JP2023164921A - pharmaceutical composition - Google Patents

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

The present invention relates to a pharmaceutical composition in which the weight loss of diphenhydramines is suppressed.

Diphenhydramines such as diphenhydramine hydrochloride are known to be able to suppress the effects of histamine, which causes allergic symptoms such as skin itching, and are used as antihistamines in pharmaceuticals or quasi-drugs for external use on the skin. . For example, Patent Document 1 describes a therapeutic effect on eczema, dermatitis, insect bites, itching, heat rash, rash, hives, etc., which contains prednisolone acetate valerate and an antihistamine such as diphenhydramine and its salts as active ingredients. A skin preparation for external use is disclosed.

Antihistamines are also used in ophthalmological compositions as well as external skin preparations. Patent Document 2 discloses that a container selected from the group consisting of an antihistamine, a vasoconstrictor, and an anti-inflammatory/astringent agent is placed in a plastic container such as polyethylene or polypropylene, which is disposable after one use, and has a neutral pH. It is stated that when an eye drop containing at least one type of component is stored, the component may be adsorbed compared to a glass container, and the desired effect may not be obtained.Means for solving this problem. As long as the pH of the solution is adjusted within a very limited range of 5 to 6, even if the plastic container mentioned above, which is disposable after one use, is filled with a solution containing an antihistamine, etc., It is described that adsorption of these substances onto the container is suppressed.

Japanese Patent Application Publication No. 2002-356430 Japanese Patent Application Publication No. 2002-249445

As a solution to the problem of suppressing the adsorption of antihistamines to plastic containers, methods have been adopted to improve the design of pharmaceutical formulations, such as adjusting the pH within a very limited range, as described above. However, even if such a method suppresses the adsorption of antihistamines and obtains the effect of suppressing weight loss, the prescription design is limited and it is not possible to respond to a variety of prescription designs.

The present invention provides methods for suppressing the weight loss of diphenhydramine in a pharmaceutical composition when the pharmaceutical composition contains diphenhydramine and/or its salts (hereinafter also referred to as "diphenhydramines"), which are antihistamines. The purpose is to provide a method.

The inventors of the present invention have conducted extensive studies and found that the weight loss of diphenhydramines can be suppressed by configuring the container surface that comes into contact with a pharmaceutical composition containing diphenhydramines with a specific resin. The present invention was completed through further studies based on this knowledge.

That is, the present invention provides the inventions of the following aspects.
Item 1. Contains diphenhydramine and/or its salt,
It is housed in a container whose inner wall is made of linear low-density polyethylene.
A pharmaceutical composition, wherein the linear low-density polyethylene has 4 or less carbon atoms in its side chain.
Item 2. Item 3. The linear low density polyethylene has a density of 0.932 to 0.940 g/cm ³ . Item 3. The pharmaceutical composition according to item 1 or 2, which is a liquid or gel.
Item 4. A method for suppressing the weight loss of diphenhydramine and/or a salt thereof in a pharmaceutical composition containing diphenhydramine and/or a salt thereof, the method comprising:
A method for suppressing weight loss, comprising accommodating the pharmaceutical composition in a container whose inner wall is made of linear low-density polyethylene and in which the number of carbon atoms in the side chain of the linear low-density polyethylene is 4 or less.

The pharmaceutical composition of the present invention is formulated by being stored in a container whose inner wall is composed of linear low-density polyethylene and in which the number of carbon atoms in the side chain of the linear low-density polyethylene is 4 or less. The weight loss of diphenhydramines can be suppressed.

1. Pharmaceutical Composition The pharmaceutical composition of the present invention is characterized in that it contains diphenhydramines and is housed in a container whose inner wall is made of a specific resin. The pharmaceutical composition of the invention will be described in detail below.

Diphenhydramine and/or its salt The pharmaceutical composition of the present invention contains diphenhydramine and/or its salt. Diphenhydramine is a known drug known to have antihistamine effects. Diphenhydramines are easily adsorbed by the polyethylene resin that makes up the inner wall of the container for pharmaceutical compositions, and especially when the pharmaceutical composition is a liquid or gel with high fluidity, it is more likely to come into contact with the inner wall of the container. Noticeably adsorbed. However, according to the present invention, the adsorption of diphenhydramines is suppressed, and the weight loss of diphenhydramines in the pharmaceutical composition can be suppressed.

