JPH04334326A - Percutaneously absorbable composition - Google Patents

Abstract

PURPOSE:To obtain the title composition improved in percutaneous absorbability by formulating a specified base with a narcotic or narcotically antagonistic analgesic. CONSTITUTION:The objective composition can be obtained by formulating (A) a base comprised of a lower alcohol, polar solvent and azacycloalkane derivative with (B) as medicinal ingredient, a narcotic or narcotically antagonistic analgesic. The present composition, which has been enhanced in the percutaneous penetrability/permeability for the medicinal ingredient, has significant absorption-promotive activity.

Description

[Detailed description of the invention]

0001

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a percutaneous absorption composition which improves percutaneous absorption by incorporating a narcotic or narcotic antagonist analgesic into a specified base.

0002

[Prior Art] Currently, narcotic and narcotic antagonist analgesics are often used as oral agents or injections for the treatment of postoperative and cancer pain. It is difficult to administer the drug to patients who do not have enough of it. In addition, in terms of home medical care, there are still practical problems such as restrictions on general usage and difficulty in controlling the dosage because the drug is a narcotic. Therefore, treatment methods using these transdermal preparations are strongly desired.

However, it is generally known that narcotic and narcotic antagonist analgesics are poorly absorbed through the skin, and various formulations have been attempted. For example, JP-A-63-132847 proposes a skin-permeable composition using the absorption-promoting compound 1-n-dodecyl azacycloheptan-2-one. Moreover, a composition using a compound such as N-(hydroxyethyl)pyrrolidone, which is an absorption-promoting compound, is also known from JP-A-60-36423. In addition, a composition for promoting percutaneous absorption using azacycloalkanes has been filed by the present applicant and has already been published in Japanese Patent Application Laid-Open No. 62-238261. There is of course no description that promotes permeation, but there is no description that suggests them.

0004

[Problems to be Solved by the Invention] However, the above-mentioned known state of the art has not been able to sufficiently absorb narcotic or narcotic antagonist analgesics through the skin, and is still insufficient in terms of practicality. Moreover, many problems remained as a means of administering the drug quantitatively over a long period of time. Therefore, an object of the present invention is to develop a transdermal absorption composition in which an amount of drug sufficient to exert a medicinal effect is effectively absorbed through the skin, and further, in which the drug is quantitatively absorbed over a certain period of time.

[0005]

[Means for Solving the Problems] Therefore, the present inventors conducted intensive research to develop a transdermal absorption composition for the above purpose, and found that azacycloalkane was added to the system of lower alcohol and polar solvent as an absorption enhancer. The inventors have discovered that the above object can be achieved by creating a composition containing a narcotic or narcotic antagonistic analgesic as a medicinal ingredient in a composition containing a derivative.

[0006] In recent years, there has been a lot of interest in transdermal absorption preparations because of their ability to maintain the persistence of drugs, the ability to control the rate of absorption of drugs and the prevention of side effects caused by overdosing, and the ability to prevent initial administration by the liver. This is because it has advantages such as avoiding the transit effect, allowing effective use of drugs, and allowing relatively safe administration of drugs that cause liver damage. However, since normal skin naturally has a protective effect against external stimuli, drug absorption and permeation are relatively difficult. Therefore, even if a drug is administered transdermally, it is currently difficult to absorb the amount of drug necessary to fully exhibit the desired medicinal effect.

However, the present inventors selected an azacycloalkane derivative as a highly useful and safe absorption enhancer that sufficiently enhances penetration, permeation, and absorption into the skin and has little local toxicity itself. The present invention was accomplished by discovering that a composition containing this in a two-component system consisting of a lower alcohol and a polar solvent is most suitable for transdermal preparations of narcotic or narcotic antagonist analgesics. .

More specifically, in the present invention, in a system combining only a polar solvent and a lower alcohol, in vitro
Although the combination of polar solvents, alcohol, and azacycloalkane derivatives did not enhance the permeability of narcotic or narcotic antagonist analgesics through the skin removed from hairless rats by RO, This is based on the fact that the permeation rate of narcotic and narcotic antagonist analgesics is significantly enhanced.

Next, each component will be explained in detail. The lower alcohol is ethanol or isopropyl alcohol, and the amount thereof in the base composition is 5 to 50 parts by weight, preferably 15 to 25 parts by weight. As the polar solvent, water, glycerin, or propylene glycol can be used alone or in combination. The blending amount thereof is 50 to 95 parts by weight, preferably 75 to 85 parts by weight in the base composition.

As the azacycloalkane derivative, 1-
[2-(decylthio)ethyl]azacyclopentane-2
-one (hereinafter abbreviated as HPE-101) or 1-dodecyl azacycloheptan-2-one (hereinafter abbreviated as Azon), and the blending amount thereof is 0.01 to 20 parts by weight, preferably It is 0.01 to 10 parts by weight.

[0011] The narcotic or narcotic antagonist analgesics as medicinal ingredients include morphine hydrochloride, pethidine hydrochloride, fentanyl citrate, codeine phosphate, pentazocine, butorphanol tartrate, eptazocine hydrobromide, buprenorphine hydrochloride, etc. Among these, morphine hydrochloride, pethidine hydrochloride, and eptazocine hydrobromide are particularly preferred. The amount used is within the range of 0.01 to 25 parts by weight.

