Pharmaceutical composition

Abstract

To provide a method for suppressing reduction in the quantity of diphenhydramines in external pharmaceutical compositions.SOLUTION: In a pharmaceutical composition containing diphenhydramine and / or a salt thereof, the pharmaceutical composition being accommodated in a container of which the inner walls are configured from linear low-density polyethylene, and being such that the carbon number of the side chain of the linear low-density polyethylene is 4 or lower, a reduction in the quantity of diphenhydramine and / or salt thereof is suppressed.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical composition which inhibits the loss of diphenhydramines. [Background technology]

[0002] Diphenhydramines such as diphenhydramine hydrochloride are known to be capable of suppressing the action of histamine, which causes allergic symptoms such as skin itching, and are used as antihistamines by blending them into pharmaceutical or quasi-drug skin preparations for external use. For example, Patent Document 1 discloses a skin preparation containing prednisolone valerate acetate and antihistamines such as diphenhydramine and its salts as active ingredients, which has a therapeutic effect against eczema, dermatitis, insect bites, itching, heat rash, rash, hives, etc.

[0003] In addition to skin external preparations, antihistamines are also used by being blended in ophthalmic compositions. Patent Document 2 describes that when an eye drop containing at least one selected from the group consisting of an antihistamine, a vasoconstrictor, and an anti-inflammatory / astringent is stored in a plastic container such as polyethylene or polypropylene, which is made to have a neutral pH range and is disposable after one use, the components are adsorbed compared to a glass container, and the intended effect may not be obtained. As a means for solving this problem, it describes that, only when the pH of the solution is adjusted to an extremely limited range of 5 to 6, even if a solution containing an antihistamine or the like is filled in the above-mentioned plastic container, which is disposable after one use, the adsorption of these to the container is suppressed. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] JP 2002-356430 A [Patent Document 2] JP 2002-249445 A Summary of the Invention [Problem to be solved by the invention]

[0005] As a solution to the problem of suppressing the adsorption of antihistamines to plastic containers, the method of designing the formulation by adjusting the pH to an extremely limited range has been adopted, as mentioned above. However, even if such a method can suppress the adsorption of antihistamines and obtain the effect of suppressing weight loss, the formulation design is limited, so it cannot accommodate various formulation designs.

[0006] The present invention aims to provide a method for suppressing a decrease in the amount of diphenhydramine and / or a salt thereof (hereinafter also referred to as "diphenhydramines") in a pharmaceutical composition, when the pharmaceutical composition contains the antihistamine. [Means for solving the problem]

[0007] The present inventors conducted extensive research and found that the loss of diphenhydramine can be suppressed by forming the surface of the container that comes into contact with the pharmaceutical composition containing diphenhydramine from a specific resin. The present invention was completed through further research based on this finding.

[0008] That is, the present invention provides the following aspects. Item 1. Contains diphenhydramine and / or its salt, The container has an inner wall made of linear low-density polyethylene. The pharmaceutical composition, wherein the linear low-density polyethylene has a side chain with 4 or less carbon atoms. Item 2. The density of the linear low-density polyethylene is 0.932 to 0.940 g / cm 3 in Item 3. The pharmaceutical composition according to Item 1 or 2, which is in the form of a liquid or gel. Item 4. A method for suppressing a decrease in the amount of diphenhydramine and / or a salt thereof in a pharmaceutical composition containing diphenhydramine and / or a salt thereof, comprising: The pharmaceutical composition is contained in a container having an inner wall made of linear low-density polyethylene, the linear low-density polyethylene having a side chain with 4 or less carbon atoms. Effect of the Invention

[0009] The pharmaceutical composition of the present invention can be contained in a container whose inner wall is made of linear low-density polyethylene and the linear low-density polyethylene has 4 or less carbon atoms in its side chains, thereby preventing loss of the diphenhydramine contained therein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] 1. Pharmaceutical Compositions The pharmaceutical composition of the present invention is characterized in that it contains diphenhydramine and is contained in a container whose inner wall is made of a specific resin. The pharmaceutical composition of the present invention will be described in detail below.

