JP2018002717A - Pharmaceutical composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutical composition that forms a molecule assembly to express viscoelasticity even when the concentration of glycyrrhizinic acid or a salt thereof is 0.3 W/V% or less and the pH of the composition is 3.0 or more.SOLUTION: A pharmaceutical composition contains (A) at least one selected from glycyrrhizinic acid and glycyrrhizinic acid salt of 0.1-0.3 W/V%, and (B) a basic substance having a cyclic structure or a polycyclic structure of 0.005-0.15 W/V%, with a mass content ratio represented by (B)/(A) of 0.017-0.6, and the pH of the composition being 3.0-6.0.SELECTED DRAWING: Figure 1

Description

  The present invention relates to a pharmaceutical composition comprising a molecular assembly that exhibits viscoelasticity.

  Thickeners and gelling agents are widely used in various industrial fields such as pharmaceuticals, cosmetics, foods, and industrial applications. Their uses and purposes are long-term stabilization of formulations, suppression of separation, provision of drug retention, handling, etc. Improvement of usability. As the thickener, polymers, organic clay minerals, waxes, thickening polysaccharides and the like are used. When using thickening gelling agents for external preparations such as cosmetics and pharmaceuticals, in addition to excellent thickening action, those that satisfy various requirements such as safety, stability to heat, and good usability desired.

  In recent years, molecular aggregates called string-like micelles formed by surfactant molecules have attracted attention as thickening liquid compositions. The string-like micelles are characterized in that rod-like micelles, which are a kind of self-association of surfactant molecules, grow and entangle with each other to form a three-dimensional network structure and exhibit viscoelasticity. As an example of the composition, a solution obtained by adding sodium salicylate to a cationic surfactant aqueous solution which is a quaternary ammonium salt is known (Non-patent Document 1). However, there is a problem that a quaternary ammonium salt which is a preservative is necessary and is not widely used.

Takeshi Yamamura; Toshiaki Kusaka; Eiichi Takatori; Masashi Inoue; Norio Nemoto; Kunihiro Ozaki; Toshiyuki Shikata; Tadao Odaka Journal of Japanese Society of Rheology Vol19, p140-146, 1991

  The present inventors pay attention to glycyrrhizic acid or a salt thereof, and in order to form a molecular assembly that expresses viscoelasticity in glycyrrhizic acid or a salt thereof, the glycyrrhizic acid or the pH thereof is set to a high concentration, It was found that it was necessary to lower it. For this reason, under conditions where the concentration of glycyrrhizic acid or a salt thereof is dilute, specifically 0.3 W / V% or less, formation of a molecular assembly that exhibits viscoelasticity is not observed unless the pH is less than 3.0. . On the other hand, when the concentration of glycyrrhizic acid is high, or when the pH is less than 3.0, irritation to the skin, mucous membranes, especially the eyes may occur, resulting in poor usability and problems in safety. There is a concern. The present invention has been made in view of the above circumstances, and a pharmaceutical composition that forms a molecular assembly that exhibits viscoelasticity even when the concentration of glycyrrhizic acid or a salt thereof is 0.3 W / V% or less and pH 3.0 or more. The purpose is to provide goods.

  As a result of intensive studies to achieve the above object, the present inventors have added a basic substance having a cyclic structure or a polycyclic structure to a low-concentration glycyrrhizic acid aqueous solution, whereby a region exceeding pH 3.0 is obtained. In addition, it has been found that a pharmaceutical composition having a molecular assembly expressing viscoelasticity can be obtained, and the present invention has been made.

Accordingly, the present invention provides the following pharmaceutical composition.
[1]. (A) One or more kinds selected from glycyrrhizic acid and glycyrrhizinate, 0.1 to 0.3 W / V%, (B) a basic substance having a cyclic structure or a polycyclic structure 0.005 to 0.15 W / A pharmaceutical composition containing V%, having a contained mass ratio represented by (B) / (A) of 0.017 to 0.6, and a pH of 3.0 to 6.0.
[2]. The pharmaceutical composition according to [1], comprising a molecular assembly that exhibits viscoelasticity.
[3]. (B) is tetrahydrozoline hydrochloride, pyridoxine hydrochloride, diphenhydramine hydrochloride, ketotifen fumarate, chlorpheniramine maleate, berberine sulfate hydrate, berberine chloride hydrate, epinephrine, phenylephrine hydrochloride, ephedrine hydrochloride, The pharmaceutical composition according to [1] or [2], which is selected from methyl ephedrine hydrochloride and naphazoline hydrochloride.
[4]. The pharmaceutical composition according to any one of [1] to [3], which is an external preparation composition.
[5]. The pharmaceutical composition according to any one of [1] to [3], which is an eye drop or an eye wash.