Salts of diphenhydramine are not particularly limited as long as they are pharmaceutically acceptable, but specific examples include hydrochloride, citrate, succinate, tartrate, fumarate, maleate, and salicylate. , diphenyl disulfonate, tannate, lauryl sulfate, sulfate and other acid addition salts. These salts may be used alone or in combination of two or more.

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

The amount of diphenhydramine compounded in the pharmaceutical composition of the present invention is not particularly limited and can be appropriately determined depending on the medicinal efficacy to be imparted, and may be, for example, 0.01 to 5% by weight. In the pharmaceutical composition of the present invention, the weight loss of diphenhydramines is well suppressed, and for example, the content of diphenhydramines after storage at 40°C for 30 days is maintained at more than 99.1% by weight of the content before storage. Therefore, even in the case of a pharmaceutical composition containing a small amount of diphenhydramines, the attenuation of the effect brought about by diphenhydramines can be satisfactorily suppressed. From this point of view, the amount of diphenhydramine compounded in the pharmaceutical composition of the present invention is preferably 0.1 to 3% by weight, more preferably 0.1 to 2% by weight.

Other Components In addition to the above-mentioned components, the pharmaceutical composition of the present invention may contain other pharmacological components as necessary. Such pharmacological ingredients include, for example, antihistamines (chlorpheniramine maleate, etc.), local anesthetics (lidocaine (and/or its salts), dibucaine, procaine, tetracaine, bupipacaine, mepipacaine, chloroprocaine, proparacaine, meprrilcaine). or their salts, benzoic acid alkyl esters (e.g. ethyl aminobenzoate, diethylaminoethyl parabutylaminobenzoate hydrochloride), orthocaine, oxesazein, oxypolyenthoxydecane, rhotoextract, percaminpase, tesitdesitin, etc.), anti-inflammatory agents (glycyrrhetinic acid, etc.) , glycyrrhetinate, allantoin, salicylic acid, glycol salicylate, methyl salicylate, indomethacin, felbinac, diclofenac sodium, loxoprofen sodium, etc.), disinfectants (benzalkonium chloride, dequalinium chloride, benzethonium chloride, cetylpyridinium chloride, isopropylmethylphenol, hydrochloric acid) Chlorhexidine, chlorhexidine gluconate, aqueous ammonia, sulfadiazine, lactic acid, phenol, etc.), antipruritics (crotamiton, thianthol, etc.), skin protectants (collodion, castor oil, etc.), blood circulation promoting ingredients (vanillylamide nonylate, benzyl nicotinic acid ester, etc.) capsaicin, hot pepper extract, etc.), cooling agents (menthol, camphor, etc.), vitamins (vitamins A, B, C, D, etc.), mucopolysaccharides (sodium chondroitin sulfate, hyaluronic acid, etc.), and the like.

In the present invention, among these pharmacological ingredients, isopropylmethylphenol and lidocaine and/or its salts (hereinafter also referred to as "lidocaines") can be used to effectively reduce their weight loss as well as diphenhydramines. It can be suppressed. Therefore, the pharmaceutical composition of the present invention preferably further contains at least one of isopropylmethylphenol and lidocaine, and more preferably both isopropylmethylphenol and lidocaine.

When blending isopropylmethylphenol into the pharmaceutical composition of the present invention, the blending amount of isopropylmethylphenol is not particularly limited and can be determined as appropriate depending on the medicinal effect to be imparted, but, for example, from 0.01 to 0. 5% by weight is mentioned. The pharmaceutical composition of the present invention can maintain the content of isopropyl methylphenol after storage for 30 days at 40° C. to more than 99.1% by weight of the content before storage. Even in the case of a pharmaceutical composition with a small amount of isopropylmethylphenol, the attenuation of the effect brought about by isopropylmethylphenol can be effectively suppressed. From this viewpoint, the amount of isopropylmethylphenol blended 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.

