JP2010229123A - Capsule agent filled with diphenhydramine-containing solution - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a solution which contains diphenhydramine or a salt thereof, is good in compliance on administration, hardly causes the softening and cracking of capsule skin membranes, and is filled into capsules, and to provide a capsule filled with the solution. <P>SOLUTION: This solution contains diphenhydramine or a salt thereof, and an organic acid. The solution preferably furthermore contains caramel. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to 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, as an aspect of a pharmaceutical oral preparation, tablets such as film-coated tablets and sugar-coated tablets, capsules such as hard capsules and soft capsules are known.
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 the capsule is filled with a liquid containing water, the capsule film softens, so that the mass 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 will be a problem in compliance because the capsules will be large (No. 000 capsules) or the number of capsules to be taken will be large (4 capsules).

Japanese Patent No. 3553562

In order to solve the compliance problem of diphenhydramine-containing capsules, the present inventor attempted to fill capsules with a solution containing diphenhydramine or a salt thereof in a high concentration.
First, in order to suppress the softening of the capsule, filling was attempted with the amount of water being less than 20% by mass as in the prior art, but the gelatin capsule was cracked only by reducing the amount of water.
On the other hand, when a filling liquid containing no diphenhydramine or a salt thereof was filled into a gelatin capsule, the capsule did not crack. Accordingly, it was found that diphenhydramine or a salt thereof had some adverse effect on the gelatin capsule.
Accordingly, an object of the present invention is to provide a solution containing diphenhydramine or a salt thereof for filling a capsule, which is good in compliance at the time of taking and hardly causes softening or cracking of the capsule film, and a capsule filled with the solution. It is.

As a result of studying to solve the above-mentioned problems, the present inventor blended an organic acid with a solution containing diphenhydramine or a salt thereof to increase the content of diphenhydramine or a salt thereof even if the content of diphenhydramine or a salt thereof is increased. It was found that no cracking occurred.
Furthermore, further investigations have unexpectedly found that although the softening and cracking of the capsule can be suppressed by blending the organic acid, the appearance change (discoloration) and the content of diphenhydramine or a salt thereof occur. . Therefore, as a result of investigations for solving these problems, by further adding caramel to the organic acid compound solution, the capsules were not softened or cracked, and the discoloration over time and the content of diphenhydramine or its salt were reduced. It was found that the decrease can be suppressed.

1) That is, the present invention provides a solution containing diphenhydramine or a salt thereof and an organic acid.
2) The present invention also provides a solution containing diphenhydramine or a salt thereof, an organic acid and caramel.
3) Furthermore, this invention provides the capsule which filled the capsule with the solution of said 1) or 2).

  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.

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. And the hydrochloride salt is preferred.

  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. That is, the content of diphenhydramine or a salt thereof in the solution is preferably 4 to 40% by mass, particularly preferably 5 to 25% by mass in the solution.

  Note that diphenhydramine or a salt thereof can be partially or entirely replaced with another antihistamine. Alternative antihistamines include, for example, doxylamine, clemastine, diphenylpyraline, carbinoxamine, promethazine, mequitazine, alimemazine, istipendil, hydroxyzine, homochlorcyclidine, cyproheptadine, chlorpheniramine, triprolidine, brompheniramine, emedastine and the like These salts are mentioned. Of these, doxylamine succinate, clemastine fumarate, diphenylpyraline theocuroate, diphenylpyraline hydrochloride, carbinoxamine maleate, and emedastine fumarate are preferred.

  In the present invention, as the organic acid, as long as the acid itself or an aqueous solution of the acid dissolves diphenhydramine or a salt thereof and does not cause softening or cracking of the capsule when filled into the capsule, Although not limited, for example, adipic acid, ascorbic acid, erythorbic acid, citric acid, glutamic acid, succinic acid, acetic acid, tartaric acid, lactic acid, fumaric acid, maleic acid, malic acid and the like can be mentioned. Of these, acetic acid and lactic acid are preferred. Note that only one organic acid may be used, or a plurality of mixtures may be used.

In this invention, as content of an organic acid, 5-50 mass% is preferable with respect to the solution whole quantity, 8-40 mass% is more preferable, 10-30 mass% is especially preferable.
The content ratio of diphenhydramine or a salt thereof and an organic acid is preferably 0.2 to 3 parts by mass, and particularly preferably 0.3 to 2.7 parts by mass with respect to 1 part by mass of diphenhydramine or a salt thereof.

