JPH1053527A - Percutaneous absorbent preparation containing caffeine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new percutaneous absorbent containing caffeine in high content by containing caffeine or its salt as an active ingredient and formulating a specific solvent and an absorption promoter in a base. SOLUTION: This absorbent is prepared by using caffeine or its pharmacologically permissible salt as an active ingredient and formulating an absorption promoter in a mixed solvent of alcohols and water containing the active ingredient. As the alcohols, monovalent alcohols such as methanol and ethanol and polyvalent alcohols such as ethylene glycol and glycerol are preferable. As the absorption promoter, refined oils (preferably 1-menthol, basil oil, eucalyptus oil, and rosemary oil are preferable. The content of caffeine in the percutaneous absorbent is 0.5-15wt.%. The whole weight of alcohols and water is 5-200 times as much as the weight of caffeine and the weight ratio of the alcohols to water is preferable to be 2:1 to 1:10. Further, the absorption promoter is contained in an amount of 0.1-10wt.% based on the whole weight of preparation. This preparation is usable as ointments, lotions, cataplasms and patchs.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a novel transdermal preparation containing caffeine.

[0002]

2. Description of the Related Art It is widely known that caffeine has a drowsiness-preventing effect by cerebral arousal action.
It has been generally practiced to add caffeine to candies, gums, etc. to have a drowsiness-preventing effect (Japanese Unexamined Patent Publication No.
251533). Further, as a transdermal preparation containing caffeine, a drug in which a drug is blended with an acrylic plaster containing caffeine (xanthine derivative) and cyclodextrin to improve the stability of the drug (Japanese Patent Application Laid-Open No. 59-18121)
Although 2) is known, caffeine-containing transdermal preparations for preventing sleepiness are not known. The cause is that caffeine has low solubility in water and organic solvents, and it is difficult to obtain a transdermal preparation with a high content. As a result, in order to obtain an effective amount, caffeine must be applied to the skin. It can be said that only a preparation having an extremely uncomfortable feeling with a widened range can be obtained, and it is difficult to percutaneously absorb an amount sufficient to expect a drowsiness-preventing effect in a usual external preparation form.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a caffeine-containing transdermal preparation containing caffeine in a high content and having improved skin permeability of caffeine.

[0004]

DISCLOSURE OF THE INVENTION The present inventors have found that when a mixture of alcohols and water is used as a solvent, the solubility of caffeine is remarkably improved, and a transdermal preparation containing caffeine in a high content can be obtained. In addition, it has been found that by incorporating an absorption enhancer into the preparation, skin permeability is remarkably improved, and a sufficient amount of caffeine for permeation prevention such as drowsiness is transdermally absorbed.

That is, the present invention relates to a transdermal preparation comprising caffeine or a pharmaceutically acceptable salt thereof as an active ingredient, and a base containing alcohol, water and an absorption enhancer. It is.

[0006]

DETAILED DESCRIPTION OF THE INVENTION In the present invention, the form as a transdermal absorption preparation is not particularly limited, and may be various forms such as an ointment, a lotion, a liniment, a poultice, a patch, a plaster and the like. be able to.

[0007] Caffeine as an active ingredient may be free or a pharmacologically acceptable salt thereof. Examples of such a salt include sodium benzoate. .

[0008] The content of caffeine in the preparation (in the case of a pharmacologically acceptable salt of caffeine, means the content of free caffeine without a salt portion) depends on the dosage form, base component, and the like. Although it slightly fluctuates, it may be usually 0.5 to 15% by weight based on the total weight of the preparation, and 1.0 to 15% by weight.
It is preferred that

In the present invention, preferred alcohols include monohydric alcohols and polyhydric alcohols.