When compounding lidocaine in the pharmaceutical composition of the present invention, the amount of lidocaine compounded is not particularly limited and can be determined as appropriate depending on the medicinal effect to be imparted, but for example, 0.01 to 10% by weight. Can be mentioned. The pharmaceutical composition of the present invention can maintain the content of lidocaine after storage for 30 days at 40° C. to more than 99.1% by weight of the content before storage, so the amount of lidocaine compounded is small. Even in the case of a pharmaceutical composition, it is possible to satisfactorily suppress the attenuation of the effects brought about by lidocaine. From this viewpoint, the amount of lidocaine compounded in the pharmaceutical composition of the present invention is preferably 0.1 to 5% by weight, more preferably 0.5 to 3% by weight.

In addition to the above-mentioned components, other bases and additives commonly used in pharmaceutical compositions and the like may be included, if necessary. Such base materials and additives are not particularly limited as long as they are pharmaceutically acceptable, but examples include water, lower alcohols (e.g. isopropanol), 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, gelled hydrocarbons, petrolatum, etc.), waxes/waxes (beeswax, carnauba wax, candelilla wax, ceresin, rice wax, microcrystalline wax, etc.), ester oils (isopropyl myristate, Isopropyl adipate, diethyl sebacate, isopropyl sebacate, 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, tri-2-ethylhexane Oily bases such as acid glyceryl, cetyl 2-ethylhexanoate, silicone oil (dimethylpolysiloxane, cyclic silicone, etc.); hydrous silicon dioxide, light anhydrous silicic acid, aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate, etc. Fluidity promoter (lubricating agent); POE (10-50 mol) phytosterol ether, POE (10-50 mol) dihydrocholesterol ether, POE (10-50 mol) 2-octyl dodecyl ether, POE (10-50 mol) moles) decyltetradecyl ether, POE (10-50 moles) oleyl ether, POE (2-50 moles) cetyl ether, POE (5-50 moles) behenyl ether, POE (5-30 moles) polyoxypropylene (5-50 moles) 30 moles) 2-decyltetradecyl ether, POE (10 to 50 moles) polyoxypropylene (2 to 30 moles) polyoxyethylene alkyl ethers such as cetyl ether, phosphoric acids and phosphates of these (POE cetyl ether phosphate) ), POE (20-60 mol) sorbitan monooleate, POE (10-60 mol) sorbitan monoisostearate, POE (10-80 mol) glyceryl monoisostearate, POE (10-30 mol) glyceryl mono Stearate, 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 (glyceryl monostearate, etc.), hydrogenated soybean Surfactants such as phospholipids and hydrogenated lanolin alcohol; 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-cyonel, citronellal, farnesol, etc.), coloring agents (tar pigments (Brown No. 201, Blue No. 201, Yellow No. 4, Yellow No. 403, etc.), cacao pigments , chlorophyll, aluminum oxide, etc.), thickening agents (carboxyvinyl polymer, hypromellose, polyvinylpyrrolidone, sodium alginate, ethyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, xanthan gum, carrageenan, etc.), pH adjusters (phosphoric acid, dihydrogen phosphate, etc.) Sodium, sodium hydrogen phosphate, hydrochloric acid, citric acid, sodium citrate, succinic acid, tartaric acid, sodium hydroxide, potassium hydroxide, triethanolamine, triisopropanolamine, etc.), wetting agent (sodium dl-pyrrolidonecarboxylate solution, D-sorbitol solution, macrogol, etc.), stabilizers (dibutylhydroxytoluene, butylhydroxyanisole, sodium edetate, sodium metaphosphate, L-arginine, L-aspartic acid, DL-alanine, glycine, sodium erythorbate, gallic acid) propyl acid, sodium sulfite, sulfur dioxide, chlorogenic acid, catechin, rosemary extract, etc.), antioxidants, ultraviolet absorbers, chelating agents, adhesives, buffers, solubilizing agents, solubilizing agents, preservatives, etc. Examples include additives.

