JPH06279266A - Percutaneously absorbable pharmaceutical preparation and its production - Google Patents

Abstract

PURPOSE:To obtain a percutaneously absorbable pharmaceutical preparation, comprising a medicine in a supersaturated state and capable of maintaining the supersaturated state for a long period and a method for producing the pharmaceutical preparation. CONSTITUTION:This pharmaceutical preparation is composed of 100 pts.wt. tacky base containing 70-95wt.% at least any one compound of polyethylene glycol having 400-6000 weight-average molecular weight, vaseline and lanolin and 30-5wt.% polyvinylpyrrolidone having 1000000-5000000 weight-average molecular weight as constituent ingredients and 1-25 pts.wt. medicine.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a transdermal preparation and a method for producing the same.

[0002]

2. Description of the Related Art Conventionally, in order to obtain systemic or local drug efficacy, percutaneous absorption preparations deliver the drug by distributing / diffusing the drug from the adhesive layer containing the drug into the skin and transferring it into the blood. To be absorbed by. In the percutaneous absorption preparation, the higher the concentration of the drug contained in the adhesive layer is, the more the amount of drug transferred from the skin to the blood is increased.
It is known that when the drug amount is equal to or lower than the saturated solubility, a sufficient drug effect cannot be obtained because the drug amount absorbed by the human body is small.

Various methods can be mentioned for increasing the skin absorption of a drug. For example, JP-A-60-1691.
No. 6, in a matrix made of a polymer material,
Disclosed is a percutaneous absorption preparation in which a bioactive substance (drug) is mixed in a stable dispersion state with a saturated solubility or higher through a poor solvent.

Further, in JP-A-60-185713, after a transdermal drug having a saturated solubility or higher is dissolved in a pressure-sensitive adhesive high molecular weight polymer in the presence of a good solvent, A percutaneous absorption preparation is disclosed which is recrystallized and dispersed in the form of recrystallized fine particles having a substantially uniform size.

Further, in JP-A-63-35521, a high-molecular-weight polymer forming a drug supply layer contains a drug having a saturated solubility or higher in a dissolved or microcrystalline state in the presence of a solvent. Pharmaceutical formulations are disclosed.

However, in any of the above-mentioned methods, the drug in a supersaturated state is deposited as crystals over time and the drug concentration is lowered, so that the skin permeation performance of the drug is reduced.

[0007] Further, with respect to a preparation in which crystals are dispersed, it is extremely difficult to disperse the crystals uniformly when the viscosity of the adhesive is high, and it is difficult to obtain a preparation of uniform quality. there were.

Further, the method of precipitating the drug in the percutaneous absorption preparation as crystals requires that the drug is blended in a supersaturated concentration or more, and the amount of the drug per preparation increases, which causes a problem of cost increase. there were.

Further, in order to contain the drug in a crystalline state, it takes time to dissolve the drug in the pressure-sensitive adhesive layer once in a supersaturated state and then slowly precipitate it, resulting in a significant decrease in production efficiency. was there.

[0010]

The present invention has been made in view of the above drawbacks, and an object thereof is a transdermal preparation containing a drug in a supersaturated state and capable of maintaining the supersaturated state for a long period of time. And to provide a manufacturing method thereof.

[0011]

The percutaneous absorption preparation of the present invention comprises at least one compound selected from polyethylene glycol, petrolatum and lanolin, an adhesive base containing polyvinylpyrrolidone as a constituent and a drug.

When the weight average molecular weight of the polyethylene glycol is low, the fluidity becomes large and the adhesion to the skin is lowered, and when the weight average molecular weight is high, the sticking property to the skin is lowered. Therefore, the polyethylene glycol is limited to 400 to 6000. To be done. Examples of such polyethylene glycol include “Macrogol ointment” of the Japanese Pharmacopoeia.

The above-mentioned petrolatum is a mixture of methane series hydrocarbons and olefin series hydrocarbons, and examples thereof include Japanese Pharmacopoeia “white petrolatum”, Japanese Pharmacopoeia “yellow petrolatum”, Japanese Pharmacopoeia “hydrophilic petrolatum” and the like. .

