JP2729859B2 - Reversible thermogelling aqueous pharmaceutical composition - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a reversible thermogelling aqueous pharmaceutical composition containing a pharmaceutically active ingredient, methylcellulose, citric acid and polyethylene glycol (hereinafter abbreviated as PEG), and more specifically to the aqueous pharmaceutical composition. When a substance is a liquid that is flowable at or below room temperature and is administered to the eye or body cavity of a mammal or applied to the skin, it gels at the body temperature of the mammal, thereby increasing the bioavailability of the medicinal ingredient. The present invention relates to an aqueous pharmaceutical composition having the property of maintaining the efficacy over a long period of time.

2. Description of the Related Art Heretofore, there have been several aqueous pharmaceutical compositions that efficiently release a pharmaceutically active ingredient to a mammal in need of treatment, which are liquid at room temperature or below and are semi-solid or gel at the body temperature of the mammal. Are also disclosed. U.S. Patent No.
No. 4,188,373 discloses a thermogelled aqueous pharmaceutical composition in which an aqueous composition of Pluronic (PLURONIC) gels by heat and a desired sol-gel transition temperature can be obtained by adjusting the concentration of Pluronic. . Also,
U.S. Pat.Nos. 4,474,751, 4,474,752, 4,474,753
No. 4,478,822 describe a drug release system using a thermogelled aqueous pharmaceutical composition. The characteristics of these systems
The ability to change the sol-gel transition temperature and / or gel hardness by adjusting the pH and / or ionic concentration and polymer concentration. More recently, an aqueous pharmaceutical composition (patent WO 91/19481) that gels locally due to simultaneous changes in pH and temperature has been proposed.

However, the gelling substances used in these aqueous compositions have not yet been established as safe at all sites requiring treatment, and the polymer concentration in the aqueous composition is high, so the liquid state Is difficult to use depending on the site (for example, the eye) requiring treatment. JP-A-62-181228 discloses an aqueous sol-gel phase transition pharmaceutical composition based on ionic strength. This is because the concentration of the substance causing the sol-gel phase transition can be reduced to 10 to 100 times lower than that of the above-mentioned thermogelling aqueous pharmaceutical composition, and the risk of gelation due to an increase in environmental temperature during storage. Although it is characterized by the absence, it can be applied only to a specific part (for example, eyes).

On the other hand, it is well known that a methylcellulose aqueous solution gels by heating and returns to a sol state by cooling, that is, the sol-gel phase transition is reversible, and much research has been conducted on the mechanism.

Ohba reports that a gel is formed by heating a methylcellulose aqueous solution at a constant rate, the correlation between the degree of polymerization and concentration of methylcellulose and the gelation temperature, and the change in the gelation temperature due to the addition of ions (Hakodate Kogyo) Bulletin of National College of Technology, No. 22, 113-120, 1987). However, there is no description about a methylcellulose-containing aqueous composition that gels around the body temperature of mammals.

E. Heymann measured the sol-gel transition temperature in combination with a salt using a methylcellulose aqueous solution having a methoxyl group content of 35.4% (methylcellulose concentration: 1.6%). However, according to the experiments of the present inventors, the methylcellulose (methoxyl group content: 26 to 33%) used in the present invention has a salt concentration of 0.2 mol aqueous solution of methylcellulose (methylcellulose concentration: 1.6%) and the body temperature of a mammal. No gelation at all.

DISCLOSURE OF THE INVENTION The present inventors have developed an aqueous gelling solution at room temperature or below in liquid form at mammalian body temperature using a gelling substance with established safety that can be applied to all sites in need of treatment. As a result of intensive studies to develop a pharmaceutical composition, an excellent aqueous solution that does not cause discomfort after administration by gelling at a local temperature by mixing methylcellulose, citric acid and PEG of a certain range of molecular weight in an appropriate amount, and The present inventors have found that a pharmaceutical composition can be obtained and completed the present invention.