  In the present invention, when acetic acid is used as the organic acid, it is preferable to further add a plasticizer. Although the smell of acetic acid may be a problem such as compliance for the user or the like, the present inventor has found that this problem can be solved by further adding a plasticizer.

  The plasticizer is not particularly limited as long as it does not adversely affect the dissolution of diphenhydramine or a salt thereof, does not cause softening or cracking of the capsule, and can suppress the smell of acetic acid. , Triethyl citrate, glycerin fatty acid ester, sesame oil, vinyl acetate resin, dimethylpolysiloxane / silicon dioxide mixture, D-sorbitol, medium chain fatty acid triglyceride, corn starch-derived sugar alcohol solution, triacetin, castor oil, diethyl phthalate, phthalic acid Dibutyl, butylphthalyl butyl glycolate, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene sorbitan fatty acid ester, cottonseed oil / soybean oil mixture, glyceryl monostearate, liquid paraffin, etc. , It is used only these one may use a plurality of mixtures. Among these, in the present invention, triethyl citrate, glycerin fatty acid ester, triacetin, and polyoxyethylene sorbitan fatty acid ester are preferable.

Here, the glycerin fatty acid ester is not particularly limited as long as it is obtained by esterifying one or more hydroxyl groups of glycerin with the same or different fatty acid. Glycerin fatty acid esters can be easily understood by those skilled in the art.
Examples of the glycerin fatty acid ester include glycerin mono-fatty acid ester, glycerin di-fatty acid ester, glycerin tri-fatty acid ester, and mixtures thereof, and those having a main component of glycerin mono-fatty acid ester and / or glycerin di-fatty acid ester are preferable.
In addition, as the fatty acid moiety, saturated or unsaturated carbon number 6 such as hexanoic acid, octanoic acid, decanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, oleic acid, linoleic acid, linolenic acid, etc. And those having 6 to 18 saturated or unsaturated carbon atoms such as hexanoic acid, octanoic acid, decanoic acid, lauric acid, myristic acid, stearic acid and oleic acid are preferred.
That is, preferred specific examples of glycerin fatty acid esters include glyceryl monohexanoate, glyceryl monooctanoate, glyceryl monodecanoate, glyceryl monolaurate, glyceryl dioctanoate, glyceryl didecanoate, glyceryl decanoate, glyceryl monomyristate, Examples thereof include glyceryl monostearate and glyceryl monooleate, and those having these as a main component are preferred.

  In the present invention, glycerin fatty acid ester derivatives, fatty acid and polyglycerin esters, and derivatives thereof may be used instead of glycerin fatty acid esters. Specific examples thereof include glycerin acetic acid fatty acid ester, glycerin lactic acid fatty acid ester, glycerin citrate fatty acid ester, glycerin succinic acid fatty acid ester, glycerin diacetyl tartaric acid fatty acid ester, glycerin acetic acid ester, polyglycerin fatty acid ester, polyglycerin condensed ricinoleic acid ester. Etc.

  Polyoxyethylene sorbitan fatty acid ester, also called polysorbate, adds ethylene oxide to sorbitan fatty acid ester obtained by esterifying one or more hydroxyl groups of sorbitan, which is a dehydrated product obtained by intramolecular dehydration of sorbite, with fatty acid. The polyoxyethylene ether obtained by this. Polysorbates can be easily understood by those skilled in the art.

  Examples of the polyoxyethylene sorbitan fatty acid ester include those having a polyoxyethylene number of 5 to 40, preferably 10 to 30, more preferably 15 to 25, and a fatty acid moiety having 6 to 18 carbon atoms. Preferred fatty acid moieties include lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, oleic acid, linoleic acid, linolenic acid and the like, and these fatty acids may be the same or different. The number of hydroxyl groups to be esterified is preferably 1 or 3.

  Specific examples of the polyoxyethylene sorbitan fatty acid ester include polysorbate 20 (also known as polyoxyethylene sorbitan monolaurate (20E.O.)) and polysorbate 40 (also known as polyoxyethylene sorbitan monopalmitate (20E.O.)). ), Polysorbate 60 (also known as polyoxyethylene sorbitan monostearate (20E.O.)), polysorbate 61 (also known as polyoxyethylene sorbitan monostearate (6E.O.)), polysorbate 65 (also known as tristearic acid) Polyoxyethylene sorbitan), polysorbate 80 (also known as polyoxyethylene sorbitan monooleate (20E.O.)), polysorbate 81 (also known as polyoxyethylene sorbitan monooleate (6E.O.)) Polysorbate 85 (also known trioleate polyoxyethylene sorbitan (20E.O.)), but can be mentioned, polysorbate 80 is particularly preferred.

