JP3066515B2 - Transdermal formulation for treatment of urinary incontinence - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a preparation for transdermal administration applied to bladder dysfunction such as urinary incontinence, urgency and urinary frequency. More specifically, the present invention relates to a transdermal administration preparation for treating urinary incontinence, which comprises oxybutynin as an active ingredient.

[0002]

2. Description of the Related Art With the aging of the population in recent years, it is expected that the number of incontinent patients will exceed 2 million.
% Are said to cause incontinence and are expected to increase further in the future. In such a situation, many attempts have been made to treat urination such as pollakiuria and urinary incontinence. For example, as an orally administered urination disorder improving drug for treating urination disorders as described above, many attempts have been made. Are already commercially available.

[0003] However, for example, patients suffering from intracerebrospinal trauma, cerebrovascular disorders, and various places after surgery for tumors that cause urinary frequency require bedridden time.
In the case of these patients, in the case of oral administration, it is often difficult to administer the drug because the drug must be taken at regular intervals. On the other hand, in recent years, transdermal administration routes have attracted attention from the concept of effective drug administration routes, that is, drug delivery systems. Drugs absorbed from the intestinal tract by conventional oral administration are necessarily sent to the liver via the portal vein for metabolism, a so-called first-pass effect, and the bioavailability is significantly reduced. Therefore, in order to maintain the effective blood concentration, it is necessary to administer a relatively large amount of the drug, and the incidence of side effects naturally increases. In this regard, according to transdermal administration, the drug immediately enters the subcutaneous capillaries and reaches the target site via the vein and heart without undergoing any substantial degradation. That is, the bioavailability of the drug is near maximal and the drug needs to be in relatively small amounts. Therefore, drugs with strong side effects, drugs that have been mainly administered orally or by injection, and drugs that have a short effective blood concentration holding time and need to be administered several times a day can reduce side effects without causing pain. Can be gradually and continuously absorbed from the skin. For this reason, transdermal administration is effective as a method for sustained release of a drug, and a transdermal administration type is expected as the urinary abnormalities improving drug.
Under such circumstances, it has been desired to develop a preparation for maintaining urinary incontinence such as delodiline, oxybutynin and the like in the blood for a long period of time, and in recent years, for example, these drugs have been transdermally absorbed. Topical preparations have been proposed. (JP-A-4-266821, JP-A-4-2
No. 73818)

[0004]

However, in these proposals, sufficient studies have not been made on drug stability, which is important in formulation, and on physical stability, skin irritation, and sustained release of the formulation. . For example, Japanese Patent Laid-Open No. 4-2
In the examples in JP-A-66821, terodiline and oxybutynin are used as hydrochloride salts and an aqueous base is studied. Sufficient drug stability is expected due to interaction with many additives and water in the formulation. Can not. Further, in actual drug administration, it is desired to administer the drug once a day or once every two days. In this respect, the aqueous base is insufficient in the application stability in long-time application. Japanese Patent Application Laid-Open No. 4-273718 similarly does not satisfy requirements such as drug stability and skin irritation.

[0005]

Means for Solving the Problems The present invention is intended to solve the problems of the above-mentioned conventional oxybutynin preparations, and aims at stably retaining oxybutynin as an active ingredient, It is an object of the present invention to provide a transdermally administrable pharmaceutical preparation which can be effectively and effectively transdermally absorbed to exhibit excellent drug efficacy. The present inventors have conducted intensive studies to achieve the above object, and as a result, it has been found that a base mainly composed of a synthetic rubber, polyisobutylene, has a drug stability of oxybutynin, a sustained release property of the drug, and a long-term skin patch. They have found that they have excellent performance in terms of adhesion, and have completed the present invention.