[0011] Diphenhydramine and / or its salts The pharmaceutical composition of the present invention contains diphenhydramine and / or a salt thereof. Diphenhydramine is a known drug known to have an antihistamine effect. Diphenhydramines are easily adsorbed to the polyethylene resin that constitutes the inner wall of the container of the pharmaceutical composition, and are more significantly adsorbed when the pharmaceutical composition is a liquid or gel with high fluidity, since it frequently comes into contact with the inner wall of the container. However, according to the present invention, the adsorption of diphenhydramines is suppressed, and the loss of diphenhydramines in the pharmaceutical composition can be suppressed.

[0012] The salt of diphenhydramine is not particularly limited as long as it is pharma- ceutically acceptable, and specific examples thereof include acid addition salts such as hydrochloride, citrate, succinate, tartrate, fumarate, maleate, salicylate, diphenyl disulfonate, tannate, lauryl sulfate, sulfate, etc. These salts may be used alone or in combination of two or more.

[0013] In the pharmaceutical composition of the present invention, one kind may be selected from diphenhydramine and its salts and used, or two or more kinds may be used in combination.

[0014] The amount of diphenhydramines in the pharmaceutical composition of the present invention is not particularly limited and can be appropriately determined depending on the efficacy to be imparted, and can be, for example, 0.01 to 5% by weight. The pharmaceutical composition of the present invention effectively prevents the diphenhydramines from decreasing in amount, and for example, the diphenhydramines content after storage at 40°C for 30 days can be maintained at more than 99.1% by weight of the content before storage. Therefore, even if the pharmaceutical composition contains a small amount of diphenhydramines, the effect of diphenhydramines can be effectively prevented from being weakened. From this viewpoint, the amount of diphenhydramines in the pharmaceutical composition of the present invention is preferably 0.1 to 3% by weight, more preferably 0.1 to 2% by weight.

[0015] Other Ingredients The pharmaceutical composition of the present invention may contain other pharmacological ingredients, if necessary, in addition to the above-mentioned ingredients. Examples of such pharmacological ingredients include antihistamines (chlorpheniramine maleate, etc.), local anesthetics (lidocaine (and / or its salt), dibucaine, procaine, tetracaine, bupivacaine, mepipacaine, chloroprocaine, proparacaine, meprylcaine or salts thereof, alkyl benzoates (e.g., ethyl aminobenzoate, diethylaminoethyl p-butylaminobenzoate hydrochloride), orthocaine, oxethazaine, oxypolyethyleneoxydecane, Scopolia extract, percaminepase, tesitdesitin, etc.), anti-inflammatory agents (glycyrrhetinic acid, glycyrrhetinic acid salts, allantoin, salicylic acid, glycol salicylate, methyl salicylate, indomethacin, ferbina, etc.), and the like. Examples of such agents include benzoyl peroxide, diclofenac sodium, and loxoprofen sodium), disinfectants (benzalkonium chloride, dequalinium chloride, benzethonium chloride, cetylpyridinium chloride, isopropylmethylphenol, chlorhexidine hydrochloride, chlorhexidine gluconate, aqueous ammonia, sulfadiazine, lactic acid, and phenol), antipruritic agents (crotamiton, thianthol, etc.), skin protectants (collodion, castor oil, etc.), blood circulation promoting ingredients (vanillylamide nonylate, benzyl nicotinate, capsaicin, and chili pepper extract, etc.), refreshing agents (menthol, camphor, etc.), vitamins (vitamins A, B, C, and D, etc.), and mucopolysaccharides (sodium chondroitin sulfate, hyaluronic acid, etc.).

[0016] In the present invention, among these pharmacological ingredients, isopropylmethylphenol and lidocaine and / or a salt thereof (hereinafter also referred to as "lidocaines") can effectively suppress the weight loss of diphenhydramines. Therefore, the pharmaceutical composition of the present invention preferably further contains at least one of isopropylmethylphenol and lidocaines, and more preferably contains both isopropylmethylphenol and lidocaines.

