JPH08175972A - Percutaneously absorbing preparation - Google Patents

Abstract

PURPOSE: To obtain a preparation high in the percutaneous absorbability of the medicinal, washable with water, easy to remove and good in use feeling, comprising a base consisting of a carboxyvinyl polymer, a medicinal except estradiol etc., and a specific percutaneous absorption promoter. CONSTITUTION: This percutaneously absorbing preparation comprises a base consisting of a carboxyvinyl polymer, a medicinal substance except 17-β-estradiol and its esters and 3-ketodesogestrel and its 17-ester, and a percutaneous absorption promoter, a fatty acid amide as a reaction product of a 8-16C aliphatic monocarboxylic acid and monoethanolamine or diethanolamine.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a percutaneous absorption preparation having high drug permeability.

[0002]

2. Description of the Related Art In order to obtain a medicinal effect on a whole body or a local area, a transdermal preparation for absorbing a drug through the skin or the like is used. Unlike the orally administered drug, this transdermal drug can be gradually absorbed without the drug being decomposed in the digestive organs, so it is possible to reduce side effects caused by short-term absorption. is there.

Ointments are often used as percutaneous absorption preparations. As the base, an ointment in a narrow sense consisting of an oily base which is poor in water washability, a cream consisting mainly of an emulsion base having water washability, and a gelling agent consisting of a solvent and a hydrophilic polymer are used. Has been. Among them, the gelling agent has high transparency and excellent aesthetics, has a washability, is easy to remove, and has a good usability.

However, in general, sufficient permeability cannot be obtained only by dissolving a drug in these bases, and a large amount of ointment must be administered to administer an effective amount. It is difficult for a user to administer a large amount of ointment, and there is a concern that a wide range of skin disorders will occur when side effects occur.

In general, when an external preparation is repeatedly applied to the same site, the mild effect of a solvent or the like, which can be neglected several times, may cause serious damage due to repeated application. However, if the application area becomes wide, there is no choice but to apply continuously, and there is a risk that side effects will occur,
Not preferred.

Japanese Patent Publication No. 5-33929 discloses a percutaneous absorption preparation containing a fatty acid dialkylolamide having a fatty acid having 8 to 15 carbon atoms as a percutaneous absorption promoter.
Although a technique for promoting absorption of a drug has been disclosed, a gelling agent has not been disclosed as this base, and its effect was unclear.

[0007]

SUMMARY OF THE INVENTION In view of the above, an object of the present invention is to provide a percutaneous absorption preparation having high drug permeability.

[0008]

The gist of the present invention is to provide a base,
A percutaneous absorption preparation comprising a drug excluding 17-β-estradiol and its ester and 3-ketodesogestrel and its 17-ester, and a percutaneous absorption enhancer,
At least one of fatty acid amides in which the base is made of carboxyvinyl polymer, and the percutaneous absorption enhancer is a reaction product of an aliphatic monocarboxylic acid having 8 to 16 carbon atoms and monoethanolamine or diethanolamine. There is a place to do.

The above-mentioned base contains, as a main component, a gelling agent obtained by dissolving a carboxyvinyl polymer, which is a polymer of acrylic acid, in a solvent. Examples of the solvent include water; alcohols such as ethanol, propanol, glycerin, propylene glycol, and polyethylene glycol; esters such as isopropyl myristate and isopropyl palmitate, and the like, and a mixture thereof in an appropriate ratio. Used. Examples of the carboxyvinyl polymer include poly (meth) acrylic acid and poly (meth)
Examples thereof include sodium acrylate.

The blending amount of the carboxyvinyl polymer in the gelling agent is 0.1% with respect to 100 parts by weight of the solvent.
1 to 20 parts by weight is preferable. It may change depending on the amount of the drug, the percutaneous absorption enhancer, etc., but if it is less than 0.1, it becomes impossible to apply it because the viscosity of the gelling agent is insufficient and it does not adhere to the skin, and if it exceeds 20 parts by weight. However, the gelling agent is hardened and it becomes difficult to spread it, and it becomes impossible to apply it. It is more preferably 0.5 to 10 parts by weight. In order to further enhance the effect, the above base may be mixed with a base usually used in ointments such as creams and oily bases.

The percutaneous absorption enhancer used in the present invention is at least one kind of aliphatic amide which is a reaction product of an aliphatic monocarboxylic acid having 8 to 16 carbon atoms and monoethanolamine or diethanolamine. . When the aliphatic monocarboxylic acid has less than 8 carbon atoms, it tends to volatilize, and when it has more than 16 carbon atoms, the effect of promoting percutaneous absorption decreases, so the range is limited to the above range. Examples of the aliphatic monocarboxylic acid having 8 to 16 carbon atoms include lauric acid, palmitic acid, myristic acid, capric acid and caprylic acid.

