JPH06247869A - Absorbent per respiratory tract and nasal absorbent - Google Patents

Abstract

PURPOSE:To obtain a cyclosporin-containing transtracheal absorbent and nasal absorbent capable of being safely administered to a human body per respiratory tract and per nose and of manifesting excellent beneficial effect. CONSTITUTION:This absorbent per respinatory tract and nasal absorbent comprises an aqueous liquid obtained by dissolving or dispersing a solution of cyclosporin in an organic solvent into water in the presence of a surfactant.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a transrespiratory and nasal absorbent containing cyclosporine. As used herein, cyclosporine refers to a mixture of one or more cyclosporin class antibiotics. Regarding this cyclosporine, for example, Japanese Patent Application Laid-Open No. 2-17
127.

[0002]

2. Description of the Related Art Cyclosporine is used as an immunosuppressant.
It is well known that it has been widely used in the field of organ transplantation including kidney transplantation. Moreover, it has been gradually revealed that cyclosporine is effective not only for organ transplantation but also for various diseases whose main cause is autoimmune reaction. For example, cyclosporin is known to have a therapeutic effect on allergic diseases and autoimmune diseases. Cyclosporine is also known to have a pharmacological effect on bronchial asthma.

The administration of cyclosporine to the human body has hitherto been carried out mainly by oral administration, but cyclosporine has nephrotoxicity and often causes renal damage. When the cyclosporin is orally administered as a therapeutic agent for bronchial asthma, there is a risk of such renal damage. Therefore, in order to avoid such a problem of cyclosporine nephrotoxicity, it is considered to be effective to directly administer cyclosporine by inhalation or to administer nasally. Airway and nasal absorbents have not yet been developed.

[0004]

DISCLOSURE OF THE INVENTION The present invention provides a cyclosporine-containing respiratory tract absorbent and nasal absorbent which can be safely administered to the human body by the respiratory tract and nasal passage and can exhibit excellent drug effects. The task is to provide.

[0005]

The present inventor has completed the present invention as a result of intensive studies to solve the above-mentioned problems. That is, according to the present invention, there is provided a transrespiratory and nasal absorbent comprising an aqueous liquid obtained by dissolving or dispersing an organic solvent solution of cyclosporine in water in the presence of a surfactant.

The nasal absorbent and nasal absorbent of the present invention (hereinafter, also simply referred to as drugs) contain cyclosporine as a medicinal component. The content ratio of cyclosporine is 0.005 to 1% by weight, preferably 0.01 to
It is 0.5% by weight.

The drug of the present invention contains an organic solvent for dissolving cyclosporine. As this organic solvent,
A substance that is liquid at room temperature (25 ° C.) and soluble in cyclosporine is used. Such organic solvents include monohydric alcohols, polyhydric alcohols, partial esters of polyhydric alcohols, alkylene oxide adducts of partial esters of polyhydric alcohols, alkylene oxide adducts of monohydric or polyhydric alcohols, polyhydric alcohols. Partial alkyl ether, aliphatic divalent carboxylic acid ester, N-alkylpyrrolidone, N, N-dialkylacetamide,
Examples thereof include dialkyl sulfoxide, alkylene carbonate, alkyl imidazolidine, squalene and the like. These organic solvents are used alone or in the form of a mixture of two or more kinds.

As the monohydric alcohol, both lower alcohols and higher alcohols can be used. The alcohol may be a straight chain or branched chain alcohol, and may have an unsaturated bond. Specific examples of monohydric alcohols include lower alcohols such as ethanol, propanol, isopropanol and butanol, as well as octyl alcohol, nonyl alcohol, decyl alcohol, 2-octyldodecanol and 2,6-
Examples thereof include dimethyl-4-heptanol and oleyl alcohol.

Examples of the polyhydric alcohol include sorbit, sorbitan, mannitol, alkylene glycols such as ethylene glycol, propylene glycol and butylene glycol, and polyalkylenes such as polyethylene glycol, polypropylene glycol and poly (ethylene / propylene) glycol. Examples thereof include glycol.

As a partial ester of polyhydric alcohol,
Monoesters of higher aliphatic carboxylic acids of polyhydric alcohols as described above, for example, monostearic acid ester of glycerin, monobehenic acid ester of glycerin, monostearic acid ester of polyethylene glycol, monostearic acid ester of propylene glycol, butylene glycol Monostearate, sorbitan monooleate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monoisostearate, propylene glycol monocaprylate, propylene glycol Monocapric acid ester, butylene glycol monocaprylic acid ester, butylene glycol monocapric acid ester, glyco Monobutyrate include pre propylene glycol monomethyl butylate.