[0017] When isopropylmethylphenol is added to the pharmaceutical composition of the present invention, the amount of isopropylmethylphenol is not particularly limited and can be appropriately determined according to the efficacy to be imparted, and can be, for example, 0.01 to 0.5% by weight. The pharmaceutical composition of the present invention can maintain the content of isopropylmethylphenol after storage at 40°C for 30 days at more than 99.1% by weight of the content before storage, so that even if the pharmaceutical composition contains a small amount of isopropylmethylphenol, the weakening of the effect caused by isopropylmethylphenol can be well suppressed. From this viewpoint, the amount of isopropylmethylphenol in the pharmaceutical composition of the present invention is preferably 0.03 to 0.3% by weight, more preferably 0.05 to 0.2% by weight.

[0018] When lidocaines are incorporated into the pharmaceutical composition of the present invention, the amount of lidocaines is not particularly limited and can be appropriately determined depending on the efficacy to be imparted, and may be, for example, 0.01 to 10% by weight. The pharmaceutical composition of the present invention can maintain the content of lidocaines after storage at 40°C for 30 days at more than 99.1% by weight of the content before storage, so that even if the pharmaceutical composition contains a small amount of lidocaines, the weakening of the effect brought about by lidocaines can be well suppressed. From this viewpoint, the amount of lidocaines incorporated in the pharmaceutical composition of the present invention is preferably 0.1 to 5% by weight, more preferably 0.5 to 3% by weight.

[0019] In addition to the above-mentioned components, other bases and additives that are usually used in pharmaceutical compositions and the like may be contained as necessary. Such bases and additives are not particularly limited as long as they are pharma- ceutically acceptable, and examples of such bases and additives include aqueous bases such as water, lower alcohols (e.g., isopropanol), and polyhydric alcohols (glycerin, propylene glycol, dipropylene glycol, 1,3-butylene glycol, etc.); oils (olive oil, safflower oil, soybean oil, camellia oil, corn oil, rapeseed oil, sunflower oil, cottonseed oil, peanut oil, lard, squalane, fish oil, etc.), mineral oils (liquid paraffin, paraffin, gelling hydrocarbon, petrolatum, etc.), waxes (beeswax, carnauba wax, candelilla wax, ceresin, rice wax, microcrystalline wax, etc.), ester oils (isopropyl myristate, isopropyl adipate, diethyl sebacate, isopropyl sebacate, palladium oxide, etc.), and the like. oily bases such as isopropyl palmitate, cetyl palmitate, ethyl oleate, etc., fatty acid alkyl esters, fatty acids (stearic acid, oleic acid, palmitic acid, behenic acid, linoleic acid, lanolin, etc.), fatty acid esters (cetyl palmitate, isopropyl palmitate, ethyl linoleate, etc.), higher alcohols (stearyl alcohol, cetanol, behenyl alcohol, myristyl alcohol, oleyl alcohol, hexadecyl alcohol, lanolin alcohol, etc.), cholesterol, glyceryl tri-2-ethylhexanoate, cetyl 2-ethylhexanoate, silicone oils (dimethylpolysiloxane, cyclic silicone, etc.); flow enhancers (lubricants) such as hydrated silicon dioxide, light anhydrous silicic acid, aluminum hydroxide gel, synthetic aluminum silicate, and magnesium silicate;Polyoxyethylene alkyl ethers such as POE (10-50 mol) phytosterol ether, POE (10-50 mol) dihydrocholesterol ether, POE (10-50 mol) 2-octyldodecyl ether, POE (10-50 mol) decyltetradecyl ether, POE (10-50 mol) oleyl ether, POE (2-50 mol) cetyl ether, POE (5-50 mol) behenyl ether, POE (5-30 mol) polyoxypropylene (5-30 mol) 2-decyltetradecyl ether, POE (10-50 mol) polyoxypropylene (2-30 mol) cetyl ether, and phosphoric acid salts thereof (e.g., sodium POE cetyl ether phosphate), POE (20-60 mol) sorbitan monooleate, and POE (10-60 mol) sorbitan monoisostearate , POE (10-80 mol) glyceryl monoisostearate, POE (10-30 mol) glyceryl monostearate, POE (20-100 mol)·polyoxypropylene modified silicone, POE·alkyl modified silicone, polyethylene glycol monolaurate, polyethylene glycol monopalmitate, polyethylene glycol monostearate, polyethylene glycol dilaurate, polyethylene glycol dipalmitate, polyethylene glycol distearate, polyethylene glycol dioleate, polyethylene glycol diricinoleate, polyoxyethylene hydrogenated castor oil (5-100), polysorbate (20-85), glycerin fatty acid ester (glycerin monostearate, etc.), hydrogenated soybean phospholipid, hydrogenated lanolin alcohol, and other surfactants;Cooling agents (menthol, camphor, borneol, peppermint water, peppermint oil, etc.), preservatives (methyl parahydroxybenzoate, propyl parahydroxybenzoate, benzoic acid, sodium benzoate, sorbic acid, etc.), flavoring agents (citral, 1,8-thioneol, citronellal, farnesol, etc.), coloring agents (tar dyes (Brown No. 201, Blue No. 201, Yellow No. 4, Yellow No. 403, etc.), cacao dyes, chlorophyll, aluminum oxide, etc.), thickeners (carboxyvinyl polymer, hypromellose, polyvinylpyrrolidone, sodium alginate, ethyl cellulose, hydroxyethyl cellulose, sodium carboxymethylcellulose, xanthan gum, carrageenan, etc.), pH adjusters (phosphoric acid, sodium dihydrogen phosphate, phosphoric acid Examples of additives include sodium hydrogen carbonate, hydrochloric acid, citric acid, sodium citrate, succinic acid, tartaric acid, sodium hydroxide, potassium hydroxide, triethanolamine, triisopropanolamine, etc.), wetting agents (sodium dl-pyrrolidone carboxylate solution, D-sorbitol solution, macrogol, etc.), stabilizers (dibutylhydroxytoluene, butylhydroxyanisole, sodium edetate, sodium metaphosphate, L-arginine, L-aspartic acid, DL-alanine, glycine, sodium erythorbate, propyl gallate, sodium sulfite, sulfur dioxide, chlorogenic acid, catechin, rosemary extract, etc.), antioxidants, ultraviolet absorbers, chelating agents, adhesives, buffers, dissolution aids, solubilizers, preservatives, etc.;