[0006] Further, the pressure-sensitive adhesive mainly composed of polyisobutylene having excellent sustained-release properties further improves drug release by containing mineral oil or shark liver oil and a thermoplastic resin, or a chemically stable filler. It controls efficiently. The pressure-sensitive adhesive in the present invention comprises polyisobutylene as a main base, and has a high-molecular-weight polyisobutylene having a viscosity-average molecular weight of 400,000 to 1800000 and a viscosity-average molecular weight of 10,000 to 20.
0000 low molecular weight polyisobutylene is an essential component. In addition, regarding the content, considering the physical properties of the preparation and the drug release, the
It contains 80% by weight, preferably 20-50% by weight.
It is preferable that the low-molecular-weight polyisobutylene is added in an amount of 10 to 80% by weight, preferably 15 to 50% by weight. The mineral oil and shark liver oil contained in the pressure-sensitive adhesive are suitably those having a viscosity in the range of 5 to 100 cp. Examples of the shark liver oil to be used include natural and synthetic squalane and squalene. 5 to 70
%, Preferably 20 to 60%. Further, squalane is known to be a stable saturated hydrocarbon, and is widely used as a cosmetic in terms of low skin irritation. It has the effect of reducing. In addition, in the preparation of the present invention, the oily additives such as mineral oil and shark liver oil can improve the releasability by increasing the content thereof. Insufficiency, which may affect the adhesiveness and stability of the formulation. In addition, by including a thermoplastic resin and a chemically stable filler in such a base, stable sustained release can be achieved for a long time without impairing the adhesiveness and cohesion of the base. Things. As the thermoplastic resin that can be used here, for example, those having a softening point of 50 to 250 ° C. in a crystalline state at ordinary temperature are preferable, and specifically, rosin or a derivative thereof, terpene resin, terpene, phenol resin, petroleum resin, alkyl resin・
Tackifying resins such as phenolic resins and xylene resins are exemplified. One or more of these resins are blended in an amount of 50% by weight or less, preferably 5 to 40% by weight. As the filler, those which are chemically stable are preferable, and specific examples thereof include titanium oxide, zinc oxide, talc, silicic anhydride, magnesium silicate, polyethylene beads, and polystyrene beads.
0 μm or less, preferably 0.5 to 10 μm is desirable. One or two of these fillers can be blended, and can be blended in an amount of 10% or less, preferably 0.1 to 5%.

That is, the present invention comprises a polyisobutylene-based pressure-sensitive adhesive excellent in sustained release containing a mineral oil for promoting the diffusion and transfer of drugs and a shark liver oil such as squalane. It is an object of the present invention to provide a transdermal preparation for treating urinary incontinence which is stable in physical properties and excellent in sustained release by blending a plastic resin and a chemically stable filler. In addition, all of the above additives are chemically stable, have no interaction with oxybutynin, and have excellent performance in drug stability over time. Oxybutynin used as an active ingredient in the pharmaceutical preparation for transdermal administration of the present invention is desirably contained in a base in an amount of 1 to 50% by weight, preferably 5 to 20% by weight in a dissolved or dispersed state. When the content is less than 1% by weight, the drug effect by oxybutynin may not be sufficiently expected or a continuous drug effect may not be expected. Also,
If the content exceeds 50% by weight, not only is it not possible to expect an improvement in drug efficacy and sustainability by increasing the amount, but also the skin adhesion of the base layer tends to decrease, which is not preferable.

[0008] The present invention can also optionally contain a skin permeation enhancer. The skin permeation enhancer used in the present pressure-sensitive adhesive is not particularly limited. Examples thereof include terpene oils such as l-menthol, peppermint oil, d-limonene, glyceryl monolaurate, glyceryl monooleate, and the like.
Fatty acid esters such as diethyl sebacate, azacycloalkanes such as Azone and 1- [2- (decylthio) ethyl] azacyclopentan-2-one, and other fatty acids such as oleic acid, lauric acid, myristic acid, and oleyl alcohol Alternatively, one or two kinds of mixtures selected from aliphatic alcohols are added in an amount of 0 to 15%, preferably 0.5 to 15%.
It can be blended in the range of ５5%. The support for use in the present invention is not particularly limited, but is preferably flexible enough to not cause a significant discomfort when applied to the skin surface. Examples thereof include polyethylene, polypropylene, and the like.
Plastic films such as polyester, polyvinyl acetate, ethylene-vinyl acetate copolymer, polyvinyl chloride, and polyurethane; metal foils such as aluminum foil and bell foil;
A single-layer film made of non-woven fabric, cloth, paper, or the like, or a laminated film thereof can be used. In addition, it is desirable that these support members be subjected to a corona discharge treatment, a plasma treatment, an oxidation treatment, or the like on the surface on which the base layer is formed in order to improve the adhesion and the adhesion to the base layer. The pharmaceutical preparation for percutaneous administration of the present invention is obtained by forming the base layer on the surface of the support, but until immediately before sticking to the skin surface, a silicone resin or the like is exposed on the exposed surface of the base layer. It is preferable to cover and protect with a release liner such as paper or plastic film that has been subjected to a release treatment by applying a fluorine resin or the like.

