WO1999063968A1

WO1999063968A1 - Aqueous preparations containing hardly soluble drug

Info

Publication number: WO1999063968A1
Application number: PCT/JP1999/003107
Authority: WO
Inventors: Hidekazu Suzuki; Hiroyuki Ogawa; Koji Ueno; Masanobu Takeuchi
Original assignee: Wakamoto Pharmaceutical Co., Ltd.
Priority date: 1998-06-10
Filing date: 1999-06-10
Publication date: 1999-12-16
Also published as: AU4061599A

Abstract

Aqueous preparations containing a hardly soluble drug, polysorbate and/or polyoxyethylene-hardened castor oil and methyl cellulose and/or hydroxypropyl cellulose preferably together with polyethylene glycol; and reversibly heat-gelling aqueous preparations containing citric acid or its salt in addition to the above composition. These aqueous preparations little irritate living bodies when administered thereto. The reversibly heat-gelling aqueous preparations are excellent in gelling properties and gel at the body temperature of a mammalian. Thus, the bioavailability of the hardly soluble drug can be enhanced and the drug effect can be sustained over a prolonged period of time.

Description

The scope of the claims

1. A preparation comprising a poorly soluble drug dissolved in water with polysorbate and / or polyoxyethylene hydrogenated castor oil and methylcellulose and / or hydroxypropylmethylcellulose.

2. The preparation according to claim 1, comprising the following components A to D.

A. poorly soluble drug

B. Polysorbate and / or polyoxetilene castor oil

C. Methyl cellulose

D. Polyethylene glycol

3. The preparation according to claim 2, comprising the following components A to E.

A. poorly soluble drug

B. Polysorbate and / or polyoxyethylene hydrogenated castor oil

C. Methyl cellulose

D. Polyethylene glycol

E. Cuic acid or pharmaceutically acceptable salt thereof

4. The poorly soluble drug is at least one selected from the group consisting of an antifungal agent, a synthetic antibacterial agent, an anti-herpesvirus agent, an antiplatelet agent, an i-blocker, and a carbonic anhydrase inhibitor. The preparation according to any one of claims 1 to 3.

5. The poorly soluble drug is at least one selected from the group consisting of dipyridamole, acyclovir, prazosin hydrochloride, acetazolamide, metazolamide, norfloxacin, ofloxacin, lomefloxacin hydrochloride, econazol nitrate, and miconazole nitrate. The preparation according to any one of claims 1 to 4, which is:

6. The preparation according to any one of claims 1 to 5, wherein the dosage form is any of an oral solution, an injection, an eardrop, a nasal drop, an eye drop, a spray, and an inhalant. 7. After dissolving diviridamol in an aqueous solution containing polysorbate and / or polyoxyethylene hydrogenated castor oil and methylcellulose and / or hydroxypropylmethylcellulose, and adjusted to pH 4 or less, add a basic component and add p. A method for preparing an aqueous diviridamol formulation wherein H is adjusted to 5 to 8.

8. The pork mouth building is prepared under an aqueous solution containing polysorbate and / or polyoxyethylene castor oil and methylcellulose and / or hydroxypropylmethylcellulose and adjusted to pH 3 or less or PH 10 or more. A method for preparing an aqueous formulation of acyclovir wherein the pH is adjusted to 5.5 to 8 by adding an acid or a basic component after dissolution.

9. At least one sparingly soluble drug selected from the group consisting of norfloxacin, ofloxacin, lomefloxacin hydrochloride, econazole nitrate, and miconazole nitrate, is added to polysorbate and / or polyoxyethylene hydrogenated castor oil and polyethylene. A method for preparing an aqueous preparation containing a poorly soluble drug by dissolving in a mixture comprising glycol and then adding water to form an aqueous preparation.

10. A solubilizer consisting of a surfactant and a water-soluble polymer for dissolving poorly soluble drugs in water.

11. The solubilizing agent according to claim 10, comprising polysorbate and / or polyoxetylene hydrogenated castor oil for dissolving a poorly soluble drug in water, and methylcellulose and / or hydroxypropylmethylcellulose.

12. The soluble according to claim 10 or 11, comprising polysorbate and / or polyoxyethylene hardened castor oil and / or methylcellulose and / or hydroxypropylmethylcellulose and polyethylene glycol for dissolving the poorly soluble drug in water. Agent. Description Aqueous formulation containing poorly soluble drug

The present invention relates to aqueous formulations of poorly soluble drugs. More specifically, the present invention relates to a mixture of polysorbate and / or polyoxyethylene hydrogenated castor oil and methylcellulose and / or hydroxypropylmethylcellulose, more preferably polyethylene glycol (hereinafter abbreviated as PEG), and is represented by diviridamol. The present invention relates to an aqueous preparation dissolved in water at a preferable pH region when a soluble drug is administered to a living body. Furthermore, by mixing citric acid or a pharmaceutically acceptable salt thereof with the above-mentioned composition containing PEG, a poorly soluble drug is solubilized and administered to mammals as a liquid that can flow at room temperature or lower. The present invention relates to a reversible thermogelling aqueous preparation containing a hardly soluble drug, which has a property of gelling at the body temperature of a mammal, thereby increasing the bioavailability of the hardly soluble drug and maintaining the efficacy over a long period of time. Background of the Invention

Dipyridamole is currently marketed internally and as an injection for the treatment of angina pectoris, myocardial infarction, ischemic heart disease and depressive heart disease. It is also known that a strong intraocular pressure-reducing effect can be obtained when an aqueous solution of dipyridamole is instilled (Japanese Patent Laid-Open No. 7-258804), and eye drops of dipyridamole are expected to be a new therapeutic agent for glaucoma. Have been.

In general, it is known that the pH of eye drops is preferably 5 to 8, more preferably 6 to 8 from the viewpoint of irritation to the eyes (Japanese Patent Application Laid-Open No. Hei 7-258804 and Japan). Pharmacopoeia 13). Also, as an injection, the pH is much higher than neutral from the aspect of irritation. It is said that it is desirable not to come apart (Japanese Pharmacopoeia No. 13).

However, since the solubility of dipyridamole in water near neutrality as described above is very low, preparing eye drops and injections near neutrality as an aqueous formulation in which dipyridamole is dissolved in water is not suitable for storage stability. Difficult. Japanese Patent Application Laid-Open No. 7-25804 only discloses a dipyridamole eye drop whose pH is adjusted to 3 to 5. Under such circumstances, an aqueous preparation having excellent storage stability in which an appropriate amount of dipyridamole is dissolved in water near neutrality is desired.

As a method for dissolving dipyridamole in water near neutrality, a method of adding acetyltryptophan or tributophan has been disclosed (Japanese Unexamined Patent Publication No. Hei 8-144375) has not been put to practical use. .

Acyclovir, an effective drug for the treatment of infectious diseases caused by simple herpes virus, varicella and shingles virus, is also poorly soluble in water, and its solubility in water is particularly low near neutrality. Are known. It is also known that drug crystals precipitate in a short period of time even when used as an aqueous preparation. Therefore, it is very difficult to dissolve the ash mouth building in water near neutrality to prepare an aqueous solution formulation that can be stored for a long time.

On the other hand, in the treatment of herpesvirus infections of the eye, it is known that the commercially available ophthalmic preparation of acyclovir is an ointment and has a poor feeling of use. It is also known that commercially available acyclovir injection is an aqueous preparation with a high pH, causing vascular pain at the time of administration, and crystal precipitation occurs due to slight pH change, so that it cannot be co-injected with other drugs. I have. Therefore, in order to solve such problems, there is an increasing expectation for aqueous formulations that can be stored for a long time by dissolving acyclovir in water near neutrality.

The following methods have been proposed for dissolving acyclovir in water near neutrality.

Japanese Patent Application Laid-Open No. Hei 8-2686882 uses polyvinylpyrrolidone as a solubilizing agent.

Two And disclosed that it is possible to prepare an aqueous 0.2% acyclovir formulation using 10% polyvinylpyrrolidone.

U.S. Pat. No. 5,472,954 discloses a method for complexing with a cyclodextrin derivative. However, the safety of cyclodextrin derivatives has not been established yet, and it has not been put to practical use.