  The content of the plasticizer in the capsule filling solution is preferably 0.1 to 15% by mass, more preferably 0.15 to 12% by mass, and particularly preferably 0.2 to 10% by mass with respect to the total amount of the solution. . The content ratio of the organic acid to the plasticizer is preferably 0.005 to 1 part by mass, and particularly preferably 0.01 to 0.8 part by mass with respect to 1 part by mass of the organic acid.

The caramel used in the present invention can be obtained by heat-treating carbohydrates such as glucose, fructose, galactose, maltose, sucrose, sucrose, invert sugar, water candy, starch hydrolysate, sugar honey and other sugars. In addition, commercially available products such as those manufactured by Ikeda Saccharified Industries, Ltd.
The concentration of caramel in the capsule filling solution is preferably 20 to 1500 mass ppm, more preferably 40 to 1200 mass ppm in the solution.
In addition, the blending mass ratio of diphenhydramine or a salt thereof and caramel is preferably 1: 0.00005 to 1: 1, and preferably 1: 0.0001 to 1: 0.5, from the viewpoint of suppressing discoloration and suppressing the decrease in diphenhydramine content. Is preferred.

Moreover, in this invention, the normal solvent used when filling a capsule with a liquid can be added.
The normal solvent is not particularly limited as long as it dissolves diphenhydramine or a salt thereof. For example, (1) water, (2) volatile or non-volatile that is not miscible with water or soluble in water Liquids (vegetable oils, aliphatic and aromatic hydrocarbons, chlorinated hydrocarbons, ethers, esters, higher alcohols, etc.), (3) non-volatile liquids miscible with water, (4) other (glycerin) And polyhydric alcohols such as propylene glycol; ketones, amines, esters, etc.). Of these, polyhydric alcohol, and a mixture of water and polyhydric alcohol are preferable in terms of improving compliance and suppressing softening of the capsule film. In addition, these normal solvents may be used alone, or a plurality of mixtures may be used.

  Although it does not specifically limit as said polyhydric alcohol, For example, macrogol, propylene glycol, glycerol, etc. are mentioned, Macrogol and glycerol are more preferable and macrogol is further more preferable.

  The average molecular weight of the macrogol is not particularly limited, but is preferably 100 to 800, more preferably 150 to 700, and further preferably 190 to 630. Among these, the macro goal 200, the macro goal 300, the macro goal 400, and the macro goal 600 are preferable, and the macro goal 400 is particularly preferable.

Moreover, when making the solution for capsule filling contain polyhydric alcohol, 10-90 mass% is preferable with respect to the solution whole quantity, and 15-85 mass% is more preferable with respect to the solution whole quantity, 20 ˜80 mass% is particularly preferred.
The content ratio of the organic acid to the polyhydric alcohol is preferably 1.5 to 40 parts by mass, particularly preferably 3 to 30 parts by mass with respect to 1 part by mass of the organic acid.

  Moreover, a pH adjuster etc. can further be added to the solution of this invention. Examples of the pH adjuster include bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, calcium carbonate, potassium hydrogen carbonate and the like. In the present invention, the pH of the solution is preferably 3 to 9, more preferably 3 to 6, still more preferably 3.3 to 5.8, and more preferably 3.6 to 5.6 in terms of capsule softening and cracking suppression. Particularly preferred.

  As the base of the capsule film used in the capsule of the present invention, gelatin, hydroxypropylmethylcellulose (abbreviated as HPMC), pullulan, polyvinyl alcohol, polyvinyl alcohol copolymer (preferably polyvinyl alcohol, methyl methacrylate and acrylic Acid or a salt thereof), macrogol and the like, and polyvinyl alcohol copolymer, macrogol and gelatin are preferred. These may be used alone or as a mixture.