The above-mentioned lanolin is an ester of a monohydric higher alcohol and a fatty acid, and can be obtained, for example, by purifying a fatty substance obtained from sheep wool. Examples of the lanolin include “Purified lanolin” in the Japanese Pharmacopoeia, “Hydrophilic petrolatum” in the Japanese Pharmacopoeia, and the like.

The polyethylene glycol, petrolatum and lanolin may be used alone or in combination.

When the content of polyethylene glycol, petrolatum and lanolin in the above-mentioned adhesive base is low, the flexibility of the adhesive base is lost and the sticking property is deteriorated. When the content is high, the fluidity of the adhesive base is high. It is limited to 70 to 95% by weight because the adhesiveness cannot be obtained.

The above-mentioned polyvinylpyrrolidone is contained in order to impart drug solubility and adhesiveness to the adhesive base, and when the weight average molecular weight thereof becomes low, the drug solubility becomes small and when it becomes high, the adhesiveness becomes poor. 1 million to 5
Limited to one million.

The content of polyvinylpyrrolidone in the above-mentioned pressure-sensitive adhesive base decreases as the drug solubility decreases, and when it increases, the flexibility of the pressure-sensitive adhesive base is lost and the sticking property becomes poor. Limited.

The drug contained in the adhesive base is not particularly limited as long as it is a drug which is usually used as a drug and has a physiologically active substance. For example, steroid compounds such as estradiol, norethisterone acetate, and desogestrel Is preferably used.

The amount of the drug added to the above-mentioned pressure-sensitive adhesive base is limited to 1 to 25 parts by weight per 100 parts by weight of the pressure-sensitive adhesive base, since the drug effect decreases as the amount decreases and the amount increases as crystals precipitate.

If necessary, a percutaneous absorption enhancer, a tackifying resin, etc. may be added to the above-mentioned adhesive base. The transdermal absorption enhancer is not particularly limited as long as it is soluble in the adhesive base, and for example, N-lauroyl sarcosine, maleic acid and the like are preferably used. Further, the tackifying resin is not particularly limited as long as it has good compatibility with an adhesive base and imparts an adhesive force. For example, a rosin ester such as ester gum (manufactured by Arakawa Chemical Co., Ltd.); YS
A terpene resin such as resin (manufactured by Yasuhara Resin Co., Ltd.) is preferably used.

The percutaneous absorption preparation of the present invention, if necessary,
An adhesive base containing the above drug may be coated on a support and used as a patch.

The support is not particularly limited as long as the drug is impermeable or hardly permeable and is usually used for patches, and examples thereof include cellulose acetate, ethyl cellulose, polyethylene terephthalate (hereinafter PET). , Plasticized vinyl acetate-vinyl chloride copolymer, nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl chloride, polyurethane, polyvinylidene chloride resin film (or sheet), woven or non-woven fabric; aluminum A sheet etc. are mentioned. These may be used as a single layer or may be used as a laminate of two or more kinds.

When it is difficult to apply the patch due to insufficient adhesiveness of the patch, it may be fixed with an adhesive tape. As such an adhesive tape, for example, Japanese Pharmacopoeia adhesive bandage, Micropore Tape (manufactured by 3M Company), Utokuban (manufactured by Yutoku Pharmaceutical Co., Ltd.) and the like can be mentioned.

The method for producing the percutaneously absorbable preparation of the present invention includes, for example, a method of coating an adhesive base on a support using a solvent coating method, a hot melt coating method, an electron beam curing emulsion coating method, or the like. Can be mentioned. Further, as another method, for example, a pressure-sensitive adhesive base containing a drug is once coated on a release paper once coated with a silicone resin or the like, dried to form a pressure-sensitive adhesive base layer, and then the pressure-sensitive adhesive base layer is formed. A method of peeling from the release paper to bring it into close contact with the support is mentioned.

The thickness of the above-mentioned adhesive base layer varies depending on the dosage form and purpose of use, but when it becomes thin, the required amount of drug cannot be contained, and when it becomes thick, the drug contained in the adhesive base layer near the support. Does not sufficiently diffuse and is difficult to be absorbed by the skin, so that it is usually preferably 30 to 200 μm.

