Pharmaceutical composition

Abstract

To provide a method for suppressing reduction in the quantity of isopropylmethylphenols in external pharmaceutical compositions.SOLUTION: In a pharmaceutical composition containing isopropylmethylphenol, 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 isopropylmethylphenol is suppressed.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition in which the reduction of isopropylmethylphenol is suppressed.

Background Art

[0002] Isopropylmethylphenol is widely used as a low-irritant bactericide in pharmaceutical compositions and the like. For example, Patent Document 1 discloses that isopropylmethylphenol is used as a bactericide in a spray for pruritic skin diseases containing an antipruritic agent, a local anesthetic, a bactericide, and the like.

[0003] On the other hand, since isopropylmethylphenol is likely to adsorb to the inner wall of a resin container, the problem often occurs that the content of isopropylmethylphenol decreases in a pharmaceutical composition contained in a resin container. As a solution to such a problem, for example, Patent Document 2 discloses a composition containing a specific amount of N-acyl acidic amino acid and dipropylene glycol together with isopropylmethylphenol.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0005] So far, as a solution to the problem of suppressing the adsorption of isopropylmethylphenol, a method of devising a formulation design has been adopted. However, even if the adsorption of isopropylmethylphenol is suppressed by such a method and a reduction suppression effect is obtained, since the formulation design is limited, it is not possible to cope with various formulation designs.

[0006] The object of the present invention is to provide a method for suppressing the reduction in the amount of isopropylmethylphenol in a pharmaceutical composition.

Means for Solving the Problems

[0007] As a result of intensive studies, the present inventors have found that the reduction in the amount of isopropylmethylphenol can be suppressed by forming the surface of the container in contact with the pharmaceutical composition containing isopropylmethylphenol with a specific resin. The present invention has been completed by further studies based on this finding.

[0008] That is, the present invention provides an invention in the following aspects. Item 1. Containing isopropylmethylphenol, Contained in a container whose inner wall is made of linear low-density polyethylene, A pharmaceutical composition, wherein the number of carbon atoms in the side chain of the linear low-density polyethylene is 4 or less. Item 2. The density of the linear low-density polyethylene is 0.932 to 0.940 g / cm 3 and Item 3. The pharmaceutical composition according to Item 1 or 2, which is a liquid preparation or a gel preparation. Item 4. The pharmaceutical composition according to any one of Items 1 to 3, further containing diphenhydramine and / or a salt thereof. Item 5. The pharmaceutical composition according to any one of Items 1 to 4, further containing lidocaine and / or a salt thereof. Item 6. A method for suppressing the reduction in the amount of isopropylmethylphenol in a pharmaceutical composition containing isopropylmethylphenol, A method for suppressing reduction, wherein the pharmaceutical composition is contained in a container whose inner wall is made of linear low-density polyethylene and the number of carbon atoms in the side chain of the linear low-density polyethylene is 4 or less.

Effects of the Invention

[0009] The pharmaceutical composition of the present invention can suppress the reduction in the amount of isopropylmethylphenol formulated by being contained in a container whose inner wall is made of linear low-density polyethylene and the number of carbon atoms in the side chain of the linear low-density polyethylene is 4 or less.

Embodiments for Carrying Out the Invention

[0010] 1. Pharmaceutical composition The pharmaceutical composition of the present invention contains isopropylmethylphenol and is characterized by being contained in a container whose inner wall is made of a specific resin. Hereinafter, the pharmaceutical composition of the invention will be described in detail.

[0011] Isopropylmethylphenol The pharmaceutical composition of the present invention contains isopropylmethylphenol (3-methyl-4-isopropylphenol, cymene-5-ol). Isopropylmethylphenol is a drug known as a bactericide and is widely used as a low-irritation component. Isopropylmethylphenol is easily adsorbed to the polyethylene-based resin constituting the inner wall of the container of the pharmaceutical composition. In particular, when the pharmaceutical composition is a highly fluid liquid or gel, it is adsorbed more significantly because the frequency of contact with the inner wall of the container is high. However, according to the present invention, the adsorption of isopropylmethylphenol is suppressed, and the reduction in the amount of isopropylmethylphenol in the pharmaceutical composition can be suppressed.