Specific examples of the monohydric alcohol include methanol, ethanol, propanol, isopropanol,
Butanol, pentyl alcohol, hexyl alcohol, heptyl alcohol, octyl alcohol, caprylic alcohol, nonyl alcohol, decyl alcohol,
Undecyl alcohol, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, hexadecyl alcohol, heptadecyl alcohol, stearyl alcohol,
Oleyl alcohol, nonadecyl alcohol, monohydric alcohols having 1 to 20 carbon atoms such as eicosyl alcohol, among which methanol, ethanol,
A monohydric alcohol having 1 to 3 carbon atoms such as propanol is preferred.

Specific examples of polyhydric alcohols include ethylene glycol, propylene glycol, trimethylene glycol, glycerin α-monochlorohydrin, and butylene glycol (1,2-butylene glycol, 1,3-
Butylene glycol, 2,3-butylene glycol,
1,4-butylene glycol), isobutylene glycol, pentamethylene glycol, trimethylethylene glycol, hexamethylene glycol, 2,5-hexanediol, 2-methyl-2,4-pentadiol, 2
-A dihydric alcohol having 2 to 8 carbon atoms such as butyne-1,4-diol, polyethylene glycol (molecular weight: 200 to
1500, preferably 200 to 400), glycerin and the like.
Propylene glycol is preferred.

One of these alcohols can be used alone, or two or more can be used.

[0013] Water can be suitably used as long as it has a property generally used in the field of pharmaceutical preparations. Further, if necessary, salts, sugars, high-molecular substances and the like may be added to the water. An acid or alkali substance for adjusting pH or pH can also be blended.

The total weight of alcohols and water in the preparation is
The weight of caffeine (in the case of a pharmacologically acceptable salt of caffeine, it means the weight of free caffeine not containing a salt portion) may be 5-200 times, and 5-70 times. Is preferred.

The mixing ratio of the alcohol and water is preferably 2: 1 to 1:10, more preferably 2: 1 to 1: 1.
6.

The absorption enhancer may be any of those usually used in transdermal preparations, such as ureas such as urea and thiourea, 2-pyrrolidone, 1-methyl-2-pyrrolidone and 5-methyl. Pyrrolidone derivatives such as -2-pyrrolidone and 1,5-dimethylpyrrolidone; fatty acid esters such as methyl myristate, butyl myristate, isopropyl myristate, isopropyl palmitate, isopropyl caprate and isopropyl caproate;
-Menthol, rosemary oil, cardamom oil, basil oil, juniper berry oil, clove oil, eucalyptus oil, vetiver oil, spearmint oil, lavender oil, geranium oil, pepper oil, hinoki oil, ylang ylang oil, cananga oil, cumin oil , Essential oils such as perilla oil, patchouli oil, fennel oil, and anise oil, Aison (chemical name: 1-dodecylazacycloheptan-2-one, manufactured by Nelson, USA) and its analogs, cyclodextrin, calcium thioglycolate And so on. Among these, essential oils are particularly preferred, and l-menthol is particularly preferred. l
-Menthol has a sleepiness preventing effect in addition to the absorption promoting effect, and a synergistic effect with caffeine can be expected.

These absorption enhancers may be used alone,
Also, two or more kinds may be used in combination. The absorption enhancer may be contained in an amount of 0.1 to 10% by weight based on the weight of the preparation.
The content is preferably set to 5 to 5%.

The present invention is a transdermal absorption preparation comprising caffeine or a pharmacologically acceptable salt thereof, alcohols, water and an absorption enhancer, but preferred combinations of alcohols and absorption enhancers are not limited. For example, a combination of ethanol and 1-menthol, a combination of 1,3-butylene glycol and 1-menthol,
Examples include a combination of butylene glycol with l-menthol and juniper berry oil, a combination of 1,3-butylene glycol with l-menthol and rosemary oil, and the like.

In the preparation of the present invention, the base is not particularly limited as long as it is commonly used in this technical field, and may be selected according to the dosage form.

For example, when the percutaneous absorption preparation of the present invention is an ointment, an oily base or an emulsion base can be used as a base.

