JP2011068636A - Liquid-filled capsule - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a capsule agent having excellent properties such as good dosing compliance, and resistance to deformation, such as softening or cracking, of capsule. <P>SOLUTION: The capsule agent is prepared by filling a capsule with a liquid containing component (A) of at least one member selected from loxoprofen or a salt thereof and diphenhydramine or a salt thereof and component (B) of glycerol. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a liquid containing loxoprofen and / or diphenhydramine, and a capsule filled with the liquid.

  In recent years, hard capsules that can be filled with liquid have been developed (for example, Japanese Pharmacopoeia gelatin capsules (Qualicaps Co., Ltd.) blended with PEG (Macrogol), PONDAC based on polyvinyl alcohol copolymer ( (Registered trademark) capsule (Nisshin Kasei Co., Ltd.), Qualie V (registered trademark) (Qualicaps Co., Ltd.) based on HPMC (hypromellose), NPcaps (registered trademark) (Capsugel Japan Co., Ltd.) based on pullulan ) Etc.), hard capsules filled with liquid are being put into practical use.

However, although it has become possible to fill liquids into hard capsules, it has not been possible to fill all possible liquids. Depending on the type of capsule skin, (Dispersoid) and solvent (dispersion medium)) are limited.
For example, it is said that the above-mentioned Querie V (registered trademark) based on HPMC cannot be filled with macrogol 400, glycerin or propylene glycol (Non-patent Document 1).
Similarly, it has been reported that filling of Quorie V (registered trademark) with water or ethanol is very difficult in terms of compatibility with capsule skin (Non-patent Document 2).

  Loxoprofen, on the other hand, is a type of non-steroidal anti-inflammatory analgesic (NSAID), including rheumatoid arthritis, osteoarthritis, low back pain, shoulder periarthritis, cervical shoulder syndrome, toothache, acute upper respiratory tract inflammation, post-surgical trauma It is known as effective for anti-inflammatory, analgesic and antipyretic after and after extraction (Non-patent Document 3).

Loxoprofen is known to be extremely difficult to form into a solid preparation because of its high adhesion. And it is known that the adhesion of the loxoprofen can be suppressed by blending an additive so that the total water absorption capacity is within a certain range (Patent Document 1), but there are various means for improving the technique for further improvement. It has been developed (Patent Documents 2 to 8).
Loxoprofen sodium hydrate is known to be very soluble in water or methanol, easily soluble in ethanol (95), and hardly soluble in diethyl ether (Non-patent Document 3).

Diphenhydramine is a kind of antihistamine and is used for urticaria, allergic rhinitis associated with skin diseases, pruritus, acute rhinitis and the like, and in recent years, it is also used as a sleep improving drug. When diphenhydramine is used for acute rhinitis etc., the dose per dose is 10 mg, whereas when used as a sleep improving agent, the dose per dose is 50 mg, and diphenhydramine is taken as a sleep improving agent. If so, compliance issues were likely to occur.
In order to solve this problem, there has been proposed a hard capsule in which a gelatin capsule containing macrogol is filled with a filling liquid obtained by dissolving diphenhydramine in a mixed liquid of macrogol and water (Patent Document 9).
Diphenhydramine is miscible with acetic anhydride, acetic acid (100), ethanol (95), and diethyl ether (Non-Patent Document 4), and diphenhydramine hydrochloride is extremely soluble in methanol or acetic acid (100). 95), is slightly soluble in acetic anhydride, and hardly dissolved in diethyl ether (Non-patent Document 5).

Japanese Patent Publication No. 7-74153 Japanese Patent Laid-Open No. 9-169641 Japanese Patent Laid-Open No. 9-255569 JP-A-10-279476 Japanese Patent Laid-Open No. 11-21236 JP-A-11-255543 JP 2000-16936 A JP 2000-178190 A JP 2009-73829 A

Qualicaps Co., Ltd., Q & A about Quarry V (HPMC capsule), Q10 “A10”, [online], Qualicaps Co., Ltd., [searched July 8, 2009], Internet <URL: http://www.qualicaps.co .jp / hpmc.htm # 10> Qualicaps Co., Ltd., Q & A about Queries V (HPMC capsules), Q10 “Click here for details on various additives and compatibility”, [online], Qualicaps Co., Ltd., [July 8, 2009 search], Internet <URL: http://www.qualicaps.co.jp/img/hpmc/TI02.SWF> Fifteenth revised Japanese Pharmacopoeia explanation book Yodogawa Shoten Co., Ltd. C-4790-4759 Fifteenth revised Japanese Pharmacopoeia explanation book Yodogawa Shoten Co., Ltd., page C-1735 Fifteenth revised Japanese Pharmacopoeia commentary Yodogawa Shoten Co., Ltd., page C-1739