  According to the present invention, even when the concentration of glycyrrhizic acid or a salt thereof is dilute, specifically 0.3 W / V% or less and pH 3.0 or more, a molecular assembly that exhibits viscoelasticity is formed. A pharmaceutical composition can be provided. Hereinafter, the pharmaceutical composition may be abbreviated as “composition”.

10 is a transmission electron micrograph of Example 9. 4 is a transmission electron micrograph of Comparative Example 2.

Hereinafter, the present invention will be described in detail.
(A) One or more types selected from glycyrrhizic acid and glycyrrhizinate As the (A) component, glycyrrhizinate, dipotassium glycyrrhizinate, disodium glycyrrhizinate, ammonium glycyrrhizinate and the like can be used. Glycyrrhizic acid and glycyrrhizinate are effective components as anti-inflammatory components.

  The amount of component (A) is 0.1 to 0.3 W / V% (mass / volume%, g / 100 mL, the same applies hereinafter) in the composition, preferably 0.12 to 0.3 W / V%. 0.15-0.3 W / V% is more preferable. Below the lower limit, no molecular assembly that exhibits viscoelasticity is formed. Exceeding the upper limit may cause irritation to the skin, mucous membranes, especially the eyes. In addition, an upper limit can also be 0.28 W / V% or less and 0.26 W / V% or less.

(B) Basic substance having a cyclic structure or a polycyclic structure (B) The component (B) is blended to promote the formation of a molecular assembly that exhibits the viscoelasticity of the component (A). By adding the component (B), a molecular assembly that exhibits viscoelasticity is formed even in a region where the component (A) has a low concentration and a low pH. Furthermore, it has the effect of increasing the storage elastic modulus of the formed molecular assembly that exhibits viscoelasticity. The component (B) is not particularly limited as long as it has a cyclic structure or a polycyclic structure, and can be used alone or in combination of two or more. Such components include tetrahydrozoline hydrochloride, pyridoxine hydrochloride, diphenhydramine hydrochloride, ketotifen fumarate, chlorpheniramine maleate, berberine sulfate hydrate, berberine chloride hydrate, epinephrine, phenylephrine hydrochloride, ephedrine Examples include hydrochloride, methylephedrine hydrochloride, and naphazoline hydrochloride. Among these, tetrahydrozoline hydrochloride, diphenhydramine hydrochloride, chlorpheniramine maleate, and naphazoline hydrochloride are preferable, and diphenhydramine hydrochloride and naphazoline hydrochloride are more preferable.

  (B) The compounding quantity of a component is 0.005-0.15 W / V% in a composition, 0.006-0.15 W / V% is preferable, More preferably, 0.006-0.12 W / V %. Moreover, the containing mass ratio represented by (B) / (A) is 0.017-0.6, 0.02-0.4 are preferable, More preferably, it is 0.04-0.4. The blending amount of the component (B) is determined by the blending amount of the component (A) and the ratio. When the blending amount of the component (B) is less than the lower limit and exceeds the upper limit, string-like micelle formation is not formed. Moreover, when the said ratio is less than a minimum and exceeds an upper limit, the molecular assembly which expresses viscoelasticity will not be formed.

  The pH (25 ° C.) of the composition is 3.0 to 6.0, preferably 4.0 to 5.3, and more preferably 4.6 to 4.9. If it is less than the lower limit, irritation may occur in the skin, mucous membranes, particularly the eyes. On the other hand, 3.0 to 4.8 is preferable, 4.0 to 4.8 is more preferable, and 4.6 to 4.8 is even more preferable from the point that a cooling process is not required in the production method. From the point that the risk of causing eye irritation is low, it is more than 4.8 and preferably 6.0 or less, and more preferably 4.8 and 5.3 or less.

  The osmotic pressure of the composition is preferably 0.1 to 5 pressure ratio, more preferably 0.2 to 2 pressure ratio.

