JPH02233621A - Percutaneous absorbefacient and medicinal pharmaceutical containing the same for external use - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention]. TECHNICAL FIELD The present invention relates to a transdermal absorption enhancer and an external pharmaceutical preparation containing the same, and more particularly, to a transdermal absorption enhancer comprising a monocaprylic acid ester of glycols and the transdermal absorption enhancer. The present invention relates to an external pharmaceutical preparation containing an accelerator and a medicinal ingredient.

In general, oral administration of drugs is widely used, but when taking into account the troublesomeness of administration and side effects such as gastrointestinal disorders, it is necessary to change the route of drug administration or to Therefore, an administration method is desired that allows pharmacological effects to be expressed more safely and side effects to be alleviated.

In recent years, as a method for administering drugs that meets these expectations, development of formulations by transdermal administration aimed at absorption of drugs through the skin has been actively conducted. However, in the case of transdermal administration, the stratum corneum, which forms the outermost layer of the skin, plays a physiological function as a protective wall against substances penetrating into the body, so the rate of drug absorption through the skin is lower than that of oral administration. Significantly slower than. Therefore, when formulating transdermal absorption preparations, it is necessary to devise ways to increase the absorption of drugs through the skin.

From this point of view, it has been common practice to incorporate a substance with a so-called transdermal absorption promoting effect into a base together with a drug. For example, alcohols and glycols that increase drug solubility in bases and skin, urea derivatives and pyrrolidones that moisturize and soften the stratum corneum, and sodium lauryl sulfate, decyl methyl sulfoxide, and octanol as amphipathic promoters. However, the mechanism of action of these substances is not yet clear, and some of them have unfavorable safety properties such as skin irritation, so there are problems when putting them into practical use. There is.

In order to understand the problem, the present inventors have previously confirmed that medium chain fatty acid glycerides have a desirable effect of promoting drug absorption (Japanese Patent Application Laid-Open No. 107916/1983), but furthermore, Regarding esters of medium-chain fatty acids that have the highest absorption, the chemical structure, that is, the optimal number of substituted ester groups and the length of the side chain, and the relationship between these and the effect of promoting transdermal absorption of drugs. As a result of extensive studies, the inventors discovered that monocaprylic acid esters of glycols have an excellent transdermal absorption promoting effect, leading to the completion of the present invention.

That is, the present invention relates to a transdermal absorption enhancer comprising a monocaprylic acid ester of glycols, and an external pharmaceutical formulation containing the transdermal absorption enhancer and a medicinal ingredient.

Specific examples of monocaprylic acid esters of glycols which are transdermal absorption enhancers of the present invention include ethylene glycol monocaprylate, brobylene glycol monocaprylate, butylene glycol monocaprylate, etc.
Monocaprylic acid esters of these glycols have no physiological activity by themselves, but when applied to the skin together with a drug, they have the effect of promoting absorption of the drug through the skin.

Furthermore, the monocaprylic acid ester of glycols of the present invention may be used as it is or dissolved, dispersed or suspended in a suitable solvent such as water or lower alcohols to prepare a preparation. When used, the transdermal absorption effect of the monocaprylic acid ester of glycols of the present invention is further promoted. It can be blended and used with a topical base, and usually, the concentration is sufficient as long as it can promote the permeation and absorption of the compounded drug through the skin, and the concentration is 1:0.5 to 50% by weight in the preparation. , preferably about 1 to 20% by weight.

In addition, there are no particular restrictions on the drugs that can be used with the transdermal absorption enhancer of the present invention, as long as the drug's skin permeability is promoted and the expression of drug efficacy is not impaired. The selection includes drugs that are preferably administered transdermally, such as drugs that require long-term administration or drugs that undergo a first-pass effect. More specifically, sedatives such as flurazepam hydrochloride, triazolam, nimetazepam, fluphenazine enanthate, thiothixene, flupenthixol hydrochloride, subiveron, bimozide, timiperone, lorazepam, mexazolam, fepramine acetate, blazepam, alprapram, clonazepam Neuropsychiatric drugs such as eperisone hydrochloride, muscle relaxants such as thikidium bromide, antispasmodics such as triprolidine hydrochloride, dimethindene maleate, clemastine fumarate, digoxin, lanatoside C, deslanoside,
Cardiac drugs such as methyldigoxin, antiarrhythmic drugs such as bucumolol hydrochloride and verapamil hydrochloride, antihypertensive drugs such as reservin, dihydroergotoxine mesylate, bunitrol hydrochloride, guanabenz acetate, and enalapril maleate, vasodilators such as pavaberine hydrochloride, diltiazem hydrochloride , coronary vasodilators such as trimetazidine hydrochloride, molsidomine, bromhexine hydrochloride, salbutanol sulfate, trimethoquinol hydrochloride, procaterol hydrochloride, tulobuterol hydrochloride, fenoterol hydrobromide, formoterol fumarate, mabuterol hydrochloride, ibratrobium bromide, fumaric acid Examples include antitussive and expectorant agents such as ketotifen, azelastine hydrochloride, and oxatomide; analgesic and antiinflammatory agents such as piroxicam, buprenorphine hydrochloride, butorphanol tartrate, butazocin hydrobromide; and follicular and progestin agents such as ethinyl estradiol and estriol.

