JPH07330602A - Pilocarpine transdermal absorption preparation - Google Patents

Abstract

PURPOSE:To obtain the preparation free from peeling even when sweated and capable of being applied for a long time by using the free base of pilocarpine in order to increase transdermal absorption of pilocarpine and compounding a moisture absorbing material in a sticky adhesive layer containing pilocarpine. CONSTITUTION:This transdermal absorption preparation is prepared by forming a drug-containing sticky adhesive layer on one side of a supporting body. The transdermal absorption preparation is composed of the free base of pilocarpine and a moisture absorbing material (especially preferably sodium carboxymethylcellulose, pectin and gelatin). The free base of pilocarpine is contained in the sticky adhesive layer preferably in an amount of 1-20wt.%. Further, preferably one or more than one kind of elastomer (especially preferably a polyisobutylene, an acrylic polymer, etc.) are compounded in the sticky adhesive layer. Further, a polyvalent metal salt, e.g. alum is preferably added. Further, a tackifier and a transdermal absorption stimulant are preferably added. This preparation can tolerate sweating caused for the sake of the side effect of pilocarpine. This preparation is preferably used for the treatment of dry mouth.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a percutaneous absorption type pilocarpine preparation, and more particularly, to percutaneous administration of pilocarpine and for a long time without peeling off perspiration caused by the action of pilocarpine. The present invention relates to a transdermal patch that can be applied to the skin surface.

[0002]

2. Description of the Related Art Recently, a disease called xerostomia has been attracting attention. Dry mouth is roughly classified into three types. That is, 1) those derived from Sjogren's syndrome or radiotherapy, 2) those caused by side effects of drugs such as anticholinergic agents, antihypertensive agents, and diuretics, and 3) those caused by senile, high blood pressure, diabetes, oral breathing, etc. . Dryness in the oral cavity due to reduced salivation caused by these various causes is collectively called xerostomia. There is a growing interest in the treatment of xerostomia from the perspective of the coming aging society and the concept of quality of life, which aims to improve the quality of life of patients, and there is a strong desire for the development of therapeutic formulations for it. Has been done.

It is already well known that pilocarpine, a parasympathetic agonist, promotes salivation (Ph
arm. Research 9 (8) 1992, 1064-1069). For example, Salegen (MGI Pharma), an oral agent under development for the treatment of xerostomia, promotes salivary secretion in patients after irradiation, but at the same time causes sweating due to side effects (Scrip No. 1849). Further, it has been reported that oral administration of pilocarpine has a transient effect and a continuous therapeutic effect cannot be obtained. Pilocarpine is designated as a poison and indicator, and caution should be exercised when administering it to patients. For this reason, it is desirable to locally use a transdermal preparation capable of interrupting administration at any time, rather than a preparation such as an oral preparation or an injection which cannot be taken out once it enters the living body. However, since the skin serves as a strong barrier against permeation of the drug from the outside, it is very difficult to transdermally absorb a sufficient amount of the drug for treatment.

Transdermal formulations of cholinergic and anticholinergic agents are disclosed in US Pat. No. 4,788,063 and US Pat. No. 4,820,263. U.S. Pat. No. 4,788,063 proposes a bandage-type transdermal absorption preparation containing a low molecular weight fatty acid such as propionic acid as an essential component for the purpose of sustaining the systemic action of cholinergic drugs and anticholinergic drugs. There is. U.S. Pat. No. 4,820,263 relates to a device for transdermal dosing by iontophoresis, which discloses the use of an adhesive sheet as an electrode and the incorporation of the drug in the adhesive.

When pilocarpine is transdermally administered for the purpose of treating xerostomia, it is expected that sweating will occur as a side effect. In the case of an ordinary pressure-sensitive adhesive tape preparation, there is a problem that the skin adhesive strength of the pressure-sensitive adhesive is lowered by perspiration and the tape is immediately peeled off. In order to improve the air permeability of the transdermal preparation, for example, Japanese Patent Publication No. 4-504515 (US Pat. No. 4,994,278) defines the moisture permeability of the backing material.

[0006]

DISCLOSURE OF THE INVENTION The object of the present invention is that pilocarpine has excellent skin permeability, and it does not peel off even when sweating occurs as a side effect of pilocarpine, and can be applied to the skin surface for a long time. Another object of the present invention is to provide a transdermal preparation of pilocarpine.

[0007]

Means for Solving the Problems As a result of intensive investigations by the present inventors, as a result, pilocarpine free base was used to enhance the skin permeability of pilocarpine, and a hygroscopic substance was added to an adhesive layer containing pilocarpine. It was found that the above-mentioned objects can be achieved by doing so. That is, as a result of the hygroscopic substance absorbing the moisture of perspiration generated by the action of pilocarpine, peeling against sweating is prevented without impairing the adhesiveness of the drug-containing pressure-sensitive adhesive layer and the skin permeability of pilocarpine, and can be applied for a long time. The present invention has been completed by finding out that a novel transdermal pilocarpine preparation is provided.