That is, the present invention is a reversible thermogelling aqueous pharmaceutical composition containing an effective amount of a drug used for pharmacological treatment or diagnosis, wherein methylcellulose (the content of methoxyl group is in the range of 26 to 33%). Stuff) 0.2-2.1 (W / V)%,
Citric acid 1.2-2.3 (W / V)%, polyethylene glycol
The above composition comprising 0.5 to 13 (W / V)% and a sufficient amount of a pharmaceutically acceptable pH adjuster to adjust the pH of the composition to a range of 3 to 10. It depends on. Since the aqueous pharmaceutical composition of the present invention has good fluidity at room temperature or below, it is easy to administer or apply a fixed amount to a site requiring treatment, and gels quickly after application, so that it is gelled at all sites. Good retention of the drug, and can maintain the drug effect for a long time.

One of the excellent properties of the composition of the present invention is that it is a low viscosity liquid at a temperature lower than the body temperature of the mammal due to the low concentration of the polymer methylcellulose, and was brought into contact with the mammal in need of treatment. Sometimes this is to quickly form a very high viscosity semi-solid or gel. Still another property is that the liquid has a low viscosity, so that it can quickly reach the treatment site and has good contact properties. Yet another property is that it is non-irritating to the eye, so that pain to the patient can be minimized even when used on the skin or body cavities.

Methylcellulose (methoxyl group content: 26% to 33%) used in the present invention may be any methylresulose as long as the viscosity of the 2% aqueous solution at 20 ° C. is in the range of 13 to 12,000 millipascal-seconds. They can be used alone or in combination. The methoxy group content is preferably in the range of 26% to 33% from the viewpoint of solubility in water.
Such methylcellulose is available from Shin-Etsu Chemical Co., Ltd. as Metrolose SM15, SM25, SM100, SM400, SM15.
00, SM4000, SM8000 (numbers are millipascal-second values at 20 ° C. viscosity of 2% aqueous solution), Marporose M from Matsumoto Yushi Pharmaceutical Co., Ltd. or Methocel A from Dow Chemical Company
And are readily available.

PEG used in the present invention is PEG-200, -300, -60
0, -1,000, -1,540, -2,000, -4,000, -6,000,-
20,000, -50,000, -500,000, -2,000,000 and -4,000
Macrogol -200, -300, -400, -600, -1,500, -1,540,-from Wako Pure Chemical Industries, Ltd.
It is sold by NOF Corporation under trade names of 4,000, -6,000, and -20,000.

The weight average molecular weight of the PEG used in the present invention is 300 to 50,0.
00 is preferable, and 1,000 to 20,000 is particularly preferable. When the weight-average molecular weight is lower than 300, gelation hardly occurs locally, and when the weight-average molecular weight is higher than 50,000, the viscosity in a liquid state is undesirably high. It is also possible to mix two or more PEGs to adjust the weight average molecular weight within the above-mentioned optimum range.

In an embodiment of the reversible thermogelling aqueous pharmaceutical composition of the present invention, the concentration ranges of methylcellulose, citric acid and PEG are limited for the following reasons.

The concentration of methylcellulose used in the present invention is 0.2
If the concentration is lower than 0.2 (W / V)%, a local gel is less likely to be formed, and 2.1 (W / V)%.
%, It is not preferable because the viscosity of the sol is too high and the dose is inaccurate.

The concentration of citric acid is in the range of 1.2 to 2.3 (W / V)%. If the concentration is lower than 1.2 (W / V)%, it is difficult to form a local gel, and the concentration is 2.3 (W / V). %) Is not preferable in terms of eye irritation.

The PEG concentration ranges from 0.5 to 13 (W / V)%,
If it is lower than (W / V)%, it is difficult to form a gel locally, and the practicality is poor. If it is higher than 13 (W / V)%, the viscosity of the sol is undesirably high.

The gelation temperature of the composition is preferably about 20 ° C. to about 40 ° C., since it is liquid at room temperature or lower and it is desired to gel at the body temperature of mammals.