[0012] The lower alcohol thus obtained,
A composition containing a narcotic or narcotic antagonistic analgesic as a medicinal ingredient in a base component consisting of a polar solvent and an azacycloalkane derivative can be applied to various formulations intended for transdermal administration. For example, various preparations such as reservoir-type patches, liniments, lotions, aerosols, and suspensions can be made. In addition, these preparations are prescribed according to known methods.

0
013]

[Examples] The present invention will be specifically explained below using examples. Of course, the present invention is not limited only to these examples. In addition, the composition of the example contains lower alcohol 5
50 parts by weight, 50 to 95 parts by weight of a polar solvent, and 0.01 to 25 parts by weight of a medicinal ingredient consisting of 0.01 to 20 parts by weight of an azacycloalkane derivative. For example, to explain Example 1, first, 40 parts by weight of ethanol, which is a lower alcohol, 55 parts by weight, water, which is a polar solvent, and 5 parts by weight, HPE-101, which is an azacycloalkane derivative, are blended, and the whole is made uniform. After thorough stirring, 15 parts by weight of morphine hydrochloride as a medicinal ingredient was added, and the composition of Example 1 was prepared by stirring sufficiently to obtain a uniform mixed solution. Further, according to the method of Example 1, compositions of other Examples and Comparative Examples shown in Table 1 can be prepared. Note that the order of blending each base is not particularly restricted,
They may be combined in any other order. Table 1 showing Examples and Comparative Examples is shown below. In addition, each numerical value in Table 1 means parts by weight.

[0014]

[Table 1]

Test Example 1 (Skin Permeation Test) For each composition shown in Table 1, 1.5 g of morphine hydrochloride was added to prepare a saturated solution (suspended state) of morphine hydrochloride. Therefore, the rate of permeation of morphine hydrochloride through skin excised from hairless rats should be similar if diffusivity through the skin of hairless rats is the only controlling factor. The data shown in Table 2 are average values derived from three series of experiments calculated from a curve plotting the amount of skin permeation for each composition versus time, and the compositions in Table 1 were tested according to the following method. It was obtained by Table 1
Prepare a sample having the composition shown in , and then add 2.7 ml of the sample to the supply tank of a two-chamber diffusion cell (horizontal cell).
and physiological saline was placed in the receptor tank and each formulation was tested. Periodically, 0.5 ml of the receptor solution in the cell was taken and replaced with 0.5 ml of fresh physiological saline. A typical sampling schedule is 1, 2, 3, 4,
After 5, 6, 7 and 8 hours. The drug concentration in the collected physiological saline was measured by high performance liquid chromatography (HPLC) after each sampling. Note that HPE-101 was used as the azacycloalkane derivative. The test results are shown in Table 2 below.

[0017]

[Table 2]

[0018]

[Effect] In the skin permeation test on the skin of hairless rats shown in Table 2, the composition containing a medicinal ingredient in a base consisting of a lower alcohol, a polar solvent, and an azacycloalkane derivative of the present invention was found to be superior to the composition of the comparative example. About 50
It has ~100 times the amount of skin permeation. Therefore, the composition of the present invention enhances the permeation and permeation of medicinal ingredients through the skin and exhibits a remarkable absorption promoting effect.

[0019]

Effects of the Invention The composition of the present invention has a remarkable effect of promoting transdermal absorption, so it can be used to administer narcotic substances or narcotic antagonist analgesics, which were conventionally available only in oral preparations, injections, and suppositories. It can be applied to various dosage forms of preparations intended for skin application. In particular, it has a very high utility value as a transdermal absorption therapeutic system, which is a formulation whose dosage can be controlled, and is very useful in the pharmaceutical industry.

Claims (5)

[Claims] 1. A transdermal absorption composition comprising a base component consisting of a lower alcohol, a polar solvent, and an azacycloalkane derivative, and a narcotic or narcotic antagonist analgesic. 2. 5 to 50 parts by weight of lower alcohol, 50 to 95 parts by weight of polar solvent, and 0 parts by weight of azacycloalkane derivative.
．． 2. The transdermal absorption composition according to claim 1, wherein a narcotic or narcotic antagonistic analgesic is blended into the base component consisting of 01 to 20 parts by weight. 3. The polar solvent is selected from water, glycerin, ethylene glycol, 1,3-butylene glycol, and propylene glycol.
The transdermal absorption composition described above. Claim 4: The azacycloalkane derivative is 1-[2
-(decylthio)ethyl]azacyclopentan-2-one or 1-dodecyl azacycloheptan-2-one, the transdermal absorption composition according to claim 1 or 2. 5. The narcotic or narcotic antagonist analgesic is morphine hydrochloride, pethidine hydrochloride, fentanyl citrate, codeine phosphate, pentazocine, butorphanol tartrate,
The transdermal absorption composition according to claim 1 or 2, which is eptazosine hydrobromide or buprenorphine hydrochloride.