[0012] The blending amount of isopropylmethylphenol in the pharmaceutical composition of the present invention is not particularly limited and can be appropriately determined according to the medicinal effect to be imparted. For example, it is 0.01 to 0.5% by weight. The pharmaceutical composition of the present invention can preferably suppress the reduction of isopropylmethylphenol. For example, the content of isopropylmethylphenol 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 in the case of a pharmaceutical composition with a small blending amount of isopropylmethylphenol, the attenuation of the effect brought about by isopropylmethylphenol can be preferably suppressed. From such a viewpoint, the blending 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.

[0013] 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") as necessary. Diphenhydramine is a known drug known to have an antihistamine effect. Diphenhydramines are likely to be adsorbed on the inner wall of the container of the pharmaceutical composition, and particularly, in the case of a highly fluid liquid or gel preparation of the pharmaceutical composition, they are more significantly adsorbed because of the high frequency of contact with the inner wall of the container. However, according to the present invention, the adsorption of diphenhydramines can also be suppressed, and the reduction of diphenhydramines in the pharmaceutical composition can be suppressed.

[0014] The salt of diphenhydramine is not particularly limited as long as it is pharmaceutically acceptable. Specifically, acid addition salts such as hydrochloride, citrate, succinate, tartrate, fumarate, maleate, salicylate, diphenyldisulfonate, tannate, lauryl sulfate, and sulfate can be mentioned. These salts may be used alone or in combination of two or more.

[0015] 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.

[0016] When diphenhydramines are formulated in the pharmaceutical composition of the present invention, the amount of diphenhydramines formulated is not particularly limited and can be appropriately determined according to the medicinal effect to be imparted. For example, 0.01 to 5% by weight can be mentioned. The pharmaceutical composition of the present invention can preferably suppress the reduction in the amount of diphenhydramines. For example, the content of diphenhydramines 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 in the case of a pharmaceutical composition with a small amount of diphenhydramines formulated, the attenuation of the effect brought about by diphenhydramines can be preferably suppressed. From such a viewpoint, the amount of diphenhydramines formulated in the pharmaceutical composition of the present invention is preferably 0.1 to 3% by weight, more preferably 0.1 to 2% by weight.

[0017] Lidocaine and / or its salt The pharmaceutical composition of the present invention can contain lidocaine and / or its salts (hereinafter also referred to as "lidocaines") as necessary. Lidocaine, also known as xylocaine, is a known drug having a local anesthetic effect.

[0018] The salts of lidocaine are not particularly limited as long as they are pharmaceutically acceptable. Specifically, inorganic acid salts such as hydrochloride can be mentioned.

[0019] In the pharmaceutical composition of the present invention, one kind may be selected from lidocaine and its salts and used alone, or two or more kinds may be used in combination. Among lidocaine and its salts, lidocaine and lidocaine hydrochloride are preferably mentioned.

[0020] When lidocaine drugs are formulated in the pharmaceutical composition of the present invention, the content of lidocaine drugs is not particularly limited and can be appropriately determined according to the medicinal effects to be imparted. For example, 0.01 to 10% by weight can be mentioned. Since the pharmaceutical composition of the present invention can maintain the content of lidocaine drugs after storage at 40°C for 30 days at more than 99.1% by weight of the content before storage, even in the case of a pharmaceutical composition with a small blending amount of lidocaine drugs, the attenuation of the effects brought about by lidocaine drugs can be preferably suppressed. From such a viewpoint, the blending amount of lidocaine drugs in the pharmaceutical composition of the present invention is preferably 0.1 to 5% by weight, more preferably 0.5 to 3% by weight.