The aqueous pharmaceutical composition of the present invention is used, for example, for treating or diagnosing diseases of the eyes, skin and body cavities. Examples of drugs or diagnostic agents which can be administered to mammalian eyes and which are contained in the composition of the present invention are shown below. Chemotherapeutic agents such as amphotericin B, norfloxacin, miconazole nitrate, ofloxacin and idoxuridine; antibiotics such as chloramphenicol, colistin sodium methanesulfonate, carbenicillin sodium and gentamicin sulfate; −
(1H-tetrazol-5-yl) oxanilic acid (hereinafter abbreviated as MTCC), ketotifen fumarate and sodium cromoglicate; betamethasone sodium phosphate, dexamethasone, fluorometholone, dipotassium glycyrrhizinate, lysozyme chloride as anti-inflammatory agents , Diclofenac sodium, pranoprofen, indomethacin, cortisone acetate, azulene, allantoin and epsilon-aminocaproic acid; pilocarpine hydrochloride and carbachol as miotics; flavin adenine dinucleotide, pyridoxal phosphate and cyanocobalamin as vasoconstrictors; Naphazoline and phenylephrine hydrochloride; chlorpheniramine maleate and diphenhydramine hydrochloride as antihistamines; tropicami as mydriatic Timolol maleate and carteolol hydrochloride for the treatment of glaucoma; glutathione and pyrenoxine for the treatment of cataract; lidocaine hydrochloride and oxybuprocaine hydrochloride as local anesthetics; sodium fluorescein as an ophthalmic diagnostic agent; cyclosporine and azathioprine as immunosuppressants; Fluorouracil and tegafur as antagonists; epinephrine hydrochloride as a decongestant; therapeutic agent for diabetic retinopathy [5-
(3-thienyl) tetrazol-1-yl] vinegar powder (hereinafter abbreviated as TAT); sodium chondroitin sulfate and aminoethylsulfonic acid as amino acids; neostigmine methyl sulfate and mixtures thereof as autonomic nerve agents. Other drugs may be used to treat eye conditions and lesions.

Examples of drugs that can be applied to mammalian skin and contained in the composition of the present invention are shown below. Agents for parasitic skin diseases include bifonazole, siccanin, bisdecalinium acetate, clotrimazole and salicylic acid; agents for purulent diseases such as sulfamethoxazole sodium, erythromycin and gentamicin sulfate; and anti-inflammatory analgesics such as indomethacin, ketoprofen, Benmethasone and fluocinolone acetonide; diphenhydramine as an antipruritic agent; procaine hydrochloride and lidocaine hydrochloride as local anesthetics; and iodine, povidone iodine, benzalkonium chloride and chlorhexidine gluconate as bactericidal disinfectants for dermis.

Examples of drugs which can be administered to the body cavity of mammals, ie, rectum, urethra, nasal cavity, vagina, ear canal, oral cavity or oral cavity, contained in the composition of the present invention are shown below. Diphenhydramine hydrochloride and chlorpheniramine maleate as antihistamines; clotrimazole, naphazolyl nitrate, ketotifen fumarate and miconazole nitrate as reproductive organs; tetrizoline hydrochloride as otolaryngological agent; aminophylline as bronchodilator; antimetabolite Drugs: fluorouracin; hypnotics and sedatives: diazepam; antipyretic analgesics and antiphlogistics: aspirin, indomethacin, sulindac, phenylbutazone and ibuprofen; adrenal hormones: dexamethasone, triamcinolone and hydrocortisone; local anesthetic: lidocaine hydrochloride Sulphosoxazole, kanamycin, tobramycin and erythromycin as agents for purulent diseases; norfloxacin and nalidixic acid as synthetic antibacterial agents It is below.

The content of the active agent varies depending on the type of the agent, but is generally preferably in the range of about 0.001% to 10% by weight.

Hydrochloric acid as a pH adjuster used in the composition of the present invention,
Examples include sulfuric acid, boric acid, phosphoric acid, and acetic acid, and bases such as sodium hydroxide, monoethanolamine, diethanolamine, and triethanolamine.

The aqueous pharmaceutical composition of the present invention can contain a pharmaceutically acceptable buffer, salt, preservative, solubilizing agent, and the like, if necessary. As preservatives, invert soaps such as benzalkonium chloride, benzethonium chloride and chlorhexidine gluconate, parabens such as methylparaben, ethylparaben, propylparaben and butylparaben, alcohols such as chlorobutanol, phenylethyl alcohol and benzyl alcohol. Organic acids and salts thereof, such as, sodium dehydroacetate, sorbic acid and sodium sorbate can be used. Further, a surfactant or a chelating agent can be appropriately added. These components are generally used in the range of about 0.001-2% by weight, preferably about 0.002-1% by weight. Examples of the buffer include alkali metal salts of acids such as phosphoric acid, boric acid, acetic acid, tartaric acid, lactic acid and carbonic acid, amino acids such as glutamic acid, epsilon aminocaproic acid, aspartic acid, glycyl, arginine and lysine, taurine, trisaminomethane and the like. Is raised. These buffers add to the composition the amount necessary to maintain the pH of the composition at 3-10.