In addition to the base, the capsule film may contain gelling agents such as gum arabic, alginic acid, carrageenan, agar, xanthan gum, guar gum, glucomannan, gellan gum, tamarind gum, far selelain, pectin, locust bean gum, etc. If necessary, a gelling aid such as ammonium chloride, potassium chloride, calcium chloride, sodium chloride, potassium citrate, sodium citrate, magnesium sulfate, or potassium phosphate can be contained.
The capsule film used in the present invention includes, for example, dyes such as legal dyes, pigments such as titanium oxide, polyvinyl acetal diethylaminoacetate, preservatives, fragrances, disintegrants, plasticizers such as glycerin, mannitol and sorbitol, etc. These sugar alcohols may be contained within a range not impairing the effects of the present invention.

  That is, the capsule film of the present invention is preferably a film containing macrogol and gelatin, and a film containing a polyvinyl alcohol copolymer containing carrageenan and potassium chloride as necessary.

  In the present invention, when using a film containing macrogol and gelatin as the capsule film, the content of macrogol may be appropriately examined in consideration of the mechanical strength of the capsule and the uniformity of the film during molding. 0.5-15 mass% is preferable with respect to capsule capsule whole quantity, and 1-10 mass% is more preferable.

  When the capsule film used in the present invention contains macrogol, the average molecular weight of the macrogol is preferably 950 to 25000, more preferably 2500 to 4000, Macrogol 1000, Macrogol 1500, Macrogol 1540, Macrogol 4000. Macrogol 6000 is more preferable, and Macrogol 4000 is particularly preferable. In addition, only one type of macrogol may be used, or a plurality of mixtures may be used.

When gelatin is contained in the capsule film used in the present invention, as the gelatin, for example, the sol-gel changes with a heat change, and acyl such as gelatin or succinated gelatin made from cattle, pigs, birds, fish, etc. And gelatinized 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.

  When the capsule film used in the present invention contains a polyvinyl alcohol copolymer (copolymer of polyvinyl alcohol, methyl methacrylate and acrylic acid or a salt thereof), the polyvinyl alcohol copolymer contains polyvinyl alcohol, methyl methacrylate and acrylic acid. Can be obtained by copolymerization. Polyvinyl alcohol may have a saponification degree of 78 mol% or more, and may be a partially saponified product (saponification degree: 78 to 96 mol%) or a complete saponification product (saponification degree: 97 mol% or more). In the present invention, polyvinyl alcohol (partially saponified product) having an average polymerization degree of 300 to 3000, methyl methacrylate and acrylic acid are copolymerized at a mass ratio of 60 to 90: 7 to 38: 0.5 to 12 to obtain. The viscosity of a 5% by mass aqueous solution of the copolymer at 25 ° C. is more preferably 5 to 40 mPa · s. The polyvinyl alcohol copolymer can be produced according to the description in International Publication WO02 / 017848, Japanese Patent Application Laid-Open No. 2007-91670, and the like.

  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.

  Moreover, the color of the capsule film used in the present invention is not particularly limited, but is preferably transparent or translucent so that the filled inner solution can be visually observed from the viewpoint of the commercial properties of the capsule. In particular, when diphenhydramine is used as a sleep-improving drug, the preparation may have a faint yellow or brown color based on the color derived from caramel, so when filling the capsule, if the capsule is transparent or translucent, the filling solution is visually It becomes possible, and the color derived from caramel is calm, brings a sense of stability and security, and can also lead to sleep comfortably.

The capsule of the present invention can be produced according to a conventional method.
For example, in the case of producing a capsule using a capsule film containing macrogol and gelatin, gelatin is absorbed and swollen, and then heated and dissolved, and then an appropriate amount of macrogol to be contained in the capsule film is added, if desired. After adding a pigment | dye, preservatives, etc. and adjusting a viscosity suitably, it defoams and obtains the jelly for capsule formation. The obtained jelly is formed into a capsule according to the present invention using a capsule forming apparatus, and filled with the solution of the present invention, whereby the capsule of the present invention (hard capsule) can be produced. Furthermore, according to a conventional method, the capsule can be sealed by a band method, a heat deposition method or the like.

  In addition, after water-swelling gelatin, it is dissolved by heating, and then an appropriate amount of macrogol to be included in the capsule film is added. Or a preservative is added to adjust the viscosity appropriately, followed by defoaming to obtain a capsule-forming jelly. Using the obtained jelly and the solution of the present invention, the capsule of the present invention (soft capsule) can be produced based on the rotary die method, the dropping method or the like.