[0021] Other components In addition to the components described above, the pharmaceutical composition of the present invention may contain other pharmacological components as necessary. Examples of such pharmacological components include antihistamines (such as chlorpheniramine maleate), local anesthetics (dibucaine, procaine, tetracaine, bupivacaine, mepivacaine, chloroprocaine, propalacaine, meprilocaine or salts thereof, alkyl benzoates (such as ethyl aminobenzoate, diethylaminoethyl paratbutylaminobenzoate hydrochloride), orthocaine, oxethazaine, oxy polyethoxydecane, rooibos extract, peroxidase, testidestin, etc.), anti-inflammatory agents (glycyrrhetinic acid, glycyrrhetinate, allantoin, salicylic acid, glycol salicylate, methyl salicylate, indomethacin, felbinac, diclofenac sodium, loxoprofen sodium, etc.), bactericides (benzalkonium chloride, decalinium chloride, benzethonium chloride, cetylpyridinium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, aqueous ammonia, sulfadiazine, lactic acid, phenol, etc.), antipruritics (crothiamide, thianthol, etc.), skin protectants (collodion, castor oil, etc.), blood circulation promoting components (nonyl vanillylamide, benzyl nicotinate, capsaicin, 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.

[0022] In addition to the aforementioned components, other bases and additives commonly used in pharmaceutical compositions and the like may be included as necessary. Such bases and additives are not particularly limited as long as they are pharmaceutically acceptable. For example, aqueous bases such as water, lower alcohols (e.g., isopropanol), polyhydric alcohols (glycerin, propylene glycol, dipropylene glycol, 1,3 - butylene glycol, etc.); oils such as 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 and fats (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, glyceryl tri - 2 - ethylhexanoate, cetyl 2 - ethylhexanoate, silicone oils (dimethylpolysiloxane, cyclic silicones, etc.) and other oily bases; fluidity promoters (lubricants) such as hydrated silicon dioxide, light anhydrous silicic acid, aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate, etc.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; their phosphates and phosphoric acid salts (such as sodium 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 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 dilinoleate, polyoxyethylene hydrogenated castor oil (5 - 100), polysorbate (20 - 85), glycerin fatty acid esters (such as glycerin monostearate); surfactants such as hydrogenated soybean phospholipid and hydrogenated lanolin alcohol;Cooling agents (menthol, camphor, borneol, peppermint water, peppermint oil, etc.), preservatives (methyl paraoxybenzoate, propyl paraoxybenzoate, benzoic acid, sodium benzoate, sorbic acid, etc.), fragrances (citral, 1,8-cineole, citronellal, farnesol, etc.), coloring agents (tar dyes (Brown No. 201, Blue No. 201, Yellow No. 4, Yellow No. 403, etc.), cocoa pigment, 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, sodium dihydrogen phosphate, disodium hydrogen phosphate, hydrochloric acid, citric acid, sodium citrate, succinic acid, tartaric acid, sodium hydroxide, potassium hydroxide, triethanolamine, triisopropanolamine, etc.), wetting agents (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, propyl gallate, sodium sulfite, sulfur dioxide, chlorogenic acid, catechin, rosemary extract, etc.), antioxidants, ultraviolet absorbers, chelating agents, adhesives, buffers, solubilizing aids, solubilizers, preservatives and other additives are included.;

[0023] 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 may be, for example, 0.1 to 5% by weight. Since the amount of isopropylmethylphenol is well suppressed by suppressing its adsorption in the pharmaceutical composition of the present invention, even in a form with high fluidity and a high contact frequency with the inner wall of the container such as a gel agent, the reduction of isopropylmethylphenol can be well suppressed. From such a viewpoint, when a thickening agent is blended in the pharmaceutical composition of the present invention, it is preferably a relatively small amount, for example, more preferably 0.1 to 2% by weight. Further, from the same viewpoint, when a thickening agent is blended in the pharmaceutical composition of the present invention, it is preferable to further blend a fluidity promoter. When a fluidity promoter is blended, the content of the fluidity promoter in the pharmaceutical composition of the present invention may be, for example, 0.1 to 10% by weight, preferably 1 to 5% by weight.

[0024] 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.

[0025] Properties, dosage form, etc. The properties of the pharmaceutical composition of the present invention are not particularly limited, and examples include liquid compositions, gel compositions, emulsion compositions, etc. Since the amount of isopropylmethylphenol is well suppressed by suppressing its adsorption in the pharmaceutical composition of the present invention, even in a form with high fluidity and a high contact frequency with the inner wall of the container, the reduction of isopropylmethylphenol can be well suppressed. From such a viewpoint, the properties of the pharmaceutical composition of the present invention preferably include liquid compositions and gel compositions.