Examples of the solubilizer include polysorbate 80, polyoxyethylene hydrogenated castor oil and cyclodextrin, and are used in the range of 0 to 15% by weight.

The method for producing the aqueous pharmaceutical composition of the present invention is not particularly limited.For example, citrate and PEG are dissolved in sterile purified water, and the pH of the solution is adjusted with a pH adjuster. After adding the preservative, a solution of methylcellulose dissolved in sterilized purified water in advance is added, the pH is adjusted again, and the mixture is stirred with sterilized purified water and ice-cooled. If necessary, this is followed by the addition of various additives, such as buffers, salts and preservatives. When the drug is hardly soluble or insoluble, it is used after being suspended or solubilized with a solubilizing agent.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows the relationship between the metroze concentration and pH in aqueous compositions and the gelation temperature. The vertical axis represents the concentration of Metrolose SM400 ((W / V)%), and the horizontal axis represents the pH.

FIG. 2 shows the relationship between the concentration of the aqueous composition in rabbit blood after instillation and time. The vertical axis represents timolol concentration (ng / ml), and the horizontal axis represents time (hr).

BEST MODE FOR CARRYING OUT THE INVENTION The following examples illustrate various aspects of the present invention and do not limit the scope of the present invention.

〔Example〕

Example 1 In 50 ml of sterile purified water, 2.3 g of citric acid and polyethylene glycol 4000 (weight average molecular weight 3000, Wako Pure Chemical Industries, Ltd.)
6.0 g) and 0.5 g of chlorobutanol. To this, a solution prepared by dissolving 0.1 g of idoxuridine in 10 ml of 3N sodium hydroxide and a solution prepared by dissolving 0.5 g of Metroze SM400 (manufactured by Shin-Etsu Chemical Co., Ltd.) in 25 ml of sterilized purified water are added. Adjust the pH to 6.0 with 3N sodium hydroxide, make up to 100 ml with sterile purified water, and stir well with ice cooling to dissolve into eye drops.

Example 2 2.3 g of citric acid and 6.0 g of polyethylene glycol 4000 were dissolved in 50 ml of sterile purified water, and the solution was adjusted to pH 5 with 3N sodium hydroxide.
Adjust to 0. To this, 0.3 g of norfloxacin and 0.005 g of benzalkonium chloride were added.
Add 0.5 g dissolved in 25 ml sterile purified water.
Adjust the pH to 5.5 with 3N sodium hydroxide, and add 1
Make up to 00 ml, stir well with ice cooling and dissolve to give eye drops.

Examples 3 to 6 According to Example 2, eye drops having the compositions shown in Table 1 were prepared in the same manner.

Example 7 Methyl paraben was added to 50 ml of sterile purified water preheated to about 60 ° C.
Add 026 g and 0.014 g of propylparaben, and stir well to dissolve. After cooling the solution to room temperature, citric acid 2.3g,
Polyethylene glycol 4000 6.0 g, chlorobutanol
Add 0.25 g to dissolve and adjust the pH with monoethanolamine.
Adjust to 5.0. To this, 0.1 g of MTCC is added, and further, 0.5 g of Metrolose SM400 dissolved in 25 ml of sterilized purified water is added. Adjust the pH to 5.5 with monoethanolamine, make up to 100 ml with sterile purified water, and stir well with ice cooling to dissolve into eye drops.

Example 8 According to Example 7, eye drops having the composition shown in Table 1 were prepared in the same manner.

Example 9 Pranoprofen 0.1 g, citric acid 2.
Add 3 g and 4000 g of polyethylene glycol 4000, stir well, and adjust the pH to 6.5 with monoethanolamine. To this, 0.005 g of benzalkonium chloride is added, and further, 0.5 g of Metrolose SM400 dissolved in 25 ml of sterilized purified water is added. Adjust the pH to 7.4 with monoethanolamine, make up to 100 ml with sterile purified water, and stir well with ice cooling to dissolve into eye drops.