[0009]

The present invention will be described more specifically with reference to the following examples. Example 1 High molecular weight polyisobutylene 15.6 parts by weight (viscosity average molecular weight 1,110,000, Oppanol B-100) Low molecular weight polyisobutylene 16.4 parts by weight (viscosity average molecular weight 40.000, Oppanol B-10) Paraffin 46.3 parts by weight Hydrogenated rosin ester (KE-311) 10.2 parts by weight A composition comprising 1.5 parts by weight of titanium oxide was dissolved in hexane to obtain a polyisobutylene solution (solid content: 25.0%). %) And mixed with oxybutynin so that the content when dried is 10%.
The composition was coated on a release liner so that the thickness after drying became 50 μm, and dried to form a base layer. Next, the base layer obtained above was transferred to a polyester film (thickness: 25 μm) to obtain a preparation for transdermal administration for treating urinary incontinence of the present invention.

Example 2 12.3 parts by weight of high molecular weight polyisobutylene (viscosity average molecular weight 1,110,000, Oppanol B-100) 13.7 parts by weight of low molecular weight polyisobutylene (viscosity average molecular weight 40,000, Oppanol B-) 10) 54.5 parts by weight of liquid paraffin Hydrogenated rosin ester (KE-311) 6.0 parts by weight A composition comprising 6.0 parts by weight of titanium oxide was treated in the same manner as in Example 1 to treat urinary incontinence according to the present invention. A transdermal preparation was obtained.

Example 3 14.6 parts by weight of high molecular weight polyisobutylene (viscosity average molecular weight 1,110,000, Oppanol B-100) 20.4 parts by weight of low molecular weight polyisobutylene (viscosity average molecular weight 40,000, Oppanol B-) 10) Squalane 40.5 parts by weight Aerosil 3.8 parts by weight Hydrogenated rosin ester (KE-311) 10.7 parts by weight The composition for treating urinary incontinence of the present invention was treated in the same manner as in Example 1 below. A skin administration formulation was obtained.

Comparative Example 1 18.5 parts by weight of high molecular weight polyisobutylene (viscosity average molecular weight 1,110,000, Oppanol B-100) 27.5 parts by weight of low molecular weight polyisobutylene (viscosity average molecular weight 40.000, Oppanol B-) 10) Add a composition consisting of 49.0 parts by weight of liquid paraffin to a polyisobutylene solution (solid content: 25.0%) prepared by dissolving in hexane so that the content of oxybutynin when dried becomes 10%. Mix,
It was applied on a release liner so that the thickness after drying was 50 μm, and dried to form a base layer. Next, the base layer obtained above was transferred to a polyester film (thickness: 25 μm) to obtain a conventional tape preparation.

Comparative Example 2 Styrene-isoprene-styrene block copolymer 20.0 parts by weight (KRATON D 1111; hereinafter abbreviated as SIS) 30.0 parts by weight of hydrogenated rosin ester (KE-311) 32.0 parts by weight of liquid paraffin 1.0 part by weight of dibutylhydroxytoluene was heated and melted at 170 ° C., added and mixed so that the oxybutynin content became 10%, applied on a silicon-treated liner, cooled to room temperature, and then cooled with a polyester film ( 25 μm thick) and transferred to oxybutynin 10
% SIS tape preparation was obtained.

Comparative Example 3 Gelatin 15.0 parts by weight Nicazole TS-620 5.0 parts by weight (88% partially saponified) polyvinyl alcohol 10.0 parts by weight Glycerin 25.6 parts by weight Methyl parahydroxybenzoate 0.2 parts by weight A composition consisting of 0.2 parts by weight of aluminum glycinate, 40.0 parts by weight of purified water, and 4.0 parts by weight of oxybutynin was added to purified water heated to 70 ° C. in gelatin, polyvinyl alcohol and Nicazole TS-62.
0 was sequentially dissolved (I), and then methyl paraoxybenzoate and oxybutynin were dissolved in glycerin also heated to 70 ° C., and then a maleic anhydride-methyl vinyl ether copolymer and aluminum glycinate were uniformly dispersed. The mixture was added to (I), mixed and then applied onto a silicon-treated release liner so that the thickness of the base layer was 300 μm, and one side was transferred to the treated surface of a PET-treated nonwoven fabric. And an oxybutynin-containing cataplasm.