On the other hand, as an aqueous pharmaceutical composition that efficiently releases a pharmaceutically active ingredient to a mammal in need of treatment, a number of aqueous pharmaceutical compositions that are liquid at room temperature or below and are semi-solid or gel at the body temperature of the mammal are disclosed. Have been. U.S. Pat. No. 4,188,373 teaches that an aqueous composition of pull mouth nick (PLURONI C) gels by heat, and the desired sol-gel transition temperature can be obtained by adjusting the concentration of the pull mouth nick. A gelled aqueous pharmaceutical composition is disclosed. Also, U.S. Pat. Nos. 4,474,751, 4,474,753 and 4,478,822 describe a drug release system using a thermogelled aqueous pharmaceutical composition. A feature of these systems is that the sol-gel phase transition temperature and Z or gel hardness can be changed by adjusting the pH and / or ion concentration and the polymer concentration. More recently, an aqueous pharmaceutical composition that gels locally by simultaneous change of pH change and temperature rise (patent WO 91/19481) has been proposed.

However, the gelled substance used in the above aqueous composition has not yet been established for safety at all sites requiring treatment, and the concentration of the polymer in the aqueous composition is high. The viscosity in the condition is high, and it is difficult to use depending on the part requiring treatment (for example, eyes).

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

Oba heated the aqueous methylcellulose solution at a constant rate to form a gel,

Three It reports the correlation between the gelation temperature and the degree of polymerization and concentration of chill cell mouth, and the change of the gelation temperature due to the addition of ion (Hakodate Technical College bulletin No. 22; 1 13—1 2 0, 1 9 8 7). However, there is no description of a methylcellulose-containing composition that gels around the body temperature of mammals.

Takeuchi et al. Reversible thermogelling aqueous pharmaceutical compositions containing an effective amount of a drug used for pharmacological treatment or diagnosis, wherein methylcellulose (having a methoxyl group content in the range of 26 to 33%) ) 0.2 to 2 W / V%, citric acid 1,2 to 2.3 W / V% and polyethylene glycol 0.5 to 13 W / V%, and the pH of the composition to 3 to 10 The above composition is disclosed containing a sufficient amount of a pharmaceutically acceptable pH adjuster to adjust to a range (Patent WO 94/237500). Summary of the Invention

An object of the present invention is to provide a formulation in which a poorly soluble drug represented by diviridamol is dissolved in water near neutrality, and a method for preparing the same.

As shown in Example 1 described below, the present inventors have found that poorly soluble drugs represented by dipyridamole include polysorbate and / or polyoxetylene hardened castor oil, methylcellulose and / or hydroxypropylmethyl. The present inventors have discovered that the addition of cellulose can provide a synergistic solubilizing effect that cannot be obtained by adding each alone, and completed the present invention.

That is, the present invention is a preparation prepared by dissolving a poorly soluble drug in water using polysorbate and / or polyoxyethylene hydrogenated castor oil and methylcellulose and / or hydroxypropylmethylcellulose.

When PEG is added to the above composition, the solubility of the poorly soluble drug in water is further synergistically improved as shown in Example 7 described later, and a more preferable aqueous preparation is obtained. Further, citric acid or a pharmaceutically acceptable salt thereof may be added to the above composition containing PEG.

Four The sparingly soluble drug was solubilized without affecting the thermal gelation characteristics described in Patent WO94 / 237500 by mixing the compound at room temperature or below. A reversible thermogelling aqueous formulation containing a poorly soluble drug that gels at the body temperature of a mammal can be obtained.

The aqueous preparation of the present invention has excellent storage stability, and is prepared in a pH range that is preferable for administration to a living body, and therefore has low irritation during administration. In addition, unlike the suspension formulation, the poorly soluble drug is dissolved in water, so there is no foreign body sensation at the time of administration, variation in the dosage, deposition of the suspension in the container, etc., which are problems with the suspension formulation . In addition, it is a liquid that can flow at or below room temperature and, when administered to mammals, gels at the body temperature of the mammal, thereby increasing the bioavailability of poorly soluble drugs and extending it over time. The medicinal effect lasts.

The present invention further provides dipyridamole in an aqueous solution containing polysorbate and / or polyoxetylene castor oil, methylcellulose and / or hydroxypropylmethylcellulose, and adjusted to pH 4 or less. After dissolution, a basic component is added to adjust the pH to 5 to 8 to prepare an aqueous preparation of dipyridamole; polysorbate and / or polyoxyethylene hydrogenated castor oil and methylcellulose and / or hydroxypropylmethylcellulose are added. After dissolving the acidic mouth building in an aqueous solution containing and adjusting the pH to pH 3 or lower or pH 10 or higher, add an acid or a basic component to adjust the pH to 5.5 to 8 A method for preparing an aqueous preparation of Bil; comprising norfloxacin, ofloxacin, lomefloxacin hydrochloride, econazole nitrate and miconazole nitrate At least one poorly soluble drug selected from the group is dissolved in a mixture of polysorbate and / or polyoxetylene hardened castor oil and polyethylene glycol, and then water is added thereto to form an aqueous formulation; It is intended to provide a method for preparing a water-containing preparation.

The present invention further provides a surfactant and a water-soluble polymer for dissolving a poorly soluble drug in water.

Five And a solubilizing agent comprising: BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail.

The poorly soluble drug used in the present invention refers to a drug which is expected to have usefulness in efficacy, but has a limited use because it is hardly soluble in water at around neutrality. Such drugs include, for example, antifungal agents, for example, fluconazole, clotrimazole, isoconazole nitrate, econazole nitrate, miconazole nitrate, bifonazole, etc., synthetic antibacterial agents, for example, ofloxacin, sivroff hydrochloride Loxacin, tosfloxacin tosylate, norfloxacin, lomefloxacin hydrochloride, pazfloxacin, etc., anti-herpes virus agents such as acyclovir, ganciclovir, idoxperidine, vidarabine, etc., antiplatelet agents such as dipyridamole, syrosylzol H-blockers, for example, brazosin hydrochloride, bunazosin hydrochloride, terazosin hydrochloride, etc., B-hydrogenase inhibitors, for example, acetazolamide, methazolamide, and the like, and pharmaceutically acceptable salts of these drugs. Lifting It is.

Examples of the polysorbate used in the present invention include polysorbates 40, 60, 65, and 80 (also known as Tweens 40, 60, 65, and 80). Available at Its outline, standards, uses, amounts used, and trade names are described in detail in the Pharmaceutical Excipients Dictionary (edited by the Japan Pharmaceutical Excipients Association, published by Pharmaceutical Daily).

Examples of the polyoxyethylene hydrogenated castor oil used in the present invention include, for example, polyoxyethylene hydrogenated castor oils 10, 40, 50, and 60 (also known as polyoxyethylene glycerin trioxystearic acid 10, 50, 50). And 60) are readily available. Its outline, standards, uses, amounts used, and trade names are described in detail in the Pharmaceutical Excipients Dictionary (edited by the Japan Pharmaceutical Excipients Association, published by Yakuji Nippo).

6 Have been.

These polysorbate or polyoxyethylene castor oil are used alone or as a mixture thereof.

Methyl cellulose (hereinafter abbreviated as MC) used in the present invention may be any MC alone or as a mixture as long as the viscosity of the 2% aqueous solution at 20 ° C. is in the range of 13 to 12000 mPa · s. Can be used. The content of the methoxyl group is preferably in the range of 26 to 33% from the viewpoint of solubility in water. In addition, MC is distinguished by the viscosity of its aqueous solution.For example, commercially available varieties have the indicated viscosities of 15, 25, 100, 400, 1500, and 8000 (the figures are millipascals at 20 ° C viscosity of a 2% aqueous solution). Seconds) and are readily available. Its outline, standards, uses, amounts used, and trade names are described in detail in the Pharmaceutical Excipients Dictionary (edited by the Japan Pharmaceutical Excipients Association, published by Yakuji Nippo).

Hydroxypropyl methylcellulose (hereinafter abbreviated as HPMC) used in the present invention is divided into three types (2208, 2906, and 2910) according to the content of methoxyl group and hydroxypropyl group, and further, each of them is based on the viscosity of the aqueous solution. For example, commercially available varieties have a viscosity of 4 to 100000 (the number is millipascal-second at 20 ° C in a 2% aqueous solution), which is easily available. The HPMC used in the present invention preferably has a display viscosity of 10,000 or less from the viewpoint of handling. The outline, standards, uses, amounts used, and trade names of HPMC are described in detail in the Pharmaceutical Excipients Dictionary (edited by the Japan Pharmaceutical Excipients Association, published by Yakuji Nippo).

