JPH06247846A - Composition for percutaneous absorption preparation of ritodrine hydrochloride - Google Patents

Abstract

PURPOSE:To enable ritodrine hydrochloride that has been used only as injections or tablets to be used as a percutaneous absorption preparation. CONSTITUTION:This composition for a percutaneous absorption preparation of ritodrine hydrochloride is produced by adding an aliphatic alcohol of 10-20C or lactic acid ester of an aliphatic alcohol of 10-20C or isopropyl alcohol ester of an aliphatic acid of 10-20C as an accelerator for percutaneous absorption.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION The present invention relates to ritodrine hydrochloride (formula C
₁₇ H ₂₂ ClNO ₃ ).

[0002]

_2. Description of the Related Art Ritodrine hydrochloride is a sympathetic β ₂ receptor stimulant and is mainly used as a therapeutic drug for imminent abortion. There are two types of preparations, drip injections and oral preparations for home treatment after discharge. The oral preparations are to be taken three times a day after eating, but to maintain stable pregnancy. It is desirable to keep the drug concentration always constant.

[0003]

An oral sustained-release preparation is generally used as a dosage form capable of keeping the drug concentration constant. However, in the case of oral agents, it is difficult to remove the administered drug from the body when side effects occur. In addition, ritodrine hydrochloride has side effects such as sudden increase in heartbeat and increase in blood glucose level during treatment, and there is a problem in the usefulness of an oral sustained release preparation. In recent years, the skin has been reconsidered as an administration site that allows a drug to act for a long time with a single use and allows interruption of administration. Therefore, the present inventors diligently studied the development of a transdermal preparation of ritodrine hydrochloride, which uses the skin as an administration route and has few side effects. However, for the living body, the skin is a protective film from the outside world, and it is generally difficult to absorb the drug from the skin.In order to obtain the therapeutic effect of ritodrine hydrochloride by applying it to a small skin area, the skin permeability of the drug is It is necessary to prepare the formulation with a promoting base.

[0004]

Therefore, as a result of various studies, the inventors of the present invention have found that the number of carbon atoms as a percutaneous absorption enhancer is 10 to 20.
Aliphatic alcohol, lactate of aliphatic alcohol having 10 to 20 carbon atoms or isopropyl alcohol having 10 carbon atoms
The inventors of the present invention found that a ritodrine hydrochloride preparation prepared by adding -20 fatty acid esters can achieve high skin absorption.

As aliphatic alcohols having 10 to 20 carbon atoms, all aliphatic alcohols having 10 to 20 carbon atoms that can be used as pharmaceutical additives are used.
The aliphatic alcohols mentioned above are included, but lauryl alcohol, myristyl alcohol and cetyl alcohol are preferable, and lauryl alcohol is more preferable. Carbon number
The lactic acid ester of 10 to 20 aliphatic alcohol includes all lactic acid ester of aliphatic alcohol having 10 to 20 carbon atoms that can be used as a pharmaceutical additive, but is preferably lauryl lactate, myristyl lactate, cetyl lactate, More preferably cetyl lactate. The fatty acid ester of isopropyl alcohol having 10 to 20 carbon atoms can be used as a pharmaceutical additive for all isopropyl alcohol having 10 to 20 carbon atoms.
The fatty acid ester of the above is included, but isopropyl laurate, isopropyl myristate, and isopropyl palmitate are preferable, and isopropyl myristate is more preferable. The aliphatic alcohol used in the present invention,
The amount of the lactic acid ester of aliphatic alcohol and the fatty acid ester of isopropyl alcohol compounded in each case is 1 to 300 mg, preferably 5 to 200 mg, and more preferably 10 to 100 mg per 1 g of the preparation. Furthermore, these additives for promoting percutaneous absorption can be used alone or in combination of two or more. The ritodrine hydrochloride contained in the formulation of the present invention cannot be limited because it varies depending on the type of dosage form to be prepared thereafter and the medical condition of the target patient, but is used in an amount of 5 to 500 mg, preferably 50 to 300 mg, per 1 g of the formulation of the present invention. Is. In the formulation of the present invention, all that can be used as a base for pharmaceuticals such as water, vegetable oil, mineral oil, polymer pressure-sensitive adhesive and lower alcohol can be used. Further, the dosage form includes tapes, ointments, liquids, poultices, plasters, etc. As a preparation method thereof, for example, in the case of tapes, it is prepared by using a polymer pressure-sensitive adhesive as another base. The composition of the present invention can be prepared by a solvent casting method, a hot melt method or the like which is a general method for preparing a tape preparation.