Among these bases and additives, when a thickening agent is included, the content of the thickening agent in the pharmaceutical composition of the present invention is, for example, 0.1 to 5% by weight. The pharmaceutical composition of the present invention can effectively suppress the amount of diphenhydramines by suppressing their adsorption, so even if the pharmaceutical composition has high fluidity and comes into frequent contact with the inner wall of the container, such as a gel, the amount of diphenhydramines can be suppressed. Weight loss can be suppressed well. From this point of view, when a thickening agent is incorporated into the pharmaceutical composition of the present invention, it is preferable that the amount incorporated is relatively small, for example, 0.1 to 2% by weight is more preferable. Furthermore, from the same point of view, when a thickening agent is incorporated into the pharmaceutical composition of the present invention, it is preferable to further incorporate a fluidity promoter. When a fluidity promoter is added, the content of the fluidity promoter in the pharmaceutical composition of the present invention is, for example, 0.1 to 10% by weight, preferably 1 to 5% by weight.

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, more preferably 7.1 to 7.5.

The properties of the pharmaceutical composition of the present invention , such as properties and formulation form, are not particularly limited, and include liquid compositions, gel compositions, emulsified compositions, and the like. The pharmaceutical composition of the present invention satisfactorily suppresses the amount of diphenhydramines by suppressing their adsorption, so even if the pharmaceutical composition has high fluidity and frequently comes into contact with the inner wall of the container, the weight loss of diphenhydramines can be suppressed well. can do. From this point of view, the preferred properties of the pharmaceutical composition of the present invention include liquid compositions and gel compositions.

The formulation form of the pharmaceutical composition of the present invention is not particularly limited, and examples include liquids (eg, lotions, emulsions), gels, ointments, creams, and the like. Among these, liquid preparations and gel preparations with high fluidity are preferably mentioned from the same viewpoint as mentioned above.

Container In the container in which the pharmaceutical composition of the present invention is accommodated, the inner wall of the container with which the pharmaceutical composition comes into contact is made of linear low-density polyethylene (hereinafter also referred to as "LLDPE"). Since LLDPE has a low density, it easily adsorbs diphenhydramines. However, the pharmaceutical composition of the present invention, despite using LLDPE for the container, can suppress adsorption of diphenhydramines and satisfactorily suppress the weight loss thereof.

In the container containing the pharmaceutical composition of the present invention, the number of carbon atoms in the side chain of LLDPE is 4 or less. When the number of carbon atoms in the side chain of LLDPE exceeds 4, the effect of suppressing the weight loss of diphenhydramines cannot be obtained. The lower limit of the number of carbon atoms in LLDPE is not particularly limited, but includes, for example, 2 or more, preferably 3 or more.

In the present invention, the density of LLDPE is 0.910 to 0.940 g/cm ³ . L
The density of LDPE is a value measured using the JIS K7112:1999 underwater substitution 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 more preferably 0.932 to 0.940 g/cm ³ .

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 number of carbon atoms in the side chain of LLDPE can be controlled by adjusting the number of carbon atoms in the α-olefin to be copolymerized. Further, the density of LLDPE can be controlled by adjusting the type and/or amount of α-olefin to be copolymerized.

In the container in which the pharmaceutical composition of the present invention is housed, 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 multilayer structure, the resin constituting the innermost layer of the container may be the above-mentioned LLDPE. A specific example of a preferred multilayer structure includes a structure in which an LLDPE layer, a base material layer, a barrier layer, and an LLDPE layer are laminated in this order from the outer layer side to the inner layer side. The layers may be stacked directly on each other or indirectly via other layers. Other layers include an adhesive layer and a functional layer. Examples of the material constituting the base layer include polyester resin such as polyethylene terephthalate, and examples of the material constituting the barrier layer include metals such as aluminum. Further, the outermost LLDPE layer can also function as a heat welding layer together with the innermost LLDPE layer. Further, the container may be a bottle or a tube, preferably a tube.

Method of 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 that requires sterilization, preferably a skin site. For application, the pharmaceutical composition may be applied by taking it from the container onto a finger or the like, or may be applied by spraying directly from the container. Areas that require sterilization include skin symptoms such as itching, rash, eczema, insect bites, dermatitis, hives, heat rash, sores, and chilblains.

