WO1992019271A1

WO1992019271A1 - Percutaneous administration and absorption promoter composition and external preparation for percutaneous administration

Info

Publication number: WO1992019271A1
Application number: PCT/JP1992/000194
Authority: WO
Inventors: Syuji Sato; Katsuya Mukae; Yoshinobu Higashi; Tatsuaki Suzuki; Mitsuhiro Mizumachi; Hirofumi Sakaguchi
Original assignee: Hisamitsu Pharmaceutical Co., Inc.
Priority date: 1991-05-02
Filing date: 1992-02-24
Publication date: 1992-11-12
Also published as: AU1205792A; TW213418B

Abstract

A percutaneous administration and absorption promoter composition which can remarkably promote the percutaneous absorption of pharmacologically active substances, characterized by containing a hydrophobic substance, water and a lower alcohol. An external preparation for percutaneous administration which permits pharmacologically active substances to be percutaneously administered efficiently to thereby attain a therapeutic effect, characterized by containing a pharmacologically active substance, a hydrophobic substance, water and a lower alcohol.

Description

Sun Moon Series »

Transdermal absorption absorption composition and transdermal topical composition

The present invention relates to a composition for external use for transdermal administration for obtaining a therapeutic effect by transdermally administering a pharmacologically active substance, and a composition for promoting absorption for transdermal administration for promoting transdermal absorption of a pharmacologically active substance. About things. Background art

Oral administration and injection-based administration are widely used as administration methods of pharmaceuticals, but such administration methods have side effects such as gastrointestinal disorders and shock. On the other hand, in the case of transdermal administration, the absorbed drug does not pass through the liver during the first circulation in the body. As a result, the metabolism in the liver does not significantly reduce the efficacy. In addition, by controlling the absorbability of the drug, it is possible to reduce the side effects caused by the absorption of a large amount of the drug in a short time. . Furthermore, if a constant drug concentration in the blood can be maintained over a long period of time, the number of drug administrations can be reduced.

However, even if the drug is administered transdermally, the drug does not easily penetrate the skin, and the bioavailability often decreases. Absorption and transmission of drugs is relatively low, especially since the stratum corneum of the skin has a barrier function that prevents foreign substances from entering the body. It is a difficult one. Therefore, even if the drug is administered alone or in the form of conventional ointments, creams, gels, or patches, the skin of the drug is sufficient to achieve the desired pharmacological effect. It is difficult to obtain the amount of transmission.

Under such circumstances, various methods have conventionally been attempted to enhance the transdermal absorbability of drugs. As one of the methods, a method using a two-component composition of alcohol and water has been known, and the drug action has been focused on the effect of alcohol on the skin. Methods to promote blotting and permeation are being considered.o For example, the Journal of Controlled Release, 12, 103-112 (1990) reports on the effect of various alcohols on percutaneous absorption. Have been.

However, even if a two-component composition consisting of alcohol and water alone is used, the permeation amount of the drug is not sufficient, and the desired pharmacological effect cannot be achieved. As is. For this reason, Japanese Patent Application Laid-Open No. 61-249934 discloses an attempt to increase the absorption promoting effect by adding fatty acid hydrocarbons to water Z lower alcohol, The effect of promoting absorption of the drug is not sufficiently high, and there is no description about improvement in permeability by adjusting pH.

Also, Japanese Patent Application Laid-Open Nos. Sho 63-126268 and European Patent No. 2555485 disclose linoleic acid, propylene glycol or i. A method is disclosed in which a mixed solution of sopropanol and an ester compound is used, and this method is used. However, the effect of promoting absorption of the drug is not sufficiently high, and there is no description regarding the water / alcohol composition or description regarding the improvement of permeability by adjusting the pH.

In addition, Japanese Patent Application Laid-Open No. 63-122263 discloses a method of adding an azole or oleic acid to an ethanol solution. In addition, Japanese Patent Application Laid-Open Publication No. Sho 63-3-21 1241 discloses a low-alcohol force and ophthalic acid and glycerol monopoly. Although a method for adding a drug or the like is disclosed, in any of the methods, the effect of promoting the absorption of a drug has not yet been sufficiently obtained. The absorption enhancer used in the above method is different from that of the present invention, and there is no description about the improvement of permeability by pH adjustment.