[0020] Among these bases and additives, when a thickening agent is added, the content of the thickening agent in the pharmaceutical composition of the present invention is, for example, 0.1 to 5% by weight. Since the amount of diphenhydramines is effectively suppressed by suppressing the adsorption of diphenhydramines in the pharmaceutical composition of the present invention, even in an embodiment such as a gel having high fluidity and frequent contact with the inner wall of the container, the loss of diphenhydramines can be effectively suppressed. From this viewpoint, when a thickening agent is added to the pharmaceutical composition of the present invention, the amount of the thickening agent is preferably relatively small, for example, 0.1 to 2% by weight is more preferable. Furthermore, from the same viewpoint, when a thickening agent is added to the pharmaceutical composition of the present invention, it is preferable to further add a flow promoter. When a flow promoter is added, the content of the flow promoter in the pharmaceutical composition of the present invention is, for example, 0.1 to 10% by weight, preferably 1 to 5% by weight.

[0021] The pH (25° C.) of the pharmaceutical composition of the present invention is adjusted to, for example, 6.5 to 7.5, preferably 7.0 to 7.5, and more preferably 7.1 to 7.5.

[0022] Properties, formulation, etc. The properties of the pharmaceutical composition of the present invention are not particularly limited, and include liquid compositions, gel compositions, emulsion compositions, etc. The pharmaceutical composition of the present invention effectively suppresses the amount of diphenhydramines by suppressing adsorption of the diphenhydramines, so that even in an embodiment in which the fluidity is high and the frequency of contact with the inner wall of the container is high, the loss of the diphenhydramines can be effectively suppressed. From this viewpoint, the properties of the pharmaceutical composition of the present invention preferably include liquid compositions and gel compositions.

[0023] The formulation of the pharmaceutical composition of the present invention is not particularly limited, and examples thereof include liquids (e.g., lotions, emulsions), gels, ointments, creams, etc. Among these, from the same viewpoint as described above, liquids and gels having high fluidity are preferred.