  Formation of a molecular assembly that exhibits viscoelasticity can be confirmed by having viscoelasticity and a network structure of the molecular assembly. Viscoelasticity can be confirmed by measuring the storage elastic modulus G 'of the following composition. The network structure of the molecular assembly can be confirmed by observation with a transmission electron microscope. Such a molecular assembly exhibiting viscoelasticity is also called a string-like micelle. For example, as shown in FIG. 1, a molecular assembly expressing viscoelasticity with a thickness of about 3 nm has been confirmed. The thickness of the molecular assembly that exhibits viscoelasticity is preferably 1 to 5 nm, and the distance between cross-linking points is preferably 50 to 200 nm.

  The composition having a molecular assembly that exhibits viscoelasticity of the present invention is characterized by a high storage elastic modulus as compared with a thickening composition of a molecular assembly that exhibits viscoelasticity due to conventional pH and high concentration. Have. The storage elastic modulus G ′ of the composition is preferably 0.5 Pa or more, 2.0 Pa or more, more preferably 10.0 Pa or more, and the retention is further enhanced in this range. The upper limit is preferably 300 Pa or less. If it is less than the lower limit, a molecular assembly that expresses viscoelasticity is not formed, and if it is more than the upper limit, stickiness may increase. The stickiness and the storage elastic modulus G ′ are in a trade-off relationship, and 0.5 to 10.0 Pa is preferable and 2.0 to 10.0 Pa is more preferable from the viewpoint of combining both. The storage elastic modulus G ′ can be adjusted by the component (A), the component (B), and the ratio thereof as shown in the examples. In addition, storage elastic modulus is 25 degreeC, frequency using a rheometer, for example, stress control type rheometer AR-2000ex (made by TI Instruments), using a cone plate system with a diameter of 4 cm and a cone angle of 1 degree. The measurement was performed in the range of 0.628 rAD / s to 6.28 rAD / s. Since G ′ takes a constant value in the measurement frequency range, G ′ at 6.28 rAD / s is a representative value.

  The composition of the present invention has a molecular assembly that exhibits viscoelasticity. Since this molecular assembly is an assembly of low-molecular compounds, the composition containing the molecular assembly is different from the conventional thickening method using a polymer compound or thickening polysaccharide by applying external force. At the same time, it has the property of reducing the apparent viscosity (thixotropic properties). Since it has such properties, it does not cause stickiness, has a good feeling of use, and is suitable for pharmaceuticals, cosmetics and the like. Furthermore, when used as an ophthalmic composition, it has a unique property that it is difficult to mix with tears. When the drug is held inside the network structure of the molecular assembly that expresses viscoelasticity, the drug can be delivered to the cornea while maintaining the concentration.

  The composition of the present invention is preferably an aqueous composition. An aqueous composition means that water is a medium and has fluidity under any stress.

  In the present invention, water can be blended, and the blending amount is preferably the remainder of the essential components, preferably 95.0 to 99.9 W / V%, more preferably 99.0 to 99.7 W / V%.

  An appropriate amount of other components can be blended in the composition of the present invention as long as the effects of the present invention are not impaired. Examples of the component include a surfactant, a polyhydric alcohol, a saccharide, a buffer, a cooling agent, a drug, a powder component, and an ultraviolet absorber. These can be used individually by 1 type or in combination of 2 or more types.

  Examples of the surfactant include glycine type amphoteric surfactants such as polyoxyethylene polyoxypropylene glycol, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, and alkyldiaminoethylglycine. When the surfactant is blended, the blending amount is preferably 0.0001 to 10 W / V% in the composition.

  Examples of the polyhydric alcohol include glycerin, propylene glycol, butylene glycol, and polyethylene glycol. When blending polyhydric alcohol, the blending amount is preferably 0.001 to 5 W / V% in the composition.

  Examples of the saccharide include glucose, cyclodextrin, xylitol, sorbitol, mannitol and the like. In addition, these may be any of d-form, l-form, or dl-form. When mix | blending saccharides, the compounding quantity has preferable 0.001-5 W / V% in a composition.

  Examples of the buffer include citric acid, sodium citrate, boric acid, borax, phosphoric acid, sodium hydrogen phosphate, sodium dihydrogen phosphate, glacial acetic acid, trometamol, sodium hydrogen carbonate and the like. When mix | blending a buffering agent, the compounding quantity has preferable 0.003-4W / V% in a composition.