  Moreover, when using the membrane | film | coat containing a polyvinyl alcohol copolymer as a capsule membrane | film | coat, a polyvinyl alcohol copolymer is melt | dissolved in water, a gelatinization adjuvant, a pigment | dye, an antiseptic | preservative, etc. are added if desired, and it heat-dissolves. A dipping solution is prepared by combining this with a solution obtained by separately dissolving a gelling agent in water. The capsule of the present invention (hard capsule) can be produced by performing dipping molding using this, forming into a capsule according to the present invention, and filling the capsule with the solution of the present invention. Furthermore, according to a conventional method, the capsule can be sealed by a band method, a heat deposition method, or the like.

Moreover, although the capsule used for the capsule of this invention can also be manufactured in accordance with the said conventional method, a commercially available hard capsule can also be used. Commercially available products include, for example, Japanese Pharmacopoeia gelatin capsule (Qualicaps Co., Ltd.) PONDAC (registered trademark) capsule (Nisshin Kasei Co., Ltd.), HPMC based on polyvinyl alcohol copolymer blended with PEG (Macrogol). Qualifier V (Qualicaps Co., Ltd.) based on NPcaps (registered trademark) (Capsugel Japan Co., Ltd.) based on pullulan.
By using these commercially available hard capsules and filling the solution of the present invention, the capsule of the present invention can be produced. Further, according to a conventional method, the capsule is sealed by a band method or a heat deposition method. It can also be applied. By applying the seal, it contributes to the leakage of the filling liquid from the capsule, the deodorization of the odor derived from the filling liquid, and the stability of the filling liquid.

  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 bottles and 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.

Reference Example 1: Production of hard capsules 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 to swell and absorb water. 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.

Reference Example 2: Production of hard capsule A capsule was molded in the same manner as Reference Example 1 except that 0.5 kg (2.5% by mass concentration) of a 50% by mass aqueous solution of Macrogol 4000 was added.

Reference Example 3: Hard Capsules 414 g of Macrogol 400 and 36 g of purified water were mixed, and then heated to about 60 ° C., 50 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. 250 mg of this filling liquid was filled into the capsule described in Reference Example 1 to produce a hard capsule having a diphenhydramine hydrochloride concentration of 10% by mass.

Reference Example 4: Hard capsule A hard capsule was produced in the same manner as in Reference Example 3 except that the capsule described in Reference Example 2 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. 250 mg of this filling solution was filled into normal size 3 gelatin hard capsules to prepare hard capsules 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 1: Evaluation of Hard Capsule Capsule cracking was evaluated for the hard capsules of Reference Examples 3 and 4 and Comparative Examples 1 and 2. After filling, the capsules are spread on a tray so that the capsules do not overlap each other, and are visually inspected for cracks and cracks after standing at room temperature for 1 day, after storage at 40 ° C for 1 month, and after storage at 40 ° C for 4 months. went. The results are shown in Tables 1 and 2.

  As is clear from Table 1, in the hard capsules of Reference Examples 3 and 4, no capsule cracking was observed either immediately after production, after storage at 40 ° C. for 1 month, or after storage at 40 ° C. for 4 months.

  As is clear from Table 2, 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 1, it was found that capsules that can be supplied as a product filled with a filling solution in which diphenhydramine hydrochloride is dissolved using normal gelatin capsules have a concentration of diphenhydramine hydrochloride 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, the hard capsules of Reference Examples 3 and 4 were not observed immediately after production, after storage at 40 ° C. for 1 month, and after storage at 40 ° C. for 4 months, and the size and number of capsules taken (1 capsule) Per diphenhydramine hydrochloride (containing 25 mg per unit area)), and it was found that compliance can be improved.

Example 1: Hard capsule 300 g of macrogol 400 and 40 g of acetic acid were heated to about 60 ° C., 50 g of diphenhydramine hydrochloride was added to this, stirred, dissolved, and used as a filling liquid. 390 mg of this filling liquid was filled into No. 1 capsules produced in the same manner as described in Reference Example 2 to produce hard capsules having a diphenhydramine hydrochloride concentration of 12.8% by mass.

Example 2: Hard capsule A hard capsule was produced in the same manner as in Example 1 except that PONDAC (registered trademark) capsule (Nisshin Kasei Co., Ltd.) was used.

Test Example 2: Evaluation of Hard Capsules The hard capsules of Examples 1 and 2 were evaluated for capsule cracking. After filling, the capsules were spread on a tray so that the capsules would not overlap each other, and were visually inspected for cracks and cracks immediately after production and after storage at 50 ° C. for 1 day. The results are shown in Table 3.