[0024] container The container in which the pharmaceutical composition of the present invention is stored has an inner wall of the container that comes into contact with the pharmaceutical composition, which is made of linear low-density polyethylene (hereinafter also referred to as "LLDPE"). LLDPE has a low density and is therefore prone to adsorb diphenhydramines. However, despite the use of LLDPE in the container, the pharmaceutical composition of the present invention is able to inhibit adsorption of diphenhydramines and effectively inhibit weight loss.

[0025] In the container in which the pharmaceutical composition of the present invention is housed, the number of carbon atoms in the side chain of LLDPE is 4 or less. If the number of carbon atoms in the side chain of LLDPE exceeds 4, the effect of inhibiting weight loss of diphenhydramines cannot be obtained. The lower limit of the range of the carbon number of LLDPE is not particularly limited, but may be, for example, 2 or more, and preferably 3 or more.

[0026] In the present invention, the density of LLDPE is 0.910 to 0.940 g / cm 3 The density of LLDPE is a value measured by the JIS K7112:1999 underwater displacement method (method A) at 25°C. From the viewpoint of obtaining a better effect of suppressing the weight loss of diphenhydramines, the density of LLDPE is 0.932 to 0.940 g / cm 3 It is more preferable that:

[0027] LLDPE can be obtained by copolymerizing ethylene and α-olefin using a single-site catalyst such as a Ziegler catalyst or a metallocene catalyst. The carbon number of the side chain of LLDPE can be controlled by adjusting the carbon number of the α-olefin to be copolymerized. In addition, the density of LLDPE can be controlled by adjusting the type and / or amount of the α-olefin to be copolymerized.

[0028] In the container in which the pharmaceutical composition of the present invention is contained, the inner wall surface may be made of the above-mentioned LLDPE, and the container wall may have a single layer structure or a multi-layer structure. In the case of a multi-layer structure, the resin constituting the innermost layer of the container may be the above-mentioned LLDPE. A specific example of a preferred multi-layer structure is a structure in which an LLDPE layer, a base layer, a barrier layer, and an LLDPE layer are laminated in this order from the outer layer side to the inner layer side. Each layer may be directly laminated to each other, or may be indirectly laminated via another layer. Examples of other layers include an adhesive layer and a functional layer. Examples of materials constituting the base layer include polyester resins such as polyethylene terephthalate, and examples of materials constituting the barrier layer include metals such as aluminum. In addition, the outermost LLDPE layer can function as a heat-sealed layer together with the innermost LLDPE layer. Furthermore, the container may be a bottle or a tube, and preferably a tube.

[0029] How to use The pharmaceutical composition of the present invention can be used as an external medicine, and can be used by applying it to a site requiring sterilization, preferably to a skin site. When applying, the pharmaceutical composition may be applied by taking it from a container onto a finger or the like, or it may be applied by spraying directly from the container. Sites requiring sterilization include skin symptoms such as itching, rash, eczema, insect bites, dermatitis, hives, heat rash, sores, and chilblains.

[0030] 2. Weight loss suppression method As described above, a container whose inner wall is made of linear low density polyethylene and whose side chains have 4 or less carbon atoms can suppress the weight loss of diphenhydramines in a pharmaceutical composition containing diphenhydramines. Therefore, the present invention further provides a method for suppressing the weight loss of diphenhydramines in a pharmaceutical composition containing diphenhydramines. Specifically, the weight loss suppression method of the present invention is characterized in that the pharmaceutical composition is contained in a container whose inner wall is made of linear low density polyethylene and whose side chains have 4 or less carbon atoms. In the weight loss suppression method of the present invention, the types and amounts of ingredients used in the pharmaceutical composition, the properties and formulation form of the pharmaceutical composition, the method of use, the container in which the pharmaceutical composition should be contained, etc. are as described in the above section "1. Pharmaceutical composition". EXAMPLES

[0031] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these.

[0032] Test Example 1 1. Preparation of pharmaceutical composition (liquid) filled in container A pharmaceutical composition (liquid) was prepared having the composition shown in Table 1. The pH of the liquid (25° C.) was 7.3.