First, from Non-Patent Documents 2, 3 and 5, filling a capsule based on HPMC with a solution of sodium loxoprofen hydrate or diphenhydramine or a salt thereof (for example, an aqueous solution or an ethanol solution) Naturally, it is expected to be extremely difficult in terms of compatibility.
Furthermore, from Non-Patent Document 1, a mixture of Macrogol 400, glycerin or propylene glycol, which is said to be unable to be filled into a capsule based on HPMC, and loxoprofen sodium hydrate, diphenhydramine or a salt thereof, It is of course expected that filling capsules will be extremely difficult.

Loxoprofen, diphenhydramine or a salt-containing liquid-filled capsule needs to be resistant to deformation such as capsule softening and cracking. Moreover, when taking, it is desirable that the compliance is good and that the capsule is a clear and clear liquid-filled capsule.
Therefore, an object of the present invention is to provide a liquid containing loxoprofen, diphenhydramine or a salt thereof, and a capsule filled with the liquid, which are preferable for capsule filling.

  As a result of intensive studies to solve the above problems, the present inventors have surprisingly found that (1) loxoprofen or a salt thereof is dissolved in glycerin and becomes a clear liquid, and (2) the loxoprofen or the salt thereof. Capsule film softening or cracking does not occur even when a salt based glycerin solution is filled into a HPMC-based capsule, (3) Diphenhydramine or a salt thereof is dissolved in glycerin, and becomes a colorless and transparent liquid. And (4) The present invention has been completed by finding that even when the glycerin solution of diphenhydramine or a salt thereof is filled in a capsule based on HPMC, the capsule film does not soften or crack.

1) That is, the present invention provides a liquid containing the following components (A) and (B).
(A) Loxoprofen or a salt thereof and one or more selected from diphenhydramine or a salt thereof (B) Glycerin 2) The present invention also provides a liquid substantially consisting of the components (A) and (B). Is.
3) Moreover, this invention provides the capsule which filled the liquid of said 1) or 2) in the capsule.
4) Moreover, this invention provides the capsule of 3) whose film | membrane of a capsule contains a hypromellose.

According to the present invention, even when one or more glycerin solutions selected from loxoprofen or a salt thereof and diphenhydramine or a salt thereof are filled in a capsule based on HPMC, the capsule film is not softened or cracked.
Therefore, according to the present invention, since one or more selected from loxoprofen or a salt thereof and diphenhydramine or a salt thereof are present in a liquid state in the capsule, one selected from loxoprofen or a salt thereof and diphenhydramine or a salt thereof Prompt expression of the above medicinal effects can be expected.
Further, the liquid according to the present invention is transparent and clear, and when a transparent or translucent capsule is used, the content liquid can be visually observed. Therefore, it is selected from loxoprofen having high commercial value or a salt thereof, and diphenhydramine or a salt thereof. Capsules containing one or more of the above can be provided. Moreover, since there is no deformation | transformation of a capsule and the normal dose as a single dose can be filled into one capsule, compliance is favorable.

Ingredient (A)
Loxoprofen or a salt thereof used in the present invention includes not only loxoprofen but also a pharmaceutically acceptable salt of loxoprofen, and further a solvate with water, alcohol and the like. These are known compounds, and can be produced by known methods, or commercially available products can be used. In the present invention, loxoprofen or a salt thereof is preferably loxoprofen sodium hydrate (chemical name: Monosodium 2- [4-[(2-oxocyclopentyl) methyl] phenyl] propanoate dihydrate).

In the present invention, when component (A) is loxoprofen or a salt thereof, the content of loxoprofen or a salt thereof in the liquid or capsule is appropriately examined according to the sex, age, symptoms, etc. of the user. What is necessary is just to determine, but the quantity which can be taken | dosed 10-300 mg per loxoprofen sodium anhydride is preferable per day, and the quantity which can be taken | dosed 30-240 mg is more preferable. The amount that can be taken 60 to 180 mg is more preferable.
Accordingly, the concentration of loxoprofen or a salt thereof in the glycerin solution may be appropriately set according to the capacity of capsules to be filled and the number of capsules to be taken as described above. The content of glycerin in the salt glycerin solution is preferably 20 to 95% by mass, more preferably 40 to 93% by mass, and particularly preferably 45 to 90% by mass in the solution from the viewpoints of solubility and stability.