These drugs can be present in the drug in a dissolved, dispersed, or suspended state, and the effects of the drug are usually determined by considering compatibility with the base material, stability of the drug, etc. For example, it is used at a concentration of 0.1 to 30% by weight, preferably 1 to 10% by weight in the ζ preparation.

In this case, if the concentration of the drug in the formulation is too low, absorption of the drug will be insufficient and the desired medicinal effect will not be achieved, whereas if it is too high, the solubility and dispersibility of the drug in the base will be affected. It is not preferable because it gives a

External preparations that can be prepared using the transdermal absorption enhancer of the present invention include various external preparations that are expected to exhibit pharmacological effects through transdermal absorption, such as gels, ointments, poultices, and patches. It can be made into a tape preparation, etc., and can be manufactured by appropriately selecting an external base suitable for the desired dosage form and formulating it according to a conventional method.

The external base used in this case is preferably a substance that does not exhibit medicinal efficacy per se, such as absorbent bases such as water-absorbing ointments, hydrophilic bases such as hydrophilic ointments, and water-soluble bases such as macrogol ointments. natural water-soluble polymers such as starch, bullulan, gelatin, dextran, methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, and hydroxybubucil cellulose; synthetic water-soluble polymers such as carboxyvinyl polymer, polyacrylic acid (sodium), and polyvinyl alcohol; Examples include molecules.

In addition, adhesive bases such as silicone-based, acrylic-based, acrylic vinyl-based, and carboxyvinyl polymers, or emulsifiers, suspending agents, humectants, and other commonly used agents such as gum arabic, lecithin, glycerin, and propylene glycol, if necessary. It is also possible to mix additives.

EXAMPLESNext, external preparations using the transdermal absorption enhancer of the present invention will be specifically explained with reference to Examples, but the technical scope of the present invention is not limited by these Examples.

Example 1 (gel formulation) Papaverine hydrochloride 0.66g Ethylene glycol monocaprylate 1. OOg Hydroxybuchi, Bill Cellulose 0.20g total amount
10. A gel preparation was obtained by mixing papaverine hydrochloride, ethylene glycol monocaprylate, hydroxypropyl cellulose, and purified water in the above amounts with stirring.

Example 2 (gel formulation) Diltiazem hydrochloride 3. OOg Ethylene Glycol Monocaprylate 1. OOg carboxyvinyl polymer 0. 2 0 g0. IN sodium hydroxide 0. 10g purified
Water 5.70g total
Amount 10. After mixing diltiazem hydrochloride, ethylene glycol monocabrilate, carboxyvinyl polymer, and purified water with stirring according to the above amounts, 0.0g. A gel formulation was obtained by adding IN sodium hydroxide. Example 3 (gel formulation) Estriol 0.20g ethylene glycol monocaprylate 1. OOg ethanol
3. OOg Hydroxybrobyl cellulose 2. O Og purified water 3.80g
A gel preparation was obtained by mixing estriol, ethylene glycol monocaprylate, ethanol, hydroxybubal cellulose, and purified water with stirring in the above amounts (total amount: 10.0 Og).

Example 4 (gel formulation) Papaverine hydrochloride 1. OOg Propylene glycol monocaprylate 1. OOg ethanol 3. OOg Hydroxyprobyl cellulose 0. 20g
Purified water 4.
80g total amount 10.
A gel preparation was obtained by mixing papaverine hydrochloride, propylene glycol monocaprylate, ethanol, hydroxybutylic cellulose, and purified water in the above amounts with stirring.

Example 5 (tape formulation) Papaverine hydrochloride 0.30g 2.65%
Isophorone diisocyanate crosslinker (in acetic acid solution) 0.275 g (Hüls product) 20% ethylene glycol monocaprylate (in acetic acid solution) 2.125 g total
Amount: 7.70 g After suspending papaverine hydrochloride and ethylene glycol monocaprylate in an ethyl acetate solution according to the above amounts, "Polysic 310-S" was added.

