JPH0640888A - Percutaneously absorbable preparation - Google Patents

Abstract

PURPOSE:To provide the preparation enhanced in the skin permeability of a medicine about each of a basic medicine and an acidic medicine. CONSTITUTION:A basic medicine percutaneously absorbable preparation contains a basic medicine and a basic polymeric substance, and an acidic medicine percutaneously absorbable preparation contains an acidic medicine and an acidic polymeric substance.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a percutaneous absorption preparation in which the skin permeability of a drug is enhanced.

[0002]

2. Description of the Related Art A drug administration method using the skin as an administration route is more effective than direct oral administration, and
There are some advantages that cannot be obtained by conventional oral or injectable administration, such as no possibility of causing gastrointestinal tract disorder and no pain or drug shock to patients as in the case of injectable administration. Because of its possession, it has been attracting attention in recent years.

[0003]

However, since the skin is originally an organ for protecting the whole body from external stimuli, drugs generally tend to be difficult to be absorbed from the skin. Therefore, to facilitate the absorption of the drug through the skin,
In other words, how to improve the skin permeability is a major issue in developing a percutaneous absorption preparation.

[0004]

Means for Solving the Problems The present inventor has conducted various studies in view of the above situation, and as a result, it has been found that the skin permeability of a basic drug is enhanced by a basic polymer and that the skin of an acidic drug is cutaneous. It has been found that permeability is enhanced with acidic polymeric substances.

The present invention was invented based on the above findings, and an object thereof is to provide a percutaneous absorption preparation in which the skin permeability of a drug is enhanced, and a basic drug and a basic polymer substance are combined. And a percutaneous absorption preparation of a basic drug, and a percutaneous absorption preparation of an acidic drug containing an acidic drug and an acidic polymer substance.

[0006] Examples of the basic drug include morphine,
Narcotic analgesics such as ethylmorphine, codeine, thebaine, dihydrocodeine, oxycodone, dihydromorphinone, oxymorphone, methyldihydromorphinone, levorphanol, pethidine, alphaprozine or anileridin or their salts, eptazocine, buprenorphene. Or non-narcotic analgesics such as butorphanol or salts thereof, Ca antagonists such as nicardipine or salts thereof, antihypertensive agents such as clonidine or brazodin or salts thereof, local anesthetics such as lidocaine or tetracaine, For example, a therapeutic agent for allergic diseases such as ketotifen fumarate, a muscle relaxant such as eperisone or a salt thereof, a therapeutic agent for Meniere syndrome such as betahistine mesylate, chlorbromazine or a salt thereof. Antihistamines can be used as a tranquilizer or diphenhydramine or a salt thereof.

Examples of the basic polymer substance used in combination with the above basic drug include chitin derivatives such as chitosan or partially deacetylated chitin, basic polyethylene derivatives such as polyethyleneimine, and basic substances such as polylysine. Amino acid polymers may be mentioned, and these may be used alone or in admixture of two or more.

The mixing ratio of the basic drug to the basic polymer is generally 10: 1 to 1:10 based on the weight.
0, preferably 5: 1 to 1:10, particularly preferably 2:
It is 1 to 1: 5.

[0009] Examples of the acidic drug include antipyretic analgesics such as sodium salicylate, aspirin, etenzamid or sazapine, barbital derivatives such as panbital or phenobarbital, penicillin derivatives such as penicillin G, or acetazolamide or furosemide. Such diuretics can be used.

Examples of acidic polymers that can be used in combination with the above acidic substances include polyacrylic acid or its derivatives, methoxyethylene maleic anhydride copolymer, sodium carboxymethyl cellulose, hyaluronic acid, alginic acid, chondroitin sulfate, hydroxypropylmethyl cellulose phthalate. Examples thereof include acidic amino acid polymers such as cellulose acetate phthalate or polyglutamic acid, and proteins such as pectin. These can be used alone or in combination of two or more.

The mixing ratio of acidic drug: acidic polymer is
Generally, based on weight, 10: 1 to 1: 100, preferably 5: 1 to 1:10, particularly preferably 2: 1 to
It is 1: 5.