As the oleaginous base, hydrocarbons, higher alcohols, higher fatty acids, higher fatty acid esters, glycols, vegetable oils, animal oils and the like can be used. Specifically, examples of the hydrocarbon include hydrocarbons having 12 to 32 carbon atoms, and a mixture of various hydrocarbons such as liquid paraffin, branched paraffin (trade name, isoper), solid paraffin, white petrolatum, etc. However, liquid paraffin, white petrolatum and the like are preferable.

As higher alcohols, for example, those having 12 carbon atoms
To 30 aliphatic monohydric alcohols, specifically, for example, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, hexadecyl alcohol, heptadecyl alcohol, stearyl alcohol, oleyl alcohol, nonadecyl Alcohol, eicosyl alcohol, seryl alcohol, melisyl alcohol and the like can be mentioned. Among them, cetyl alcohol, hexadecyl alcohol, stearyl alcohol, oleyl alcohol and the like are preferable, and stearyl alcohol, oleyl alcohol and cetyl alcohol are particularly preferable. Examples of the higher fatty acids include, for example, saturated or unsaturated fatty acids having 6 to 32 carbon atoms. Specifically, for example, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, tridecylic acid , Myristic acid, pentadecylic acid, palmitic acid, heptadecylic acid, stearic acid, oleic acid, nonadecanoic acid, arachiic acid, arachiic acid, linoleic acid, linolenic acid, behenic acid, lignoceric acid, serotinic acid, heptacosanoic acid, montanic acid, melysin Acids, laccelic acid, elaidic acid, brassic acid and the like. Of these, myristic acid and oleic acid are preferred.

Examples of the higher fatty acid ester include (A)
Esters of fatty acids having 10 to 32 carbon atoms and aliphatic monohydric alcohols having 14 to 32 carbon atoms, (B) 10 to 22 carbon atoms
And esters of saturated or unsaturated fatty acids with glycerin or hydrogenated products thereof. Specific examples of (A) include myristyl palmitate, stearyl stearate, myristyl myristate, ceryl lignocerate, lacceryl serotinate, Fatty acid esters such as lacceryl laccerate, natural waxes derived from animals such as lanolin, beeswax, spermaceti, shellac wax, and natural waxes derived from plants such as carnauba wax and candelilla wax.

(B) glyceryl monolaurate, glyceryl monomyristylate, glyceryl monooleate, glyceryl monostearate, glyceryl dilaurate, glyceryl dimyristylate, glyceryl distearate, glyceryl trilaurate, glyceryl Trimyristylate, glyceryl tristearate and the like can be mentioned. Of these, glyceryl monooleate, glyceryl monostearate, glyceryl distearate, glyceryl tristearate and the like are preferable, and glyceryl monooleate, glyceryl monostearate and glyceryl tristearate are particularly preferable.

Examples of the glycols include ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol, 1,3-butylene glycol and the like. For example, polyethylene glycol having a low polymerization degree (such as Macrogol 400) and polyethylene having a high polymerization degree A mixture of glycol (such as Macrogol 4000) in an appropriate ratio can also be suitably used.

As vegetable oils, castor oil, olive oil,
Examples include sesame oil, gentian oil, safflower oil, cottonseed oil, turpentine oil, and hydrogenated vegetable oils and fats. Of these, castor oil, olive oil, turpentine oil and the like are preferred. Mink oil, egg yolk oil,
Squalane, squalene, lanolin and derivatives thereof. The above-mentioned bases may be used alone, or two or more of them may be used as an appropriate mixture.