The PEG used in the present invention includes PEG-200, PEG-300, PEG-600, PEG-1000, PEG-1540, PEG-2000, PEG-14000, PEG-6000, PEG-20000, PEG-50000, P EG-500,000, PEG-2000000 and PEG-400000

7 Product names sold by Wako Pure Chemical Industries, Ltd., Macrogo-I-Lu 200, Macro-Gol-I-300, Macro-Gol-I-400, Macro-Gol-I-600, Macro-Go-I-Rue 1000, Macro-Go-I-Rue 1540, Macro-Gol One 4000, Macrogol-6000, Macrogo-I-Lu 20000 are trade names sold by NOF Corporation.

The weight average molecular weight of PEG used in the present invention is preferably from 300 to 50,000, particularly preferably from 1,000 to 20,000. When the weight average molecular weight is 300 or more, gelation due to body temperature occurs, and when the weight average molecular weight is 50,000 or less, the viscosity in a liquid state is not excessively high, and thus it is preferable. It is also possible to adjust the weight average molecular weight within the above-mentioned optimum range by mixing two or more kinds of PEG. Examples of the pharmaceutically acceptable salts of citric acid used in the present invention include sodium salts and potassium salts.

The aqueous preparation containing a poorly soluble drug of the present invention contains a poorly soluble drug, polysorbate and Z or polyoxyethylene hydrogenated castor oil, MC and / or HPMC, preferably further contains PEG, more preferably PEG and quinone. Contains acids or salts thereof.

The use concentration of polysorbate and / or polyoxyethylene hydrogenated castor oil is preferably 0.01 to 2 W / V%. A concentration of 2 W / V% or less is preferable because it has few side effects such as eye irritation and corneal damage, and a concentration of 0.01 W / V% is necessary for dissolving the amount of a poorly soluble drug necessary for obtaining a medicinal effect. It is preferable that this is the case.

The working concentration of MC and / or HPMC is preferably 0.01 to 4 W / V%. A concentration of 4 W / V% or less is preferable because the viscosity of the aqueous preparation can be adjusted to a range that is easy to handle, and a concentration of 0.01 W is necessary for dissolving the amount of poorly soluble drug necessary for obtaining the efficacy. It is preferably at least / V%. Especially reversible thermogelation

8 The concentration of MC used in an aqueous preparation is preferably 0.2 to 2 W / V%. A concentration of MC of 2 W / V% or less is preferable because the viscosity can be adjusted to an easily manageable range, and a concentration of MC of 0.2 W / V% or more is preferable because gelation due to body temperature is likely to occur. .

The working concentration of PEG is preferably 0.1 to 13 W / V%. In the case of reversible thermogelling aqueous preparations, if the concentration of PEG is 13 W / V% or less, it is preferable because the viscosity of the aqueous preparation is in a manageable range, and if it is 0.1 W / V% or more, it depends on body temperature. This is preferable because gelation is likely to occur.

The use concentration of citric acid or a salt thereof in the reversible thermogelling aqueous preparation is preferably 0.1 to 2.3 W / V%, more preferably 1 to 2.3 W / V%. When the concentration of citric acid or a salt thereof is 2.3 W / V% or less, it is preferable because the eye irritation is small especially when administered to the eye as an eye drop, and when it is 0.1 WZV% or more, gelation due to body temperature may occur. It is preferable because it easily occurs.

The concentration of the poorly soluble drug is not particularly limited as long as the desired drug effect can be obtained and it can be prepared as an aqueous preparation.

The concentration of diviridamol (hereinafter abbreviated as DPY) is preferably from 0.001 to 0.05 W / V%, more preferably from 0.005 to 0.05 W / V%. A DPY concentration of 0.05 W / V% or less is preferred because DPY is completely dissolved in water, and when administered as an eye drop to the eye, side effects such as conjunctival hyperemia are small. Is preferably 0.001 W / V% or more because sufficient drug efficacy can be expected.

The concentration of a synthetic antibacterial agent such as norfloxacin, ofloxacin, or lomefloxacin hydrochloride is preferably 0.01 to: LW / V%. A concentration of 1 W / V% or less is preferable because the drug is completely dissolved in water, and a concentration of 0.01 W / V% or more is preferable because sufficient drug efficacy can be expected.

9 The concentration of antifungal agents such as econazole nitrate, miconazole nitrate is preferably

It is 0.01 to 0.2 W / V%. A concentration of 0.2 W / V% or less is preferable because the drug is completely dissolved in water, and a concentration of 0.01 W / V% or more is preferable because sufficient drug efficacy can be expected.

The gelation temperature of the reversible thermogelling aqueous preparation containing a poorly soluble drug should be about 20 to about 40 ° C because it is liquid at room temperature or below and it is desirable to gel at the body temperature of mammals. Is preferred.

The aqueous preparation of the present invention is preferably adjusted to have a pH of 5 to 8 in terms of irritation. Furthermore, for example, when the poorly soluble drug is DPY, the pH is preferably 5 to 7 and more preferably 5 to 6 in the case of an aqueous preparation from the viewpoint of the stability of the DPY solution. From the viewpoint of gelling due to sex and body temperature, pH 5 to 8 is preferable, and pH 6 to 7.5 is more preferable. When the poorly soluble drug is acyclovir, the pH is preferably 5.5 to 8.

Various pH modifiers are used to adjust the pH of the aqueous formulations of the present invention. Examples of the acids include organic acids such as ascorbic acid, gluconic acid, acetic acid, lactic acid, and citric acid, and inorganic acids such as hydrochloric acid, boric acid, phosphoric acid, and sulfuric acid. Examples of the bases include potassium hydroxide, calcium hydroxide, sodium hydroxide, magnesium hydroxide, monoethanolamine, diethanolamine, triethanolamine, and the like. Other pH adjusters include glycine, histidine, amino acids such as epsilon aminocaproic acid, and the like.

In preparing the aqueous preparation of the present invention, pharmaceutically acceptable isotonic agents, preservatives, preservatives, and the like are added to the aqueous preparation of the present invention as needed, as long as the effects of the present invention are not impaired. can do.

Examples of the tonicity agent include saccharides such as xylitol, mannitol and budou sugar, propylene glycol, glycerin, sodium chloride, potassium salt and the like.

Ten As preservatives, reversible stones such as penzalconium chloride, benzethonium chloride and chlorhexidine gluconate, parabens such as methyl parahydroxybenzoate, propyl parahydroxybenzoate and butyl parahydroxybenzoate, and Alcohols such as ethanol, phenylethyl alcohol and benzyl alcohol, organic acids such as sodium dehydroacetate, sorbic acid and sorbic acid potassium and their salts can be used.

As other additives, thickeners such as hydroxyethyl cellulose, polyvinyl virolidone, polyvinyl alcohol, propylene glycol, diethylene glycol or sodium polyacrylate, EDTA (ethylenediaminetetraacetic acid) and pharmaceutically acceptable salts thereof. And tolerable salts, tocopherol and derivatives thereof, and sodium sulphite.

The aqueous preparation of the present invention can be sterilized by filtration sterilization using a membrane filter, intermittent sterilization, or the like.

The aqueous preparation of the present invention can be filled in a plastic eye dropper and used as an eye drop. To preserve this for a long time, it may be packaged in a polyethylene film and aluminum foil laminated bag together with an oxygen scavenger (eg, Ageless®, Mitsubishi Gas Chemical Co., Ltd.).

The aqueous preparation of the present invention can be filled in a plastic drop bottle and used as an eardrop. In order to preserve this for a long period of time, it may be packaged together with a deoxidizer (eg, Ageless®, Mitsubishi Gas Chemical Co., Ltd.) in a laminated bag of polyethylene film and aluminum foil.

The aqueous preparation of the present invention can be filled as a nasal spray and used as a nasal drop. In order to preserve this for a long period of time, it may be packaged in a polyethylene film and aluminum foil laminated bag together with an oxygen scavenger (eg, Ageless®, Mitsubishi Gas Chemical Co., Ltd.).

11 The aqueous formulation of the present invention is filled into an ampoule and sealed, and then injected (intravenous injection, intraarterial injection, subcutaneous injection, intradermal injection, intramuscular injection, intrathecal injection, intraperitoneal injection, intraocular injection, etc.). Etc.), oral liquid, inhalant and spray. Depending on the usage, it is used by filling it into a plastic drug bottle for internal liquids, an electric nebulizer for inhalants, and an atomizer for sprays.

Next, a method for producing the aqueous preparation of the present invention will be described. For example, in order to prepare DPY as an aqueous preparation, it is preferable to dissolve 0 丫 in an aqueous solution of 113 or less, and then adjust the pH to a predetermined value by adding a base component.