As described above, many methods for mixing two or more kinds of solvents or adding a transdermal absorption enhancer have been disclosed in the past. The method has not been able to achieve a sufficient drug absorption-promoting effect, and there is no description about the improvement of permeability by adjusting pH. In addition, most of the absorption enhancers used in these conventional methods have no precedent for use as pharmaceuticals, and have cost problems. It cannot be said that it is still sufficient in terms of safety and usability.

The present invention solves the drawbacks of the conventional methods and provides a novel absorption promoting composition having an excellent transdermal absorption promoting effect on a drug, and a composition containing the composition and a pharmacologically active substance. The purpose of the present invention is to provide a composition for external use for transdermal application. There. DISCLOSURE OF THE INVENTION

The present inventors have conducted intensive studies to solve the above problems, and as a result, by appropriately mixing water, a lower alcohol and a hydrophobic substance, and preferably adjusting the pH. It has also been found that a novel absorption-enhancing composition capable of realizing an excellent transdermal absorption-enhancing effect on drugs can be obtained.

More specifically, the inventors have found that binary systems of water and lower alcohols or hydrophobic substances alone do not significantly enhance the skin permeability of drugs. However, these compositions are combined and formulated as a ternary system, and the skin permeability of the drug is remarkably promoted only when the blending ratio and the pH are adjusted, preferably. The inventors have found that the object can be achieved, and have completed the present invention.

That is, the composition for promoting absorption through transdermal administration of the present invention is characterized by comprising a hydrophobic substance, water and lower alcohol.

Further, the composition for topical administration for transdermal administration of the present invention is characterized by comprising a pharmacologically active substance, a hydrophobic substance, water and a lower alcohol.

Hereinafter, first, the composition for promoting absorption through transdermal administration of the present invention will be described more specifically.

The hydrophobic substance used in the present invention is palmitic acid. Cethyl, methyl cetyl citrate, getyl sebacate, sorbitan sodium oleate, polystyrene monophosphate, polyethylene glycol, Butyl hydroxy anisol and chlorazole are listed as being preferred. These hydrophobic substances are preferably contained in an amount of 0.1 to 0.1% by weight based on the total amount of 100% by weight of the composition, and more preferably 1 to 5% by weight. Is

As the lower alcohol used in the present invention, those having 1 to 4 carbon atoms are preferably used, and those having 2 to 3 carbon atoms are particularly preferable. . Specifically, methyl alcohol, ethyl alcohol, n-propyl alcohol, iso-propyl alcohol, n-butyl alcohol, iso-butyl alcohol Reile, sec-butyl alcohol, etc. are preferred, and are listed as those of particular preference, particularly preferred are ethyl alcohol, n-butamate pirualcohol, isobropiruasolco. It is a rule. These lower alcohols are preferably from 1 to 70% by weight, more preferably from 20 to 40% by weight, based on 100% by weight of the total composition. It is blended. Further, it is particularly preferable to appropriately determine the mixing ratio according to the type of alcohol to be used.

Further, purified water or the like is appropriately used as water used in the present invention. The water is preferably contained in an amount of 1 to 90% by weight, more preferably 60 to 80% by weight, based on 100% by weight of the total composition. In addition, the combined It is particularly preferable to appropriately determine the mixing ratio of water according to the type of the roll. The water according to the present invention may contain a salt and a buffer used for adjusting pH, and may be contained in the composition of the present invention as a physiological saline, a buffer or the like.

Next, the composition for external use for transdermal administration of the present invention will be described more specifically.

The hydrophobic substance, water, and lower alcohol used in the composition for transdermal administration of the present invention are as described above.