As the alkylene oxide adduct of a partial ester of polyhydric alcohol, an ethylene oxide adduct or a propylene oxide adduct of glycerin monostearate or an ethylene oxide adduct or propylene oxide of polyethylene glycol monostearate. Addition product, ethylene oxide addition product or propylene oxide addition product of propylene glycol monostearate ester, ethylene oxide addition product or propylene oxide addition product of polypropylene glycol monostearate ester, ethylene oxide addition product of propylene glycol monostearate ester or propylene Oxide adduct, sorbitan monofatty acid ester (lauric acid ester, palmitic acid ester, stearic acid ester Tel, oleic acid ester, etc.) ethylene oxide adduct or propylene oxide adduct, and batyl alcohol ethylene oxide adduct or propylene oxide adduct.

Examples of the alkylene oxide adducts of monohydric alcohols or polyhydric alcohols include ethylene oxide adducts, propylene oxide adducts and butylene oxide adducts of the above-mentioned monohydric alcohols or polyhydric alcohols. As the partial alkyl ether of polyhydric alcohol, a partial alkyl ether of the above polyhydric alcohol, for example, β-oxyethyl methyl ether,
Examples include various alkyl cellosolves (ethylene glycol ether) such as β-oxyethyl ethyl ether and β-oxyethyl propyl ether.

As the aliphatic dicarboxylic acid diester,
Examples include those represented by the following general formula. R ¹ OOC- (CH ₂ ) n-COOR ² (1) In the above formula, R ¹ and R ² represent an aliphatic group, and n is 2 to 10.
Indicates an integer. The aliphatic group includes an alkyl group and an alkenyl group, the carbon number of which is 1 or more, and usually 1 to 12
Is. Specific examples of the aliphatic dicarboxylic acid diester include diethyl succinate, diisopropyl succinate,
Diethyl adipate, diisopropyl adipate, dibutyl adipate, diisooctyl adipate, dioctyl adipate, didecyl adipate, decylisooctyl adipate, diethyl azelate, diisopropyl azelate, diisopropyl azelate, diethyl sebacate, diisopropyl sebacate, Examples thereof include dibutyl sebacate and dioctyl sebacate.

Examples of the N-alkylpyrrolidone include N-methylpyrrolidone, examples of the N, N-dialkylacetamide include N, N-dimethylacetamide, examples of the dialkyl sulfoxide include dimethyl sulfoxide, and alkylene carbonate. Examples include propylene carbonate. Examples of the alkyl imidazolidine include 1,3-dimethyl-2-imidazolidine.

Particularly preferred organic solvents for use in the present invention are lower alcohols, alkylene glycols, N
-Alkylpyrrolidone, alkylene carbonate, alkylimidazolidine, higher alcohols (particularly higher branched chain alcohols), adipic acid esters, sebacic acid diesters and the like. All of these organic solvents dissolve 5% by weight or more, especially 10% by weight or more of cyclosporine.

The drug of the present invention contains a surfactant.
As the surfactant in this case, various anionic, cationic, nonionic and amphoteric surfactants can be used, but from the viewpoint of mildness to the skin, the nonionic surfactant is It is used to advantage. Examples of the nonionic surfactant include ethylene oxide-based surfactants, polyhydroxy-based surfactants, polymer-based surfactants and the like.
Examples of the ethylene oxide-based surfactant include ethylene oxide adducts of higher alcohols, ethylene oxide adducts of higher fatty acids, ethylene oxide adducts of alkylphenols, ethylene oxide adducts of aliphatic amines, ethylene oxide adducts of aliphatic amides, and polyhydric alcohols. Ethylene oxide adduct, ethylene oxide /
Examples include propylene oxide block copolymers.
Examples of the polyhydroxy surfactant include glycerin monofatty acid ester, pentaerythritol fatty acid ester, sorbitan fatty acid ester, sucrose fatty acid ester, fatty acid amide of ethanolamine, and alkylene oxide adducts thereof. In the present invention, particularly, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene glyceryl monofatty acid ester, polyoxypropylene monofatty acid ester, sorbitan fatty acid ester, polyoxyethylene alcohol ether and the like are advantageously used. These surfactants are used alone or in the form of a mixture.