In order to prepare acyclovir as an aqueous preparation, it is preferable to dissolve acyclovir in an aqueous solution having a pH of 3 or less or 10 or more, and then adjust the pH to a predetermined value by adding a basic component or an acidic component.

In order to prepare a reversible thermogelling aqueous formulation containing norfloxacin, ofloxacin, lomefloxacin hydrochloride, econazole nitrate or miconazole nitrate, these drugs are combined with polysoltate and / or polyoxyethylene hydrogenated castor oil. After dissolving in the PEG mixture, water is preferably added to make an aqueous preparation.

To exemplify the preparation of a D PY-containing aqueous eye drop, D P Y, polysorbate and / or polyoxyethylene hydrogenated castor oil are added to sterile purified water and dispersed. An acid is added to the solution to adjust the pH to 3 or less, and all the added components are dissolved. To this, add the MC and / or HPMC solution previously dissolved in sterile purified water, and mix well. Next, the pH is adjusted to a predetermined value by adding a base, and the volume is adjusted to a predetermined volume with sterilized purified water. If necessary, various additives such as buffers, tonicity agents, preservatives, and stabilizers can be added.

Further, as an example of the preparation of a reversible thermogelling aqueous eye drop containing DPY, DPY is added to a mixture of polysorbate and / or polyoxyethylene hydrogenated castor oil and PEG, and after mixing, sterile purified water is added. Mix well. Add MC to sterile purified water

12 Add the solution and mix well under ice-cooling. To this solution is added citric acid and, if desired, other acids to lower the pH to 3 or less and dissolve all the added components. Next, the pH is adjusted to a predetermined value by adding bases, and the volume is adjusted to a predetermined volume with sterile purified water. If necessary, various additives such as a buffering agent, a tonicity agent, a preservative, and a stabilizing agent can be added.

Furthermore, these prepared aqueous DPY eye drops can be filled into a plastic eye drop bottle after heat sterilization such as filtration sterilization or low-temperature intermittent sterilization.

Hereinafter, the present invention will be described in more detail with reference to Examples, but is not intended to limit the scope of the present invention. Example 1

0.025 § 0? ¥, 0.5 g of polysorbate 80 (Reodol (registered trademark) TW-0120, Kao Corporation, hereinafter abbreviated as Tween-80) in 3 OmL of sterilized purified water or polyoxyethylene cured in 3 OmL Castor oil 60 (Nikkor (registered trademark) HCO60, Nikko Chemicals Co., Ltd., hereinafter abbreviated as HCO-60), 2 g of glycerol, 0.005 g of EDTA · 2Na, 0.007 g of benzalco chloride Num (hereinafter abbreviated as BZK) was added, and 1N hydrochloric acid was further added with stirring until the pH became 3 or less. Add 0.3 g of MC (SM15, Metrolz (registered trademark), Shin-Etsu Chemical Co., Ltd.) or HPMC (60 SH50, Metrolz (registered trademark), Shin-Etsu Chemical Co., Ltd.) to sterile purified water. One dissolved in 4 OmL was added. The pH was adjusted to 5.5 with 10 WZV% of monoethanolamine, and sterilized purified water was added to make 100 mL to obtain an aqueous preparation (formulation # α1 to 4) of the present invention.

As a comparison, a comparative DP Y aqueous preparation to which none of Tween-80, HCO-60, SM-15 and 60 SH 50 was added to the DP aqueous preparation of the present invention

(Formulations NOL5, 6) were prepared in a similar manner. In addition, the aqueous DP Y formulation of the present invention

13 On the other hand, a comparative DP Y aqueous preparation (Formulation Nos. 7 to 10) containing either SM-15 or 60 SH50 and without adding Tween-80 or HC〇-60 was prepared by the same method. did. Furthermore, a comparative DP Y aqueous preparation containing either Tween-80 or HCO-60 and not adding either SM-15 or 60 SH 50 to the aqueous DP Y preparation of the present invention (formulations Ntxl 1 to 14 ) Was prepared in a similar manner. In addition, two kinds of DPY aqueous preparations for comparison were prepared with a DPY concentration of 0.01 and 0.025 W / V%.

Table 1 shows the results of observation of the appearance of the prepared DPY aqueous formulation up to 24 hours (storage at 25 ° C) after preparation. The DPY aqueous preparation (formulation # α1-4) of the present invention, which contains polysorbate or polyoxyethylene-hardened castor oil and MC or HPMC, is prepared using either polysorbate or polyoxyethylene hardened castor oil, or MC or HPMC. The solubility of DPY in water is higher than that of the comparative D-II preparation containing either one of them, even though the DPY concentration is more than 2 times higher than that of the aqueous preparation (Formulation Να 7, 9, 11, 13). ,It is shown that. This indicates that the combination of polysorbate and / or polyoxyethylene hydrogenated castor oil with MC and / or HPMC synergistically improves the solubility of poorly soluble drugs in water.

14 Table 1

Category * !!; No. οργ Tween-80 HCO-60 MC HPMC Appearance w / v% w / v w / v¾ w / v% W / V% Invention 1 0.025 0.5 SM15 0.3 τ ί '

2 0.025 0.5 60SH50 0.3 Male

3 0.025 0.5 SMI 5 0.3

4 0.025 0.5 60SH50 0.3

5 0.01

6 0.025

7 0.01 SM15 0.3

8 0.025 S 15 0.3

9 0.01 60SH50 0.3

10 0.025 60SH50 0.3 Si solution

11 0.01 0.5 irom precipitation '12 0.025 0.5 Yuzuru i after ^{precipitation,}

13 0.01 0.5 Concentration precipitation 14 0.025 0.5 Solution HC1 BZK 0.007WV% EDTA-2NA 0.00

mono! ^ -Le 7min ififl glycerol 2W / V% ΡΗ5.5

Precipitation immediately after 8¾ϊ *: Preparation Preparation of DPY crystal within 2¾ temples Example 2

To 30 mL of sterile purified water, add 0.025 g of DPY, 0.5 g of Tween-80, 2 g of glycerol, 0.005 g of EDTA · 2Na, and 0.007 g of BZK, and add 1 N while stirring. Of HC1 was added until the pH was 3 or less. In addition, 0.3g of various MCs (SM15, SMI00, SM400, SM1500, all of Metrolz (registered trademark), Shin-Etsu Chemical Co., Ltd.) or HPMC (60 SH5 Os 65 SH400, 65 SH 1500, 90 SH400, each of which was obtained by dissolving Metrolz (registered trademark), Shin-Etsu Chemical Co., Ltd.) in 4 OmL of sterilized purified water was added. The pH was adjusted to 5.5 with 10 W / V% monoethanolamine, and sterile purified water was added to make 100 mL to obtain an aqueous preparation of the present invention (Formulation Nos. 15 to 21).

As a comparison, instead of MC or HPMC, polyethylene glycol 400 (PEG400, manufactured by Wako Pure Chemical Industries, Ltd.) and polyvinyl alcohol were used for the aqueous DPY preparation of the present invention.

Fifteen Rubiloridone-K25 (PVP K25, manufactured by BASF, Kollidon (registered trademark) 25), 1 part of polyvinyl alcohol 1000 partially saponified product (PVA100, manufactured by Wako Pure Chemical Industries, Ltd.), and 1 g of added Y aqueous preparations (Formulation # α23-25) were prepared in a similar manner.

Table 1 shows the results of observation of the appearance of the prepared aqueous DP-II formulation up to 24 hours after storage (storage at 25 ° C). The DPY7JC-based preparation of the present invention can be prepared as an aqueous preparation regardless of the type and grade of MC or HPMC.