The pharmacologically active substance that can be contained in the composition for external use for transdermal administration of the present invention is not particularly limited as long as it is a drug that can be absorbed transdermally, but it may be a general anesthetic, a hypnotic / sedative, and an anti-inflammatory drug. Antiepileptics, antipyretic analgesics and anti-inflammatory agents, stimulants, stimulants, agents for psychiatric nerves, local anesthetics, skeletal muscle relaxants, agents for autonomic nerves, anticonvulsants, anti-parkinson agents, ophthalmic agents, otolaryngology Pharmaceutical agents, antihistamines, cardiotonic agents, antihypertensive agents, vasoconstrictors, coronary vasodilators, peripheral vasodilators, circulatory agents, respiratory stimulants, antitussives, digestive drugs Anti-thyroid, anti-thyroid hormone, narcotics, anabolic steroid m, adrenocortical hormone, male hormone, follicular luteal hormone Agents, genitourinary and genitalia agents, germicidal disinfectants for skin, wound protection , Suppurative disease external medicine, analgesic, antipruritic, Osamu Kin, anti-inflammatory agents, parasitic skin disease for agents, emollients, corrosion agents, bi- data Mi emissions agents, blood coagulation inhibitor, addictive poisoning for agents, pain Wind remedies, enzyme preparations, diabetic drugs, etc. are used, among which hypnosis, sedatives, antipyretic analgesics, mental nerve agents, local anesthetics, skeletal muscle relaxants, autonomic nerve agents, Analgesic, anti-parkinson, anti-histamine, cardiotonic, antihypertensive, vasoconstrictor, coronary vasodilator, peripheral vasodilator, cholagogue, antithyroid Lumons, narcotics, adrenal cortical hormones, follicular luteal hormones, agents for parasitic skin diseases, gout remedies, diabetes drugs, etc. are preferred.

Further, the drug (pharmacologically active substance) according to the present invention is preferably water-soluble, and when the drug is acidic, the drug is ionically dissociated in the composition. It is possible to adjust the pH of the above composition or a preparation containing the composition to an alkaline region more than pK a that can be present, that is, pH 6 to 8. I like it. On the other hand, when the drug is basic, the composition is more acidic than pKa at which the drug can exist as the ionic dissociated form in the composition, that is, the pH is about 3 to 6. In addition, it is preferable to adjust the pH of the composition or a preparation containing the composition. The pH adjusting agent used for the above-mentioned pH adjustment includes acids (for example, inorganic acids such as hydrochloric acid, sulfuric acid, and acetic acid, succinic acid, maleic acid, and triethanol). Organic acids such as amines), alkalines (hydroxy hydradium, potassium hydroxide, etc.), and various buffers, etc., which are commonly used. It is appropriately selected from the pH adjusters and the like to be used. The above-mentioned drugs are used alone or in a mixture of two or more kinds, and are compounded in the range of 0.001 to 20% by weight based on 100% by weight of the whole composition. This is preferred.

The composition of the present invention may further contain additives such as an ultraviolet absorbent, an antioxidant, and a preservative, if necessary.

For example, as an ultraviolet absorber, known P-amino benzoic acid derivatives, anthranilic acid derivatives, salicylic acid derivatives, coumarin derivatives, amino acid compounds, Benzotriazole derivative, tetrazol derivative, imidazoline derivative, pyrimidin derivative, dioxane derivative, fran derivative, pyrone derivative, down off § over derivatives, nucleic acid derivatives, § run-preparative Lee emissions derivatives, two co Chi phosphate derivatives, have in co two emissions may include Vita Mi emissions B ₆ derivatives, Tokunibe emission zone off two Roh down Derivatives, for example, 2-hydroxy-4-methoxenbenzophenone derivatives are preferably used.

Examples of the antioxidant include ascorbic acid, ester stearate, sodium ascorbate, and tocopherol (α-tocolate). Ferrole, 3-Tocopherol, Ryoichi Tokoferol, δ-Tocopherol, d-body, 1 body, (dl-body) and These ester derivatives, nordihydroxy glycerate, dibutyl hydroxytoluene, tert-butyl hydroquinone gallate ester (Esters such as ethyl, propylyl, and isoamyl), 1-year-old kisso 31-methyl-4-isopropyl benzene, and others Anti An oxidizing agent is exemplified.

Examples of preservatives include benzoic acid, sodium benzoate, ethyl benzoate, ethyl benzoate pill, butyl parabenzoate, and the like. Is preferably used.

Said UV absorber or antioxidant is preferably from 0.01 to 5% by weight, more preferably from 0.1 to 100% by weight of the total amount of each composition. ~: L weight% is blended. The above-mentioned preservative is preferably contained in an amount of 0.01 to 5% by weight, more preferably 0.05 to 1% by weight, based on 100% by weight of the whole composition. .