[0033] [Table 1]

[0034] The prepared pharmaceutical composition was filled into a laminate tube having an LLDPE layer as the innermost layer. The laminate tube has a multilayer structure in which an LLDPE layer, a polyethylene terephthalate layer, an aluminum layer, an adhesive layer, and an LLDPE layer are laminated in this order from the outer layer side to the inner layer side, and the outermost LLDPE layer and the innermost LLDPE layer are heat-welded. In this test example, seven types of laminate tubes with different LLDPE layers were prepared, specifically, laminate tube A (manufactured by Takeuchi Press Kogyo Co., Ltd.), laminate tube B (manufactured by Kansai Tube Co., Ltd.), laminate tube C (manufactured by Takeuchi Press Kogyo Co., Ltd.), laminate tube D (manufactured by Takeuchi Press Kogyo Co., Ltd.), laminate tube E (manufactured by Takeuchi Press Kogyo Co., Ltd.), and laminate tube F (manufactured by Kansai Tube Co., Ltd.). The carbon number and density of the side chain of the LLDPE constituting the innermost layer in each laminate tube are as shown in Tables 2 to 4.

[0035] 2. Weight loss measurement test The containers filled with the pharmaceutical compositions were stored for 30 days at 40° C. The degree of weight loss of the pharmacological ingredients in the pharmaceutical compositions after storage was measured by the following method.

[0036] (1) Approximately 0.5 g of each of the pharmaceutical compositions (samples) of the Examples, Comparative Examples, and Reference Examples after storage was weighed, and ethanol (95) / sodium lauryl sulfate solution (9:1 (volume ratio)) was added to make exactly 50 mL. This liquid was shaken well and irradiated with ultrasound to obtain a sample solution.

[0037] (2) Separately, approximately 0.5 g of diphenhydramine for quantitative determination was weighed out, and ethanol (95) was added to make exactly 50 mL to obtain a diphenhydramine standard stock solution. (3) Lidocaine for quantitative determination was dried in a desiccator (reduced pressure, silica gel) for 24 hours, about 1 g of it was taken and weighed, and ethanol (95) was added to make exactly 50 mL to obtain a lidocaine standard stock solution. (4) Approximately 0.5 g of isopropylmethylphenol for quantitative determination was weighed out, and ethanol (95) was added to make exactly 50 mL to obtain an isopropylmethylphenol standard stock solution.

[0038] (5) 5 mL of diphenhydramine standard stock solution, 5 mL of lidocaine standard stock solution, and 5 mL of isopropyl methylphenol standard stock solution were each accurately measured, and ethanol (95) was added to make exactly 50 mL to obtain standard solutions. (6) Take exactly 15 μL of each of the sample solution and the standard solution, and measure them by liquid chromatography under the conditions described below. Ta (from sample solution) and A Sa (from standard solution), lidocaine peak area A Tb (from sample solution) and A Sb (from standard solution), peak area A of isopropyl methylphenol Tc (from sample solution) and A Sc (from standard solution).

[0039] (7) The amount (%) of each pharmacological ingredient in the sample solution relative to the initial value (amount mixed at the time of preparation) was calculated based on the following formula.

[0040] (a) The amount (%) of diphenhydramine in the sample solution relative to the initial value (amount added at the time of preparation) = (Weight of diphenhydramine for quantitative analysis (g)) × 1 / 10 × 1 / 10 × (A Ta / A Sa ) x 1 / (Weight of sample (g)) x 100 / (Amount of diphenhydramine in 100 g of sample (g)) x 100

[0041] (b) The amount (%) of lidocaine in the sample solution relative to the initial value (amount added at the time of preparation) = (Weight of lidocaine for quantitative determination (g)) × 1 / 10 × 1 / 10 × (A Tb / A Sb ) x 1 / (Weight of sample (g)) x 100 / (Amount of lidocaine in 100 g of sample (g)) x 100