Example 10 Methylparaben was added to 50 ml of sterile purified water preheated to about 60 ° C.
Add 026 g and 0.014 g of propylparaben, and stir well to dissolve. After the solution is cooled to room temperature, 0.05 g of naphazoline nitrate, 3.5 g of trisodium citrate dihydrate and 4000 6.0 g of polyethylene glycol are added and dissolved. To this, a solution prepared by dissolving 0.5 g of Metrolose SM400 in 25 ml of sterilized purified water is added, and the mixture is stirred well. Adjust the pH to 5.8 with 1N hydrochloric acid, make up to 100 ml with sterile purified water, and stir well with ice cooling to dissolve into eye drops.

Examples 11 to 13 According to Example 10, eye drops having the compositions shown in Table 1 were prepared in the same manner.

Example 14 In 50 ml of sterile purified water, 0.34 g of timolol maleate, 3.5 g of trisodium citrate dihydrate, 6.0 g of polyethylene glycol 4000, and 0.005 g of benzalkonium chloride are added and dissolved. To this, a solution prepared by dissolving 0.5 g of Metrolose SM400 in 25 ml of sterilized purified water is added, and the mixture is stirred well. Adjust the pH to 6.8 with 1N hydrochloric acid or 1N sodium hydroxide, make up to 100 ml with sterile purified water, and stir well with ice cooling to dissolve into eye drops.

Examples 15 to 19 According to Example 14, eye drops having the composition shown in Table 1 were prepared in the same manner.

Examples 20 to 22 According to Example 14, a dermatological composition having the composition shown in Table 1 is obtained in the same manner.

Example 23 According to Example 10, a dermatological agent having the composition shown in Table 1 was prepared in the same manner.

Examples 24 to 31 In accordance with Example 14, a body cavity preparation having the composition shown in Table 1 was prepared in the same manner.

Test Example 1 (Metroase concentration, pH and gelation concentration) Trisodium citrate dihydrate 3.5 in 50 ml of sterile purified water
g, dissolving 6.0 g of polyethylene glycol 4000, adding 0.3-2.0 g of Metrolose SM400 dissolved in 25 ml of sterile purified water, and adding 3N hydrochloric acid or 3N sodium hydroxide to pH.
Was adjusted to 3.0 to 10.0, the volume was adjusted to 100 ml with sterile purified water, and the mixture was dissolved with sufficient stirring while cooling with ice to prepare an aqueous composition. The gelation temperature was measured for each of the aqueous compositions. The results obtained are shown in FIG.

Test Example 2 (Human usability test) Dissolve 1.9-2.9 g of citric acid and 4.2 g of polyethylene glycol 4000 in 50 ml of sterile purified water, adjust the pH to 6.8 with 3N sodium hydroxide, and make up to 100 ml with sterile purified water. And dissolve by stirring well with ice cooling.
~ 4 were prepared. In addition, citric acid 1.9 in 50 ml of sterile purified water
2.9 g and 4.2 g of polyethylene glycol 4000 are dissolved, and the pH is adjusted to 6.0 with diethanolamine. A solution prepared by dissolving 0.7 g of Metrolose SM400 in 25 ml of sterilized purified water was added, the pH was adjusted to 6.8 with diethanolamine, the volume was increased to 100 ml with sterilized purified water, and the mixture was stirred well with ice cooling to dissolve. Aqueous compositions 5 to 8 were prepared.

A sensory test was conducted by 20 panelists on the eye irritation of each aqueous composition. Evaluation criteria are "-" for "no stimulation",
“Slightly see” is “+”, and “slightly” is “++”. Tables 2 and 3 show the results of the test.

As is clear from the results of Tables 2 and 3, eye irritation occurs when the concentration of citric acid is set to 2.5 (W / V)% or more regardless of the type of citrate. In contrast, the aqueous composition of the present invention did not cause eye irritation.

Test Example 3 (Rabbit aqueous humor transfer test) An aqueous composition 9 was prepared by adding 0.9 g of sodium chloride instead of methylcellulose, sodium citrate and PEG in Example 14. Also, the embodiment
Prepare the one without the PEG in 14, the aqueous composition 10
And The aqueous humor transferability of Example 14, aqueous compositions 9 and 10 was tested using male white rabbits (body weight 2.5 to 3.5 kg) with 6 eyes per group. 50 μl was instilled into rabbits, and 10 minutes after administration, 30 minutes
The timolol concentration in the aqueous humor was measured for minutes, 1 hour, 2 hours, and 4 hours. Table 4 shows the results of the test.

