JP7334030B2 - Pharmaceutical composition - Google Patents

Description

TECHNICAL FIELD The present invention relates to a pharmaceutical composition in which weight loss of isopropylmethylphenol is suppressed.

Isopropylmethylphenol is widely used in pharmaceutical compositions and the like as a mild disinfectant. For example, Patent Document 1 discloses that isopropylmethylphenol is used as a disinfectant in a spray for pruritic skin diseases containing an antipruritic, a local anesthetic, a disinfectant, and the like.

On the other hand, since isopropylmethylphenol is likely to be adsorbed on the inner wall of resin-made containers, there often arises a problem that the content of isopropylmethylphenol decreases in the pharmaceutical composition stored in resin-made containers. As a solution to such problems, for example, Patent Document 2 discloses a composition containing a specific amount of an N-acyl acidic amino acid, dipropylene glycol, together with isopropylmethylphenol.

JP-A-11-279053 JP 2012-107146 A

So far, as a solution to the problem of suppression of adsorption of isopropylmethylphenol, a method of devising the design of formulation has been adopted. However, even if such a method suppresses the adsorption of isopropylmethylphenol and obtains the effect of suppressing weight loss, the formulation design is limited, and it is not possible to respond to various formulation designs.

An object of the present invention is to provide a technique for suppressing weight loss of isopropylmethylphenol in pharmaceutical compositions.

As a result of intensive studies, the present inventor found that the weight loss of isopropylmethylphenol can be suppressed by forming the surface of the container that comes into contact with the isopropylmethylphenol-containing pharmaceutical composition with a specific resin. The present invention was completed by further studies based on this finding.

That is, the present invention provides inventions in the following aspects.
Section 1. Contains isopropylmethylphenol,
It is housed in a container whose inner wall is made of linear low-density polyethylene,
A pharmaceutical composition, wherein the side chain of the linear low-density polyethylene has 4 or less carbon atoms.
Section 2. The density of the linear low-density polyethylene is 0.932 to 0.940 g/cm ³ and item 3. Item 3. The pharmaceutical composition according to Item 1 or 2, which is a liquid or gel.
Section 4. Item 4. The pharmaceutical composition according to any one of items 1 to 3, further comprising diphenhydramine and/or a salt thereof.
Item 5. Item 5. The pharmaceutical composition according to any one of Items 1 to 4, further comprising lidocaine and/or a salt thereof.
Item 6. A method for suppressing weight loss of isopropylmethylphenol in a pharmaceutical composition containing isopropylmethylphenol, comprising:
A method for suppressing weight loss, comprising placing the pharmaceutical composition in a container having an inner wall composed of linear low-density polyethylene and having a side chain of 4 or less carbon atoms in the linear low-density polyethylene.

The pharmaceutical composition of the present invention is formulated by being housed in a container whose inner wall is composed of linear low-density polyethylene and the side chain of said linear low-density polyethylene has 4 or less carbon atoms. It is possible to suppress the weight loss of isopropylmethylphenol.

1. Pharmaceutical Composition The pharmaceutical composition of the present invention is characterized by containing isopropylmethylphenol and contained in a container whose inner wall is made of a specific resin. The pharmaceutical composition of the invention is described in detail below.

Isopropylmethylphenol The pharmaceutical composition of the present invention contains isopropylmethylphenol (3-methyl-4-isopropylphenol, cymen-5-ol). Isopropylmethylphenol is a known bactericidal agent and widely used as a mild ingredient. Isopropylmethylphenol is easily adsorbed by the polyethylene resin that forms the inner wall of the container of the pharmaceutical composition. more prominently adsorbed. However, according to the present invention, the adsorption of isopropylmethylphenol is suppressed, and the weight loss of isopropylmethylphenol in the pharmaceutical composition can be suppressed.