The diphenhydramine or a salt thereof used in the present invention includes not only diphenhydramine but also a pharmaceutically acceptable salt of diphenhydramine, and further a solvate with water, alcohol or the like. These are known compounds, and can be produced by known methods, or commercially available products can 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 the present invention, hydrochloride is preferable.
In the present invention, when component (A) is diphenhydramine or a salt thereof, the content of diphenhydramine or a salt thereof in the liquid or capsule is appropriately examined according to the sex, age, symptoms, etc. of the user. It may be determined, but from the viewpoint of improving compliance when taking 50 mg once as a sleep improving drug, it is preferably adjusted to contain 20 to 75 mg in one capsule, and adjusted to contain 50 mg or 25 mg. Is more preferable. The content of diphenhydramine or a salt thereof in the glycerin liquid of diphenhydramine or a salt thereof as a filling liquid is preferably 3 to 50% by mass, and particularly preferably 5 to 25% by mass in the liquid.
In this invention, 3-95 mass% is preferable in a liquid, and, as for content of the component (A) in a glycerol liquid, 5-93 mass% is more preferable.

Ingredient (B)
The glycerin used in the present invention has a chemical name of 1,2,3-propanetriol, and “glycerin” and “concentrated glycerin” described in the 15th revised Japanese Pharmacopoeia Description are preferable. As the liquid according to the present invention, a liquid in which water is added and mixed with glycerin can be used as long as the effects of the present invention are not impaired. Here, as glycerol mixed with water, what contains 2-17 mass% of water | moisture content is mentioned, for example.
Further, the content of glycerin in the liquid is preferably 50 to 87% by mass in the liquid.

  The liquid according to the present invention is preferably a transparent liquid or a clear liquid.

The liquid according to the present invention may further contain additives such as a pH adjuster, a dye, and a surfactant within a range that does not impair the effects of the present invention.
Examples of the pH adjuster include acids such as adipic acid, ascorbic acid, erythorbic acid, hydrochloric acid, citric acid, glutamic acid, succinic acid, acetic acid, tartaric acid, lactic acid, fumaric acid, maleic acid, and malic acid. Regarding loxoprofen or a salt thereof, a pH regulator that can be adjusted to an acidic region is preferable in consideration of the stability of loxoprofen or a salt thereof in the liquid.
Examples of the pigment include food red No. 2, food red No. 3, food red No. 40, food red No. 102, food red No. 106, food yellow No. 4, food yellow No. 5, food blue No. 1, food blue No. No. 2, caramel and the like.

  Examples of the surfactant include glyceryl monohexanoate, glyceryl monooctanoate, glyceryl monodecanoate, glyceryl monolaurate, glyceryl dioctanoate, glyceryl didecanoate, glyceryl decanoate, glyceryl monomyristate, glyceryl monostearate, Glycerin fatty acid esters such as glyceryl monooleate; sorbitan fatty acid esters such as sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, sorbitan monooleate, sorbitan trioleate, sorbitan sesquioleate; Polyoxyethylene alkyl ethers such as macrogol; polyoxyl stearate 40, polyoxyl stearate 45, polystearate Polyoxyethylene fatty acid esters such as oxyl 55; Nonionic surfactants such as polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85, and other polyoxyethylene sorbitan fatty acid esters Is mentioned.

The content of other additives such as pH adjusters, dyes, and surfactants is preferably small, and is preferably 0 to 5% by mass in the filling liquid, and more preferably substantially not contained.
That is, the liquid according to the present invention is preferably substantially composed of loxoprofen or a salt thereof, and / or diphenhydramine or a salt thereof, and glycerin.