Test Example 1 Stability test over time The preparations prepared in Examples and Comparative Examples were
Stability tests over time were performed on the residual amount of the drug and physical properties. The storage was performed at 40 ° C. in a form sealed in an aluminum packaging. The residual amount of oxybutynin was measured by the HPLC method. Further, in terms of physical properties, appearance and adhesion were observed. The adhesiveness was observed by using a Rigaku probe tack tester and the change in adhesive force over time was observed. Oxybutynin in the transdermal formulation for treating urinary incontinence of this example was stable, whereas the stability of oxybutynin in the formulations in Comparative Examples 2 and 3 was insufficient. (The test results are shown in Table 1.) In addition, all of the transdermal administration preparations for treating urinary incontinence of Examples 1 to 3 exhibited sufficient physical stability for commercialization, whereas the preparations of the comparative examples did not. It was not enough. (Table 2 shows the test results.)

[0016]

[Table 1]

[0017]

[Table 2]

Example 4 13.5 parts by weight of high molecular weight polyisobutylene (viscosity average molecular weight 1,110,000, Oppanol B-100) 22.5 parts by weight of low molecular weight polyisobutylene (viscosity average molecular weight 40,000, Oppanol B-) 10) A composition comprising 47.0 parts by weight of squalane and 4.0 parts by weight of talc was dissolved in hexane to give a polyisobutylene solution (solid content concentration: 30.0% titanium oxide in a dispersed state). After adding and mixing so as to have a content of 10%, the resultant was coated and dried on a silicon-treated release liner so as to have a thickness of 50 μm after drying to form a base layer. Next, the base layer was transferred onto a polyester film (25 μm in thickness) to obtain a preparation for transdermal administration for treating urinary incontinence of the present invention.

Example 5 14.5 parts by weight of high molecular weight polyisobutylene (viscosity average molecular weight 1,500,000, Oppanol B-120) 22.5 parts by weight of low molecular weight polyisobutylene (viscosity average molecular weight 40,000, Oppanol B- 10) A composition comprising 45.5 parts by weight of liquid paraffin and 15.5 parts by weight of hydrogenated rosin ester (KE-311) was prepared in the same manner as in Example 4 to obtain a transdermal administration preparation for treating urinary incontinence of the present invention. Was.

Example 6 16.0 parts by weight of high molecular weight polyisobutylene (viscosity average molecular weight 1,110,000, Oppanol B-100) 17.5 parts by weight of low molecular weight polyisobutylene (viscosity average molecular weight 40,000, Oppanol B-) 10) Liquid paraffin 47.5 parts by weight Hydrogenated rosin ester (KE-311) 17.0 parts by weight Aerosil 4.0 parts by weight was treated in the same manner as in Example 4 for the treatment of urinary incontinence of the present invention. A transdermal formulation was obtained.

Example 7 A transdermal preparation for treating urinary incontinence of the present invention was obtained in the same manner as in Example 4, except that the oxybutynin content was changed to 20%.

Comparative Example 4 75.0 parts by weight of 2-ethylhexyl acrylate 15.0 parts by weight of methyl methacrylate 10.0 parts by weight of acrylic acid 0.02 parts by weight of azobisisobutyronitrile was treated with ethyl acetate. / Toluene (1/1) solvent at 60 ° C., 48
The polymerization reaction was carried out for a period of time, 0.1 part of an isocyanate-based crosslinking agent was added to the resulting polymer solution, and oxybutynin was added so that the dry content of oxybutynin was 10%. 50 thickness
After coating, drying and transfer onto a polyester film (thickness 25 μm), an oxybutynin-containing acrylic tape preparation was obtained.

Comparative Example 5 Styrene-isoprene-styrene block copolymer 20.0 parts by weight (KRATON D 1107P, hereinafter abbreviated as SIS) Hydrogenated rosin ester (KE-311) 30.0 parts by weight Liquid paraffin 32.0 parts by weight A composition consisting of 1.0 part by weight of dibutylhydroxytoluene was heated and melted at 170 ° C., added and mixed so that the oxybutynin content became 10%, applied on a silicon-treated liner, and cooled to room temperature. And transferred onto a polyester film (thickness: 25 μm) to obtain an SIS tape preparation containing 10% oxybutynin.