Next, the method for producing the percutaneous absorption preparation of the present invention 2 will be explained. First, in order to uniformly mix the adhesive base and the drug, they are heated and melted to form a liquid substance. When the heating temperature is low, the viscosity of the adhesive base itself becomes high and sufficient mixing cannot be performed, and when it is high, decomposition of the drug occurs, so it is limited to 60 to 120 ° C. Further, the heating time varies depending on the thermal stability of the drug, but since the decomposition of the drug occurs when it is prolonged, it is preferably within 3 hours.

Then, the above liquid substance is coated on the above support and then cooled to room temperature to obtain a percutaneous absorption preparation. Since the crystallization of the drug is promoted and the supersaturated state is lost when the cooling time is extended, the cooling time is limited to 1 hour or less to prevent the precipitation of crystals.

[0029]

The percutaneously absorbable preparation of the present invention contains polyvinylpyrrolidone having a specific molecular weight, so that the drug can be contained in the adhesive base in a supersaturated state, and thus exhibits excellent skin permeability. The supersaturated state can be stably maintained for a long period of time. Further, since the adhesive force of the base material is moderate, the stratum corneum of the skin is not peeled off at the time of peeling, and irritation is not given. According to the production method of the present invention 2, the adhesive base and the drug can be uniformly dissolved by heating for a short time, and thermal decomposition of the drug does not occur.

[0030]

EXAMPLES Examples of the present invention will be specifically described below. (Example 1) 77 parts by weight of “Macrogol ointment” (manufactured by Maruishi Pharmaceutical Co., Ltd.) of the Japanese Pharmacopoeia, 15 parts by weight of polyvinylpyrrolidone (“K-90” manufactured by Tokyo Kasei, molecular weight 1.2 million) and 17 parts by weight.
8 parts by weight of -β-estradiol (manufactured by Diosynth) was placed in a separable flask, and 90 ° C under a nitrogen atmosphere.
And stirred for 1 hour. After confirming that the crystals of 17-β-estradiol and polyvinylpyrrolidone were dissolved in the adhesive base, the adhesive base containing the drug was placed on a release paper treated with a silicone release treatment of a PET film having a thickness of 40 μm. , 60 after coating to a thickness of 60 μm
It dried at 30 degreeC for 30 minutes, and formed the adhesive base layer. Then
The above-mentioned pressure-sensitive adhesive base layer was attached to a 60 μm-thick support (a laminate of PET and an ethylene-vinyl acetate copolymer) to obtain a percutaneous absorption preparation.

Example 2 Transdermal absorption was performed in the same manner as in Example 1 except that 70 parts by weight of macrogol ointment, 22 parts by weight of polyvinylpyrrolidone and 8 parts by weight of 17-β-estradiol were used in Example 1. A formulation was obtained.

Example 3 Transdermal absorption was performed in the same manner as in Example 1 except that 85 parts by weight of macrogol ointment, 7 parts by weight of polyvinylpyrrolidone and 8 parts by weight of 17-β-estradiol were used in Example 1. A formulation was obtained.

Example 4 The same procedure as in Example 1 was carried out except that 77 parts by weight of lanolin hydrolyzed in Japanese Pharmacopoeia was used in place of the macrogol ointment in Example 1, and the immersion was carried out.
A transdermal preparation was obtained in the same manner as in Example 1 except that the intermediate layer was formed by drying.

Example 5 A transdermal preparation was obtained in the same manner as in Example 1 except that 77 parts by weight of hydrophilic petrolatum of the Japanese Pharmacopoeia was used in place of Macrogol ointment. .

(Example 6) The adhesive base containing the drug obtained in Example 1 was not coated on a support, but was rapidly cooled in an atmosphere of 4 ° C as it was and percutaneously absorbed. A formulation was obtained.

(Example 7) The adhesive base containing the drug obtained in Example 4 was not coated on a support, but was rapidly cooled in an atmosphere of 4 ° C as it was and percutaneously absorbed. A formulation was obtained.

(Example 8) The adhesive base containing the drug obtained in Example 5 was not coated on a support, but was rapidly cooled in an atmosphere of 4 ° C as it was and percutaneously absorbed. A formulation was obtained.