  As a pH adjuster, an inorganic acid or an inorganic alkali agent is mentioned, for example. For example, (diluted) hydrochloric acid is mentioned as an inorganic acid. Examples of the inorganic alkaline agent include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like. The pH is measured at 20 ° C. using a pH osmometer (HSMO-1, Toa DKK).

  Examples of the isotonic agent include sodium chloride and potassium chloride. The compounding amount of the isotonic agent is preferably 0.001 to 3 W / V% in the composition. Examples of the stabilizer include sodium edetate, cyclodextrin, sulfite, dibutylhydroxytoluene and the like. When the stabilizer is blended, the blending amount is preferably 0.003 to 2 W / V% in the composition.

  Examples of the refreshing agent include menthol, camphor, borneol, geraniol, cineol, linalool and the like. When blending a refreshing agent, the blending amount is preferably 0.0001 to 0.2 W / V% in the composition.

Examples of ophthalmic drugs (pharmaceutical active ingredients) include decongestants, anti-inflammatory / astringents (eg, ε-aminocaproic acid, zinc sulfate, zinc lactate, sodium azulene sulfonate), antihistamines, antiallergic agents ( For example, sodium cromoglycate, etc.), water-soluble vitamins (vitamin B _12, etc.), fat-soluble vitamins (acetic d-alpha-tocopherol, retinol palmitate, etc.), amino acids (e.g., potassium L- aspartic acid, L- aspartic acid Magnesium, aminoethylsulfonic acid, polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinyl alcohol, sodium chondroitin sulfate, glutathione, etc.), sulfa drugs, and mydriatics. When a drug is blended, the compounding amount can be selected as an effective appropriate amount of each drug. From the viewpoint of irritation, stability of the composition, etc., 0.001 to 5 W / V% in the composition Is preferred.

  Although it does not restrict | limit especially as a drug for dermatology (pharmaceutical active ingredient), For example, prednisolone valerate ester acetate, d-α-tocopherol acetate, allantoin, methyl salicylate, isopropylmethylphenol, lidocaine, l-menthol, bread Examples include tenol, heparin-like substance, urea and the like.

  Examples of the humectant include chondroitin sulfate, hyaluronic acid, mucoitin sulfate, caronic acid, atelocollagen, cholesteryl-12-hydroxystearate, sodium lactate, bile salt, dl-pyrrolidone carboxylate, short chain soluble collagen, diglycerin. (EO) PO adduct, Izayoi rose extract, Achillea millefolium extract, Merirot extract and the like. When mix | blending a moisturizer, the compounding quantity has preferable 0.003-3W / V% in a composition.

  Examples of the powder component include inorganic powders (for example, talc, kaolin, mica, sericite (sericite), muscovite, phlogopite, synthetic mica, saucite, biotite, vermiculite, magnesium carbonate, calcium carbonate, silicic acid. Aluminum, barium silicate, calcium silicate, magnesium silicate, strontium silicate, metal tungstate, magnesium, silica, zeolite, barium sulfate, calcined calcium sulfate (baked gypsum), calcium phosphate, fluorine apatite, hydroxyapatite, ceramic powder Metal soap (eg, zinc myristate, calcium palmitate, aluminum stearate), boron nitride, etc .; organic powder (eg, polyamide resin powder (nylon powder), polyethylene powder, polymethyl methacrylate powder, Styrene powder, copolymer resin powder of styrene and acrylic acid, benzoguanamine resin powder, polytetrafluoroethylene powder, cellulose powder, etc.); inorganic white pigment (for example, titanium dioxide, zinc oxide, etc.); inorganic red pigment ( For example, iron oxide (Bengara), iron titanate, etc.); inorganic brown pigment (for example, γ-iron oxide, etc.); inorganic yellow pigment (for example, yellow iron oxide, loess, etc.); inorganic black pigment (for example, Black iron oxide, low-order titanium oxide, etc.); inorganic purple pigments (eg, mango violet, cobalt violet, etc.); inorganic green pigments (eg, chromium oxide, chromium hydroxide, cobalt titanate, etc.); inorganic blue pigments (For example, ultramarine, bitumen, etc.); pearl pigments (for example, titanium oxide coated mica, titanium oxide coated bismuth oxychloride, titanium oxide coated titanium) Lac, colored titanium oxide coated mica, bismuth oxychloride, fish scale foil, etc.); metal powder pigments (eg, aluminum powder, copper powder, etc.); organic pigments such as zirconium, barium, or aluminum lake (eg, red 201, red 202) , Red 204, red 205, red 220, red 226, red 228, red 405, orange 203, orange 204, yellow 205, yellow 401, and blue 404 Red No. 3, Red No. 104, Red No. 106, Red No. 227, Red No. 230, Red No. 401, Red No. 505, Orange No. 205, Yellow No. 4, Yellow No. 5, Yellow No. 202, Yellow No. 203, Green No. 3 and Blue No. 1); natural pigments (for example, chlorophyll, β-carotene, etc.) and the like.