As described above in detail, the composition for promoting absorption for transdermal administration of the present invention contains water, alcohol, and a hydrophobic substance, and preferably has a compounding ratio and pH adjustment. By doing so, the pharmacologically active substance has high skin permeability. In addition, the composition for external application for transdermal administration of the present invention comprises the above-mentioned composition for enhancing percutaneous administration for absorption by absorption as a percutaneously absorbable pharmacologically active substance as an active ingredient. When the pharmacologically active substance is present in the ionic dissociated form in the above, the skin permeability of the pharmacologically active substance is extremely high.

The composition for external use for transdermal administration of the present invention is applied to the transdermal skin as it is or by adding a known pharmaceutically acceptable third component or the like as an external preparation. Further, if necessary, an ultraviolet absorbent, an antioxidant, a preservative and the like may be added. The present invention Examples of the dosage form of the external preparation include gels, gel creams, liniments, aerosols, reservoir-type patches, patches, and the like.

First, the gel is described. The gel preparation according to the present invention comprises the above-mentioned water, lower alcohol and hydrophobic substance (for example, cetyl palmitate, getyl separate) according to the present invention together with a pharmacologically active substance in a gel base. Etc.), and can be obtained by blending an antioxidant, an ultraviolet absorber and a preservative as necessary. The gel base may be a conventionally known gel base. Examples of the gel base include gelling agents (for example, carboxyvinyl polymer, hydroxyshethyl cellulose, hydroxyxyl bilcellulose, Carreboxyl methylcellulose, etc.), neutralizing agents (for example, triethanolamine, diisobromobanolamine, sodium hydroxide, etc.), surfactants (for example, sodium hydroxide) Sorbitan lioleate, Sorbitan monooleate, Sorbitan monostearate, Sorbitan monolaurate, Polyoxyethylene Examples thereof include those appropriately mixed with a base selected from ensetyl ether, polyoxyethylene lauryl ether, and the like.

As an example of the production of the above gel agent, first, the gel agent is added to water and allowed to swell. On the other hand, the pharmacologically active substance is dissolved or suspended in an appropriate amount of the dissolving agent, and then the mixture is mixed with the above-mentioned hydrophobic substance and a lower alcohol, or the above-mentioned hydrophobic substance. Dissolved in a mixture of the three components of the substance, lower alcohol and glycols Let me do it. The obtained solution is applied to the gelling agent swelled with water as described above, and a neutralizing agent is further added to the gelling agent to adjust the pH to 3 to 8, thereby obtaining the present invention. To obtain a gel. It should be noted that this production example is merely an example, and it goes without saying that the above-mentioned gel agent is appropriately produced by a known or similar method and formulation.

Next, the gel cream is described. The gel cream according to the present invention includes the above-mentioned water, lower alcohol and water-phobic substance according to the present invention in addition to a cream base and a pharmacologically active substance. It can be obtained by blending antioxidants, ultraviolet absorbers and preservatives as needed. The above-mentioned cream base may be a conventionally known cream base, for example, white petrolatum, liquid paraffin, higher fatty acid esters (for example, Esters such as ester titanate, ester palmitate, hexyl laurate, and ethyl isooctanoate), emulsifiers (eg, polyoxyethylene alkyl ether) Ters, fatty acid esters, etc.), gelling agents (for example, carboxyl polymer, hydroxyshethylcellulose, hydroxypropyl propylcellulose, methylcellulose) , Carboxymethylcellulose, etc.) and neutralizing agents (for example, triurea noramine, diisobromononolamine, sodium hydroxide, etc.) Examples include those in which the base selected from the above is appropriately blended.

As an example of the production of the above gels and creams, Fatty acid ester, high-grade alcohol, emulsifier and the above-mentioned hydrophobic substance were mixed, and the mixture was heat-dissolved at 50 to 100 ° C and then preservative was added to preheated water. Then, the lower alcohol and the pharmacologically active substance dissolved or suspended were added, and then cooled to 50 ° C, and the gelling agent was added to sufficiently disperse. Thereafter, the pH is adjusted to 4 to 8 by adding a neutralizing agent to obtain the gel cream according to the present invention. It should be noted that this production example is only one example, and it goes without saying that the above gel and cream are appropriately produced by a known or similar method and formulation.