Examples of the capsule film base used in the capsule of the present invention include gelatin, hypromellose (sometimes abbreviated as HPMC), pullulan, polyvinyl alcohol, and a polyvinyl alcohol copolymer (preferably polyvinyl alcohol and methyl methacrylate). A copolymer of acrylic acid or a salt thereof), macrogol and the like. These may be used alone or as a mixture. In the present invention, HPMC is particularly preferable.
HPMC means a mixed ether of cellulose methyl and hydroxypropyl, which can be produced by a known method, and is a commercially available product (for example, manufactured by Shin-Etsu Chemical Co., Ltd., manufactured by Dow Chemical Japan Co., Ltd., Matsumoto Yushi Seiyaku Co., Ltd., etc.) can also be used.
In the present invention, the substitution degree of the methoxy group and the hydroxypropoxy group in HPMC is not particularly limited, and a desired substitution degree can be obtained by presetting the substitution degree when etherifying cellulose. Can do. In the present invention, those containing 10-50% of methoxy groups are preferred, and those containing 16.5-30% are more preferred. Moreover, what contains 2-35% of hydroxypropoxy groups is preferable, and what contains 4-32% is still more preferable. Particularly preferred is HPMC containing 16.5-30% methoxy groups and 4-32% hydroxypropoxy groups. Among these, those of the substitution degree type such as hypromellose 1828, hypromellose 2208, hypromellose 2906, and hypromellose 2910 are preferable.

  In addition to the base, the capsule film may contain a gelling agent 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, edible red No. 2, edible red No. 3, edible red No. 40, edible red No. 102, edible red No. 106, edible yellow No. 4, edible yellow No. 5, edible Blue No. 1, Edible Blue No. 2, pigments such as caramel, pigments such as titanium oxide, polyvinyl acetal diethylaminoacetate, preservatives, fragrances, disintegrants, plasticizers such as glycerin, sugar alcohols such as mannitol and sorbitol, etc. You may make it contain in the range which does not impair the effect of this invention.

  The capsule film of the present invention is preferably a film containing HPMC, more preferably a film containing HPMC containing a gelling agent and / or a gelling aid. Among these, a film containing carrageenan as a gelling agent, potassium chloride and HPMC as gelling aids is preferable.

  In the above-described coating containing HPMC, when the gelling agent is contained, it is preferable to contain 0.35 to 1% by mass of the gelling agent in the capsule coating. When the gelling aid is contained, it is preferable to contain 0.35 to 0.5% by mass of the gelling aid in the capsule film.

  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 the present invention, by using a warm color system for the capsule, when loxoprofen or a salt thereof is used as an active ingredient of an antipyretic analgesic or a cold medicine, it brings an image of warmth, calmness, stability and security. It is preferable because it can relax and relieve symptoms. Similarly, when using diphenhydramine or a salt thereof as a sleep-improving drug, the capsule color is warm to bring a warmth, calmness, a sense of stability and security, and lead to a relaxing and comfortable sleep. It is possible to connect to it and it is preferable.
To produce a warm-colored capsule, the coating liquid is made transparent or semi-transparent so that the content liquid can be visually observed, and the content liquid is colored or warmed with a pigment or the like. This can be achieved by coloring the transparent or translucent coating in a warm color system to such an extent that the inner solution is visible.

When using HPMC as the capsule skin, the capsule of the present invention can be produced, for example, according to the methods described in JP-A-3-179325 and JP-A-2000-136126.
That is, first, a capsule base solution containing HPMC and a gelling agent, and optionally a gelling aid is prepared. The capsule molding pin is dipped in this, then the molding pin is pulled up from the capsule base solution, and the capsule base solution attached to the pin is gelled to mold the capsule. By filling this with the liquid of the present invention, 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. Applying the seal 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.

  Moreover, although the capsule used for the capsule of this invention can be shape | molded and manufactured in accordance with the said conventional method, a commercially available hard capsule can also be used. Commercially available products include, for example, Qualie V (registered trademark) (Qualicaps Co., Ltd.) based on HPMC, Japanese Pharmacopoeia gelatin capsule (Qualicaps Co., Ltd.), PEG (Macrogol), and polyvinyl alcohol copolymer. PONDAC (registered trademark) capsule (Nisshin Kasei Co., Ltd.) as a base, NPcaps (registered trademark) (Capsugel Japan Co., Ltd.) as a base, and the like can be mentioned. In the present invention, Qualie V (registered trademark) (Qualicaps Co., Ltd.) based on HPMC is preferred.

  Using these commercially available hard capsules, the capsule of the present invention can be produced by filling the liquid of the present invention, and further, according to a conventional method, the capsule is sealed by a band method or a heat deposition method. It can also be applied. Applying the seal 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.