  As is clear from Table 3, the hard capsules of Examples 1 and 2 contain diphenhydramine hydrochloride in a higher concentration than the preparations of Comparative Examples 1 and 2, but immediately after production and after storage at 50 ° C. for 1 day. In any of these cases, no capsule cracking was observed, and it was found that the size and number of capsules taken (containing 50 mg of diphenhydramine hydrochloride per capsule) 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.

Example 5: hard capsule 160 g of macrogol 400 and 40 g of acetic acid were heated to about 60 ° C., 50 g of diphenhydramine hydrochloride was added and stirred, and after dissolution, 10.4 g of 10% aqueous sodium hydroxide solution was added. The pH was adjusted to about 5, and after cooling, 1.6 g of polysorbate 80 (NIKKOL TO-10MV: manufactured by Nippon Surfactant Co., Ltd.) was added and stirred to obtain a filling liquid. A capsule of size 3 produced in Reference Example 2 was filled with 262 mg of this filling liquid to produce a hard capsule having a diphenhydramine hydrochloride concentration of 19.1% by mass.

Example 6: Hard capsule A hard capsule was produced in the same manner as in Example 5 except that polysorbate 80 was replaced with triethyl citrate.

Example 7: Hard capsule A hard capsule was produced in the same manner as in Example 5 except that polysorbate 80 was replaced with triacetin.

Example 8: Hard capsule A hard capsule was produced in the same manner as in Example 5 except that polysorbate 80 was replaced with glycerin fatty acid ester (Inviter 742: manufactured by Sasol).

Example 9: Hard capsule 160 g of Macrogol 400 and 40 g of acetic acid were heated to about 60 ° C., 50 g of diphenhydramine hydrochloride was added and stirred, and after dissolution, 10.4 g of 10% aqueous sodium hydroxide solution was added. The pH was adjusted to about 5 to obtain a filling liquid. A capsule of size 3 produced in Reference Example 2 was filled with 260.4 mg of this filling liquid to produce a hard capsule having a diphenhydramine hydrochloride concentration of 19.2% by mass.
That is, this hard capsule remove | excludes each plasticizer from each hard capsule of the said Examples 5-8.

Test Example 3: Evaluation of Hard Capsules The hard capsules of Examples 5 to 9 were evaluated for capsule cracking and acetic acid odor. Evaluation of capsule cracking was performed by filling the trays so that the capsules do not overlap after filling, and visually inspecting for cracks and cracks immediately after production and after storage at 50 ° C. for 1 day. Further, the degree of odor of acetic acid immediately after production and after storage at 50 ° C. for 1 week was evaluated according to the 15th revision of the Japanese Pharmacopoeia as a three-stage evaluation with the odor immediately after production of Example 9 as +++ (explanation of degree) +++: smells of intense acetic acid, ++: smells of acetic acid slightly, +: smells of acetic acid slightly). The results are shown in Table 4.

As is clear from Table 4, in any of the hard capsules (Examples 5 to 9), capsule cracking was not observed immediately after production and after storage at 50 ° C. for 1 day. Regarding the smell of acetic acid, the hard capsules of Examples 5 to 8 containing a plasticizer were significantly suppressed as compared to the hard capsule of Example 9 containing no plasticizer.
Therefore, the hard capsules of Examples 5 to 8 were found to be capsules containing diphenhydramine or a salt thereof having good commercial value, excellent compliance, easy to take, and excellent stability.

Example 10: Hard capsule 160 g of macrogol 400 and 40 g of acetic acid were heated to about 60 ° C., 50 g of diphenhydramine hydrochloride was added and stirred, and after dissolution, 0.06 g of caramel (Caramel S: Ikeda Gakka Kogyo Co., Ltd.) Product) and 10.4 g of 10% aqueous sodium hydroxide solution were added to adjust the pH to about 5 to obtain a filling solution. A capsule of size 3 produced in Reference Example 2 was filled with 260.4 mg of this filling liquid to produce a hard capsule containing 50 mg of diphenhydramine hydrochloride.

Test Example 4: Evaluation of Hard Capsule The appearance changes of the hard capsules of Example 9 and Example 10 were evaluated. After filling, the capsules were spread on a tray so as not to overlap each other, and the appearance change immediately after production and after storage at 50 ° C. for 2 weeks was evaluated by visual inspection. The results are shown in Table 5.