2. Method for suppressing weight loss As described above, a container whose inner wall is made of linear low-density polyethylene and in which the number of carbon atoms in the side chain of the linear low-density polyethylene is 4 or less is suitable for use in pharmaceutical compositions containing diphenhydramines. It is possible to suppress the weight loss of species. Accordingly, the present invention further provides a method for inhibiting the weight loss of diphenhydramines in pharmaceutical compositions containing diphenhydramines. Specifically, the method for suppressing weight loss of the present invention involves placing a pharmaceutical composition in a container whose inner wall is made of linear low-density polyethylene and in which the linear low-density polyethylene has 4 or less carbon atoms in the side chain. It is characterized by accommodating. In the method for suppressing weight loss 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 is to be stored, etc., are described in "1. As described in the "Pharmaceutical composition" column.

EXAMPLES The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited thereto.

Test example 1
1. Preparation of a Pharmaceutical Composition (Liquid) Filled in a Container A pharmaceutical composition (liquid) having the composition shown in Table 1 was prepared. The pH (25°C) of the solution was 7.3.

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 order from the outer layer to the inner layer, with the LLDPE layer being the outermost layer and the LLDPE layer being the innermost layer. The LLDPE layer is thermally welded. In this test example, seven types of laminate tubes with different LLDPE layers were used, specifically, laminate tube A (manufactured by Takeuchi Press Kogyo Co., Ltd.), laminate tube B (manufactured by Kansai Tube Co., Ltd.), and laminate tube C (manufactured by Takeuchi Press Kogyo Co., Ltd.). (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.) were prepared. The carbon number and density of the side chain of LLDPE constituting the innermost layer in each laminate tube are as shown in Tables 2 to 4.

2. Weight Loss Measurement Test The container filled with the pharmaceutical composition was stored at 40° C. for 30 days. The degree of weight loss of the pharmacological component in the pharmaceutical composition after storage was measured by the following method.

(1) About 0.5 g of the pharmaceutical compositions (sample) of Examples, Comparative Examples, and Reference Examples after storage was weighed, and ethanol (95)/sodium lauryl sulfate solution (9:1 (volume ratio)) was prepared. was added to make exactly 50 mL. This liquid was thoroughly shaken and irradiated with ultrasonic waves to obtain a sample solution.

(2) Separately, about 0.5 g of diphenhydramine for quantitative measurement was taken and weighed, and ethanol (95) was added to make exactly 50 mL to obtain a diphenhydramine standard stock solution.
(3) Lidocaine for quantitative use was dried in a desiccator (vacuum, silica gel) for 24 hours, about 1 g of it was weighed, and ethanol (95) was added to make exactly 50 mL to obtain a standard stock solution of lidocaine.
(4) Approximately 0.5 g of isopropyl methylphenol for quantitative measurement was taken and weighed, and ethanol (95) was added to make exactly 50 mL to obtain a standard stock solution of isopropyl methyl phenol.

(5) Accurately weighed 5 mL of diphenhydramine standard stock solution, 5 mL of lidocaine standard stock solution, and 5 mL of isopropylmethylphenol standard stock solution, and added ethanol (95) to make exactly 50 mL to obtain a standard solution.
(6) Accurately take 15 μL of each of the sample solution and standard solution and measure by liquid chromatography under the conditions described below. The peak areas of diphenhydramine A _Ta (from the sample solution) and A _Sa (from the standard solution), and the peak area of lidocaine. A _Tb (from the sample solution) and A _Sb (from the standard solution), and the peak areas of isopropylmethylphenol A _Tc (from the sample solution) and A _Sc (from the standard solution) were determined.

(7) Based on the following formula, the amount (%) of each pharmacological component in the sample solution relative to the initial value (amount added at the time of preparation) was calculated.