  Moreover, the capsule (soft capsule) of this invention can also be manufactured by using well-known methods, such as a rotary die method and the dripping method, and the liquid of this invention.

  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.

  Moreover, since the capsule of this invention contains the said component (A), it is useful as a cold medicine, an antipyretic analgesic, a sleep improvement medicine, etc.

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

Example 1 Hard Capsules 68.1 g of loxoprofen sodium hydrate and 68.1 g of glycerin were mixed to prepare a glycerin solution of loxoprofen sodium hydrate, which was used as a filling liquid. 136.2 mg of this filling liquid was filled into a transparent hard capsule (trade name: Quarry V (registered trademark); manufactured by Qualicaps Co., Ltd.) based on HPMC of size 5 and 68. Hard capsules containing 1 mg (60 mg as loxoprofen sodium anhydride) were prepared.
The obtained hard capsule was a transparent capsule filled with a transparent liquid.

Example 2: Hard capsule 68.1 g of loxoprofen sodium hydrate and 197 g of glycerin were mixed to prepare a glycerin liquid of loxoprofen sodium hydrate, which was used as a filling liquid. 265.1 mg of this filling liquid was filled into a transparent hard capsule based on HPMC of size 3 (trade name: Quarry V (registered trademark); manufactured by Qualicaps Co., Ltd.), and loxoprofen sodium hydrate was added to 68. Hard capsules containing 1 mg (60 mg as loxoprofen sodium anhydride) were prepared.
The obtained hard capsule was a transparent capsule filled with a transparent liquid.

Comparative Example 1: Hard capsule 68.1 g of loxoprofen sodium hydrate and 197 g of Macrogol 400 were mixed. As a result, loxoprofen sodium hydrate was not dissolved in Macrogol 400 and became a suspension. Using this suspension as a filling liquid, hard capsules were produced in the same manner as in Example 2.
The obtained hard capsule was a transparent capsule filled with a suspension.

Comparative Example 2: Hard capsule A hard capsule was produced in the same manner as in Example 2 except that glycerin was replaced with propylene glycol.
The obtained hard capsule was a transparent capsule filled with a transparent liquid.

Test Example 1: Evaluation of Hard Capsule Deformation of the hard capsules of Examples 1 and 2 and Comparative Examples 1 and 2 was evaluated. After filling, spread the capsules so that the capsules do not overlap, and visually check for deformation (cracking, cracking, softening, etc.) after storage at 40 ° C for 2 weeks, 1 month, 2 months, and 6 months. This was done by inspection. The results are shown in Table 1.

As is clear from Table 1, in the hard capsules of Comparative Examples 1 and 2, capsule deformation (cracking, leakage of the filling liquid) was observed after storage at 40 ° C. for 2 weeks. In addition, observation after this was not performed because it was not worthy of evaluation.
That is, it was confirmed that it is not preferable to fill the macrogol 400 or propylene glycol into a capsule based on HPMC, which is consistent with the description in Non-Patent Document 1.

On the other hand, no deformation was observed in the hard capsules of Examples 1 and 2 even after storage at 40 ° C. for 6 months.
That is, although it was thought that glycerin could not be filled into a capsule based on HPMC (see Non-Patent Document 1), surprisingly, the glycerin solution of loxoprofen sodium hydrate was It has been found that deformation does not occur when filled into capsules based on HPMC.

Further, loxoprofen sodium hydrate is known to be extremely soluble in water or methanol, easily dissolved in ethanol (95), and hardly dissolved in diethyl ether (Non-patent Document 3). From the results, it was found that loxoprofen sodium hydrate and glycerin were mixed to form a transparent liquid.
That is, the hard capsule of Examples 1 and 2 can be a hard capsule containing a transparent liquid in a transparent capsule.

In addition, the hard capsules of Examples 1 and 2 contain 68.1 mg loxoprofen sodium hydrate in one capsule.
Therefore, in the hard capsules of Examples 1 and 2, the content of loxoprofen sodium hydrate in the capsule is set to 68.1 mg (60 mg as loxoprofen sodium anhydrous) which is a normal dose as a single dose. Therefore, it has been found that it is extremely preferable for compliance.
As described above, from the results of Test Example 1, it was found that the hard capsules of Examples 1 and 2 were preparations with extremely high commercial value.