On the other hand, in Comparative Examples to which a water-soluble polymer other than MC or HPMC was added, DPY was precipitated within 24 hours after preparation. Table 1 2

Category Formulation No. DPY Tween-80 Water-soluble polymer Appearance

W / V W / V Type W / V% Invention 15 0.025 0.5 MC SM15 0.3 Aqueous solution

16 0.025 0.5 MC SM100 0.3 Aqueous solution

17 0.025 0.5 MC SM400 0.3 Aqueous solution

18 0.025 0.5 MC SM1500 0.3 Aqueous solution

19 0.025 0.5 HPMC 60SH50 0.3 aqueous solution

20 0.025 0.5 HPMC 65SH400 0.3 Aqueous solution

21 0.025 0.5 HPMC 65SH1500 0.3 Aqueous solution

22 0.025 0.5 HPMC 90SH400 0.3 aqueous solution Comparative Example 23 0.025 0.5 PEG 400 1 Precipitation immediately after preparation

24 0.025 0.5 PVP K25 1 Precipitation immediately after preparation '

25 0.025 0.5 PVA 1000 1 Precipitation immediately after preparation 'Common for each recipe HC1 appropriate amount Mo Evening-lamine appropriate amount EDTA-2NA 0.005W / W

BZK 0.007W / V% glycerol 2W / V% PH5.5

Precipitation immediately after preparation ': DPY crystal precipitation within 24 hours after preparation Example 3

To 30 mL of sterile purified water, add 0.5 Og of DPY, 0.5 g of Tween-80, 2 g of glycerol, 0.5 g of EDTA2Na, and 0.007 g of BZK, and stir. Meanwhile, 1N hydrochloric acid was further added until the pH became 3 or less. Then, 0.3g of SM15 (Metroze (registered trademark), Shin-Etsu Chemical Co., Ltd.) was sterilized and purified.

16 A solution dissolved in 4 OmL of water production was added. The pH was adjusted to 5.0 to 7.0 with 10WZV% monoethanolamine, and sterilized purified water was added to make up to 10 OmL to obtain an aqueous preparation (formulation # α26 to 29) of the present invention.

For comparison, a DP aqueous preparation of the present invention was adjusted to pH 7.5 or 8.0 with 10 W / V% monoethanolamine to prepare a comparative DPY aqueous preparation (Formulation No. 30, 31). Further, comparative DPY aqueous preparations (Formulation # α32 to 34) to which neither Tween-80 nor SM-15 was added were prepared by the same method. In this case, the pH was adjusted to 4.0 to 5.5 with 1 OW / V% of monoethanolamine.

Table 3 shows the results of observation of the appearance of the prepared DP Y aqueous preparation for up to 24 hours (stored at 25 ° C) after preparation. The aqueous DPY preparation of the present invention was an aqueous solution in which DPY was dissolved in the pH range of 5.0 to 7.0. However, DPY precipitated within 24 hours after preparation even when dissolved when the pH was 7.5 or more. When neither Tween-80 nor SM-15 was added, DPY did not dissolve when the pH became 5.0 or more. Table 1 3

Category Prescription No. DPY PH Tween-80 MC Appearance

W / V% / V¾ Type W / V%

The present invention 26 0.01 5.0 0.5 SM15 0.3 aqueous solution

27 0.01 5.5 0.5 SM15 0.3 Aqueous solution

28 0.01 6.0 0.5 SM15 0.3 Aqueous solution

29 0.01 7.0 0.5 SM15 0.3 Aqueous solution Comparative example 30 0.01 7.5 0.5 SM15 0.3 Precipitation immediately after preparation ^f

31 0.01 8.0 0.5 SM15 0.3 Precipitation immediately after preparation '

32 0.01 4.0 Aqueous solution

33 0.01 5.0 thought; 'liquid

34 0.01 5.5 concept; 'fe solution Common for each formulation HC1 appropriate amount glycerol 2W / V% BZK 0.007W / VX

Monoethano-pamine suitable amount EDTA.2NA 0.005W / V¾

Precipitation immediately after preparation ': DPY crystal precipitation within 24 hours after preparation

17 Example 4

To 3 OmL of sterile purified water, add the specified amount of DPY, Tween-80, 1.5 g of glycerol, 0.005 g of EDTA2Na, 0.007 g of BZK, and 1 g of citric acid. With stirring, the DPY was dissolved. To this, a predetermined amount of SM15 dissolved in 4 OmL of sterile purified water was added. The pH was adjusted to 5.5 with 1N NaOH, and sterilized purified water was added to make up to 10 OmL to obtain a DPYzR preparation. Table 4 shows the results of observing the appearance of the DPY aqueous preparation containing various concentrations of DPY, Tween_80 and SMI5 up to 24 hours (storage at 25 ° C) after preparation. When 0% was 0.06 W / V% or more, or when the concentration of SM15 became 0.005 WZV% or less, the dissolved DPY precipitated out within 2 hours after preparation. Table 1 4

Formulation No. DPY I ween- 80 SM15 Appearance

W / V W / V W / V%

35 0. .06 2 2 Precipitation immediately after preparation

36 0. .05 2 2 Aqueous solution

37 0. .03 1 1.5 Aqueous solution

38 0. .01 0.1 4 Aqueous solution

39 0,, 01 0.5 0.01 Aqueous solution

40 0. .01 0.5 0.005 Precipitation immediately after preparation

41 0,, 005 0.1 1 Aqueous solution

42 0. .001 0.01 2 Aqueous solution

Common for each formulation Cunic acid 1W / V¾ EDTA-2NA 0.005W / V%

NaOH appropriate amount BZK 0.007W / V%

glycerol 1.5W / V% pH5.5

Precipitation immediately after preparation ^; DPY crystal precipitation within 24 hours after preparation

Example 5

Predetermined amount of DPY, Tween-80 or HC 0-60, 1.5 g glycerol, 0.005 g EDTA2Na, 0.007 g BZK and 1 g queen in 3 OmL of sterile purified water The acid was added and the DPY was dissolved with stirring. this

18 A solution obtained by dissolving a predetermined amount of SM 15 in 4 OmL of sterilized purified water was added to the mixture. The pH was adjusted to 5.5 with 1N Na〇H and made up to 100 mL by adding sterile purified water. Further, the prepared aqueous DPY solution was filtered through a 0.45 μm membrane filter and filled into a polyethylene eye drop bottle to obtain an eye drop of the present invention.

Table 1 shows that the DPY ophthalmic solution of the present invention containing various concentrations of DPY, Tween-80 or HCO-60 and SM15 was stored at 7, 25 or 40 ° C for 3 months. The results of observing the change in the appearance of are shown. In any of the formulations (formulations Nos. 43 to 48), the DPY ophthalmic solution of the present invention showed no change in appearance such as crystal precipitation of DPY during storage, indicating that it was stable.

¾-5

DPY Tween-80 S 15 60SH5O m

W / V% W / V% W / V% W / V% 7 ° 〇¾Γmonth 25 ° C3! R month 40PC3! R month

43 0.02 0.5 0.1 Water

44 0.02 0.5 2 Water

45 0.015 0.5 0.01 Water ¾ Solution Transformation Transformation

46 0.015 2 1 Water Stroke Transformation Transformation Transformation Transformation

47 0.015 0.5 1 7 赚赚ィ変ィィ

48 0.005 0.2 1 Insect Insect Insect Insect

^ C 1W / V% BZK 0.0O7W / V% EDTA-2NA 0.005W / V%

BZK 0.007W / V% glycerol 1.5W / V aOH vegetables pH5.5

Example 6

0.35 or 0.2 g of acyclovir, 0.5 g of Tween-80, 2 g of glycerol, 0.005 g of EDTA2Na, and 0.007 g of BZK were added to 3 OmL of sterile purified water. . While stirring the solution, 1N NaOH was added until the pH reached 10, to dissolve acyclovir. To this was added 0.5 ^ 31 ^ 15 dissolved in 4 OmL of sterile purified water. The pH was adjusted to 8.0 with 1N HCl, and sterile purified water was added to make up to 10 OmL. Further prepared acyclovir

19 The aqueous solution was filtered through a 0.45 m membrane filter, and filled in a polyethylene ophthalmic bottle to obtain the ophthalmic solution of the present invention (formulation Nos. 49 and 50).

To 30 mL of sterile purified water was added 0.2 g of acyclovir, 0.5 g of Tween-80, 2 g of glycerol, 0.005 g of EDT A.2Na, and 0.007 g of BZK. While stirring the solution, 1N HCl was added until the pH became 3, thereby dissolving acyclovir. To this was added 0.5 g of SM15 dissolved in 4 OmL of sterile purified water. The pH was adjusted to 5.5 with 1N NaOH, and sterilized purified water was added to adjust to 10 OmL. Further, the prepared aqueous solution of acyclovir was filtered through a 0.45 / m membrane filter and filled in a polyethylene eye drop bottle to obtain an eye drop of the present invention (formulation No. 51).