[0026] The dosage form of the pharmaceutical composition of the present invention is not particularly limited, and examples include solutions (for example, lotions, emulsions), gels, ointments, creams, etc. Among these, from the same viewpoint as above, solutions and gels with high fluidity are preferably mentioned.

[0027] Container The container that houses the pharmaceutical composition of the present invention has an inner wall of the container in contact with the pharmaceutical composition made of linear low-density polyethylene (hereinafter also referred to as "LLDPE"). Because LLDPE has a low density, it easily adsorbs isopropylmethylphenol. However, the pharmaceutical composition of the present invention can suppress the adsorption of isopropylmethylphenol and can well suppress its weight loss despite using LLDPE in the container.

[0028] In the container that houses 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 isopropylmethylphenol cannot be obtained. The lower limit of the range of the number of carbon atoms of LLDPE is not particularly limited, but for example, 2 or more can be mentioned, and preferably 3 or more can be mentioned.

[0029] In the present invention, the density of LLDPE is 0.910 - 0.940 g / cm 3 It is. The density of LLDPE is the value measured under the conditions of JIS K7112:1999 water substitution method (Method A) at 25°C. From the viewpoint of obtaining a better effect of suppressing the weight loss of isopropylmethylphenol, the density of LLDPE is more preferably 0.932 - 0.940 g / cm 3 It is.

[0030] 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 control of the number of carbon atoms in the side chain of LLDPE can be carried out by adjusting the number of carbon atoms of the α-olefin to be copolymerized. Also, the control of the density of LLDPE can be carried out by adjusting the type and / or amount of the α-olefin to be copolymerized.

[0031] In the case of a container containing the pharmaceutical composition of the present invention, it is only necessary that the inner wall surface thereof is 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. Specific examples of a preferred multi-layer structure include 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. 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 the material constituting the base material layer include polyester resins 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-sealing layer together with the innermost LLDPE. Furthermore, the container may be a bottle or a tube, but preferably a tube.

[0032] 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. In the application, the pharmaceutical composition may be taken from the container with a finger or the like and applied, or may be directly applied by spraying from the container. Examples of the site requiring sterilization include skin symptoms such as itching, swelling, eczema, insect bites, dermatitis, urticaria, sweat rash, blisters, and chilblains.

[0033] 2. Weight loss suppression method As described above, a container having an inner wall made of linear low-density polyethylene and having 4 or less carbon atoms in the side chain of the linear low-density polyethylene can suppress the reduction in isopropylmethylphenol in a pharmaceutical composition containing isopropylmethylphenol. Therefore, the present invention further provides a method for suppressing the reduction in isopropylmethylphenol in a pharmaceutical composition containing isopropylmethylphenol. Specifically, the reduction suppression method of the present invention is characterized in that the pharmaceutical composition is housed in a container having an inner wall made of linear low-density polyethylene and having 4 or less carbon atoms in the side chain of the linear low-density polyethylene. Also as described above, when the pharmaceutical composition further contains diphenhydramines in addition to isopropylmethylphenol, similarly, the reduction in diphenhydramines can be suppressed, and when the pharmaceutical composition further contains lidocaine in addition to isopropylmethylphenol, similarly, the reduction in lidocaine can be suppressed. Therefore, the present invention also provides a method for suppressing the reduction in isopropylmethylphenol and diphenhydramines and / or lidocaine in a pharmaceutical composition containing isopropylmethylphenol, diphenhydramines, and / or lidocaine. In the reduction suppression method of the present invention, the types and blending amounts of the components used in the pharmaceutical composition, the properties and dosage forms of the pharmaceutical composition, the method of use, the container in which the pharmaceutical composition should be housed, etc. are as described in the column of "1. Pharmaceutical Composition" above.

Example

[0034] Examples are shown below to more specifically explain the present invention, but the present invention is not limited thereto.