  Examples of the solid fat include cacao butter, palm oil, horse fat, hydrogenated palm oil, palm oil, beef tallow, sheep fat, hydrogenated beef tallow, palm kernel oil, pork fat, beef bone fat, owl kernel oil, hydrogenated oil, cattle Leg fats, moles, hydrogenated castor oil and the like. Examples of the solvent include oleyl alcohol, squalane, liquid paraffin, dimethylpolysiloxane, isopropyl myristate, and the like.

  Examples of the ultraviolet absorber include benzoic acid-based ultraviolet absorbers (for example, paraaminobenzoic acid (hereinafter abbreviated as PABA), PABA monoglycerin ester, N, N-dipropoxy PABA ethyl ester, N, N-diethoxy PABA ethyl ester. N, N-dimethyl PABA ethyl ester, N, N-dimethyl PABA butyl ester, N, N-dimethyl PABA ethyl ester, etc.); anthranilic acid ultraviolet absorbers (for example, homomenthyl-N-acetylanthranylate, etc.); Salicylic acid UV absorbers (eg, amyl salicylate, menthyl salicylate, homomenthyl salicylate, octyl salicylate, phenyl salicylate, benzyl salicylate, p-isopropanol phenyl salicylate); (For example, octylmethoxycinnamate, ethyl-4-isopropylcinnamate, methyl-2,5-diisopropylcinnamate, ethyl-2,4-diisopropylcinnamate, methyl-2,4-diisopropylcinnamate, propyl-p- Methoxycinnamate, isopropyl-p-methoxycinnamate, isoamyl-p-methoxycinnamate, octyl-p-methoxycinnamate (2-ethylhexyl-p-methoxycinnamate), 2-ethoxyethyl-p-methoxycinnamate, Cyclohexyl-p-methoxycinnamate, ethyl-α-cyano-β-phenylcinnamate, 2-ethylhexyl-α-cyano-β-phenylcinnamate, glyceryl mono-2-ethylhexanoyl-diparamethoxycinnamate, etc. ); 3- (4′-methylbenzylidene) -d, l-camphor, 3-benzylidene-d, l-camphor; 2-phenyl-5-methylbenzoxazole; 2,2′-hydroxy-5-methylphenyl 2- (2'-hydroxy-5'-t-octylphenyl) benzotriazole; 2- (2'-hydroxy-5'-methylphenyl) benzotriazole; dibenzalazine; dianisoylmethane; 4-methoxy-4 '-T-butyldibenzoylmethane; 5- (3,3-dimethyl-2-norbornylidene) -3-pentan-2-one, dimorpholinopyridazinone and the like.

  Examples of the polymer emulsion include an acrylic resin emulsion, a polyethyl acrylate emulsion, an acrylic resin liquid, a polyacryl alkyl ester emulsion, a polyvinyl acetate resin emulsion, and a natural rubber latex.

The production method of the present invention includes, for example, the following steps.
(1) When pH is 3.0 to 4.8 (i) Step of adding all components except (B) component to purified water and mixing (ii) pH adjustment of this mixture (target pH 3. The process of heating to 60-90 degreeC after doing 0-4.8) In addition, although heating time is not specifically limited, 10-20 minutes are preferable.
(Iii) A step of further adding the component (B) to the pH-adjusted mixed solution and further mixing The mixing time is not particularly limited, but is appropriately selected within a range of 10 to 20 minutes.
Then, pH adjustment is performed as needed. In addition, you may perform the following (iv) cooling process after the (iii) process.

