a salt thereof used in the present invention is preferably adjusted to contain 50 mg or 25 mg in one capsule from the viewpoint of improving compliance when taken as a sleep improving drug. Accordingly, the concentration of diphenhydramine or a salt thereof is preferably 4 to 25% by mass, and particularly preferably 5 to 20% by mass in the solution.

  Diphenhydramine or a salt thereof can be replaced with other antihistamines. Examples of antihistamines that can be substituted include, for example, doxylamine, clemastine, diphenylpyralin, carbinoxamine, promethazine, mequitazine, alimemazine, istipendil, hydroxyzine, homochlorcyclidine, cyproheptadine, chlorpheniramine, triprolidine, brompheniramine and the like. Salt. Of these, doxylamine succinate, clemastine fumarate, diphenylpyraline theocuroate, diphenylpyraline hydrochloride, and carbinoxamine maleate are preferable.

  The solvent for the solution of diphenhydramine or a salt thereof used in the present invention is not particularly limited as long as it is usually used when filling a capsule with a liquid. For example, (1) water, (2 ) Volatile or non-volatile liquids that are immiscible with water or insoluble in water (vegetable oils, aliphatic and aromatic hydrocarbons, chlorinated hydrocarbons, ethers, esters, higher alcohols, organic acids), (3 ) Non-volatile liquids miscible with water, (4) Others (glycerin, propylene glycol, ketones, acids, amines, esters, etc.). Of these, only one kind may be used, or a plurality of mixtures may be used.

Among these, from the viewpoint of improving compliance and promptly developing the efficacy, a mixture of water, a lower alcohol, acetic acid or the like that dissolves diphenhydramine well, and a solvent that does not soften the capsule film and dissolves diphenhydramine or a salt thereof. Is preferably used, and a mixed solution of water and a polyhydric alcohol is more preferable.
The content of the polyhydric alcohol in the filling liquid may be appropriately examined, but is preferably 40 to 96.9% by mass, more preferably 50 to 96% by mass, and more preferably 55 to 95% by mass with respect to the total amount of the filling liquid. Particularly preferred.
The content of water, lower alcohol, acetic acid and the like in the mixed solution may be appropriately examined, but is preferably 0.1 to 30% by mass, more preferably 1 to 27.5% by mass, based on the total amount of the filling liquid. 2 to 25% by mass is particularly preferable.
The content ratio of water, lower alcohol, acetic acid and the like to the polyhydric alcohol is preferably 1 to 50 parts by mass, and particularly preferably 2 to 20 parts by mass with respect to 1 part by mass of water and the like.

Although it does not specifically limit as a polyhydric alcohol which is a solvent used for this invention, For example, macrogol, propylene glycol, glycerol etc. are mentioned, Macrogol is especially preferable. Of these, only one kind may be used, or a plurality of mixtures may be used.
The average molecular weight of the macrogol used as the solvent of the present invention is not particularly limited, but is preferably 100 to 800, more preferably 150 to 700, still more preferably 190 to 630, macrogol 200, macrogol 300, macrogol. 400 and macrogol 600 are particularly preferred. One macrogol may be used, or a plurality of mixtures may be used.

  Further, an additive such as a pH adjuster can be further added to the filling liquid. Examples of the pH adjuster include acids such as hydrochloric acid, citric acid, acetic acid and tartaric acid, and bases such as sodium hydroxide and potassium hydroxide. In this invention, 3-9 are preferable and, as for pH of a filling liquid, 3.5-8 are more preferable.

The capsule of the present invention can be produced according to a conventional method.
For example, gelatin is swollen with water, dissolved by heating, then added an appropriate amount of macrogol to be contained in the capsule film, and if necessary, a dye or a preservative is added, and the viscosity is adjusted appropriately, followed by defoaming treatment Thus, a capsule-forming jelly is obtained. The obtained jelly is formed into a capsule according to the present invention using a capsule forming apparatus, and the capsule filling liquid according to the present invention is filled therein to produce the capsule (hard capsule) of the present invention. Can do.
In addition, gelatin is water-swelled and then dissolved by heating, and then an appropriate amount of macrogol to be contained in the capsule film is added. If desired, a plasticizer such as a polyhydric alcohol such as glycerin or a sugar alcohol such as sorbitol, a pigment Or a preservative is added to adjust the viscosity appropriately, followed by defoaming to obtain a capsule-forming jelly. The capsule (soft capsule) of the present invention can be produced by using the obtained jelly and the capsule filling liquid according to the present invention based on a rotary die method, a dropping method or the like.