The amount of isopropylmethylphenol to be added in the pharmaceutical composition of the present invention is not particularly limited, and can be appropriately determined according to the efficacy to be imparted. In the pharmaceutical composition of the present invention, the amount of isopropylmethylphenol is well suppressed. Therefore, even in the case of a pharmaceutical composition containing a small amount of isopropylmethylphenol, it is possible to satisfactorily suppress the attenuation of the effect brought about by isopropylmethylphenol. From this point of view, the amount of isopropylmethylphenol in the pharmaceutical composition of the present invention is preferably 0.03-0.3% by weight, more preferably 0.05-0.2% by weight.

Diphenhydramine and/or its salt The pharmaceutical composition of the present invention can contain diphenhydramine and/or its salt (hereinafter also referred to as "diphenhydramines"), if necessary. Diphenhydramine is a known drug known to have antihistamine properties. Diphenhydramines are easily adsorbed by the polyethylene resin that forms the inner wall of the container of the pharmaceutical composition. Remarkably adsorbed. However, according to the present invention, the adsorption of diphenhydramines is also suppressed, and the weight loss of diphenhydramines in the pharmaceutical composition can also be suppressed.

The salt of diphenhydramine is not particularly limited as long as it is pharmaceutically acceptable. Specific examples include hydrochloride, citrate, succinate, tartrate, fumarate, maleate, and salicylate. , diphenyldisulfonate, tannate, lauryl sulfate, and acid addition salts such as sulfate. These salts may be used singly or in combination of two or more.

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

When a diphenhydramine compound is added to the pharmaceutical composition of the present invention, the amount of the diphenhydramine compound is not particularly limited and can be appropriately determined according to the efficacy to be imparted. be done. In the pharmaceutical composition of the present invention, the weight loss of diphenhydramines is well suppressed. 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, it is possible to satisfactorily suppress the attenuation of the effects brought about by the diphenhydramines. 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.

Lidocaine and/or Salts Thereof The pharmaceutical composition of the present invention may optionally contain lidocaine and/or salts thereof (hereinafter also referred to as “lidocaines”). Lidocaine, also called xylocaine, is a known drug known to have local anesthetic effects.

The salt of lidocaine is not particularly limited as long as it is pharmaceutically acceptable, and specific examples include inorganic acid salts such as hydrochloride.

In the pharmaceutical composition of the present invention, one of lidocaine and its salts may be selected and used alone, or two or more thereof may be used in combination. Among lidocaine and its salts, lidocaine and lidocaine hydrochloride are preferred.

When lidocaines are added to the pharmaceutical composition of the present invention, the content of lidocaines is not particularly limited, and can be appropriately determined according to the efficacy to be imparted. mentioned. In the pharmaceutical composition of the present invention, the content of lidocaines after storage at 40°C for 30 days, for example, can be maintained at more than 99.1% by weight of the content before storage, so that the amount of lidocaines is small. Even if it is a pharmaceutical composition, it is possible to satisfactorily suppress the attenuation of the effects brought about by lidocaines. From this point of view, 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.

Other Ingredients The pharmaceutical composition of the present invention may, if necessary, contain other pharmacological ingredients in addition to the ingredients described above. Examples of such pharmacological components include antihistamines (chlorpheniramine maleate, etc.), local anesthetics (dibucaine, procaine, tetracaine, bupipacine, mepipacaine, chloroprocaine, proparacaine, meprilcaine or salts thereof, alkyl benzoates, (e.g., ethyl aminobenzoate, diethylaminoethyl parabutylaminobenzoate hydrochloride), orthocaine, oxethazain, oxypolyethoxydecane, rot extract, percamimpase, tecittodecitin, etc.), anti-inflammatory agents (glycyrrhetinic acid, glycyrrhetinate, allantoin, salicylic acid, Glycol salicylate, methyl salicylate, indomethacin, felbinac, diclofenac sodium, loxoprofen sodium, etc.), fungicides (benzalkonium chloride, decalinium chloride, benzethonium chloride, cetylpyridinium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, aqueous ammonia, sulfadiazine, lactic acid, phenol, etc.), antipruritic agents (crotamiton, thianthol, etc.), skin protective agents (collodion, castor oil, etc.), blood circulation-promoting ingredients (nonylic acid vanillylamide, benzyl nicotinate, 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 addition to the components described above, 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. , 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 oil (liquid paraffin, paraffin, gelatinized hydrocarbon, vaseline, etc.), waxes/waxes (beeswax, carnauba wax, candelilla wax, ceresin, rice wax, microcrystalline wax, etc.), ester oil (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 glyceryl acid, 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 (lubricant); 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 to 50 mol) polyoxyethylene alkyl ether such as polyoxypropylene (2 to 30 mol) cetyl ether, their phosphoric acid/phosphate (POE cetyl ether phosphate sodium, etc.), 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 soybeans 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-cionell, 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.), thickeners (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, UV absorbers, chelating agents, adhesives, buffers, solubilizers, solubilizers, preservatives, etc. Additives are included.