(2) When pH is over 4.8 and 6.0 (i) Step of adding all components except (B) component to purified water and mixing (ii) Adjusting pH of this mixture (target pH 4 Step of heating at 60 to 90 ° C. after exceeding .8 to 6.0) Although the heating time is not particularly limited, it is preferably 10 to 20 minutes.
(Iii) A step of further adding the component (B) to the pH-adjusted mixed solution and further mixing The mixing time is not particularly limited, but is appropriately selected within a range of 10 to 20 minutes.
(Iv) Step of cooling the liquid mixture obtained in (iii) Thereafter, pH adjustment is performed as necessary.

  In addition, when pH exceeds 4.8 and 6.0, a cooling process is required for formation of the molecular assembly which expresses viscoelasticity. (Iv) The cooling temperature is preferably 0 to 25 ° C, more preferably 0 to 15 ° C, and further preferably 0 to 10 ° C. Below the lower limit, freezing of the liquid occurs, and above the upper limit, formation of a molecular assembly that exhibits viscoelasticity is incomplete. The cooling time is preferably 3 to 48 hours, more preferably 6 to 48 hours, and even more preferably 12 to 48 hours. There are cases where the formation of molecular aggregates that exhibit viscoelasticity is incomplete below the lower limit, and the manufacturing time is longer above the upper limit.

  The composition of the present invention is suitable as an external preparation such as a dermatological composition and an ophthalmic composition. By applying the composition as an external preparation, it is possible to provide a highly safe and non-sticky feeling. In particular, it is expected to be applied to ophthalmic compositions (mucosal application agents) such as eye drops, eye drops for contact lenses, and eyewashes. If kept inside the body network structure, the drug can be delivered to the cornea at a high concentration. As an ophthalmic composition, it can be suitably used as an eye drop.

  EXAMPLES Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example. In the following examples, unless otherwise specified, “%” in the composition indicates W / V%, and the ratio indicates a mass ratio.

[Examples 1 to 49, Comparative Examples 1 to 18]
(B) All the components except the component were dispersed in purified water and adjusted for pH, and then heated and dissolved under the conditions of 80 ° C. Subsequently, a predetermined amount of component (B) was added, stirred for 10 minutes with a stirrer, and then cooled to room temperature to prepare a composition. In addition, about the thing exceeding pH 4.8, (B) component was added, after stirring for 10 minutes with a stirrer, it cooled at 5 degreeC for 12 hours, and prepared the composition. The following evaluation was performed about the obtained composition. For Example 2 and Comparative Example 2, the residence time was also evaluated. The results are also shown in the table.

[Formation of network structure of molecular assembly]
Formation of the network structure was confirmed by observation with a transmission electron microscope. The case where the formation of the network structure of the molecular assembly was formed was designated as “◯”, and the case where the formation was not formed was designated as “X”.
<Confirmation of network structure formation by transmission electron microscope>
(1) Sample preparation / equipment: Rapid freezing device EM-CPC (manufactured by LEICA)
・ Quick freezing condition Freezing refrigerant: liquid ethane, freezing temperature: less than -170 ° C Procedure 1) Drop sample (about 4 microliters) on grid 2) Absorb excess with filter paper and make thin (<300nm)
3) Instant freezing into liquid ethane for rapid freezing (formation of amorphous ice)
(2) Observation / apparatus: Transmission electron microscope H-7650 (manufactured by Hitachi High-Technologies)
Observation conditions: acceleration voltage: 120 kV, emission current: 3 microamperes, spot size: 1 micrometer, observation temperature: <−170 ° C.
Low Dose ConDition moDe
Cryotransfer CT-3500 (manufactured by OxfordD Instruments)

  FIG. 1 shows the results of observation with a transmission electron microscope of Example 9 and FIG. In FIG. 1, an entangled structure was observed depending on the network structure of string-like micelles having a thickness of about 3 nm.

[Storage modulus G ']
The gel strength was evaluated using a storage elastic modulus G ′ obtained by dynamic viscoelasticity measurement (frequency-dependent measurement) using a stress control type rheometer AR-2000EX manufactured by TA Instruments. The measurement was performed using a cone plate system having a diameter of 4 Cm and a cone angle of 1 ° at 25 ° C. and a frequency of 0.628 rAD / s to 6.28 rAD / s. Since G ′ takes a constant value in the measurement frequency range, G ′ at 6.28 rAD / s was used as a representative value. In addition, when a thickener is mix | blended, it evaluates using G 'before a mixing | blending.