Next, the liniment will be described. The regenerating agent according to the present invention includes lower alcohols (for example, ethanol, isopropanol, etc.), water, and hydrophobic substances (for example, cetyl palmitate, The compound can be obtained by adding a pharmacologically active substance to a mixture such as getylsebacate and, if necessary, adding an ultraviolet absorber, an antioxidant, and a preservative. In addition, if necessary, a neutralizing agent for pH adjustment, or methylcellulose, carboxyl vinyl polymer, hydroxiv mouth, virucellulose, etc. A viscosity-imparting agent can be added. It should be noted that this production example is merely an example, and it cannot be overemphasized that the above-mentioned liniment is appropriately produced by a known or similar method and formulation.

Next, the aerosol is described. The azole agent according to the present invention includes lower alcohols (for example, ethanol, Add a pharmacologically active substance to a mixture of isopropanol, a hydrophobic substance (for example, cetyl palmitate, getylsebacate, etc.) and water. Filling an aerosol container with LPG under pressure with added inorganic materials such as talc, ultraviolet absorbers, antioxidants, preservatives, dimethyl ether, etc. You can get it by It should be noted that this production example is merely an example, and it goes without saying that the above-mentioned aerosol is appropriately produced by a known or similar method and formulation.

Next, the patch is described. The patch according to the present invention includes lower alcohols (for example, ethanol, isopropanol, etc.), water-soluble polyhydric alcohol, water, and ethanol. To a mixture of the unsaturated unsaturated monomer, methacrylate and the crosslinking component, a water-phobic substance (for example, cetyl palmitate, getyl sebacate, etc.) and a pharmacologically active ingredient are added. In addition, an antioxidant and a preservative may be added as necessary, and a polymerization crosslinking reaction may be carried out in the presence of a polymerization initiator to obtain the compound. This production example is merely an example, and it goes without saying that the above-mentioned patch is appropriately produced by a known or similar method and formulation.

Finally, we will describe the reservoir-type patch. The reservoir used in this reservoir patch is a mixture of a pharmacologically active substance and the composition for promoting transdermal administration and absorption of the present invention. The gel according to the present invention, gel 'clear -Time agent, ∎ You can in this and force ⁵ we are use the re-twin-down Bok agents, and the like. The porous membrane or polymer membrane used as the control membrane used herein is, for example, polyethylene, polypropylene, polyestermethacrylate ester, or the like. , Polyurethane, Polyester, Polyvinyl alcohol, Polyethylene copolymer, Polyvinyl azole, Polyvinyl chloride, Polyamide Ethylene monomethacrylic acid or an ethylene-acrylic acid copolymer is used. The support includes polypropylene, polyester, polychlorinated vinylidene, polyacrylyl, polyurethan, ethylene-pinyl acetate copolymer, Cloth, non-woven fabric, etc. are used. There may be no case where there is an adhesive layer on the surface that comes into wide contact with the porous layer or polymer membrane in the supporter reservoir, but there is no case where the adhesive layer is provided. The composition of the layer is constituted by an adhesive composition containing a pharmacologically active substance. When there is no adhesive layer, the present invention provides an adhesive layer based on an adhesive base containing no pharmacologically active substance on the outer side of the porous membrane or the molecular membrane as the release surface, and according to the present invention. A formulation can be obtained. This production example is only an example, and it goes without saying that the above-mentioned reservoir-type patch is appropriately produced by a known or similar method and formulation.

The above pharmacologically active substances, hydrophobic substances, water and lower alcohols

The topical composition for transdermal administration of the present invention, preferably containing PH and having its pH adjusted, is a conventional composition obtained by dissolving a drug in a two-component mixture of water and ethanol. Enhanced drug absorption compared to It is very effective and can be absorbed by drugs of low transdermal absorbability (skin permeability) by the use of the composition of the present invention to the extent that there is no practical problem. It is possible to increase the performance. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples, but the present invention is not limited thereto.

Examples 1 to 41 and Comparative Examples 1 to 6

To demonstrate the effectiveness of the composition of the present invention, a transdermal composition for external use for transdermal administration of the present invention containing various hydrophobic substances and pharmacologically active substances (drugs) (Example), and a hydrophobic substance Using the same compositions (comparative examples) except for the above, the permeability of various drugs to hairless skin was measured and compared.