[0006]

[Function] The preparation of the present invention is prepared by adding another base to a transdermal absorption enhancer such as ritodrine hydrochloride and an aliphatic alcohol and mixing them, and adding the base to the prepared product to prepare a preparation. When the product is attached to the skin, a percutaneous absorption enhancer such as an aliphatic alcohol acts to promote the absorption of ritodrine hydrochloride into the skin.

[0007]

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

Example 1 The composition shown in Table 1 was mixed to prepare a composition,
These were dissolved in chloroform and coated on polyethylene terephthalate so that the thickness when dried was 110 μm using an applicator to prepare a tape preparation. Then, the effects of these tape agents were compared and examined by the following test methods.

[0009]

[Table 1]

Test method The skin of the abdomen of a hairless rat is sandwiched between vertical diffusion cells (effective area 1 cm ² ), 4.5 ml of water is placed in the dermis side cell, and the mixture is stirred at 37 ° C. The composition of the present invention 1, 2, 3, 4, 5
Formulation 1, Formulation 2, Formulation 3, Formulation 4, prepared from 6 and 6
Comparative Example Formulation 1 prepared from Formulation 5, Formulation 6 and Comparative Example Composition 1 were each applied, and the amount of the drug transferred to the dermis side with time was measured. The results are shown in Table 2.

[0011]

[Table 2]

As is clear from the results shown in Table 2, the addition of a percutaneous absorption enhancer such as lauryl alcohol, cetyl lactate or isopropyl myristate gives a skin permeation-promoting effect of ritodrine hydrochloride, and the drug permeation per unit area is high. I was able to get the speed.

Example 2 Formulation 2 of the present invention prepared from the composition 2 of the present invention shown in Table 1.
Regarding the permeability of the drug to the human skin according to the above-mentioned test method, the results are shown in Table 3 below.

[0014]

[Table 3]

From these results, the 24-hour average skin permeation rate of ritodrine hydrochloride was calculated to be 3.3 μg / cm ² / h. Since the systemic clearance of ritodrine hydrochloride is 65 l / h, assuming an effective plasma drug concentration of 3 ng / ml,
The required application area (A) of this preparation can be calculated. A = 3 × 10
^-9 (g / cm ³ ) × 65 × 10 ³ (cm ³ /h)÷{3.3×10 ^-6 (g / cm ² /
h)} and A = 59 cm ² . (8 cm × 8 cm or less) From this value, it is shown that the preparation according to the present invention is sufficiently practicable, suggesting the effectiveness of the present invention.

[0016]

[Effect] As described above, the preparation containing the percutaneous absorption enhancer according to the present invention can obtain a high skin permeation rate per unit area with respect to ritodrine hydrochloride, and can also obtain stable absorption over a long period of time. You can

Front page continuation (51) Int.Cl. ⁵ Identification code Office reference number FI technical display location A61K 47/10 AAU E 7433-4C 47/14 E 7433-4C

Claims (5)

[Claims] 1. A transdermal absorption enhancer comprising an aliphatic alcohol having 10 to 20 carbon atoms, a lactic acid ester of an aliphatic alcohol having 10 to 20 carbon atoms or isopropyl alcohol.
A composition for percutaneous absorption of ritodrine hydrochloride, which comprises adding 10 to 20 fatty acid esters. 2. The composition for percutaneous absorption preparation of ritodrine hydrochloride according to claim 1, wherein the percutaneous absorption promoter is blended in an amount of 0.01 to 30% by weight of the whole preparation. 3. The composition for percutaneous absorption preparation of ritodrine hydrochloride according to claim 2, wherein the aliphatic alcohol having 10 to 20 carbon atoms is lauryl alcohol, myristyl alcohol or cetyl alcohol. 4. The composition for percutaneous absorption of ritodrine hydrochloride according to claim 2, wherein the lactic acid ester of an aliphatic alcohol having 10 to 20 carbon atoms is lauryl lactate, myristyl lactate or cetyl lactate. 5. Isopropyl alcohol having 10 to 20 carbon atoms
The composition for percutaneous absorption of ritodrine hydrochloride according to claim 2, wherein the fatty acid ester is isopropyl laurate, isopropyl myristate or isopropyl palmitate.