Further, examples of the emulsion base include an O / W base, a W / O base, and a suspension base. As the O / W base, components such as lanolin, propylene glycol, stearyl alcohol, petrolatum, silicone oil, liquid paraffin, and glyceryl monostearate are emulsified and dispersed in an aqueous phase in the presence or absence of a surfactant. What is called a so-called cream,
The W / O type base is obtained by emulsifying and dispersing components such as petrolatum, higher aliphatic alcohol, and liquid paraffin with water in the presence of a nonionic surfactant having few hydrophilic groups. can give. Further, examples of the suspending base include gels obtained by adding a suspending agent such as starch, glycerin, high-viscosity carboxymethylcellulose, hydroxypropylcellulose, and carboxyvinyl polymer to water.

When the preparation of the present invention is a lotion, any type of suspension lotion, emulsion lotion and solution lotion may be used.
As a base of the suspension type lotion, rubbers, celluloses, a mixture of water and a suspending agent such as clays, and, as the rubbers, for example, sodium alginate, gum arabic, pectin, tragacanth, and the like, Examples of the celluloses include methyl cellulose, hydroxyethyl cellulose, hydroxyethyl starch and the like. Examples of the clays include bentonite and veegum HV. Further, examples of the emulsion type lotion include a base in which water and an oily substance such as a fatty acid and a higher alcohol are emulsified, and examples of the base of the solution type lotion include water and alcohol.

Examples of the base of the liniment include vegetable oils such as olive oil, sesame oil, gentian oil, cottonseed oil, turpentine oil, and alcohols such as ethanol, propanol, isopropanol and a mixture thereof with water. .

Examples of the base of the poultice include a water-soluble polymer such as polyacrylic acid or a salt thereof, polyvinyl alcohol and polyvinylpyrrolidone or a cross-linked product thereof. Cross-linked by a polyvalent metal salt such as alum, or cross-linked by subjecting a water-soluble polymer to a physical treatment such as irradiation with radiation.

Further, in the case of patches and plasters, the components constituting the preparation such as a support, an elastic body, a filler, a tackifier and a release agent are preferably those commonly used in plasters. Can be used for Examples of the support include a nonwoven fabric and the like, and examples of the elastic body include natural rubber, SBR, butyl rubber, polyisobutylene, polyvinyl alkyl ether, poly (meth) acrylate, polyurethane, polyamide, ethylene-vinyl acetate copolymer, acrylic acid,
Acrylic ester-acrylic acid copolymer, dimethyl polysiloxane, polyisoprene rubber, styrene-isoprene-styrene block copolymer rubber, styrene butadiene rubber, polyisobutylene, butyl rubber, and the like can be given. One or more of these components may be mixed,
Further, if necessary, a tackifier, a softener, an antioxidant, and the like can be added. The tackifier preferably has good compatibility with the elastic body, and examples thereof include polyterpene resin, rosin or its ester, and phenol resin.

The percutaneous absorption preparation of the present invention can further contain a preservative such as paraoxybenzoic acid, methylparaben, ethylparaben, propylparaben, chlorobutanol, and benzyl alcohol, as well as a flavoring agent. Depending on the purpose, various emulsifiers, dispersants, wetting agents, stabilizers, preservatives, suspending agents and the like can be contained therein.

The preparation of the present invention can be produced by a conventional method of a transdermal absorption preparation. For example, an ointment is prepared by kneading, emulsifying or suspending a base material to prepare a base, and then preparing caffeine. Or a pharmaceutically acceptable salt thereof, alcohols, water,
It can be produced by adding and mixing an absorption promoter and various additives, and at the time of mixing, a mixer usually used in this field, such as a screw mixer, a homomixer, a kneader, and a roll mill, can be employed.

The lotion is prepared, for example, by adding various base components to purified water, mixing and stirring, and then adding caffeine or a pharmaceutically acceptable salt thereof, alcohols, water, an absorption promoter and various additives. It can be manufactured by adding and mixing the agent, and performing filtration as required.

The liniment can be prepared by dissolving caffeine or a pharmacologically acceptable salt thereof, alcohols, water and an absorption enhancer in a base, adding desired components, and mixing. .

A cataplasm can be produced by mixing caffeine or a pharmaceutically acceptable salt thereof, alcohols, water, an absorption promoter and desired additives with a base, heating and cooling. .