The dosage form of the transdermal preparation includes, for example, a solution, a poultice, a cream, an ointment, a gel or a tape, but a preferable dosage form is one which stabilizes an accurate dose of the drug. It is a gel agent having a shape-retaining property that can be obtained as a result.

The amount of the basic drug or acidic drug compounded in 1 g of the preparation varies depending on the type of drug, the dosage form, the age, weight and condition of the patient, but generally 1 to 500 mg, preferably 5 to 100 mg, especially Preferably 10 to 50 mg
Is.

The percutaneous absorption preparation of the present invention, if necessary,
In addition, bases such as solvents or bases used in conventional formulations, thickeners, percutaneous absorption enhancers, such as terpenes or essential oils, or containing 2 to 5 carbon atoms in the molecule Auxiliary agents such as transdermal absorption auxiliaries consisting of alcohol and water and / or additives such as stabilizers, diluents or fragrances may be included.

[0015]

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

Example 1 Morphine hydrochloride and the polymer substances shown in Table 1 were dissolved in a solvent consisting of ethanol, menthol and water to prepare a solution, to which a small amount of acetic acid and triethylamine were added to adjust the pH of each solution to 5 Inventive Sample 1 and Comparative Samples 1 to 6 having the compositions shown in Table 1 were prepared by adjusting to 6 to 6, respectively.

The abdominal skin of the hairless rat was extracted and sandwiched in a horizontal diffusion cell. 2.5m of water on the dermis side of the cell
1 and each of the above samples 2.5 on the stratum corneum side part.
ml was added. The whole cell was kept at 37 ° C., and the amount of drug transferred to the dermis side portion was measured with time. The results are shown in Table 2.

Table 1 Inventive Sample Comparative Sample 1 1 2 3 4 5 6 Morphine Hydrochloride 1 1 1 1 1 1 1 1 Polyethyleneimine (basic) 3 0 0 0 0 0 0 Hydroxypropyl 0 0 3 0 0 0 0 Cellulose ( Neutral) Polyethylene oxide (neutral) 0 0 0 3 0 0 0 Polyvinyl pyrrolidone (neutral) 0 0 0 0 3 0 0 Methoxyethylene anhydrous 0 0 0 0 0 3 0 Maleic acid copolymer (acidic) Polyacrylic acid (Acidity) 0 0 0 0 0 0 1 Ethanol 40 40 40 40 40 40 40 40 40 Menthol 5 5 5 5 5 5 5 Water 51 54 51 51 51 51 51 53 Table 2 Permeation amount (mg / cm ² ) time Inventive sample Comparative sample (Time) 1 1 2 3 4 5 6 2 1.6 0.8 0.8 0.5 0.5 0.5 0.6 0.2 0.2 4 3.4 1.9 1.2 1.1 1.1 1.5 0 5 0.3 6 4.8 2.7 1.9 1.8 2.3 0.7 0.4 0.4 8 5.9 3.3 2.4 2.4 3.0 0.9 0.5 From the results, the skin permeation amount of morphine hydrochloride is significantly increased in the sample 1 of the present invention in which polyethyleneimine, which is a basic polymer, coexists, compared with the comparative sample 1 in which no polymer does not coexist. Comparative samples 2-4 and 5-6 using hydroxypropyl cellulose, polyethylene oxide or polyvinylpyrrolidone as polymeric substances or methoxyethylene maleic anhydride copolymer or polyacrylic acid as acidic polymeric substances, respectively.
On the contrary, it can be seen that it decreases.

Example 2 Inventive sample 2 and comparative sample 7 having the compositions shown in Table 3
-10 were prepared as in Example 1.

The abdominal skin of the hairless rat was extracted and sandwiched in a horizontal diffusion cell. 2.5m of water on the dermis side of the cell
1 and each of the above samples 2.5 on the stratum corneum side part.
ml was added. The whole cell was kept at 37 ° C., and the amount of drug transferred to the dermis side portion was measured with time. The results are shown in Table 4.