Comparative Example 6 Gelatin 3.0 parts by weight Maleic anhydride-methyl vinyl ether copolymer 3.0 parts by weight (GANTREZ 169) Partially saponified polyvinyl alcohol 5.0 parts by weight Sodium polyacrylate 2.0 parts by weight Glycerin 31.0 parts by weight Methyl balaoxybenzoate 0.2 parts by weight Essential water 49.6 parts by weight A composition consisting of 4.0 parts by weight oxybutynin was added to gelatinous water and sodium polyacrylate heated to 70 ° C. And a maleic anhydride-methyl vinyl ether copolymer are sequentially dissolved (I). Next, glycerin partially saponified polyvinyl alcohol, methyl paraoxybenzoate, and oxybutynin, which were also heated to 70 ° C., were dissolved, added to (I) and mixed, and then the thickness of the base layer was formed on a silicon-treated release liner. Saga, 300
It was applied so as to have a thickness of μm, and was transferred onto the treated surface of a nonwoven fabric that had been PET-treated on one side to obtain an oxybutynin-containing cataplasm.

Test Example 2 Skin Irritation Test A patch test (applying for 48 hours) on healthy men was carried out on the preparations of Examples 4 to 6 and Comparative Examples 4 to 6. The transdermal administration preparations for treating urinary incontinence of Examples 4 to 6 have excellent performance in terms of low irritation. (Test results are shown in Table 3.)

[0026]

[Table 3]

Test Example 3 Percutaneous Absorption Experiments with Rats Percutaneous absorption was examined in vivo in rats. In the experiment, a preparation adjusted to a circular shape having a diameter of 2 cm was applied to the abdomen of a dehaired rat, and the blood concentration over time was measured by gas chromatography. The transdermal preparations for treating urinary incontinence of the present invention of Examples 6 and 7 have excellent sustained release properties. (The experimental results are shown in FIG. 1.)

[0028]

The pharmaceutical preparation for transdermal administration of the present invention is in the form of a patch, and the oxybutynin contained therein is continuously released directly into the circulating blood via the skin, so that it is produced in the liver by oral administration. It does not undergo metabolism due to the first-pass effect and does not cause any side effects due to a temporary increase in blood concentration. The bioavailability of oxybutynin contained in the preparation is increased, and it can be efficiently administered to the living body. Since the base layer containing oxybutynin does not contain a conventional drug-dissolving carrier because oxybutynin is free and liquid, it can be easily compatible with various oily bases, and Shows good transdermal absorption by itself. Therefore, the pressure-sensitive adhesive base mainly composed of polyisobutylene is a thermoplastic resin used as an additive, fillers and the like are all chemically stable, have little interaction with oxybutynin, and the Very good stability. If desired, by containing the skin permeation enhancer,
Further, excellent transdermal absorbability can be obtained, and an excellent effect is exhibited. Furthermore, by blending a thermoplastic resin, a filler, and the like in the pressure-sensitive adhesive of the present invention, the diffusion and transfer of oxybutynin in the base are appropriately inhibited without impairing the physical properties of the base and sustained release. The performance of the composition is further improved, and the performance is excellent in maintaining the effective blood concentration, that is, maintaining the effect. As a result, the number of administrations (the number of administrations per unit time) can be reduced, so that skin irritation can be further reduced. The number of administrations of this formulation is appropriate once a day or once every two days.
It is possible to make the preparation once every three days or more, which is effective as a pharmaceutical.

[Brief description of the drawings]

FIG. 1 shows the results of a percutaneous absorption experiment using rats.

[Explanation of symbols]

 □ Formulation of Example 6 ○ Formulation of Example 7 ▲ Formulation of Comparative Example 4 ■ Formulation of Comparative Example 5

────────────────────────────────────────────────── ─── Continued on the front page (58) Fields surveyed (Int. Cl. ⁷ , DB name) A61K 31/216 A61K 9/70 A61P 13/10 CA (STN) EMBASE (STN) MEDLINE (STN)

Claims (2)

(57) [Claims] 1. A transdermal preparation for treating urinary incontinence, comprising oxybutynin as an active ingredient in a polyisobutylene-based pressure-sensitive adhesive. 2. A pressure-sensitive adhesive having a viscosity average molecular weight of 100
The transdermal preparation for treating urinary incontinence according to claim 1, comprising a mixture of low molecular weight polyisobutylene having a molecular weight of 00 to 200,000, high molecular weight polyisobutylene having a viscosity average molecular weight of 400,000 to 1800000 and polybutene.