Table 6 shows the results obtained by storing the acyclovir ophthalmic solution of the present invention at 25 ° C. for 2 weeks to 1 year and observing changes in appearance after storage. The acyclovir ophthalmic solution of the present invention was stable after storage for 2 weeks or longer, with no crystal precipitation of acyclovir observed in any of the formulations (formulations α49 to 51). Table 1 6

Common to each formulation: EDTA -2NA 0.005W / V%;

BZK 0.007W / V; NaOH appropriate amount; glycerol 2W / V%

Example 7

To 4 g of PE G400 (Macrogol 400, manufactured by NOF Corporation) heated to 60 ° C, add 0.05 g or 0.04 g of DPY and 0.2 g of Tween -80. After the addition and mixing, 50 mL of sterile purified water was added to the mixture. After cooling to room temperature, 5 g

20 Of SMI5 dissolved in 10 OmL of sterile purified water, 1 OmL, 10:11 of 82 K and 0.74 g of NaC1 were added and mixed well. To this was added 0.2 mL of 1N HC1 and the mixture was stirred and mixed until all the added components were dissolved. Next, after adding and dissolving 0.5 ε-aminocaproic acid, ρΗ was adjusted to 5.5 with 1N NaOH. Further, sterilized purified water was added to make up to 10 OmL to obtain an aqueous preparation of the present invention (Formulation N (x52, 57)).

For comparison, the aqueous preparations of the present invention (formulation N (x52, 57) were replaced with 8 g of PEG4000 and Tween-80 was not added. Aqueous comparative preparation without 80 g of 0.4 g and without PEG 4000 (formulation Νο · 54, 59) or 8 g of PEG 4000 and 0.4 g of Tween_ 80 with no SM15 Formulation (α55, 60) was prepared in the same manner as the aqueous preparation of the present invention.

In addition, the aqueous formulation of the present invention (formulation No. α52, 57) was replaced with SM15 by adding 2 OmL, and PEG4000 and Tween-80 were not added.

(Prescription # α56, 61) was prepared by the same method as the aqueous preparation of the present invention, but DPY did not dissolve and could not be prepared as an aqueous preparation.

The prepared aqueous preparation of the present invention or the comparative preparation (excluding prescriptions α56 and 61) was filtered through a 0.45 μm membrane filter, filled in a glass bottle with a lid, and stored at 25 ° C. The time required for DPY crystals to precipitate was observed. The DP Υ deposition delay was defined as the degree to which the DP Υ deposition time of each formulation was delayed with respect to the D Υ deposition time of the comparative example (prescription 54, 59) using Tween-80 and SM 15 alone. And the results are shown in Table 17 below.

DPY precipitation delay =

(DPY deposition time-DPY deposition time of recipe No. 54 or 59) X 100 / DPY deposition time of recipe No. 54 or 59

twenty one The aqueous preparation of the present invention (formulation Not 52, 57) using polysorbate and PEG together is a comparative aqueous preparation (formulation No. α54, 59) containing polysorbate alone or a comparison aqueous preparation containing PEG alone. This shows that the time required for crystal precipitation is longer than that of the preparations (Formulation Nos. 53 and 58), despite the fact that the amount added is half. This indicates that polysorbate and PEG have a synergistic solubilizing effect on poorly soluble drugs such as DPY.

In addition, the aqueous formulation of the present invention (formulation # α52, 57) using polysorbate, PEG and MC in combination was compared with the comparative aqueous formulation (formulation # α55, 60) using only polysorbate and PEG alone or MC alone. This shows that the time required for crystallization is longer than that of aqueous preparations (formulation No. α56, 61), although the amount of each additive is half. This indicates that polysorbate, PEG, and methylcellulose have a synergistic solubilizing effect on poorly soluble drugs such as DP III.

twenty two Table 7

Example 8

60. To 1 to 10 g of PEG4000 heated to C, lmg to 0.05 g of DPY and 0.05 to 2 g of Tween-80 were added and mixed, and then 5 OmL of sterile purified water was added. After allowing to cool to room temperature, 2 to 40 mL of 5 g of SM15 dissolved in 10 OmL of sterile purified water, 10 mg of BZK and 0.74 g of NaC1 were added, mixed well, and mixed well. 0.2 mL of 1N HC1 was added and mixed with stirring until all the added components were dissolved. Next, 0.5-amino propyl acid was added, and after mixing and dissolving, the pH was adjusted to 5.5 with 1N NaOH. Add sterilized purified water and add 100 m

twenty three L to prepare an aqueous preparation of the present invention. The prepared aqueous preparation of the present invention was filtered through a 0.45 m membrane filter, and then filled in a polypropylene ophthalmic bottle to obtain a DPY-containing eye drop of the present invention. When this was stored at 25 ° C for 3 months, no precipitation of DPY crystals was observed and it was stable. The results are shown in Table 18. Table 1 8

Example 9

4 g or 10 g PEG 1000 (Wako Pure Chemical Industries, Ltd.) heated to 60 ° C was added to 0.01 g DPY or 0.05 g prazosin hydrochloride, and 0.5 g Tween—80 Alternatively, after adding and mixing HCO-60, 3 OmL of sterile purified water was added and mixed well. To this, 0.7 g or 1.5 g of SM15 and 0.7 g or 0.5 g of SM400 dissolved in 40 mL of sterile purified water were added, and mixed well under ice-cooling. 2.3 g of citric anhydride was added thereto and mixed by stirring until all the added components were dissolved. Next, the pH was adjusted to 6.5 with 5N NaOH, and sterilized purified water was added to make up to 10 OmL to obtain an aqueous preparation (formulation # α68, 70) of the present invention.

Separately, 8 g PEG 1000 or 4 g PEG heated to 60 ° C

twenty four Add 0.2 g of acyclovir, 2 g of acetazolamide or 1 g of metazolamide, and 0.5 g of Tween-80 or HCO-60 to 4000 and mix, then sterile purified water 3 OmL And then mixed well. A solution prepared by dissolving 1.5 g of SM15 and 0.4 g of SM400 in 4 OmL of sterile purified water was added to the mixture, and mixed well under ice-cooling. 1.9 or 2.3 g of citric anhydride was added thereto, and 5 N NaOH was added under stirring until all the added components were dissolved. Next, 11 was adjusted to 6.5 with 3N HCl, and sterilized purified water was added to make 10 OmL, thereby obtaining an aqueous preparation (formulation Nos. 69, 71, and 72) of the present invention.

Table 9 shows the results of observation of the appearance of the aqueous preparations of the present invention containing various poorly soluble drugs prepared up to 24 hours (stored at 25 ° C) after preparation, and 25 mL of the aqueous preparations of the present invention and artificial tears. (0. 67W / V% NaCl, 0. 2W / V% NaHC0 3, 0. 00 8 W / V% CaC 1 2) showed 3. results of measurement of the gelation temperature of the aqueous solution mixed with 5 mL. The appearance after storage at 25 ° C was observed after cooling the sample on ice. The aqueous preparation of the present invention can be prepared as an aqueous preparation in which a drug is dissolved in water, and has been shown to gel at a temperature near body temperature even when mixed with a body fluid such as tear fluid.

twenty five Table 9

Common to each prescription: PH6.5 Example 10

4 or 8 g PEG 1000 heated to 60 ° C; After adding and mixing 0.50 g of Tween-80 and 0.5 g of Tween-80, 3 OmL of sterilized purified water was added to the mixture and mixed well. To this were added 0.7 g of SM15 and 0.7 of 3! ^ 1400 dissolved in 4 OmL of sterile purified water, and mixed well under ice-cooling. To this, 2.3 g of citric anhydride was added and mixed by stirring until all the added components were dissolved. Next, the pH was adjusted to 6.5 with 5N NaOH, and sterilized purified water was added to make 100 mL, thereby obtaining an aqueous preparation of the present invention.

As a comparison, the above DPY was adjusted to 6 Omg, and a comparative DPY aqueous preparation was prepared in the same manner as the aqueous preparation of the present invention.

Table 10 shows the results of observation of the appearance of the prepared DP Y aqueous preparation for up to 24 hours (stored at 25 ° C) after preparation, and the mixing of 25 mL of the aqueous preparation of the present invention with 3.5 mL of artificial tears. The results of measuring the gelation temperature of the aqueous solution are shown. The appearance after storage at 25 ° C is

26 The sample was observed after ice cooling. The aqueous DPY formulation of the present invention can be prepared as an aqueous formulation with a DPY concentration in the range of 0.001 to 0.05 W / V%. It was shown to gel at temperature.