  The packaging form of the capsule of the present invention is not particularly limited, and for example, it can be packaged in a normal capsule packaging form such as a bottle or PTP packaging.

  EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

Production Example 1: Hard capsule (1)
After mixing 140 g of Macrogol 400 and 36 g of purified water, the mixture was heated to about 60 ° C., dissolved, adjusted to pH 6 with a 10% aqueous sodium hydroxide solution, and used as a filling solution. 250 mg of this filling solution was filled into normal size 3 gelatin hard capsules to produce 15 capsules having a purified water concentration of 20.5% by mass.

Production Example 2: Hard capsule (2)
After mixing 140 g of Macrogol 400 and 36 g of purified water, the mixture was heated to about 60 ° C., 50 g of diphenhydramine hydrochloride was added and stirred, dissolved, adjusted to pH 6 with 10% aqueous sodium hydroxide solution, did. 250 mg of this filling solution was filled into ordinary size 3 gelatin hard capsules to produce 15 hard capsules with a purified water concentration of 15.9% by mass.

Production Example 3: Hard capsule (3)
15 hard capsules having a purified water concentration of 11.2% by mass were produced in the same manner as in Production Example 2 except that 172 g of Macrogol 400 and 28 g of purified water were used.

Test Example 1: Examination of the effect of diphenhydramine on gelatin capsules The hard capsules (1) to (3) of Production Examples 1 to 3 were stored for 2 days after production to produce the effects over time (capsule cracking) 2 Observed after 1 hour and 2 days later. The results are shown in Table 1.

As is clear from Table 1, it was found that even if 20% by mass or more of water was contained in the capsule filling liquid, capsule cracking did not occur unless diphenhydramine hydrochloride was contained (hard capsule (1)). On the other hand, when diphenhydramine hydrochloride was contained in the capsule filling liquid, it was found that cracking occurred in the capsule film even when the water was adjusted to less than 20% by mass (hard capsules (2) and (3) ).
Therefore, it has been found that when diphenhydramine hydrochloride is contained, it is impossible to control the cracking of the capsule film only by adjusting the mass% of water.

Production Example 4 Production of Hard Capsule 18.0 liters of purified water was added to 10.0 kg of gelatin and allowed to stand naturally for about 1 to 2 hours for water absorption and swelling. After the gelatin swells sufficiently, warm to 60 ° C. and stir to dissolve the gelatin uniformly. Further, add 1.0 kg (5 mass% concentration) of a 50 mass% macrogol 4000 solution to the gelatin solution. After stirring and adjusting the viscosity, defoaming treatment was performed to obtain a capsule-forming jelly. This jelly was charged into a capsule forming apparatus to form a size 3 capsule.

Production Example 5: Production of hard capsule A capsule was formed in the same manner as in Production Example 4 except that 0.5 kg (2.5 mass% concentration) of a 50 mass% aqueous solution of Macrogol 4000 was added.

Example 1: Hard capsule 414 g of Macrogol 400 and 36 g of purified water were mixed and heated to about 60 ° C., 50 g of diphenhydramine hydrochloride was added to this, stirred, dissolved, and then dissolved in 10% aqueous sodium hydroxide solution to pH 6 To make a filling liquid. 250 mg of this filling liquid was filled into the capsule described in Production Example 4 to produce a hard capsule having a diphenhydramine hydrochloride concentration of 10% by mass.

Example 2: Hard capsule A hard capsule was produced in the same manner as in Example 1 except that the capsule described in Production Example 5 was used.