Test Example 2: Stability Evaluation of Hard Capsules Regarding the hard capsules of Example 2, the stability of the content of loxoprofen sodium hydrate in the hard capsules after storage at 40 ° C for 6 months was evaluated by the HPLC method. Moreover, the disintegration degree (minute) was evaluated according to the disintegration test method of the 15th revision Japanese Pharmacopoeia. The respective results are shown in Table 2.

As apparent from Table 2, even after storage at 40 ° C. for 6 months, almost no decrease in the content was observed. There was no change in the degree of disintegration.
As a result, it was found that the hard capsule of Example 2 had high content stability, and the degree of disintegration did not change even after storage at 40 ° C. for 6 months.
As described above, from the results of Test Examples 1 and 2, it was found that the hard capsule of Example 2 was a preparation with extremely high commercial value.

Example 3: Hard capsules 68.1 g of loxoprofen sodium hydrate and 197 g of glycerin were mixed, and caramel was added to a concentration of 300 ppm to prepare a glycerin solution of loxoprofen sodium hydrate. did. 265.1 mg of this filling liquid was filled into a transparent hard capsule based on HPMC of size 3 (trade name: Quarry V (registered trademark); manufactured by Qualicaps Co., Ltd.), and loxoprofen sodium hydrate was added to 68. Hard capsules containing 1 mg (60 mg as loxoprofen sodium anhydride) were prepared.
The obtained hard capsule was a transparent capsule filled with an amber clear liquid.

Example 4: Hard capsule A hard capsule was produced in the same manner as in Example 3 except that caramel was replaced with edible yellow No. 5.
The obtained hard capsule was a transparent capsule filled with a clear orange liquid.

Test Example 3: Evaluation of hard capsules The hard capsules of Examples 3 and 4 were evaluated for deformation and discoloration of the filling liquid. After filling, the capsules are spread on a tray so that the capsules do not overlap each other, and whether there is any deformation (cracking, cracking, softening, etc.) after storage at 40 ° C for 2 weeks, 40 ° C for 1 month, 40 ° C for 2 months, and 50 ° C for 1 month, and The presence or absence of discoloration of the filling liquid was checked by visual inspection. The results are shown in Table 3.

As is apparent from Table 3, no deformation was observed in the hard capsules of Examples 3 and 4 even after 2 months at 40 ° C and 1 month at 50 ° C.
Further, in the hard capsules of Examples 3 and 4, no discoloration was observed even after 2 months at 40 ° C and after 1 month at 50 ° C.
From these results, the hard capsules of Examples 3 and 4 are of a warm color system (dark blue clear, orange clear) that can image relaxation, which can lead to the relief of symptoms for cold and antipyretic analgesics. It turns out that the color can be maintained.

In the hard capsules of Examples 3 and 4, the content of loxoprofen sodium hydrate in the capsule is 68.1 mg (60 mg as anhydrous loxoprofen sodium), which is a normal dose as a single dose. Therefore, it has been found that it is extremely preferable for compliance.
As described above, from the results of Test Example 3, it was found that the hard capsules of Examples 3 and 4 were preparations with extremely high commercial value.

Reference Example 1: Filling solution Loxoprofen sodium hydrate is a kind of non-steroidal anti-inflammatory analgesic (NSAID), but diclofenac sodium is also a kind of NSAID.
There is known a capsule in which a No. 2 HPMC capsule is filled with a solution containing diclofenac sodium and glycerin (see Example 11 of JP-A-10-152431).
Therefore, a supplementary test was conducted on this filling liquid.

First, when 5 parts by mass of diclofenac sodium and 95 parts by mass of glycerin were mixed, diclofenac sodium was not dissolved in glycerin and became a suspension in which white diclofenac sodium was dispersed in glycerin.
Furthermore, even when this suspension was heated, diclofenac sodium was not dissolved in glycerin and remained as a suspension.

  In general, it is said that the suspension cannot be maintained in a suspended state for a long time. Even if the suspension is filled in a capsule, the suspended state cannot be maintained. It is clear that sodium settles in the capsule.

Reference Example 2: Filling liquid A soft capsule is known in which a drug containing loxoprofen sodium hydrate and glycerin is blended in a soft capsule composed of gelatin, concentrated glycerin and purified water (JP 2001-31565 A, formulation example) 12).
Therefore, a supplementary test was conducted on this filling liquid.