Among these bases and additives, when a thickening agent is blended, the content of the thickening agent in the pharmaceutical composition of the present invention is, for example, 0.1 to 5% by weight. In the pharmaceutical composition of the present invention, the amount of isopropylmethylphenol is suppressed by suppressing adsorption of isopropylmethylphenol. The weight loss of phenol can be suppressed satisfactorily. From this point of view, when a thickening agent is blended in the pharmaceutical composition of the present invention, the blending amount is preferably a relatively small amount, and more preferably 0.1 to 2% by weight. Furthermore, from the same point of view, when the pharmaceutical composition of the present invention contains a thickening agent, it is preferable to further incorporate a fluidity enhancer. When a fluidity enhancer is added, the content of the fluidity enhancer 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, 6.5-7.5, preferably 7.0-7.5, more preferably 7.1-7.5.

The properties of the pharmaceutical composition of the present invention , such as properties and dosage forms, are not particularly limited, and include liquid compositions, gel compositions, emulsified compositions, and the like. In the pharmaceutical composition of the present invention, the amount of isopropylmethylphenol is well suppressed by suppressing the adsorption of isopropylmethylphenol. can be suppressed to From such a point of view, the pharmaceutical composition of the present invention preferably includes a liquid composition and a gel composition.

The formulation form of the pharmaceutical composition of the present invention is not particularly limited, and examples thereof include liquids (eg, lotions, emulsions), gels, ointments, creams and the like. Among these, highly fluid liquid agents and gel agents are preferred from the same viewpoint as described above.

Container The container containing the pharmaceutical composition of the present invention has an inner wall that contacts the pharmaceutical composition and is made of linear low-density polyethylene (hereinafter also referred to as "LLDPE"). Due to its low density, LLDPE readily adsorbs isopropylmethylphenol. However, although the pharmaceutical composition of the present invention uses LLDPE for the container, it can suppress the adsorption of isopropylmethylphenol and satisfactorily suppress its weight loss.

In the container in which the pharmaceutical composition of the present invention is accommodated, 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 weight loss suppressing effect of isopropylmethylphenol cannot be obtained. Although the lower limit of the carbon number range of LLDPE is not particularly limited, it is, for example, 2 or more, preferably 3 or more.

In the present invention, the density of LLDPE is 0.910-0.940 g/cm ³ . The density of LLDPE is a value measured under the conditions of JIS K7112:1999 submersion method (method A) at 25°C. From the viewpoint of obtaining a better weight loss suppressing effect of isopropylmethylphenol, 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 chains of LLDPE can be controlled by adjusting the number of carbon atoms in the α-olefin to be copolymerized. Also, the density of LLDPE can be controlled by adjusting the type and/or amount of α-olefin to be copolymerized.