Patches and plasters can be produced by a conventional method such as a solution method or a hot-press method. For example, when a hot-press method is used, caffeine or a pharmaceutically acceptable salt thereof, alcohols, Water, absorption promoter and each component are uniformly kneaded with a roll machine or the like, and applied to release paper using a calender to which heat and pressure are applied so as to have a uniform thickness to form a drug-containing layer. May be laminated and adhered to the surface of the support.

In preparing the preparation of the present invention, caffeine or a pharmaceutically acceptable salt thereof, alcohols,
When mixing the water and the absorption promoter with the base, if the desired alcohols and water are already contained in the base, it is not necessary to particularly add a new one, or if only the necessary amount is added. Good.

Now, the present invention will be described in further detail with reference to Experimental Examples and Examples.

[0040]

【Example】

Experimental Example 1 Caffeine 500 m was added to a solution having the composition shown in Table 1.
g was added and shaken at 25 ° C. for 24 hours. This is 0.2
After filtration with a 4 μm filter, the filtrate was appropriately diluted with purified water, and the solubility was measured with an absorptiometer (UV-365: manufactured by Shimadzu Corporation).

As a result, the solubility of caffeine was remarkably improved by using a mixed solution of water and alcohol, rather than using water or alcohol alone.

[0042]

[Table 1]

Experimental Example 2 Using the poultice prepared in Example 1 in vitro
A drug permeability test was performed using a diffusion cell. The opening diameter is 2c
An m Franz diffusion cell (3.14 cm ² ) was prepared, physiological saline was poured into the receptor (volume: 13 ml) of the cell, and warm water of 37 ° C. was circulated on the outer wall of the cell to reduce the temperature of the receptor. Kept constant. After a test piece of a cataplasm is stuck to the abdominal depilated skin of a male Wistar rat, the skin is attached to a cell. The receptor liquid was sampled over time, and the drug concentration was measured by high performance liquid chromatography to calculate the drug permeation amount. As a comparative control, a cataplasm (comparative preparation 1) without an absorption enhancer (l-menthol, juniper berry oil) was also prepared, and the same experiment was performed.

As a result, as apparent from FIG. 1, the skin permeability was significantly improved by the addition of the absorption enhancer.

Experimental Example 3 Using the poultice prepared in Example 1, an in vivo absorption test was carried out. Wista with abdominal hair removed in advance
Male r-rats were anesthetized by intraperitoneal administration of pentobarbital sodium (55 mg / kg) and a cataplasm was applied to the abdomen. At that time, the cataplasm was covered with a wrap film of approximately the same size, and a medical tape (Silky Tex) was wrapped around the body and fixed. Blood was collected over time (300 μl / time), and the plasma concentration of caffeine was measured. The applied cataplasm was removed 4 hours after the start of the experiment. Further, as a comparative control, the same experiment was carried out for Comparative Formulation 1 (Experimental Example 2).

As a result, as apparent from FIG. 2, the skin permeability was improved and a high plasma concentration was obtained by adding the absorption enhancer.

Example 1 First, (a) sodium polyacrylate (Alonbis S)
S: Nippon Pure Chemical Co., Ltd.) 2 g, sodium alginate 0.5
g, Silicic anhydride (Aerosil: Nippon Aerosil) 1
g, aluminum glycinate 0.05 g, glycerin 3 g, 1,3-butylene glycol 10 g were added and mixed uniformly. Next, (b) 1 g of l-menthol, 1.5 g of juniper berry oil, 0.25 g of TL-10 (chemical name: polyoxyethylene (20) sorbitan monolaurate, manufactured by Nikko Chemicals), ethanol 1 ml, polyacrylic acid ( Julimer AC10SH: Nippon Junyaku) 6
g, water 5 g, and (c) caffeine 1 g, 1
10 g of a 0% (w / w) sodium carboxymethylcellulose solution was dissolved by heating in 8.7 g of water. (A),
(B) and (c) were mixed, spread evenly on caulking paper (release paper) (caffeine 1 mg / cm ² ), and a nonwoven fabric was stuck to obtain a caffeine-containing cataplasm.