Table 1 10

Category Invention Comparative example Formulation No. 73 68 74 75 76

DPY W / V% 0.001 0.01 0.03 0.05 0.06

MC type SM15 SM15 S15 S15 S15

W / V% 0.7 0.7 0.7 0.7 0.7 Type S 400 SM400 S 400 SM400 S 400

W / V% 0.7 0.7 0.7 0.7 0.7

PEG type 1000 1000 1000 1000 1000

W / V% 4 4 8 8 8 Cunic acid w / v% 2.3 2.3 2.3 2.3 2.3

Tween-80 w / v% 0.5 0.5 0.5 0.5 0.5 Appearance Aqueous solution Aqueous solution Aqueous solution Aqueous solution deposition '

* Gelation temperature (° C) 32 34 28 28

PH6.5 common for each prescription

Precipitation *: DPY crystal precipitation within 24 hours after preparation: Not measured

Example 11

Add 10 or 2 Omg of DPY and 0.5 g of Tween-80 to 4 to 10 g of PEG1000 or PEG4000 heated to 60 ° C, mix, and add 3 OmL of sterile purified water And mixed well. Then, dissolve 0.2-1.5 g of the specified MC (SM15, SM25, SM100, SM400, SM4000, all Metrols (registered trademark), Shin-Etsu Chemical Co., Ltd.) in 4 OmL of sterilized purified water. The mixture was added and mixed well under ice cooling. 1.0 or 2.3 g of citric anhydride was added thereto, and the mixture was stirred and mixed until all the added components were dissolved. Then adjust the pH to 6.5 with 5N NaOH, add sterile purified water to 10 OmL,

27 A formulation was prepared.

As a comparison, a comparative DPY aqueous preparation was prepared in the same manner as the aqueous preparation of the present invention, except that the MC was replaced with 0.1 g SM100.

Table 11 shows the results of observation of the appearance of the prepared DP Y aqueous formulation for up to 24 hours (stored at 25 ° C) after preparation and the mixing of 25 mL of the aqueous formulation of the present invention with 3.5 mL of artificial tears The results of measuring the gelation temperature of the aqueous solution are shown. The appearance after storage at 25 ° C was observed after cooling the sample on ice. The DPY7JC preparation of the present invention can be prepared as an aqueous preparation with an MC in the range of 0.2 to 2 W / V%, and gels at a temperature near body temperature even when mixed with a body fluid such as tear fluid. It has been shown.

Table 1 1 1

Category Present invention Comparative example Formulation No. 77 78 79 80 81 82 83

DPY W / V 0.01 0.01 0.02 0.01 0.01 0.01 0.01

MC type SM15 S 15 SM25 SM1500 SM4000 SM100 SM100

W / V% 1.5 0.7 1.5 0.4 0.4 0.2 0.1 type SM400 SM400 S 100

W / V% 0.5 0.7 0.4

PEG type 1000 1000 4000 4000 4000 1000 1000 w / v% 10 7 4 4 4 10 10 Kuic acid w / v% 1 2.3 2.3 2.3 2.3 2.3 2.3

Tween-80 w / v 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Appearance Aqueous solution Aqueous solution Aqueous solution Aqueous solution Aqueous solution Aqueous solution Gelation temperature (.c) 32 28 28 40 40 40> 40 Common for each formulation PH6.5

Example 12

60. To 10 g of PEG 1000 heated in C, 1 Omg of DPY and 0.5 g of Tween-80 were added and mixed, and then 30 mL of sterile purified water was added and mixed well. To this, dissolve 315 of 1.5 and 0.5 g of SM400 in 4 OmL of sterile purified water.

28 Thawed was added and mixed well under ice cooling. 0.1 to lg of citric anhydride was added thereto, and the mixture was stirred and mixed until all the added components were dissolved. Next, the pH was adjusted to 6.5 with 5N NaOH, and sterilized purified water was added to 10 OmL to obtain an aqueous preparation of the present invention.

As a comparison, a comparative DPHY aqueous preparation was prepared in the same manner as the aqueous preparation of the present invention, except that the above citric anhydride was replaced with 0.05 g.

Table 12 shows the results of observation of the appearance of the prepared DP Y aqueous formulation for up to 24 hours (stored at 25 ° C) after preparation, and the aqueous solution obtained by mixing 25 mL of the aqueous formulation of the present invention with 3.5 mL of artificial tears. The results of measurement of the gelation temperature of the sample were shown. The appearance after storage at 25 ° C was observed after cooling the sample on ice. The aqueous DPY formulation of the present invention can be prepared as an aqueous formulation at a citrate concentration of 0.1 W / V% or more, and shows that even when mixed with a body fluid such as tear fluid, it gels at a temperature near body temperature. Was done. Table 1 1 2

Category Present invention Comparative example

Formulation No. 77 84 85

DPY W / V% 0.01 0.01 0.01

C type SM15 SM15 S 15

W / V 1.5 1.5 1.5

Type SM400 SM400 SM400

w / v 0.5 0.5 0.5

PEG type 1000 1000 1000

w / v% 10 10 10

Cuic acid w / v¾ 1 0.1 0.05

Tween-80 w / v% 0.5 0.5 0.5

Appearance Aqueous solution Aqueous solution Aqueous solution

Gelation temperature (.c) 32 40> 40

Common for each formulation pH 6.5 Example 13

Add 0.113 g of PEG400 or PEG1000 heated to 60 ° C, add 0? ¥ of 10111 and 0.5 g of Tween-80, mix, and mix.

29 OmL was added and mixed well. To this, a solution prepared by dissolving 3 ^ 15 of 1.5 and 0.5 g of SM400 in 4 OmL of sterilized purified water was added, and mixed well under ice-cooling. Further, 2.3 g of citric anhydride was added and mixed by stirring until all the added components were dissolved. Next, 5N NaOH was added to adjust the pH to 6.5, and sterile purified water was added to make up to 10 OmL, thereby obtaining an aqueous preparation of the present invention.

As a comparison, a comparative DPHY aqueous preparation was prepared in the same manner as the aqueous preparation of the present invention, except that the above PEG was replaced with 0.05 g of PEG1000.

Table 13 shows the results of observation of the appearance of the prepared DP Y aqueous formulation for up to 24 hours (stored at 25 ° C) after preparation, and the mixing of 25 mL of the aqueous formulation of the present invention with 3.5 mL of artificial tears The results of measuring the gelation temperature of the aqueous solution are shown. The appearance after storage at 25 ° C was observed after cooling the sample on ice. The aqueous DPY preparation of the present invention can be prepared as an aqueous preparation at a PEG concentration of 0.1 to: L3W / V%, and gels at a temperature near body temperature even when mixed with a body fluid such as tear fluid. It was shown that.

Table 1 1 3

Category Date of occurrence Comparative example Prescription No. 86 87 88 89 90

DPY W / V ⁰ /, 0.01 0.01 0.01 0.01 0.01

C type S 15 SM15 SM15 SM15 SM15

W / V% 1.5 1.5 1.5 1.5 1.5

Type SM400 SM400 SM400 S 400 SM400

W / V% 0.5 0.5 0.5 0.5 0.5

PEG type 1000 400 1000 1000 1000

w / v 13 10 1 0.1 0.05

Cuic acid w / v 2.3 2.3 2.3 2.3 2.3

Tween-80 w / v% 0.5 0.5 0.5 0.5 0.5

Appearance Aqueous solution Aqueous solution Aqueous solution Aqueous solution Gelling temperature (.c) 24 28 36 40> 40

PH6.5 common for each prescription

30 Example 14

Add 1 to 20 mg of DPY and 0.01 to 2 g of Tween-80 or 0.5 g of HCO-60 to 1 to 10 g of PEG1000 or PEG4000 heated to 60 ° C, mix, and sterilize. 30 mL of purified water was added and mixed well. A solution prepared by dissolving 315 of 1.5 and 0.5 g of SM400 in 4 OmL of sterilized purified water was added thereto, and mixed well under ice-cooling. 2.3 g of citric anhydride was added thereto, and the mixture was stirred and mixed until all the added components were dissolved. Next, 5N NaOH was added to adjust the pH to 6.5, and sterile purified water was added to make 100 mL, thereby obtaining an aqueous preparation of the present invention.

For comparison, a formulation was prepared without the addition of Tween-80 or HC0-60, and a comparative DPHY aqueous preparation was prepared in the same manner as the aqueous preparation of the present invention.

Table 14 shows the results of observation of the appearance of the prepared DP Y aqueous formulation up to 24 hours after storage (stored at 25 ° C), and the aqueous solution obtained by mixing 25 mL of the aqueous formulation of the present invention with 3.5 mL of artificial tears. The results of measurement of the gelation temperature of the sample were shown. The appearance after storage at 25 ° C was observed after cooling the sample on ice. The aqueous DPY formulation of the present invention can be prepared as an aqueous formulation at a polysorbate or polyoxyethylene hydrogenated castor oil concentration of 0.01 to 2 W / V%, and is near body temperature even when mixed with body fluids such as tear fluid. It was shown that gelation occurred at this temperature.