The present invention is a transdermal preparation in which a drug-containing pressure-sensitive adhesive layer is formed on one surface of a support, wherein the pressure-sensitive adhesive layer comprises pilocarpine free base as a drug and one or more kinds. The present invention provides a transdermal preparation containing the hygroscopic substance.

The support for use in the transdermal preparation of the present invention supports a drug-containing pressure-sensitive adhesive layer for sticking to the skin surface, which is formed on one surface thereof, and imparts self-supporting property to the preparation. From the standpoint of (improvement in sticking operability) and prevention of a rugged feeling after sticking, a sticker having a thickness of about 5 to 25 μm is usually used. Materials for obtaining such a support include various plastic films made of urethane, polyester, polyolefin, polyvinyl chloride, polyvinylidene chloride, ethylene / vinyl acetate copolymer, pulp, metal foil, and laminated layers of these. The composite film or the like can be used.

In order to prevent the drug contained in the pressure-sensitive adhesive layer from being dissolved and transferred to the support and strike through to reduce the amount of the effective drug, a non-migratory drug such as polyester or metal foil is used. It is preferable to use a support. Also,
The support is not only a non-perforated sheet, but also a perforated sheet obtained by performing perforation processing such as punching or needling on the non-perforated sheet,
Foamed sheets such as independent foaming, continuous foaming, and semi-continuous foaming, woven cloth, non-woven cloth, knitted cloth, and porous fibrous sheets using hollow fiber threads can be used.

The pressure-sensitive adhesive layer formed on one surface of the support is
It is a layer that exhibits adhesiveness to the skin and contains pilocarpine free base and one or more hygroscopic substances. The thickness of the pressure-sensitive adhesive layer may be appropriately changed, but is usually 20 to 300 μm, preferably 40 to 200 μm from the viewpoint of the adhesiveness to the skin and the feeling of sticking. The percutaneous absorption-type pharmaceutical preparation of the present invention is in a form in which substantially no water is contained in the drug-containing pressure-sensitive adhesive layer before use. If the pressure-sensitive adhesive layer contains water, the stability of pilocarpine-free base, which is an active ingredient, during storage may be poor, and the content may be reduced.

Pilocarpine is used in the form of a free base to enhance its percutaneous absorption. The content of pilocarpine free base may be an amount sufficient to exert a desired drug effect, and can be appropriately set depending on the drug release ability of the pressure-sensitive adhesive layer, etc. It is in the range of 60% by weight, preferably 1 to 20% by weight. If the content is less than 0.1% by weight, an effective release cannot be expected,
If it exceeds 60% by weight, the amount released with respect to the drug content in the preparation becomes small, which is inefficient.

An elastomer may be contained in the pressure-sensitive adhesive layer in order to impart pressure-sensitive adhesiveness and shape retention to the pressure-sensitive adhesive layer due to an appropriate cohesive force. The elastomer is usually 30 to 90% by weight, preferably 50 to 70% by weight of the pressure-sensitive adhesive layer.
It is mixed in the range of. Examples of such elastomers include synthetic rubbers such as polyisobutylene, polyisoprene, and polybutadiene, styrene-isoprene-styrene (SIS), styrene-butadiene-styrene (S).
BS) and other block copolymers (particularly ABA type block copolymers), natural rubber, acrylic polymers obtained by polymerizing (meth) acrylic acid alkyl ester as a main component, polymethylsiloxane, etc. It is possible to use a silicone-based polymer, a polyvinyl ether-based polymer, or the like containing as a component. Of these, polyisobutylene, an acrylic polymer, and a styrene-isoprene-styrene block copolymer are preferably used as the elastomer component from the viewpoints of purity, thermoplasticity, and economical efficiency (cost).

As the polyisobutylene, those having a viscosity average molecular weight of 500 to 2100000 are preferably used, and a mixture of two or more kinds of polyisobutylene having different molecular weights may be used. For example, low molecular weight polyisobutylene having a viscosity average molecular weight of 500 to 4000, 10,000 to
A mixture of two or more selected from medium molecular weight polyisobutylene having a viscosity average molecular weight of 200,000 and high molecular weight polyisobutylene having a viscosity average molecular weight of 900,000 to 2100000 can be used. Each of the above polyisobutylene has a high molecular weight polyisobutylene of 10
-80 wt%, preferably 20-50 wt%, low molecular weight polyisobutylene 0-80 wt%, preferably 10-
It is preferable to add 60% by weight and medium molecular weight polyisobutylene in the range of 0 to 90% by weight, preferably 10 to 80% by weight.