As is clear from Table 5, no change in appearance was observed in any of the hard capsules (Example 9 and Example 10) immediately after production. On the other hand, in Example 9 to which no caramel was added, a change in appearance was observed, but in the hard capsule of Example 10 filled with a filling liquid to which caramel was added, no change in appearance was observed.
Therefore, it was found that caramel is effective for stabilizing diphenhydramine or a salt thereof.
Therefore, it was found that the hard capsule of Example 10 was a capsule containing diphenhydramine or a salt thereof having good compliance, easy to take, superior stability, and extremely high commercial value.

Example 11: Hard capsule 320 g of Macrogol 400 and 80 g of lactic acid were heated to about 60 ° C., 100 g of diphenhydramine hydrochloride was added to this, stirred and dissolved, and then 30 g of 10% aqueous sodium hydroxide solution was added and filled. Liquid. A capsule of size 3 produced in Reference Example 2 was filled with 265 mg of this filling liquid to produce a hard capsule containing 50 mg (18.9% by mass) of diphenhydramine hydrochloride.

Example 12: Hard capsule 320 g of Macrogol 400 and 80 g of lactic acid were heated to about 60 ° C., 100 g of diphenhydramine hydrochloride was added to this, stirred and dissolved, and then 0.05 g of caramel (Caramel S: Ikeda Sakka Kogyo Co., Ltd.) Product) and 30 g of 10% aqueous sodium hydroxide solution were added to form a filling liquid. A capsule of size 3 produced in Reference Example 2 was filled with 265 mg of this filling liquid to produce a hard capsule containing 50 mg (18.9% by mass) of diphenhydramine hydrochloride.

Example 13: Hard capsule 320 g of Macrogol 400 and 80 g of lactic acid were heated to about 60 ° C., 100 g of diphenhydramine hydrochloride was added to this, stirred and dissolved, and then 0.05 g of caramel (Caramel S: Ikeda Gakka Kogyo Co., Ltd.) Product) and 20 g of 20% aqueous sodium hydroxide solution were added to obtain a filling solution. A capsule of size 3 produced in Reference Example 2 was filled with 260 mg of this filling liquid to produce a hard capsule containing 50 mg (19.2% by mass) of diphenhydramine hydrochloride.

Example 14: Hard capsule 320 g of Macrogol 400 and 80 g of lactic acid were heated to about 60 ° C., 100 g of diphenhydramine hydrochloride was added to this, stirred and dissolved, and then 0.05 g of caramel (Caramel S: Ikeda Sakka Kogyo Co., Ltd.) Product) and 30 g of 20% aqueous sodium hydroxide solution were added to form a filling solution. A capsule of size 3 produced in Reference Example 2 was filled with 265 mg of this filling liquid to produce a hard capsule containing 50 mg (18.9% by mass) of diphenhydramine hydrochloride.

Test Example 5: Evaluation of hard capsules The hard capsules of Examples 11 to 14 were evaluated for capsule cracking, change in appearance, and residual rate of diphenhydramine hydrochloride.
The hard capsules after filling were spread on a tray so that they would not overlap each other, and the presence or absence of cracks or cracks was evaluated by visual inspection immediately after production and after storage at 50 ° C. for 1 day.
In addition, the hard capsules obtained are packed in PTP, further packed in an aluminum pillow, and stored at 50 ° C. for 2 weeks and 40 ° C. for 2 months, and then visually inspected for the presence or absence of cracks, cracks, and appearance changes. Evaluation was performed. The results are shown in Table 6.

As is clear from Table 6, all of the hard capsules (Examples 11 to 14) were broken immediately after production, after storage at 50 ° C. for 1 day, after storage at 50 ° C. for 2 weeks and after storage at 40 ° C. for 2 months. Was not observed.
Therefore, it was found that the size and number of capsules taken (containing 50 mg of diphenhydramine hydrochloride per capsule) can be minimized, and compliance can be improved.
Further, in Example 11 where no caramel was added, an appearance change (discoloration tendency) was observed after storage at 50 ° C. for 2 weeks and after storage at 40 ° C. for 2 months, but the example was filled with a filling solution to which caramel was added. No change in appearance was observed in the capsules of 12-14.
Therefore, it was found that caramel is effective for stabilizing diphenhydramine or a salt thereof.
As is clear from the results, the hard capsules of Examples 12 to 14 to which caramel was added contain diphenhydramine or a salt thereof, which is particularly excellent in compliance, easy to take, excellent in stability, and extremely high in commercial value. It was found to be a capsule.