31 Table 14

Common to all recipes: ΡΗ6.5 Precipitation *: DPY crystal precipitation not measured within 24 hours after preparation Example 15

To 4 or 8 g of PEG 4000 heated to 60 ° C, add 10 or 2 Omg of 0 丫 and 0.5 g of Tween_80, mix, add 30 mL of sterile purified water, and mix well. . To this was added 0.7 or 1.5 g of SM15 and 0.5 or 0.7 g of SM400 dissolved in 4 OmL of sterile purified water, and mixed well under ice-cooling. To this was added 2 or 2.3 g of citric anhydride, and the mixture was stirred and mixed until all the added carohydrate components were dissolved. Next, 5 N NaOH was added to adjust the pH to 5.0 to 8.0, and sterile purified water was added to make 100 mL to obtain an aqueous preparation of the present invention.

Table 15 shows the results of observation of the appearance of the prepared DP Y aqueous preparation for up to 24 hours (stored at 25 ° C) after preparation, and mixing of 25 mL of the aqueous preparation of the present invention with 3.5 mL of artificial tears The results of measuring the gelation temperature of the aqueous solution thus obtained are shown. The appearance after storage at 25 ° C was observed after cooling the sample on ice. The aqueous DP Y formulation of the present invention is aqueous-based at pH 5.0 to 8.0.

32 It can be prepared as an agent, and it has been shown to gel at temperatures around body temperature even when mixed with body fluids such as tears.

Table 1 1 5

Formulation No. 101 102 103 104 105 106

DPY W / V% 0.01 0.01 0.01 0.02 0.02 0.01

MC type SM15 SM15 S15 SM15 SM15 SM15

W / V% 1.5 1.5 0.7 0.7 0.7 1.5 Type SM400 SM400 SM400 SM400 SM400 SM400

W / V% 0.5 0.5 0.7 0.7 0.7 0.5

PEG type 4000 4000 4000 4000 4000 4000

W / V% 8 8 4 4 4 8 Cuic acid w / v% 2.3 2.3 2 2.3 2.3 2.3

Tween-80 w / v% 0.5 0.5 0.5 0.5 0.5 0.5

PH 5.0 5.5 6.0 7.0 7.5 8.0 Appearance aqueous solution aqueous solution aqueous solution aqueous solution aqueous solution aqueous solution Gelation temperature (° C) 36 30 34 32 32 28

Example 16

Heated to 60 ° C:! ~ 10 g of PEG1000 or PEG4000, add 1 ~ ¥ of 5 ~ 40111 and 0.05 ~ 2 g of Tween-80, mix and add 30 mL of sterile purified water , Well mixed. To this, a solution prepared by dissolving 7 or 1.5 g of SM15 and 0.5 or 0.7 g of SM400 in 4 OmL of sterilized purified water was added, and mixed well under ice-cooling. 1 to 2.3 g of citric anhydride and 0.005 g of BZK were added thereto, and the mixture was stirred and mixed until all the added components were dissolved. Next, 5N NaOH was added to adjust the pH to 6.0 to 7.5, and sterilized purified water was added to make up to 10 OmL. The prepared aqueous DPY solution was filtered through a 0.45 μm membrane filter and filled in a polyethylene eye drop bottle to give the eye drop of the present invention. Table 16 shows the appearance of the prepared DP Y aqueous formulation and the results after storage at 7 ° C for 3 months.

33 Changes in appearance and results of measurement of the gelation temperature of an aqueous solution obtained by mixing 25 mL of the DPY ophthalmic solution of the present invention with 3.5 mL of artificial tears are shown. The DPY ophthalmic solution of the present invention can be stored for a long period of time, and was shown to gel at a temperature near body temperature even when mixed with tears. Table—1 6

Example 17

1 to: L 0 g of PEG400, PEG 1000 or PEG 4000 and 0.1 to 2 g of HC0-60 or Tween-80 were mixed while heating to 60 ° C. To this was added 0.01-1 g of norfloxacin, ofloxacin or romefloxacin hydrochloride, and mixed well until the crystals of these synthetic antibacterial agents were dissolved. In addition, 1 to 2.3 g of citric anhydride and 0.4 to 1.5 g of MC (SM15, SM25, SMI00, SM400) are added, and the added components are evenly heated while heating to 60 ° C. Mix well to make one. 8 OmL of hot water was added thereto, dispersed until the added components became uniform, and then mixed well under ice-cooling. Here 5 N until pH reaches 5.5

34 NaOH was added and mixed under ice cooling until all the added components were dissolved. Further, 5N NaOH was added to adjust the pH to 6.5 to 7.5, and then sterile purified water was added to make 100 mL. The prepared aqueous solution containing a synthetic antibacterial agent was filtered through a 0.45 μm membrane filter, and then filled in a glass bottle with a lid to obtain an aqueous preparation of the present invention. Table 17 shows the results of observation of the appearance of the prepared aqueous preparation containing a synthetic antimicrobial agent for up to 24 hours (stored at 25 ° C) after preparation, and the mixing of 25 mL of the aqueous preparation of the present invention with 3.5 mL of artificial tears. The results of measuring the gelation temperature of the aqueous solution thus obtained are shown. The appearance after storage at 25 ° C was observed after cooling the sample on ice. Further, Table 18 shows the results of examining the change in appearance of the prepared aqueous preparation (Noil 15, 120, 121, 124 or 126) after storage at 7 ° C for 6 months. The aqueous preparation containing a synthetic antibacterial agent of the present invention can be prepared as an aqueous solution of the synthetic antibacterial agent, and it was shown that even when stored in a cold place, there was no crystal precipitation of the drug and the drug was stable for a long period of time. It was also shown that even when mixed with bodily fluids such as tears, gelation occurred at a temperature near body temperature. Table 1 17

35

Table 18

Example 18

3-: L Og of PEG 1000 and 0.1 to 2 g of HCO-60 or Tween-80 were mixed while heating to 60 ° C. Here 0.01 to 0.2 g of econa nitrate

36 Zor or miconazole nitrate was added and mixed well until the crystals of these antifungal agents were dissolved. 0.5 to 1.5 g of MC (SM15, SM400) was added and mixed well while heating to 60 ° C so that the added components became uniform. To this was added 70 mL of hot water, dispersed until the added components became uniform, and mixed well under ice-cooling. To this, an aqueous solution in which 1.3 to 2.3 g of sodium citrate was dissolved in 15 mL of sterile purified water was gradually added, and mixed well under ice cooling. Further, 5N Na〇H was added to adjust the pH to 6.2 to 7.5, and then sterilized purified water was added to make 10 OmL. The prepared antifungal agent-containing aqueous solution was filtered through a 0.45 m membrane filter and filled in a glass bottle with a lid to obtain an aqueous preparation of the present invention.

For comparison, an aqueous preparation containing a comparative antifungal agent was prepared in the same manner as in the present invention except that the aqueous preparation (formulation # α128) of the present invention was not added with HC 0-60.

Table 19 shows the results of an examination of the appearance change of the prepared antifungal agent-containing aqueous formulation after storage at 7 ° C for 2 months, and the mixing of 25 mL of the aqueous formulation of the present invention with 3.5 mL of artificial tears The results of measuring the gelation temperature of the aqueous solution are shown.

The antifungal agent-containing aqueous preparation of the present invention can be prepared as an aqueous solution of the antifungal agent, and was shown to be stable for a long time without crystal precipitation of the drug even when stored in a cold place. On the other hand, the aqueous formulation containing the antifungal agent for comparison, to which HCO-60 or Tween-80 was not added, was unable to dissolve econazole nitrate crystals from the time of preparation, and was prepared as an aqueous formulation in which the drug was dissolved in water. I couldn't. In addition, it was shown that the antifungal agent-containing aqueous preparation of the present invention gelled at a temperature near body temperature even when mixed with a body fluid such as tear fluid.

37 Table 1 1 9

Not measured Industrial applicability

The poorly soluble drug-containing aqueous preparation of the present invention has a poorly soluble drug dissolved in water near neutrality, and has excellent storage stability without generation of crystals or foreign substances. Furthermore, the reversible thermogelling aqueous preparation containing a poorly soluble drug of the present invention is excellent in gelling properties and storage stability.

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