As is clear from the results in Table 4, the aqueous composition of the present invention maintained a high concentration for a long time as compared to an ophthalmic solution that did not gel locally.

Test Example 4 (Rabbit Blood Transfer Test) Regarding the blood transfer property of Example 14, aqueous composition 9, male white rabbits (body weight 2.5 to 3.5 kg) were tested as a group of 5 to 6 birds. 50 μl was instilled into rabbits, 10 minutes, 30 minutes, 1 minute after administration.
Time, 2 hours, 4 hours and 6 hours, blood timolol concentration was measured. FIG. 2 shows the results of the test.

As is evident from the results of FIG. 2, the aqueous composition of the present invention suppresses the transfer of timolol into the blood and reduces systemic side effects as compared to an ophthalmic solution that does not gel locally.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Hiroki Maruyama 1-3-5 Nihonbashi Muromachi, Chuo-ku, Tokyo Inside Wakamoto Pharmaceutical Co., Ltd. (72) Inventor Miyako Fukushima 1-3-5 Nihonbashi Muromachi, Chuo-ku, Tokyo Wakamoto Pharmaceutical Co., Ltd. (72) Keiko Masuda, Inventor 1-5-3, Nihonbashi Muromachi, Chuo-ku, Tokyo Wakamoto Pharmaceutical Co., Ltd. (72) Inventor Toru Oguma 1-3-5, Nihonbashi-Muromachi, Chuo-ku, Tokyo (72) Inventor Masayoshi Goto 1-5-3 Nihonbashi Muromachi, Chuo-ku, Tokyo Wakamoto Pharmaceutical Co., Ltd.

Claims (14)