[0035] Test Example 1 1. Preparation of a pharmaceutical composition (liquid preparation) filled in a container A pharmaceutical composition (liquid preparation) having the composition shown in Table 1 was prepared. The pH (25 ° C) of the liquid preparation was 7.3.

[0036]

Table 1

[0037] The prepared pharmaceutical composition was filled into a laminated tube having an LLDPE layer as the innermost layer. The laminated tube has a multi-layer 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 as the outermost layer and the LLDPE layer as the innermost layer are heat-sealed. In this test example, 7 types of laminated tubes with different LLDPE layers were prepared, specifically, laminated tube A (manufactured by Takeuchi Press Industry Co., Ltd.), laminated tube C (manufactured by Takeuchi Press Industry Co., Ltd.), laminated tube D (manufactured by Takeuchi Press Industry Co., Ltd.), laminated tube E (manufactured by Takeuchi Press Industry Co., Ltd.), and laminated tube F (manufactured by Kansai Tube Co., Ltd.). The number of carbon atoms and density of the side chains of the LLDPE constituting the innermost layer in each laminated tube are as shown in Tables 2 to 4.

[0038] 2. Weight loss measurement test The container filled with the pharmaceutical composition was stored at 40 °C for 30 days. The degree of reduction of the pharmacological components in the pharmaceutical composition after storage was measured by the following method.

[0039] (1) About 0.5 g of the pharmaceutical compositions (samples) of the examples, comparative examples, and reference examples after storage were weighed, ethanol (95) / sodium lauryl sulfate solution (9:1 (volume ratio)) was added to make exactly 50 mL. This solution was shaken well and irradiated with ultrasonic waves to obtain a sample solution.

[0040] (2) Separately, about 0.5 g of diphenhydramine for quantification was weighed, ethanol (95) was added to make exactly 50 mL, and a diphenhydramine standard stock solution was obtained. (3) Lidocaine for quantification was dried in a desiccator (under reduced pressure, silica gel) for 24 hours, about 1 g of it was weighed, ethanol (95) was added to make exactly 50 mL, and a lidocaine standard stock solution was obtained. (4) About 0.5 g of isopropylmethylphenol for quantification was weighed, ethanol (95) was added to make exactly 50 mL, and an isopropylmethylphenol standard stock solution was obtained.

[0041] (5) Accurately measure 5 mL of diphenhydramine standard stock solution, 5 mL of lidocaine standard stock solution, and 5 mL of isopropylmethylphenol standard stock solution respectively, add ethanol (95) to make exactly 50 mL, and obtain the standard solution. (6) Accurately take 15 μL each of the sample solution and the standard solution, perform measurement by liquid chromatography under the conditions described below, and obtain the peak area A of diphenhydramine Ta (from the sample solution) and A Sa (from the standard solution), the peak area A of lidocaine Tb (from the sample solution) and A Sb (from the standard solution), the peak area A of isopropylmethylphenol Tc (from the sample solution) and A Sc (from the standard solution).

[0042] (7) Based on the following calculation formulas, calculate the amount (%) with respect to the initial value (the amount formulated during preparation) of each pharmacological component in the sample solution.

[0043] (a) The amount (%) with respect to the initial value (the amount formulated during preparation) of diphenhydramine in the sample solution = (the weighed value (g) of diphenhydramine for quantification) × 1 / 10 × 1 / 10 × (A Ta / A Sa ) × 1 / (the weighed value (g) of the sample) × 100 / (the amount of diphenhydramine formulated in 100 g of the sample (g)) × 100

[0044] (b) The amount (%) with respect to the initial value (the amount formulated during preparation) of lidocaine in the sample solution = (the weighed value (g) of lidocaine for quantification) × 1 / 10 × 1 / 10 × (A Tb / A Sb ) × 1 / (the weighed value (g) of the sample) × 100 / (the amount of lidocaine formulated in 100 g of the sample (g)) × 100

[0045] (c) The amount (%) with respect to the initial value (the amount formulated during preparation) of isopropylmethylphenol in the sample solution =(Weight of isopropylmethylphenol for quantification (g)) × 1 / 20 × 1 / 10 × (A Tc / A Sc ) × 1 / (Weight of sample (g)) × 100 / (Amount of isopropylmethylphenol in 100 g of sample (g)) × 100

[0046] (Measurement conditions) 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 5 μm, 4.6 mm × 150 mm) 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.