(a) Amount (%) of diphenhydramine in the sample solution relative to the initial value (amount added at the time of preparation)
= (Weighed value of diphenhydramine for quantitative determination (g)) × 1/10 × 1/10 × (A _Ta /A _Sa ) ×
1/(Weighed value of sample (g)) x 100/(Amount of diphenhydramine blended in 100g of sample (g)) x 100

(b) Amount (%) of lidocaine in the sample solution relative to the initial value (amount added at the time of preparation)
= (Weighed value of lidocaine for quantitative use (g)) x 1/10 x 1/10 x (A _Tb /A _Sb ) x 1/ (Weighted value of sample (g)) x 100/ (Lidocaine composition in 100 g of sample) Amount (g))×100

(c) Amount (%) of isopropylmethylphenol in the sample solution relative to the initial value (amount added at the time of preparation)
= (Weighed value of isopropylmethylphenol for quantitative determination (g)) x 1/20 x 1/10 x (A _Tc
/A _Sc )×1/(Weighed value of sample (g))×100/(Amount of isopropylmethylphenol blended in 100g of sample (g))×100

(Measurement condition)
Detector: Ultraviolet absorption photometer (measurement wavelength 220 nm)
Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm was filled with 5 μm octadecylsilylated silica gel for liquid chromatography. (Specifically, Inertsil ODS-3 5μm, 4.6mm x 150mm)
Column temperature: Approximately 30°C, constant temperature 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.

3. Evaluation of weight loss suppression The amount (wt%) of each pharmacological component in the sample solution relative to the initial value (amount added at the time of preparation) obtained in (7) above is classified based on the following criteria, and -6 Scored up to +5. The higher the score, the higher the degree of suppression of the weight loss of the pharmacological component.
+5 More than 99.9% +4 More than 99.7% and not more than 99.9% +3 More than 99.5% and not more than 99.7% +2 More than 99.3% and not more than 99.5% +1 More than 99.1% and not more than 99.3% -1 More than 98.9% and not more than 99.1% -2 More than 98.7% and not more than 98.9% -3 More than 98.5% and not more than 98.7% -4 More than 98.3% and not more than 98.5% -5 More than 98.1% but not more than 98.3% -6 Not more than 98.1%

4. Results The scores for weight loss inhibition 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, a remarkable decrease in the amount of diphenhydramine, isopropylmethylphenol, and lidocaine was observed. It was done. On the other hand, as shown in Examples 1 to 7, in the pharmaceutical compositions stored in contact with LLDPE having 4 carbon atoms in the side chain, the weight loss of diphenhydramine was significantly suppressed. Similarly, weight loss was significantly suppressed for isopropylmethylphenol and lidocaine. Furthermore, as shown in Examples 1 to 6, in a pharmaceutical composition stored in contact with LLDPE whose side chain has 4 carbon atoms and a density of 0.932 to 0.940 g/cm ³ , , the weight loss of diphenhydramine was very significantly suppressed. Similarly, the weight loss of isopropylmethylphenol and lidocaine was also significantly suppressed.

Test example 2
Pharmaceutical compositions (gel preparations) of Formulation Examples 1 to 3 shown in Table 5 were prepared. The pH of the gel (25°C) was 7.3. The laminate tube A, laminate tube B, or laminate tube C used in Test Example 1 was filled and stored under the same conditions as Test Example 1. As a result, when the pharmaceutical compositions of Formulation Examples 1 to 3 were filled into any laminated tube, the weight loss of pharmacological ingredients including diphenhydramine was significantly suppressed. The weight loss of pharmacological components was more significantly suppressed when the drug was filled with

Claims (4)

Contains diphenhydramine and/or its salt,
It is housed in a container whose inner wall is made of linear low-density polyethylene.
A pharmaceutical composition, wherein the linear low-density polyethylene has 4 or less carbon atoms in its side chain. The pharmaceutical composition according to claim 1, wherein the linear low density polyethylene has a density of 0.932 to 0.940 g/cm ³ . The pharmaceutical composition according to claim 1 or 2, which is a liquid or a gel. A method for suppressing the weight loss of diphenhydramine and/or a salt thereof in a pharmaceutical composition containing diphenhydramine and/or a salt thereof, the method comprising:
A method for suppressing weight loss, comprising accommodating the pharmaceutical composition in a container whose inner wall is made of linear low-density polyethylene and in which the number of carbon atoms in the side chain of the linear low-density polyethylene is 4 or less.