The amount of the above-mentioned percutaneous absorption enhancer added is preferably 0.1 to 20% by weight in the percutaneous absorption preparation. If it is less than 0.1% by weight, the effect of promoting the percutaneous absorption of the drug cannot be obtained, and if it exceeds 20% by weight, the compatibility with the base is lowered. It is more preferably 2 to 12% by weight.

The drug used in the present invention is a drug capable of penetrating a biological membrane upon percutaneous administration, and other than 17-β-estradiol and its ester and 3-ketodesogestrel and its 17-ester. It is a thing. As such, for example, antipyretic anti-inflammatory analgesics, steroidal anti-inflammatory agents, vasodilators, hypertensive / arrhythmic agents, antihypertensive agents, antitussive agents, antitumor agents, local anesthetics, hormone agents, asthma・ Remedies for nasal allergy, antihistamines, anticoagulants, antispasmodics, cerebral circulation / metabolic agents, antidepressants / anxiety agents, vitamin D agents, hypoglycemic agents, antiulcer agents, sleeping agents, antibiotics, etc. .

Examples of the antipyretic and anti-inflammatory drug include indomethacin, salicylic acid, aspirin, acetaminophen, diclofenac sodium, ibuprofen, sulindac, naproxen, ketoprofen, ferfenamic acid, ibufenac, fenbufen, alclofenac, phenylbutazone, nehenam. Examples thereof include acids, bendazac, piroxicam, flurbiprofen, bentazosin, bublenorphine hydrochloride, butorphanol tartrate, and the like.

Examples of the above-mentioned steroidal anti-inflammatory agents include hydrocortisone, prednisolone, fluocinolone acetonide, fludoxycortide, methylprednisolone, hydrocortisone acetate, triamcinolone acetonide, dexamethasone, hetamethasone acetate, diflucortron valerate, Propion clohetazole, fluocinonide, etc. are mentioned.

Examples of the vasodilator include diltiazem, verapamil, pentaerythritol tetranitrate, dipyridamole, isosorbide nitrate, and nifedipine. Examples of the hypertensive / arrhythmic agent include propanolol, atenolol, pindolol, quinidine sulfate. , Azmarin, alprenolol hydrochloride, metoprolol tartrate, nadolol, timolol maleate, disopyramide and the like.

Examples of the antihypertensive agent include clonidine hydrochloride, captolyl, prozocine hydrochloride, benpentol sulfate, guanabenz acetate, guanfacine hydrochloride, bunazosin hydrochloride, elanabril maleate, arotinolol hydrochloride, bunitrolol hydrochloride and the like.

Examples of the antitussive and antitussive agent include, for example, procaterol hydrochloride, terbutaline sulfate, fenoterol hydrobromide, tulobuterol hydrochloride, ambroxol hydrochloride, pyruviterol hydrochloride, mabuterol hydrochloride, clenbuterol hydrochloride, trimetoquinol hydrochloride, formofumaric acid. Examples thereof include terol.

Examples of the above antitumor agents include 5-fluorouracil and 1- (2-tetrahydrofuryl) -5-
Examples include fluorouracil and mantomycin C.
Examples of the local anesthetic include benzocaine, procaine, lidocaine, tetracaine and the like.

Examples of the hormonal agents include steroid hormones such as estriol, estrone, testosterone, norethisterone acetate and prostaglandins; peptide hormones such as insulin.

As the above-mentioned therapeutic agent for asthma / nasal allergy,
Examples thereof include ketotifen fumarate, azelastine hydrochloride, sodium cromoglycate and the like. Examples of the antihistamine include cycloheptazine hydrochloride, diphenhydramine hydrochloride, phenbenzamine, mequitazine and the like.

Examples of the anticoagulant include heparin and the like. Examples of the antispasmodic include scopolamine, clofluperol and the like. Examples of the cerebral circulatory metabolism improver include pinpocetine, flunarizine hydrochloride, nicardipine hydrochloride, propynecamine fumarate, dihydroergotoxine mesylate, ifenprodil tartrate, isoxuprine hydrochloride and the like. Examples of the above-mentioned antidepressant / anti-labile agent include mabrotiline hydrochloride, etizolam, diazepam, promazepam, amitriptyline hydrochloride, mianserin hydrochloride and the like.

Examples of the vitamin D agent include α-
Examples include calcidol and ergocasiferol.
Examples of the hypoglycemic agent include glibenclamide,
Gliclazide and the like can be mentioned. As the above-mentioned anti-ulcer agent,
Examples thereof include grepopride malate, famotidine, glycovironium bromide and the like. Examples of the sleeping pills include phenobarbital and amobarbital. Examples of the above antibiotics include tetracycline and chloramphenicol. The compounding amount of the above-mentioned drug varies depending on the kind of the drug, the purpose of use of the preparation, etc., but it is preferably contained in the ointment base in a proportion of 0.001 to 30% by weight.