Comparative Example 1: Hard capsule 414 g of Macrogol 400 and 36 g of purified water were mixed, heated to about 60 ° C., 15 g of diphenhydramine hydrochloride was added and stirred, dissolved, and then dissolved in 10% aqueous sodium hydroxide solution to pH 6 To make a filling liquid. This filling solution was filled into normal size 3 gelatin hard capsules in an amount of 250 mg each to produce a hard capsule having a diphenhydramine hydrochloride concentration of 3% by mass.

Comparative Example 2: Hard capsule A hard capsule having a diphenhydramine hydrochloride concentration of 10% by mass was produced in the same manner as in Comparative Example 1 except that 50 g of diphenhydramine hydrochloride was used.

Test Example 2: Evaluation of Hard Capsules The hard capsules of Examples 1 and 2 and Comparative Examples 1 and 2 were evaluated for capsule cracking. After filling, the capsules are spread on a tray so that they do not overlap each other, and after standing at room temperature for 1 day, visually inspected for cracks and cracks after storage at 40 ° C for 1 month and after storage at 40 ° C for 4 months. went. The results are shown in Tables 2 and 3.

  As can be seen from Table 2, the hard capsules of Examples 1 and 2 were not observed to be broken or cracked immediately after production, after storage at 40 ° C. for 1 month, or after storage at 40 ° C. for 4 months.

As is apparent from Table 3, in the hard capsule of Comparative Example 1, no capsule cracking was observed immediately after production and after storage at 40 ° C. for 1 month, but after storage at 40 ° C. for 4 months, the capsule softened. Observed. In the hard capsule of Comparative Example 2, capsule cracking was observed immediately after production.
Therefore, from Test Example 2, it was found that a capsule that can be supplied as a product filled with a filling solution in which diphenhydramine hydrochloride is dissolved using a normal gelatin capsule has a diphenhydramine hydrochloride concentration of up to 3%. However, at a concentration of 3%, if the single dose is 50 mg, it is necessary to enlarge the capsule or increase the number of capsules to be taken, which is not preferable for compliance. On the other hand, in the capsules of Examples 1 and 2 according to the present invention, no capsule cracking or cracking was observed immediately after production, after storage at 40 ° C. for 1 month, or after storage at 40 ° C. for 4 months. It has been found that the number can be minimized and compliance can be improved.

Example 3: Soft capsules 10.0 liters of purified water was added to 9.0 kg of gelatin and allowed to stand naturally for about 1-2 hours to swell and absorb water. After the gelatin sufficiently swells, the mixture is heated to 60 ° C. and stirred to uniformly dissolve the gelatin. Further, 1 kg of concentrated glycerin and 1.0 kg (5 mass) of macrogol 4000 are added to the gelatin solution. % Concentration) or 0.5 kg (2.5% by mass concentration) was added and stirred to adjust the viscosity, followed by defoaming treatment to obtain a capsule forming jelly. Using this jelly, the filling liquid produced in Example 1 was filled with a rotary capsule filling machine to produce a soft capsule.

Example 4: Soft capsule A soft capsule was produced in the same manner as in Example 3 except that 0.5 kg (2.5% by mass) of a 50% by mass aqueous solution of Macrogol 4000 was added.

Claims (6)

  A capsule prepared by filling a capsule comprising a capsule film containing macrogol and gelatin with a solution containing diphenhydramine or a salt thereof.   The capsule according to claim 1, wherein the content of macrogol in the capsule film is 0.5 to 15% by mass with respect to the total amount of the capsule film.   The capsule according to claim 1 or 2, wherein the macrogol in the capsule film is a macrogol having an average molecular weight of 950 to 25000.   The capsule according to any one of claims 1 to 3, which contains 25 mg or 50 mg of diphenhydramine or a salt thereof per capsule.   The capsule according to any one of claims 1 to 4, wherein the solvent of the solution containing diphenhydramine or a salt thereof contains a polyhydric alcohol.   The capsule according to any one of claims 1 to 5, wherein the solvent of the solution containing diphenhydramine or a salt thereof is a mixed solution of one or more selected from water, lower alcohols and acetic acid and a polyhydric alcohol. Agent.