Further, a crosslinking agent was added under stirring, and the resulting solution was spread on PET film (Toray ■ product) and dried at 100° C. for 90 seconds to obtain a tape preparation.

Example 6 (Cream) Clonazepam 1.0g Ethylene Glycol Monocaprylate 10. Og diethyl sebacate 10.0g cetanol
8.0g Polyoxyethylene sorbitan monostearate 5.0g White petrolatum 10.0g Total amount
A cream was obtained by heating and mixing the substances other than purified water at 70° C., adding purified water, emulsifying the mixture, and cooling it.

The present invention will be further explained in terms of airfoils using test examples. Test Example 1 (Skin permeation test in i3vitro) (
Method) A male hairless rat (body weight 150 g) was anesthetized with bentobarbital sodium, and the abdominal skin was cut out and placed in a skin permeation experimental cell (Two-Cha-mber D).
iffusion Cell, cell area 0.95c,
The volume was 2.5°C and the temperature was 37°C.

Samples were prepared using the present invention preparation and control preparation prepared according to the formulation example shown in Table 1-1 in the donor cell, and 2 days after the start of the experiment.
, 4.6, 8, 10, 24. At 26 and 28 hours, 20 Oue samples were collected from the receiver side cell, and the same amount of physiological saline was added each time after collection.

The collected sample (pavaberine hydrochloride) was quantified using high performance liquid chromatography (HPLC).

(Results) Shown in Table 1-2.

Test Example 2 (in vitro skin permeation test)
(Method) A male hairless rat (body weight 150 g) was anesthetized with bentobarbital sodium, the abdominal skin was cut out, and a cell for skin permeation experiments (Franz Taib, cell area 3.
14cd, volume 18.5IIll, temperature 37°C).

For the sample, a gel preparation of papaverine hydrochloride 3.5-cm prepared according to Example 1 was used in the donor-side cell, and physiological saline 18.5-cm was filled in the receiver-side cell.

The experimental method and drug quantification were carried out in the same manner as in Test Example 1.

As a control, a gel preparation prepared according to the operating procedure of Example 1 but excluding ethylene glycol monocabrilate was used.

(Results) Shown in Table 2.

Average value of 4 cases Test Example 3 (in vitro skin permeation test)
(Method) A male hairless rat (weight 150 g) was anesthetized with bentobarbital sodium, the abdominal skin was cut out, and a cell for skin permeation experiments (Fran type, cell area 3.
14cj, volume 18.5d, temperature 37℃). For the sample, a gel formulation of diltiazem hydrochloride 3.5-cm prepared according to Example 2 was used in the donor-side cell, and a physiological saline solution 18.5-cm was filled in the receiver-side cell.

The experimental method and drug quantification were conducted in the same manner as in Test Example 1. As a control, the operating procedure of Example 2 was followed, and the results are shown in Table 3. Test Example 4 (In vivo blood concentration test) (
Method) 2.0 g of the gel preparation of papaverine hydrochloride prepared in Example 1 was soaked in ゜Cathery Bad゜ (trade name: Nichiban ■ product), applied to the abdomen of the rat, and then covered with a vinyl sheet. It was fixed with Elastopore゜《Product name: Nichiban ■Product》.

The applied area was 22 cd (5.5 x 4 CIl).

Rats were housed in Pohlmann cages, and after chestnut application, 2, 4,
6. At 10 and 24 hours, 200 meters of blood was collected from the jugular vein and used as a sample for blood concentration measurement.

Quantification of samples was performed using HPLC method. (result)
It is shown in Table 4. mυ11 The glycol mono-caprylic acid ester used in the present invention can be used as a transdermal absorption enhancer for various drugs, and by being included in the formulation together with the drug, it improves the permeability of the drug through the skin. It is possible to increase the blood concentration of the drug and obtain a good blood concentration of the drug.

Claims (4)

[Claims] (1) A transdermal absorption enhancer consisting of monocaprylic acid ester of glycols. (2) The monocaprylic acid ester of glycols is ethylene glycol monocaprylate (Claim No. 1)
The transdermal absorption enhancer described in section 1). (3) The transdermal absorption enhancer according to claim (1), wherein the monocaprylic acid ester of glycol is propylene glycol monocaprylate. (4) An external pharmaceutical preparation containing a medicinal ingredient and a monocaprylic acid ester of glycols.