[0024]

Since the transdermal preparation of the present invention uses a gelling agent as a base, it has good transdermal absorbability of a drug, is washable, easy to remove, has a good feeling in use, and is easy to apply. Since the above fatty acid amide is contained as a skin absorption promoter, a high drug permeation amount can be achieved, and the amount of ointment applied to administer the required amount can be reduced.

[0025]

The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

Example 1 1 part by weight of Carbopol (carboxyvinyl polymer),
0.75 parts by weight of indomethacin and lauric acid diethanolamide 3 in a base consisting of 25 parts by weight of water, 40 parts by weight of 2-propanol and 30 parts by weight of polyethylene glycol.
An ointment was obtained by adding parts by weight and mixing in a mortar until dissolved.

Comparative Example 1 1 part by weight of Carbopol (carboxyvinyl polymer),
0.75 parts by weight of indomethacin was added to a base consisting of 25 parts by weight of water, 40 parts by weight of 2-propanol and 30 parts by weight of polyethylene glycol, and mixed in a mortar until dissolved to obtain an ointment.

Using the obtained ointment, a permeation test was conducted with the diffusion cell 1 shown in FIG. The diffusion cell 1 is formed of a bottomed cylindrical receptor tank 2 and a bottomed cylindrical donor tank 3 arranged on the tank 2. An opening 4 is provided at the center of the bottom wall of the donor tank 3, and the bottom wall is provided with a flange 5 extending in the circumferential direction. A flange 6 is provided on the upper portion of the receptor tank 2, and a side wall is provided with a sampling port projecting laterally. The flange 5 and the flange 6 are overlapped with each other so as to face each other, and the donor tank 3 and the receptor tank 2 are airtightly and concentrically stacked. A magnetic stirrer 9 is placed inside the receptor tank 2.

Hairless mice (6 weeks old, male) were sacrificed by cervical dislocation, and immediately the back skin was peeled off to remove subcutaneous fat and muscle layer to obtain a skin piece 8 of about 5 cm × 5 cm.
The obtained skin piece 8 was sandwiched between the flange 5 and the flange 6 of the diffusion cell 1, and the opening 4 of the donor tank 3 was completely closed by the skin piece 8. 200 mg of the obtained percutaneous absorption preparation is uniformly applied to one surface of a circular (diameter 10 cm) polyethylene terephthalate film 10, and the percutaneous absorption preparation layer forms a skin piece 8.
It was affixed to the central part of the skin piece 8 so as to be in contact with.

The receptor tank 2 is filled with receptor liquid
And place it in a constant temperature bath maintained at 37 ° C,
Rotate the magnetic stirrer with a stirrer
Was. Sampling port at 5, 18, and 24 hours after starting the test
1 ml of receptor fluid from 7 and the collected receptor
-Measure the amount of drug in liquid by high performance liquid chromatography
did. When collecting the receptor collection solution,
The liquid was replenished. The test is performed with n = 3, and the average value is calculated.
I calculated. The results are shown in Fig. 1. The receptor fluid is
5 × 10 sodium dihydrogen phosphate^-Fourmol / l, phosphorus
2 × 10 disodium hydrogen hydrate^-Fourmol / l, sodium chloride
1.5 × 10 ^-1mol / l and gentamicin
Of sodium hydroxide was added to the aqueous solution containing 10 ppm of
Aqueous solution 8 whose pH was adjusted to 7.2 by adding a 1N aqueous solution
20 parts by weight of polyethylene glycol 400 in 0 parts by weight
Obtained by dissolving.

[0031]

EFFECTS OF THE INVENTION Since the transdermal preparation of the present invention is constructed as described above, a high drug permeation amount can be achieved and the amount of ointment applied to administer the required amount can be reduced. Can be easily applied to the user,
Even when side effects occur, skin disorders can be reduced more than ever before. Also, since the applicable area is small,
It can be applied to various parts of the body, and the risk of side effects due to continuous application can be avoided.

[Brief description of drawings]

FIG. 1 is a graph showing the results of a permeation test of Example 1 and Comparative Example 1. The vertical axis represents the amount of indomethacin (μg) in 1 ml of the receptor solution. The horizontal axis shows the collection time (hours). Black-filled ⋄ represents the value of Example 1, and black-filled □ represents the value of Comparative Example 1.

FIG. 2 is a perspective view showing a diffusion cell.

[Explanation of symbols]

 1 Diffusion cell 2 Receptor tank 3 Donor tank

Claims (1)

[Claims] 1. A percutaneous absorption preparation comprising a base, a drug excluding 17-β-estradiol and its ester, 3-ketodesogestrel and its 17-ester, and a transdermal absorption enhancer, which comprises: The base is made of carboxyvinyl polymer, and the transdermal absorption enhancer has 8 to 1 carbon atoms.
6. A percutaneous absorption preparation, which is at least one kind of fatty acid amide which is a reaction product of aliphatic monocarboxylic acid of 6 and monoethanolamine or diethanolamine.