Table 3 Inventive sample Comparative sample 2 7 8 9 10 Sodium salicylate 1 1 1 1 1 Methoxyethylene maleic anhydride 3 0 0 0 0 Copolymer (acidic) Polyethylene oxide (neutral) 0 0 3 0 0 Polyvinyl Pyrrolidone (neutral) 0 0 0 3 0 Polyethylenimine (basic) 0 0 0 0 3 Ethanol 40 40 40 40 40 40 Menthol 5 5 5 5 5 5 Water 51 54 51 51 51 51 Table 4 Permeation rate (mg / cm ² ) hours Inventive Sample Comparative Sample (Time) 2 7 8 9 10 2 1.2 1.1 0.7 0.7 0.9 0.2 4 2.7 2.5 2.5 1.3 1.8 0.4 6 4.1 3 .4 1.7 2.5 0.5 8 5.2 5.2 4.0 2.1 3.0 0.5 From these results, the skin permeation amount of sodium salicylate was methoxyethylene, which is an acidic polymer. The sample 2 of the present invention in which the maleic acid water copolymer was allowed to coexist significantly increased as compared with the comparative sample 7 in which no polymeric substance was allowed to coexist, but polyethylene oxide or polyvinylpyrrolidone of the neutral polymeric substance or the basic polymer was used. It can be seen that in Comparative Samples 8 to 9 and 10 in which the substance polyethyleneimine is used, respectively, it is rather decreased.

Example 3 Inventive samples 3 and 4 and comparative samples 11 to 15 having the compositions shown in Table 5 were prepared in the same manner as in Example 1.

The abdominal skin of the hairless rat was extracted and sandwiched in a horizontal diffusion cell. 2.5m of water on the dermis side of the cell
l, and put 0.2% of each of the above samples on the stratum corneum side part.
ml was added. The whole cell was kept at 37 ° C., and the amount of drug transferred to the dermis side portion was measured with time. The results are shown in Table 6.

Table 5 Samples of the present invention Comparative samples 3 4 11 12 13 14 15 15 Morphine hydrochloride 1 1 1 1 1 1 1 1 Chitosan (basic) 1 0 0 0 0 0 0 Polyethyleneimine (basic) 0 3 0 0 0 0 0 0 Hydroxypropyl 0 0 0 3 0 0 0 Cellulose (neutral) Polyethylene oxide (neutral) 0 0 0 0 3 0 0 Polyacrylic acid (acidic) 0 0 0 0 0 0 1 0 Methoxyethylene anhydrous 0 0 0 0 0 0 0 0 3 Maleic acid copolymer (acidic) Ethanol 40 40 40 40 40 40 40 40 Menthol 5 5 5 5 5 5 5 5 Water 53 53 51 54 51 51 53 53 51 Table 6 Permeation amount (mg / cm ² ) time Inventive sample Comparative sample ( Time) 3 4 11 12 13 14 14 15 2 0.8 0.5 0.5 0.4 0.3 0.3 0.3 0.1 0.0 4 1.4 1.1 1.1 0.8 0.7 0.7 0.2 0.1 6 1.8 1.6 1.1 1.1 1.0 1.0 0.3 0.1 8 1.9 1.8 1.3 1.2 1.2 0.4 0.1 From these results, the skin permeation amount of morphine hydrochloride was the same as that of Comparative Sample 11 in which no polymeric substance was present in Samples 3 and 4 of the present invention in which the basic polymeric substance chitosan or polyethyleneimine was allowed to coexist. Although significantly increased, comparative samples 12 to 13 and 14 to 14 using neutral polymer hydroxypropyl cellulose or polyethylene oxide or acidic polymer polyacrylic acid or methoxyethylene maleic anhydride copolymer, respectively. It can be seen that the value of 15 rather decreases.

[0025]

As is clear from the above description, according to the present invention, there is provided a percutaneous absorption preparation in which the skin permeability of each of a basic drug and an acidic drug is enhanced.

Claims (2)

[Claims] 1. A percutaneous absorption preparation of a basic drug, which comprises a basic drug and a basic polymer substance. 2. A percutaneous absorption preparation of an acidic drug, which comprises the acidic drug and an acidic polymer substance.