That is, each sample was mixed so that it might become 68.1 mg of loxoprofen sodium hydrate, 138.0 mg of soybean oil, 56.5 mg of polyethylene glycol, 25.0 mg of glycerol fatty acid ester, and 12.5 mg of glycerol in one capsule.
As a result, loxoprofen sodium hydrate was not dissolved but became a suspension (note that Formula 5 which is a formulation similar to Formula 12 is a dispersion, as described in paragraph 0022).

  From the above, it is clear that even if this suspension is filled, the suspended state cannot be maintained, and loxoprofen sodium hydrate settles in the capsule after long-term storage.

Example 5: Hard capsule 50 g of diphenhydramine hydrochloride and 215 g of glycerin were mixed to prepare a glycerin liquid of diphenhydramine hydrochloride, which was used as a filling liquid. 265 mg of this filling liquid is filled into a hard capsule (trade name: Qualie V (registered trademark); manufactured by Qualicaps Co., Ltd.) based on a transparent HPMC of size 3 and contains 50 mg of diphenhydramine hydrochloride Manufactured.
The obtained hard capsule was a transparent capsule filled with a transparent liquid.

Comparative Example 3: Hard capsule 50 g of diphenhydramine hydrochloride and 215 g of propylene glycol were mixed to prepare a propylene glycol solution of diphenhydramine hydrochloride, which was used as a filling liquid. 265 mg of this filling liquid is filled into a hard capsule (trade name: Qualie V (registered trademark); manufactured by Qualicaps Co., Ltd.) based on a transparent HPMC of size 3 and contains 50 mg of diphenhydramine hydrochloride Manufactured.
The obtained hard capsule was a transparent capsule filled with a transparent liquid.

Test Example 4: Evaluation of Hard Capsule The deformation of the hard capsules of Example 5 and Comparative Example 3 was evaluated. After filling, the capsules are spread on a tray so that the capsules do not overlap each other, and whether there is any deformation (cracking, cracking, softening, etc.) after storage at 50 ° C for 1 day, 50 ° C for 1 month, 40 ° C for 2 months, and 40 ° C for 3 months, and The presence or absence of discoloration of the filling liquid was checked by visual inspection. The results are shown in Table 4.

As is apparent from Table 4, in the hard capsule of Comparative Example 3, deformation (cracking, leakage of the filling liquid) of the capsule was observed after storage at 50 ° C. for 1 day. Note that observations after the second day of storage were not performed because they were not worthy of evaluation.
From this result, it was confirmed that it was not preferable to fill propylene glycol into a capsule based on HPMC, which was consistent with the description in Non-Patent Document 1.

On the other hand, in the hard capsule of Example 5, no deformation or discoloration was observed even after storage at 50 ° C. for 1 month and 40 ° C. for 3 months.
That is, although it was thought that glycerin could not be filled into capsules based on HPMC (see Non-Patent Document 1), surprisingly, glycerin solution of diphenhydramine hydrochloride was replaced with HPMC. It was found that deformation does not occur even when the capsule as the base is filled.
Furthermore, diphenhydramine hydrochloride is known to be extremely soluble in methanol or acetic acid (100), easily soluble in water or ethanol (95), slightly insoluble in acetic anhydride, and hardly soluble in diethyl ether (non-insoluble). Patent Document 5) showed that a transparent liquid was obtained from the results of Test Example 4 when diphenhydramine hydrochloride and glycerin were mixed.
That is, the hard capsule of Example 5 can be a hard capsule containing a transparent liquid in a transparent capsule.

Moreover, the hard capsule of Example 5 contains 50 mg of diphenhydramine hydrochloride in one capsule.
Accordingly, the hard capsule of Example 5 is extremely preferable in terms of compliance because the content of diphenhydramine hydrochloride in the capsule can be 50 mg which is a normal dose as a sleep improving agent single dose. There was found.
From the above, it was found that the preparation of Example 5 had a very high commercial value.

Example 6: Hard capsules 100.0 g of diphenhydramine hydrochloride and 430 g of glycerin were mixed, and caramel was added to a concentration of 300 ppm to prepare a glycerin solution of diphenhydramine hydrochloride to obtain a filling solution. 265 mg of this filling liquid is filled into a hard capsule (trade name: Qualie V (registered trademark); manufactured by Qualicaps Co., Ltd.) based on a transparent size 3 HPMC, and contains 50.0 mg of diphenhydramine hydrochloride. Capsules were produced.
The obtained hard capsule was filled with a clear liquid in a transparent capsule, and had an appearance in which fluidity could be visually recognized.