Example 2 Polyvinyl alcohol (Kuraray Poval PVA-40)
5: Kuraray Co., Ltd.) was heated and dissolved in 31.8 g of purified water, and a carboxyl vinyl polymer (Hivis Wako HW
104: Wako Pure Chemical Industries, Ltd.) 0.8 g is dissolved in ethanol 25 g at room temperature and then mixed. Next, 10 g of caffeine and 5 of l-menthol 5 were stirred while stirring the mixed solution.
g, 5 g of ethanol, 0.4 g of diisopropanolamine dissolved in 5 g of ethanol and 5 g of 1,3-butylene glycol were sequentially added and mixed at 40 ° C. for 20 minutes to obtain a gel ointment.

Example 3 5 g of polyvinyl alcohol (Gohsenol NM-11Q: manufactured by Nippon Gohsei), 5 g of calcium chloride, and 10 g of 1,3-butylene glycol were dissolved by heating in 32.5 g of purified water, and then 1-menthol was added. 5 g was dissolved in 5 g of ethanol and added. Caffeine (115 mg) was blended with 10 g of the obtained solution, placed in a Petri dish so as to have a uniform thickness, frozen at -20 ° C for 24 hours, and then thawed at room temperature. This was punched to a diameter of 2.5 cm to obtain a patch.

Example 4 1 g of caffeine and 0.5 g of l-menthol were dissolved in 1 g of ethanol at room temperature, and 5.5 g of purified water was added. Hydroxypropylcellulose (HPC
-L: manufactured by Nippon Soda), and kneaded uniformly to obtain a gel ointment.

[0051]

Industrial Applicability The caffeine-containing transdermal preparation of the present invention has a high content and excellent skin permeability.

[Brief description of the drawings]

FIG. 1. In vitro of the preparation obtained in Example 1.
3 shows the cumulative amount of caffeine permeated in a skin permeability test.

FIG. 2 shows changes in the plasma concentration of caffeine in an in vivo absorption test of the preparation obtained in Example 1.

Claims (9)

[Claims] 1. A transdermal absorption preparation comprising caffeine or a pharmaceutically acceptable salt thereof as an active ingredient, and a base containing alcohol, water and an absorption enhancer. 2. The percutaneous absorption preparation according to claim 1, wherein the alcohol is one or more selected from the group consisting of monohydric alcohols and polyhydric alcohols. 3. The monohydric alcohol is one or two selected from the group consisting of methanol, ethanol and propanol.
Species or more, the polyhydric alcohol is ethylene glycol,
The percutaneous absorption preparation according to claim 2, which is one or more selected from the group consisting of propylene glycol, butylene glycol, polyethylene glycol and glycerin. 4. The percutaneous absorption preparation according to claim 1, wherein the absorption enhancer is an essential oil. 5. The transdermal absorption preparation according to claim 4, wherein the essential oil is one or more selected from the group consisting of l-menthol, basil oil, eucalyptus oil, rosemary oil and juniper berry oil. 6. The caffeine content is 0.5% by weight of the preparation.
The percutaneous absorption preparation according to claim 1, wherein the amount is from 15 to 15% by weight. 7. The transdermal preparation according to claim 1, wherein the total weight of the alcohol and water is 5 to 200 times the weight of caffeine. 8. The weight ratio of alcohols to water is 2: 1 to 1.
The percutaneous absorption preparation according to claim 1, wherein the ratio is 1:10. 9. The method according to claim 9, wherein the absorption enhancer is contained in an amount of 0.1 to 1% by weight of the preparation.
The transdermal absorption preparation according to claim 1, which is 0% by weight.