[0047] 3. Evaluation of weight loss suppression The amounts (weight %) of the respective pharmacological components in the sample solution obtained in (7) above with respect to the initial values (amounts formulated during preparation) were classified based on the following criteria and scored from -6 to +5. The larger the score, the higher the degree of suppression of the reduction of the pharmacological component. +5 Over 99.9% +4 Over 99.7% and 99.9% or less +3 Over 99.5% and 99.7% or less +2 Over 99.3% and 99.5% or less +1 Over 99.1% and 99.3% or less -1 Over 98.9% and 99.1% or less -2 Over 98.7% and 98.9% or less -3 Over 98.5% and 98.7% or less -4 Over 98.3% and 98.5% or less -5 Over 98.1% and 98.3% or less -6 98.1% or less

[0048] 4. Results The scores of the reduction inhibition are shown in Tables 2 to 4. In the table, for the evaluation of -6, the % values obtained in the above (7) are also described as appropriate. 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, among isopropylmethylphenol, diphenhydramine, and lidocaine, the reduction of isopropylmethylphenol was particularly remarkable. This was the same whether the respective pharmacological components were mixed and formulated or formulated alone, as shown by the comparison with Reference Examples 1 to 4. Also, although not as much as isopropylmethylphenol, significant reduction was also observed for diphenhydramine and lidocaine. On the other hand, as shown in Examples 1 to 5, in the pharmaceutical compositions stored in contact with LLDPE having 4 carbon atoms in the side chain, the reduction of isopropylmethylphenol was significantly suppressed. Similarly, the reduction of diphenhydramine and lidocaine was also significantly suppressed. Furthermore, as shown in Examples 1 to 4, in the pharmaceutical compositions stored in contact with LLDPE having 4 carbon atoms in the side chain and a density of 0.932 g / cm 3 In the pharmaceutical compositions stored in contact with LLDPE having 4 carbon atoms in the side chain and a density of 0.932 g / cm, the reduction of isopropylmethylphenol was extremely significantly suppressed. Similarly, the reduction of diphenhydramine and lidocaine was also extremely significantly suppressed.

[0049] [Table 2]

[0050] [Table 3]

[0051] [Table 4]

[0052] Test Example 2 The pharmaceutical compositions (gel preparations) of Formulation Examples 1 to 3 shown in Table 5 were prepared. The pH (25°C) of the gel preparation was 7.3. They were filled into the laminate tube A or laminate tube C used in Test Example 1 and stored under the same conditions as in Test Example 1. As a result, in the case of the pharmaceutical compositions of Formulation Examples 1 to 3, regardless of which laminate tube they were filled into, the reduction in the amount of pharmacological components including isopropylmethylphenol was significantly suppressed, and moreover, the reduction in the amount of pharmacological components was more significantly suppressed when filled into laminate tube A.

[0053]

Table 5

Claims

1. Contains 3-methyl-4-isopropylphenol, It is contained in a container whose inner wall is made of linear low-density polyethylene, the density of the linear low-density polyethylene is 0.910 to 0.940 g / cm 3 ; A pharmaceutical composition, wherein the linear low-density polyethylene has a side chain with 2 or 3 carbon atoms.

2. 10. The pharmaceutical composition of claim 1, which is a liquid or gel.

3. 3. The pharmaceutical composition according to claim 1, further comprising diphenhydramine and / or a salt thereof.

4. The pharmaceutical composition according to any one of claims 1 to 3, further comprising lidocaine and / or a salt thereof.

5. A method for suppressing loss of 3-methyl-4-isopropylphenol in a pharmaceutical composition containing 3-methyl-4-isopropylphenol, comprising: The pharmaceutical composition is contained in a container having an inner wall made of linear low-density polyethylene, the density of the linear low-density polyethylene being 0.910 to 0.940 g / cm 3, and the number of carbon atoms in the side chains of the linear low-density polyethylene being 2 or 3.