Example 15: Hard capsule 160 g of macrogol 400 and 40 g of acetic acid were mixed and then heated to about 60 ° C., 50 g of diphenhydramine hydrochloride was added and stirred, and after dissolution, 0.06 g of caramel (Caramel S: Ikeda) The pH was adjusted to about 5 by adding 10.4 g of 10% sodium hydroxide aqueous solution). After cooling, 1.5 g of polysorbate 80 (NIKKOL TO-10MV: manufactured by Nippon Surfactant Kogyo Co., Ltd.) was added and stirred to obtain a filling liquid. A capsule of size 3 produced in Reference Example 2 was filled with 262 mg of this filling liquid to produce a hard capsule containing 50 mg of diphenhydramine hydrochloride.

Example 16: Hard capsule A hard capsule was produced in the same manner as in Example 15 except that polysorbate 80 was replaced with triethyl citrate.

Example 17: Hard capsule A hard capsule was produced in the same manner as in Example 15 except that polysorbate 80 was replaced with triacetin.

Example 18: Hard capsule A hard capsule was produced in the same manner as in Example 15 except that polysorbate 80 was replaced with glycerin fatty acid ester (Inviter 742: manufactured by Sasol).

Test Example 6: Evaluation of hard capsules The hard capsules of Example 5 and Examples 15 to 18 were evaluated for capsule cracking, acetic acid odor, appearance change, and residual rate of diphenhydramine hydrochloride.
The hard capsules after filling were spread on a tray so that they would not overlap each other, and the presence or absence of cracks or cracks was evaluated by visual inspection immediately after production and after storage at 50 ° C. for 1 day.
In addition, the degree of odor of acetic acid immediately after production and after storage at 50 ° C. for 2 weeks was evaluated according to the 15th revision of the Japanese Pharmacopoeia. +++: smells of intense acetic acid, ++: smells of acetic acid slightly, +: smells of acetic acid slightly).

  Furthermore, the obtained hard capsules were PTP packaged, further packaged with an aluminum pillow, and stored at 50 ° C. for 2 weeks, and then visually inspected to evaluate the presence or absence of cracks and cracks and the appearance change. In addition, the content of diphenhydramine hydrochloride in the hard capsule was measured by the HPLC method, and the residual ratio relative to the initial content was calculated. The results are shown in Table 7.

As is clear from Table 7, in any of the hard capsules (Examples 15 to 18 and Example 5), capsule cracking was not observed immediately after production, after storage at 50 ° C. for 1 day, and after storage at 50 ° C. for 2 weeks. It was. Moreover, about the smell of acetic acid, all the hard capsules were slight.
In Example 5 to which no caramel was added, an appearance change and a decrease in the content of diphenhydramine hydrochloride were observed, but the capsules of Examples 15 to 18 filled with a filling solution to which caramel was added were changed in appearance and diphenhydramine hydrochloride. No decrease in the content of was observed.
Therefore, it was found that caramel is effective for stabilizing diphenhydramine or a salt thereof.
Therefore, it was found that the hard capsules of Examples 15 to 18 were diphenhydramine or a salt thereof having good compliance, easy to take, excellent stability, and extremely high commercial value.

Claims (8)

  A solution containing diphenhydramine or a salt thereof and an organic acid.   Furthermore, the solution of Claim 1 containing a caramel.   Furthermore, the solution of Claim 1 or 2 containing a polyhydric alcohol.   The solution according to any one of claims 1 to 3, wherein the organic acid is at least one selected from acetic acid and lactic acid.   The capsule which filled the capsule with the solution of any one of Claims 1-4.   The capsule according to claim 5, wherein the content of diphenhydramine or a salt thereof is 25 mg or 50 mg per capsule.   The capsule according to claim 5 or 6, wherein the capsule film contains one or more bases selected from the group consisting of gelatin, hydroxypropylmethylcellulose, pullulan, polyvinyl alcohol, polyvinyl alcohol copolymer and macrogol. Agent.   The capsule according to any one of claims 5 to 7, wherein the capsule film contains macrogol and gelatin, or a polyvinyl alcohol copolymer.