The container containing the pharmaceutical composition of the present invention may have an inner wall surface composed of the above-described 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 forming the innermost layer of the container may be the LLDPE described above. A specific example of a preferred multilayer structure includes a structure in which an LLDPE layer, a substrate 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 with each other, or may be indirectly laminated via another layer. Other layers include adhesive layers and functional layers. 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. The outermost LLDPE layer can also function as a heat-sealing layer together with the innermost LLDPE layer. Furthermore, 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 requiring sterilization, preferably a skin site. For application, the pharmaceutical composition may be applied by picking it up from the container onto a finger or the like, or may be applied by spraying directly from the container. Sites requiring sterilization include skin symptoms such as itching, rashes, eczema, insect bites, dermatitis, urticaria, 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 whose side chain has 4 or less carbon atoms is used in a pharmaceutical composition containing isopropylmethylphenol. It is possible to suppress the weight loss of isopropylmethylphenol. Accordingly, the present invention further provides a method for inhibiting weight loss of isopropylmethylphenol in a pharmaceutical composition containing isopropylmethylphenol. Specifically, the method for suppressing weight loss of the present invention includes placing a pharmaceutical composition in a container having an inner wall made of linear low-density polyethylene and having side chains of 4 or less carbon atoms in the linear low-density polyethylene. It is characterized by housing. Further, as described above, when the pharmaceutical composition further contains diphenhydramines in addition to isopropylmethylphenol, the weight loss of diphenhydramines can be similarly suppressed, and the pharmaceutical composition contains lidocaines in addition to isopropylmethylphenol. When further containing, similarly, the reduction of lidocaines can be suppressed. Accordingly, the present invention also provides a method for inhibiting weight loss of isopropylmethylphenol and diphenhydramines and/or lidocaines in a pharmaceutical composition containing isopropylmethylphenol and diphenhydramines and/or lidocaines. 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 dosage forms of the pharmaceutical composition, the method of use, the container to contain the pharmaceutical composition, etc. are described in the above "1. "Pharmaceutical Compositions" section.

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

Test example 1
1. Preparation of Pharmaceutical Composition (Liquid Formulation) Filled in Container A pharmaceutical composition (liquid form) 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 side to the inner layer side, and the LLDPE layer is the outermost layer and the innermost layer. The LLDPE layer is heat-sealed. In this test example, seven types of laminate tubes with different LLDPE layers, specifically, laminate tube A (manufactured by Takeuchi Press Industry Co., Ltd.), laminate tube C (manufactured by Takeuchi Press Industry Co., Ltd.), laminate tube D (Takeuchi Press Industry Co., Ltd.) Kogyo Co., Ltd.), Laminate Tube E (Takeuchi Press Industry Co., Ltd.), and Laminate Tube F (Kansai Tube Co., Ltd.) were prepared. Tables 2 to 4 show the carbon number and density of side chains of LLDPE constituting the innermost layer of each laminate tube.

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

(1) About 0.5 g of the pharmaceutical compositions (samples) of Examples, Comparative Examples and Reference Examples after storage were 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 ultrasonic waves to obtain a sample solution.

(2) Separately, about 0.5 g of diphenhydramine for quantitative determination was weighed, and ethanol (95) was added to make exactly 50 mL to obtain a diphenhydramine standard undiluted solution.
(3) Lidocaine for quantitative determination was dried in a desiccator (vacuum, silica gel) for 24 hours, weighed about 1 g, and ethanol (95) was added to make exactly 50 mL to obtain a lidocaine standard undiluted solution.
(4) About 0.5 g of isopropylmethylphenol for quantitative determination was weighed, and ethanol (95) was added to make exactly 50 mL to obtain an isopropylmethylphenol standard undiluted solution.

(5) 5 mL of the diphenhydramine standard stock solution, 5 mL of the lidocaine standard stock solution, and 5 mL of the isopropylmethylphenol standard stock solution were accurately measured, and ethanol (95) was added to make exactly 50 mL to obtain standard solutions.
(6) Accurately take 15 μL of _each of the _sample solution and the standard solution, and measure by liquid chromatography under the conditions described later. A _Tb (from sample solution) and A _Sb (from standard solution), peak areas A _Tc (from sample solution) and A _Sc (from standard solution) of isopropylmethylphenol were determined.