Comparative Example 1 A transdermal preparation was obtained in the same manner as in Example 1 except that 92 parts by weight of macrogol ointment was used and that polyvinylpyrrolidone was not used at all.

(Comparative Example 2) In Example 1, the molecular weight was 6
Except for using millions of polyvinylpyrrolidone,
A transdermal preparation was obtained in the same manner as in Example 1.

(Comparative Example 3) In Example 1, the molecular weight was 5
A transdermal preparation was obtained in the same manner as in Example 1 except that 0,000 polyvinylpyrrolidone was used.

Comparative Example 4 In Example 1, 50 parts by weight of macrogol ointment was used, and polyvinylpyrrolidone 4 was used.
A transdermal preparation was obtained in the same manner as in Example 1 except that 2 parts by weight was used.

[Evaluation of Percutaneous Absorption Formulation] (1) Preparation of Samples Two types of the transdermal absorption formulations obtained in Examples and Comparative Examples were left immediately at the time of production and left in a packaging material for one year at room temperature. The following evaluation was performed. A sample was prepared by punching out the above-mentioned percutaneous absorption preparation into a circle with a diameter of 20 mm, and for Examples 6-8, a sample was prepared by uniformly coating 100 mg on a PET film punched out into a circle with a diameter of 20 mm. did.

(2) Drug Skin Permeability Test The drug skin permeability test is carried out using the device 1 shown in FIG.
It was First, hairless mice slaughtered by cervical dislocation
(♂, 6 weeks old) After removing, remove subcutaneous adipose tissue
A mouse skin permeation tester for rapidly removing mouse skin 3
It was set in the cell. Then, on the top of this device 1,
Sample 2 prepared in (1) is attached, and the receptor tank at the bottom is attached.
4, dissolved in distilled water, Na₂PO_Four5 x 10 ^-Four
M, NaHPO_Four2 x 10^-FourM, NaCl 1.5 x 10
^-1M and gentamicin to have a concentration of 10 ppm
The pH of the prepared solution was adjusted to 7.2 with NaOH,
Add ethylene glycol 400 to 20% by weight.
The added buffer solution was added and kept at 37 ° C from the start of the test.
The device 1 was installed in a constant temperature bath. Start the above test
24 hours later, from the sampling port 5 to the receptor tank
1 ml of the liquid in 4 was collected and
The concentration of diol was measured by the HPLC method, and the skin of the drug
It was defined as the amount of permeation. In addition, this drug skin permeability test
The number of samples is 3 for each, and the results are shown in Table 1.
It was

[0044]

[Table 1]

[0045]

The composition of the percutaneously absorbable preparation of the present invention is as described above, and since the drug is stably contained in a supersaturated state for a long period of time, excellent skin permeation performance is maintained for a long period of time. The method for producing the percutaneous absorption preparation of the present invention 2 is
A percutaneous absorption preparation containing a drug in a supersaturated state is provided, and equipment such as exhaust and fire prevention necessary for the solvent coating method is not required, and the manufacturing can be performed at low cost.

[Brief description of drawings]

FIG. 1 is a schematic view showing an apparatus used for a drug skin permeability test of a percutaneous absorption preparation of the present invention.

[Explanation of symbols]

 1 device 2 sample 3 mouse excised skin 4 receptor tank 5 sampling port 6 stirrer

Claims (2)

[Claims] 1. A compound of 70 to 95% by weight of at least one of polyethylene glycol, petrolatum and lanolin having a weight average molecular weight of 400 to 6000 and polyvinylpyrrolidone 3 having a weight average molecular weight of 1 to 5 million.
A percutaneous absorption preparation comprising 100 parts by weight of an adhesive base containing 0 to 5% by weight and 1 to 25 parts by weight of a drug. 2. A drug is added to the adhesive base according to claim 1, 6
After heating to 0 to 120 ° C. and melting to form a liquid material, the liquid material is applied on a support to form a drug-containing pressure-sensitive adhesive base layer, and the pressure-sensitive adhesive base layer is brought to room temperature within 1 hour. A method for producing a percutaneous absorption preparation, which comprises cooling.