Example 7: Hard capsule A hard capsule was produced in the same manner as in Example 6 except that caramel was replaced with edible yellow No. 5.
The obtained hard capsule was filled with an orange clear liquid in a transparent capsule, and had an appearance in which fluidity could be visually recognized.

Test Example 5: Evaluation of hard capsules The hard capsules of Examples 6 and 7 were evaluated for deformation and discoloration of the filling liquid. After filling, the capsules are spread on a tray so that the capsules do not overlap each other, and whether there is any deformation (cracking, cracking, softening, etc.) after storage at 40 ° C for 2 weeks, 40 ° C for 1 month, 40 ° C for 2 months, and 50 ° C for 1 month, and The presence or absence of discoloration of the filling liquid was checked by visual inspection. The results are shown in Table 5.

As is apparent from Table 5, no deformation was observed in the hard capsules of Examples 6 and 7 even after 2 months at 40 ° C and 1 month at 50 ° C.
Further, in the hard capsules of Examples 6 and 7, no discoloration was observed even after 2 months at 40 ° C. and after 1 month at 50 ° C.

  From these results, the hard capsules of Examples 6 and 7 can maintain a warm color (dark blue clear, orange clear) color that can image relaxation as it can comfortably lead the sleep improver to sleep. I understood.

In addition, the hard capsules of Examples 6 and 7 are extremely preferable in terms of compliance because the content of diphenhydramine hydrochloride in the capsule can be 50 mg which is a normal dose as a single dose of the sleep improving drug. There was found.
As described above, from the results of Test Example 5, it was found that the hard capsules of Examples 6 and 7 were preparations with extremely high commercial value.

Test Example 6: Stability Evaluation of Hard Capsule Regarding the hard capsule of Example 5, the content stability of diphenhydramine hydrochloride in the hard capsule after storage at 40 ° C for 6 months was evaluated by HPLC. The results are shown in Table 6.

As is clear from Table 6, even after storage at 40 ° C. for 6 months, almost no decrease in content was observed.
As a result, the hard capsule of Example 5 was found to have high content stability.
As described above, from the results of Test Example 6, it was found that the hard capsule of Example 5 was a preparation with extremely high commercial value.

  According to the present invention, a capsule filled with a clear and clear liquid containing at least one selected from loxoprofen or a salt thereof and diphenhydramine or a salt thereof can be provided, and the capsule is transparent or translucent Since the content liquid can be visually observed, a capsule containing one or more selected from loxoprofen having a very high commercial value or a salt thereof, and diphenhydramine or a salt thereof can be provided. Moreover, since the capsule is not deformed, the content stability is excellent, and the normal dose as a single dose can be filled in one capsule, so that the compliance of the user is good. Therefore, the capsule of the present invention is excellent as a cold medicine, antipyretic analgesic, sleep improving drug and the like.

Claims (12)

A liquid containing the following components (A) and (B).
(A) Loxoprofen or a salt thereof and one or more selected from diphenhydramine or a salt thereof (B) Glycerin A liquid substantially consisting of the following components (A) and (B).
(A) Loxoprofen or a salt thereof and one or more selected from diphenhydramine or a salt thereof (B) Glycerin   The liquid according to claim 1 or 2, wherein the component (A) is loxoprofen sodium hydrate or diphenhydramine hydrochloride.   The capsule which filled the capsule with the liquid of any one of Claims 1-3.   The capsule according to claim 4, wherein the capsule film contains hypromellose.   The capsule according to claim 4 or 5, wherein the capsule film contains hypromellose, a gelling agent and a gelling aid.   The capsule according to any one of claims 4 to 6, wherein the capsule film contains hypromellose, carrageenan and potassium chloride.   The capsule according to any one of claims 4 to 7, wherein the component (A) is loxoprofen or a salt thereof, and the loxoprofen or a salt thereof contains 10 to 300 mg as a daily dose in terms of loxoprofen sodium anhydride.   The capsule according to any one of claims 4 to 7, wherein the component (A) is diphenhydramine or a salt thereof, and 25 mg or 50 mg of the diphenhydramine or a salt thereof is contained in one capsule.   The capsule according to any one of claims 4 to 9, wherein the capsule film is transparent or translucent.   The capsule according to claim 8 or 10, which is for cold medicine or antipyretic analgesic.   The capsule according to claim 9 or 10, which is used for a sleep improving drug.