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

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

(b) Amount (%) relative to the initial value of lidocaine in the sample solution (amount added at the time of preparation)
= (weighed value of lidocaine for quantitative determination (g)) x 1/10 x 1/10 x (A _Tb /A _Sb ) x 1/(weighed value of sample (g)) x 100/(mixture of lidocaine in 100 g of sample) Amount (g)) x 100

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

(Measurement condition)
Detector: UV absorption photometer (measurement wavelength 220 nm)
Column: A stainless steel tube having 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 × 150 mm)
Column temperature: about 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 about 17 minutes.

3. Evaluation of suppression of weight loss The amount (% by weight) of each pharmacological component 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 -6 Scored to ~+5. A higher score indicates a higher degree of suppression of weight loss of the pharmacological component.
+5 More than 99.9% +4 More than 99.7% to 99.9% +3 More than 99.5% to 99.7% +2 More than 99.3% to 99.5% +1 More than 99.1% to 99.3% -1 More than 98.9% to 99.1% -2 More than 98.7% to 98.9% -3 More than 98.5% to 98.7% -4 More than 98.3% to 98.5% -5 More than 98.1% and 98.3% or less -6 98.1% or less

4. Results Weight loss inhibition scores are shown in Tables 2-4. In the table, in the evaluation of -6, the % value obtained in (7) above is also written as appropriate. As shown in Comparative Examples 1 to 8, in the pharmaceutical composition stored in contact with LLDPE having 6 or 8 carbon atoms in the side chain, among isopropylmethylphenol, diphenhydramine, and lidocaine, especially isopropylmethylphenol As shown in the comparison with Reference Examples 1 to 4, it is the same whether each pharmacological ingredient is mixed or blended alone. there were. In addition, diphenhydramine and lidocaine also showed significant weight loss, though not as much as isopropylmethylphenol. In contrast, as shown in Examples 1 to 5, in the pharmaceutical composition stored in contact with LLDPE having 4 carbon atoms in the side chain, the weight loss of isopropylmethylphenol was remarkably suppressed. Diphenhydramine and lidocaine also significantly inhibited weight loss. Furthermore, as shown in Examples 1-4, in pharmaceutical compositions stored in contact with LLDPE having a side chain of 4 carbon atoms and a density of 0.932 g/cm ³ , isopropylmethylphenol weight loss was significantly suppressed. Similarly, diphenhydramine and lidocaine also significantly inhibited weight loss.

Test example 2
Pharmaceutical compositions (gels) of Formulation Examples 1 to 3 shown in Table 5 were prepared. The pH (25°C) of the gel was 7.3. The lamination tube A or the lamination tube C used in Test Example 1 was filled and stored under the same conditions as in Test Example 1. As a result, when the pharmaceutical compositions of Formulation Examples 1 to 3 were filled in any of the laminated tubes, the weight loss of the pharmacological ingredients including isopropylmethylphenol was remarkably suppressed. The decrease in the amount of the pharmacological component was suppressed more remarkably in the case of

Claims (6)

containing 3-methyl-4-isopropylphenol,
It is housed in a container whose inner wall is made of linear low-density polyethylene,
The linear low-density polyethylene has a density of 0.910 to 0.940 g/cm ³ ,
The pharmaceutical composition, wherein the side chain of the linear low-density polyethylene has 4 carbon atoms. The pharmaceutical composition according to claim 1, wherein the linear low density polyethylene has a density of 0.932-0.940 g/cm ³ . 3. The pharmaceutical composition according to claim 1 or 2, which is a liquid or gel. The pharmaceutical composition according to any one of claims 1 to 3, further comprising diphenhydramine and/or a salt thereof. The pharmaceutical composition according to any one of claims 1 to 4, further comprising lidocaine and/or a salt thereof. A method for suppressing weight loss of 3-methyl-4-isopropylphenol in a pharmaceutical composition containing 3-methyl-4-isopropylphenol, comprising:
The inner wall of the pharmaceutical composition is composed of linear low-density polyethylene , the density of the linear low-density polyethylene is 0.910 to 0.940 g/cm 3 , ^and the linear low-density polyethylene A method for suppressing weight loss by storing in a container having a side chain with 4 carbon atoms.