(57) [Claims] 1. A reversible thermogelling aqueous pharmaceutical composition containing an effective amount of a drug used for pharmacological treatment or diagnosis, comprising methylcellulose (having a methoxyl group content of 26 to 33).
%) 0.2-2.1 (W / V)%, citric acid 1.2%
~ 2.3 (W / V)%, polyethylene glycol 0.5 ~ 13 (W / V)
V) A composition as described above, characterized in that it contains% and a sufficient amount of a pharmaceutically acceptable pH adjuster to adjust the pH of the composition to the range of 3-10. 2. Pharmaceutically effective drugs include chemotherapeutic drugs, antibiotics, antiallergic drugs, antiinflammatory drugs, miotics, vitamins,
Vasoconstrictors, antihistamines, mydriatics, glaucoma treatments,
Claims selected from the group consisting of cataract therapeutic agents, local anesthetics, ophthalmic diagnostic agents, immunosuppressants, antimetabolites, decongestants, autonomic nervous agents, diabetic retinopathy agents, amino acids, and mixtures thereof. Item 6. The ophthalmic aqueous pharmaceutical composition according to Item 1. (3) The drug is amphotericin B, norfloxacin, miconazole nitrate, ofloxacin, idoxuridine, chloramphenicol, colistin sodium methanesulfonate, carbenicillin sodium, gentamicin sulfate, ketotifen fumarate, sodium cromoglicate, 3 '-( 1H-tetrazol-5-yl) oxanilic acid, betamethasone sodium phosphate, dexamethasone, fluorometholone, dipotassium glycyrrhizinate, lysozyme chloride, diclofenac sodium, planoprofen, indomethacin, cortisone acetate, azulene, allantoin, epsilon-aminocaproic acid , Pilocarpine hydrochloride, carbachol, flavin adenine dinucleotide, pyridoxal phosphate, cyanocobalamin, sodium nitrate Azorin, phenylephrine hydrochloride,
Chlorpheniramine maleate, diphenhydramine hydrochloride, tropicamide, timolol maleate, carteolol hydrochloride, glutathione, pyrenoxine, oxybuprocaine hydrochloride, lidocaine hydrochloride, fluorescein sodium, cyclosporine, azathioprine, fluorouracil, tegafur, epinephrine hydrochloride, neostigmine methyl sulfate, 5- (3-thienyl) tetrazole-1-
3. The composition according to claim 2, wherein the composition is selected from the group consisting of compounds consisting of acetic acid and sodium chondroitin sulfate. 4. A chemotherapeutic drug is idoxuridine or norfloxacin, an antibiotic is gentamicin sulfate, an antiallergic drug is 3 '-(1H-tetrazol-5-yl) oxanilic acid or sodium cromoglycate, and an antiinflammatory drug is Betamethasone phosphate or planoprofen,
The vitamins are flavin adenine dinucleotide, the local anesthetic is lidocaine hydrochloride, the vasoconstrictor is naphazoline nitrate, the miotic is pilocarpine hydrochloride, the glaucoma treatment is timolol maleate, the cataract treatment is pyrenoxine, the immunosuppressant is cyclosporine, Antimetabolites are fluorolaucil, ophthalmic diagnostics are fluorescein sodium, mydriatics are tropicamide and diabetic retinal therapeutics are [5- (3-
The composition according to claim 2, which is [thienyl) tetrazol-1-yl] acetic acid. 5. The pharmacologically effective drug is selected from the group consisting of a drug for parasitic skin diseases, a drug for purulent diseases, an anti-inflammatory analgesic, an antipruritic, a local anesthetic, and a bactericidal disinfectant for skin.
A topical or dermatological aqueous pharmaceutical composition as described. (6) the drug is clotrimazole, salicylic acid, bifonazole, siccanin, bisdecalinium acetate, sulfamethoxazole sodium, erythromycin,
The composition according to claim 5, which is selected from a compound consisting of gentamicin sulfate, indomethacin, ketoprofen, diphenhydramine, procaine hydrochloride, lidocaine hydrochloride, iodine, povidone iodine, benzalkonium chloride, chlorhexidine gluconate, betamethasone valerate, and fluocinolone acetonide. . 7. The agent for a parasitic skin disease wherein clotrimazole,
6. The composition according to claim 5, wherein the agent for purulent diseases is gentamicin sulfate, the anti-inflammatory and analgesic agent is indomethacin, the antipruritic agent is diphenhydramine, the local anesthetic is lidocaine hydrochloride, and the germicidal antiseptic for dermis is povidone-iodine. 8. A pharmacologically effective agent comprising an antihistamine, a reproductive organ agent, an otolaryngological agent, a bronchodilator, an antimetabolite,
2. The aqueous medicine for administration to a body cavity according to claim 1, which is selected from the group consisting of a hypnotic analgesic, an antipyretic analgesic anti-inflammatory agent, an adrenal hormone agent, a local anesthetic, an agent for purulent diseases, a synthetic antibacterial agent and a mixture thereof. Composition. 9. The drug may be diphenhydramine hydrochloride, chlorpheniramine maleate, clotrimazole, miconazole nitrate, tetrizoline hydrochloride, naphazoline nitrate, ketotifen fumarate, aminophylline, fluorouracil,
9. The method according to claim 8, wherein the compound is selected from diazepam, aspirin, indomethacin, sulindac, phenylbutazone, ibuprofen, dexamethasone, triamcinolone, hydrocortisone, lidocaine hydrochloride, sulfisoxazole, kanamycin, tobramycin, erythromycin, norfloxacin and nalidixic acid. Composition. 10. An antihistamine agent: diphenhydramine hydrochloride, a reproductive organ agent: miconazole nitrate, an otolaryngological agent: tetrizoline hydrochloride, a bronchodilator: aminophylline, an antimetabolite: fluorouracil, a hypnotic sedative: diazepam,
9. The composition according to claim 8, wherein the antipyretic analgesic is indomethacin, the adrenal hormonal agent is dexamethasone, the local anesthetic is lidocaine hydrochloride, the purulent agent is erythromycin, and the synthetic antibacterial agent is norfloxacin. 11. A 2.0% aqueous solution of methyl cellulose at 20 ° C.
2. The composition according to claim 1, wherein the composition has a viscosity of 13 to 12,000 millipascal-seconds. 12. The composition according to claim 1, wherein the polyethylene glycol has a weight average molecular weight of 300 to 50,000. 13. The composition has a gelation temperature of about 20 ° C. to about 40 ° C.
The composition of claim 1, wherein the composition is liquid at a temperature below this temperature. 14. The method according to claim 1, which comprises at least one of a pharmaceutically acceptable buffer, salt, preservative and solubilizer.
A composition as described.