  A network structure is confirmed as described above, and a storage elastic modulus G ′ of 0.5 or more is a molecular aggregate that exhibits viscoelasticity.

[Evaluation of non-stickiness]
Two healthy subjects were instilled with 2 drops each, and the stickiness at the time of instillation was scored according to the following criteria. 3 points: no sticky feeling, 2 points: almost no sticky feeling, 1 point: slightly sticky feeling, 0 points: sticky feeling A result is shown by the following references | standards from the average score of 3 persons. “◎”, “◯”, “△” are acceptable.
<Evaluation criteria for non-stickiness>
◎: 2.5 points or more ○: Less than 2.5 points 1.5 points or more Δ: Less than 1.5 points 0.5 points or more ×: Less than 0.5 points

[Residence time]
After adding 0.05 mass% of fluorescent dye fluorescein sodium to the prepared composition, 20 μL was instilled into the conjunctival sac of 5 subjects. The average value of the time until the fluorescent color of sodium fluorescein could not be confirmed in the conjunctival sac was defined as the residence time. A slit lamp (SL-D8Z, manufactured by Topcon Corporation) was used for observation. The determination was made visually based on the following criteria.
<Criteria>
◎: More than 60 minutes ○: More than 30 minutes and less than 60 minutes △: More than 10 minutes and less than 30 minutes ×: Less than 10 minutes

[Prescription Examples 1 to 5]
An external skin solution and eye drops having the composition shown in the following table were prepared based on the production methods of the above Examples.

The raw materials used in preparing the examples and comparative examples are shown below. Unless otherwise specified, the amount of each component in the table is a pure conversion amount.
Dipotassium glycyrrhizinate (manufactured by Maruzen Pharmaceutical Co., Ltd.)
Pyridoxine hydrochloride (Daiichi Fine Chemical Co., Ltd.)
Diphenhydramine hydrochloride (manufactured by Wako Pure Chemical Industries, Ltd.)
Tetrahydrozoline hydrochloride (Okami Chemical Co., Ltd.)
Naphazoline hydrochloride (MP Biomedicals, Inc.)
Ketotifen fumarate (manufactured by Wako Pure Chemical Industries, Ltd.)
Chlorpheniramine maleate (manufactured by Kongo Chemical Co., Ltd.)
Berberine Chloride Hydrate (Alps Pharmaceutical Co., Ltd.)
Berberine sulfate hydrate (manufactured by Tokyo Chemical Industry Co., Ltd.)
Epinephrine (manufactured by Wako Pure Chemical Industries, Ltd.)
Phenylephrine hydrochloride (manufactured by Wako Pure Chemical Industries, Ltd.)
Ephedrine hydrochloride (Maruishi Pharmaceutical Co., Ltd.)
Methylephedrine hydrochloride (manufactured by Alps Pharmaceutical Co., Ltd.)
HPMC (hydroxypropylmethylcellulose) (manufactured by Shin-Etsu Chemical Co., Ltd.) 90SH-4000
Sodium alginate (Kimika Co., Ltd.) I-8

Claims (5)

  (A) One or more kinds selected from glycyrrhizic acid and glycyrrhizinate, 0.1 to 0.3 W / V%, (B) a basic substance having a cyclic structure or a polycyclic structure 0.005 to 0.15 W / A pharmaceutical composition containing V%, having a contained mass ratio represented by (B) / (A) of 0.017 to 0.6, and a pH of 3.0 to 6.0.   The pharmaceutical composition according to claim 1, comprising a molecular assembly that exhibits viscoelasticity.   (B) is tetrahydrozoline hydrochloride, pyridoxine hydrochloride, diphenhydramine hydrochloride, ketotifen fumarate, chlorpheniramine maleate, berberine sulfate hydrate, berberine chloride hydrate, epinephrine, phenylephrine hydrochloride, ephedrine hydrochloride, The pharmaceutical composition according to claim 1 or 2, selected from methylephedrine hydrochloride and naphazoline hydrochloride.   The pharmaceutical composition according to any one of claims 1 to 3, which is an external preparation composition.   The pharmaceutical composition according to any one of claims 1 to 3, which is an eye drop or an eye wash.