Specifically, each test was performed as follows.

First, water and ethanol were mixed at a mixing ratio of 60% by weight and 40% by weight, respectively, to 95% by weight of the mixed solution, and the various hydrophobic properties shown in Table 1 were used. Each of the drug substances shown in Table 1 was added to a solution obtained by adding and mixing 5% by weight of an active substance to a saturated amount, and dissolved at 37 ° C to prepare each sample solution.

Next, the skin extirpated from the ventral part of the female hairless mouse is sandwiched between two horizontal chambers, and the cell is stratum corneum. 2.7 ml of the above sample solution, 2.7 ml of saline in the cell on the dermis side, and transfer from the supply tank side to the receiving tank side.

The permeation amount of each drug at 37 ° C was measured over time. Drug quantification was performed using HPLC. Table 1 shows the obtained results.

*: A water Z ethanol (60Z40% by weight) solution (without hydrophobic substances) was used as a control solution.

**: Ratio of the maximum permeation rate of a drug using each sample solution divided by the maximum permeation rate of a similar drug using a control solution. As is evident from the results shown in Table 1, the composition for transdermal administration of the present invention containing the composition for promoting absorption of transdermal administration of the present invention (Examples 1 to 41). As a result, the transdermal absorbability of the drug was remarkably high as compared with the conventional composition containing no hydrophobic substance (Comparative Examples 1 to 6). Industrial applicability

The composition for transdermal administration according to the present invention, which contains the above-mentioned pharmacologically active substance, hydrophobic substance, water and lower alcohol, and is preferably adjusted to have a pH, comprises water and d. Compared to a conventional composition in which a drug was dissolved in a two-component mixture with ethanol, the permeability of the drug to the skin was very high, and the absorption efficiency of the drug was very high. Therefore, by employing the composition for transdermal administration for external use of the present invention, it is possible to increase the absorbability of a drug having a low transdermal absorbability to the extent that there is no practical problem. And are possible.

Further, the transdermal composition of the present invention, which contains the above-mentioned hydrophobic substance, water and lower alcohol, and is preferably adjusted in pH. The administration absorption promotion composition has a remarkable effect on the absorption of drugs, and thus greatly contributes to the development of transdermal preparations for percutaneous absorption of poorly absorbable drugs. It is very useful in the pharmaceutical industry.

Claims

Claims range HI

1. A composition for promoting percutaneous absorption, which comprises a hydrophobic substance, water and a lower alcohol.

2. The hydrophobic substance is selected from the group consisting of petroleum hydroxyanisole, chlorazole, cetyl palmitate, methyl kylate, and getyl cenosinate. It is characterized in that it is at least one selected from the group consisting of sesquioleic acid solvitan and monostearic acid polyethylene glycol. The composition for promoting percutaneous absorption according to Claim 1

3. The composition contains 0.1 to 10% by weight of the hydrophobic substance, 1 to 90% by weight of the water, and 1 to 70% by weight of the lower alcohol. 2. The composition for promoting percutaneous absorption according to item 1 above.

4. A transdermal composition for external use characterized by containing a pharmacologically active substance, a hydrophobic substance, water and a lower alcohol.

5. The hydrophobic substance is selected from the group consisting of petroleum hydroxanisol, chlorcresol, cetyl palmitate, methyl citrate, getyl cenoate, and cetyl citrate. That it is at least one member selected from the group consisting of sorbitan squarate and polyethylene glycol monostearate. 5. The composition for external use for transdermal administration according to claim 4, which is characterized by the features.

6. 0.001 to 20% by weight of the pharmacologically active substance, 0.1 to 10% by weight of the hydrophobic substance, 1 to 90% by weight of the water, and the lower alcohol. 5. The composition for transdermal administration according to claim 4, wherein the composition contains 1 to 0% by weight of each.

7. The composition for transdermal administration according to claim 4, wherein the pharmacologically active substance is acidic and the pH of the composition is adjusted to 6 to 8. .

8. The composition for transdermal administration according to claim 4, wherein the pharmacologically active substance is basic, and the pH of the composition is adjusted to 3 to 6. object.