The agent of the present invention may optionally contain an alkanolamine as a skin absorption enhancer of cyclosporine. Examples of the alkanolamine include diethanolamine, triethanolamine, isopropanolamine, diisopropanolamine, triisopropanolamine, dibutanolamine, tributanolamine and the like.

The agents of the present invention are, if necessary, tonicity agents (glycerin, sodium chloride, etc.), thickeners (polymer compounds), colorants, fragrances, emulsion stabilizers, bactericides, fungicides. Etc. can be included.

In the drug of the present invention, the content of cyclosporine is 0.005-0.1 wt% based on the total drug,
It is preferably 0.01 to 0.5% by weight. The content of the organic solvent is not less than the amount necessary to dissolve cyclosporine, but is not more than 5% by weight, preferably not more than 3% by weight, more preferably not more than 2% by weight, based on the total amount of the drug. If the amount of the organic solvent is too large, irritation problems occur, which is not preferable. The amount of the surfactant is not particularly limited, but is usually 0.05 to 10% by weight, preferably 0.1.
~ 5% by weight.

The drug of the present invention can be obtained by dissolving or dispersing a solution of cyclosporine in an organic solvent in water in the presence of a surfactant. As the surfactant, one having an HLB value of 8 or more, preferably 11 or more is used. Further, it is preferable to add the surfactant in advance to the solution of cyclosporin in the organic solvent. When the water-soluble organic solvent is used in the drug of the present invention, the drug in which the organic solvent of cyclosporine is dissolved in water is obtained. On the other hand, when a non-water-soluble organic solvent is used, the organic solvent solution of cyclosporine gives a drug in a state of being dispersed (emulsified) in water.

[0021]

EFFECTS OF THE INVENTION Since the drug of the present invention comprises cyclosporin as a solution in a state of being dissolved or dispersed in water, it can be easily absorbed into the human body through the respiratory tract and the nose. . In addition, since the drug of the present invention can reduce the content of the organic solvent, it is possible to avoid the problem of irritation to the skin and mucous membranes. Furthermore, since the drug of the present invention is administered by the respiratory tract or airway, the dose per administration is small,
Asthma attack can be effectively suppressed. The chemical | medical agent of this invention is filled with a spray container or an aerosol can, and is used for sale.

[0022]

EXAMPLES Next, the present invention will be described in more detail by way of examples.

Example 1 A solution prepared by dissolving cyclosporin and a surfactant in an organic solvent was uniformly dissolved or dispersed in purified water in which glycerin was dissolved as an isotonicity agent, and the composition of components (wt) shown in Table 1 was used.
%) Liquid drug was prepared. Next, the irritation of this product was evaluated by the eye irritation test method. The reason for adopting the eye irritation test method for the irritation test of the drug of the present invention is that there is currently no irritation test for evaluating irritation of a respiratory tract absorbent, and that the eye irritation test is against mucosal irritation. According to what is considered the most sensitive. The specific contents of the surfactants A and B shown in Table 1 are as follows. (1) Surfactant A Polyethylene glycol monostearate (40EO) (2) Surfactant B Sorbitan monostearate

[0024]

[Table 1]

Drug No. of the present invention 1-No. When the irritant properties of No. 6 were compared with 0.9 wt% NaCl aqueous solution, the drug No. 1-No. None of 6 showed a significant increase in the number of blinks. The corneal disorder was examined by staining spots with fluorescein. 1-No. 6 also showed no significant increase. From the above, it is clear that the drug of the present invention has no problem of irritation and that the drug of the present invention is useful as a transrespiratory and nasal absorbent.

Example 2 With respect to 9 patients with severe asthma, the above-mentioned No. One drug was administered by isohalation at a rate of 0.25 mg of cyclosporine, three times a day. As a result, the subjective symptoms and the morning PEF and evening PEF were significantly improved. Moreover, the acetylcholine threshold of the respiratory tract was also significantly improved (before administration: 142 μg /, 6 weeks after administration:
223 μg / ml, 12th week of administration: 386 μg / m
l).

Claims (3)

[Claims] 1. A respiratory tract absorbent and a nasal absorbent comprising an aqueous liquid in which a solution of cyclosporine in an organic solvent is dissolved or dispersed in water in the presence of a surfactant. 2. The content of the organic solvent is 5 in the total aqueous liquid.
The airway absorbent and nasal absorbent according to claim 1, which are contained in an amount of not more than 5% by weight. 3. The transrespiratory and nasal absorbents according to claim 1, wherein the content of cyclosporine is 0.005 to 1% by weight in the total aqueous liquid.