[0042] (c) The amount (%) of isopropyl methylphenol in the sample solution relative to the initial value (amount added at the time of preparation) = (Weight of isopropyl methylphenol for quantitative analysis (g)) × 1 / 20 × 1 / 10 × (A Tc / A Sc ) x 1 / (Weight of sample (g)) x 100 / (Amount of isopropyl methylphenol in 100 g of sample (g)) x 100

[0043] (Measurement conditions) Detector: UV spectrophotometer (measurement wavelength 220 nm) Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm was packed with 5 μm octadecylsilylated silica gel for liquid chromatography (specifically, Inertsil ODS-3 5 μm, 4.6 mm x 150 mm). Column temperature: constant temperature at about 30°C Mobile phase: Sodium lauryl sulfate solution / acetonitrile mixture (13:12 (volume ratio)) Flow rate: Adjusted so that the retention time of diphenhydramine was approximately 17 minutes.

[0044] 3. Evaluation of weight loss suppression The amount (wt%) of each pharmacological ingredient in the sample solution relative to the initial value (amount added at the time of preparation) obtained in (7) above was classified based on the following criteria and scored from -6 to +5. A higher score indicates a higher degree of inhibition of weight loss of the pharmacological ingredient. +5 Over 99.9% +4 More than 99.7% and less than 99.9% +3 More than 99.5% and less than 99.7% +2 More than 99.3% and less than 99.5% +1 More than 99.1% and less than 99.3% -1 More than 98.9% and less than 99.1% -2 More than 98.7% and less than 98.9% -3 More than 98.5% and less than 98.7% -4 More than 98.3% and less than 98.5% -5 More than 98.1% and less than 98.3% -6 98.1% or less

[0045] 4.Results The weight loss suppression scores are shown in Tables 2 to 4. As shown in Comparative Examples 1 to 8, in the pharmaceutical compositions stored in contact with LLDPE having 6 or 8 carbon atoms in the side chain, significant weight loss was observed for diphenhydramine, isopropylmethylphenol, and lidocaine. In contrast, as shown in Examples 1 to 7, in the pharmaceutical compositions stored in contact with LLDPE having 4 carbon atoms in the side chain, weight loss for diphenhydramine was significantly suppressed. Similarly, weight loss for isopropylmethylphenol and lidocaine was significantly suppressed. Furthermore, as shown in Examples 1 to 6, weight loss was significantly suppressed for LLDPE having 4 carbon atoms in the side chain and a density of 0.932 to 0.940 g / cm 3 In the pharmaceutical composition stored in contact with LLDPE, the weight loss of diphenhydramine was significantly suppressed. Similarly, the weight losses of isopropyl methylphenol and lidocaine were also significantly suppressed.

[0046] [Table 2]

[0047] [Table 3]

[0048] [Table 4]

[0049] Test Example 2 Pharmaceutical compositions (gels) of Formulation Examples 1 to 3 shown in Table 5 were prepared. The pH (25°C) of the gels was 7.3. The gels were filled into the laminated tube A, laminated tube B, or laminated tube C used in Test Example 1, and stored under the same conditions as Test Example 1. As a result, the pharmaceutical compositions of Formulation Examples 1 to 3 significantly suppressed the loss of diphenhydramine and other pharmacological ingredients when filled into any of the laminated tubes, and the loss of the pharmacological ingredients was more significantly suppressed when filled into laminated tube A or laminated tube B.

[0050] [Table 5]

Claims

1. Contains diphenhydramine and / or a salt thereof, The container has an inner wall made of linear low-density polyethylene. A pharmaceutical composition, wherein the linear low-density polyethylene has a side chain with 4 or less carbon atoms.

2. The density of the linear low density polyethylene is 0.932 to 0.940 g / cm 3 The pharmaceutical composition of claim 1 ,

3. 3. The pharmaceutical composition according to claim 1 or 2, which is in the form of a liquid or gel.

4. A method for suppressing a loss of diphenhydramine and / or a salt thereof in a pharmaceutical composition containing diphenhydramine and / or a salt thereof, comprising: The pharmaceutical composition is contained in a container having an inner wall made of linear low-density polyethylene, the linear low-density polyethylene having a side chain with 4 or less carbon atoms.

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