The hygroscopic substance contained in the pressure-sensitive adhesive layer has a function of appropriately absorbing moisture of perspiration due to the action of pilocarpine to prevent cohesive failure of the pressure-sensitive adhesive layer and prevent peeling during application. In order to sufficiently exert such effects, the hygroscopic substance is usually contained in the range of 5 to 60% by weight, preferably 10 to 50% by weight of the pressure-sensitive adhesive layer.
If the content is less than 5% by weight, the amount of water absorption is small and the effect of preventing peeling is insufficient, and if it exceeds 60% by weight, the tackiness decreases and it becomes difficult to adhere to the skin, which is not desirable.

As such a hygroscopic substance, not only a substance which absorbs and dissolves water but also a substance which becomes a so-called jelly by absorbing moisture and a substance called a water-absorbing polymer can be used. . Examples of hygroscopic substances that absorb and dissolve water include carboxymethyl cellulose sodium, pectin, guar gum, locust bean gum, karaya gum, xanthan gum, sodium alginate, calcium alginate, carrageenan, polyvinylpyrrolidone, and dextrin. Examples of the hygroscopic substance that becomes a jelly by absorbing moisture include carboxymethyl cellulose calcium, gelatin, collagen, hydroxypropyl cellulose and the like. As the water-absorbent polymer, for example, trade name Sumikagel SP-520 (Sumitomo Chemical Co., Ltd.), trade name Aqua Keep 4SH (Sumitomo Seika Co., Ltd.), trade name ALASORP 800F (Arakawa Chemical Co., Ltd.), trade name ALASORP S-100F (Arakawa Chemical Industry Co., Ltd.), product name Sunwet 1M-300MP
S (Sanyo Chemical Co., Ltd.), product name Sunwet 1M-1
Commercial products such as 000MPS (Sanyo Kasei Co., Ltd.) can be mentioned. These hygroscopic substances may be used alone or in combination of two or more. Among these, sodium carboxymethyl cellulose, pectin, and gelatin are preferably used from the viewpoint of gel forming property and hygroscopicity.

In the transdermal preparation of the present invention, the hygroscopic substance is contained to have an action of appropriately absorbing moisture during application, but the water absorption rate is 50% or less of the weight of the pressure-sensitive adhesive layer before water absorption. It is preferable to adjust the type and amount of the compound so that the range is preferably 3 to 30%. When the water absorption rate is less than 3%, most of the water is not absorbed, and there is a high possibility of peeling during application, and the desired effect of the present invention cannot be exhibited. Further, if the water absorption rate exceeds 50%, it is not desirable because the possibility of a cohesive failure phenomenon in which a large amount of the adhesive remains on the skin surface when the preparation is peeled off increases.

In order to improve the tackiness, tackifiers such as pentaerythritol ester of rosin, trimethylolpropane ester, betapinene resin, cyclopentadiene resin, and Arakawa cyclic tackifier can be added to the tackiness agent layer. . When the tackifier is added, the amount of the tackifier added is 1 to 60% by weight of the weight of the adhesive layer, and particularly 20 to 5%.
It is desirable to blend in the range of 0% by weight.

Other additives for the adhesive layer are alum, aluminum hydroxide, zinc oxide, calcium oxide, aluminum oxide, calcium oxalate, potassium alum, calcium citrate, aluminum alum, calcium chloride, calcium hydroxide. Alternatively, a polyvalent metal salt such as calcium carbonate may be added. These polyvalent metal salts have a function of improving the cohesive force of the pressure-sensitive adhesive layer. Alum and aluminum hydroxide are preferably used. When the polyvalent metal salt is added, the addition amount is 0.1 to 10% by weight, particularly 0.5 to 5% by weight of the pressure-sensitive adhesive layer.
It is desirable to add in the range of.

Further, in order to improve the skin permeability of pilocarpine, the pressure-sensitive adhesive layer may contain one or more percutaneous absorption enhancers. Examples of such percutaneous absorption enhancers include: Can be used. Linear, branched or cyclic aliphatic hydrocarbons having 5 to 30 carbon atoms which may be substituted with halogen: As the halogen of the substituent, bromine and chlorine are preferable. The aliphatic hydrocarbon moiety is preferably an alkane having a saturated or 1 or 2 unsaturated bond having 5 to 30 (preferably 6 to 24) carbons in the case of a chain, and a monocycle in the case of a cyclic, Two
A membered ring is preferable. The number of carbon atoms in a monocyclic ring is 6 to 10
It is preferable that it is substituted with one or more alkyl or alkenyl groups having 1 to 4 carbon atoms such as methyl and ethyl. In addition, two or more monocycles may be bonded via alkylene. In the case of a 2-membered ring, it preferably has 10 to 12 carbon atoms, which is, for example, 1
It may be substituted with an alkyl group having 1 to 4 carbon atoms such as methyl as described above. Specifically, n-pentane, n-hexane, n-heptane, n-octane, n-nonane, n-
Decane, n-undecane, n-dodecane, n-tetradecane, n-hexadecane, n-octadecane, 2-methylpentane, 2-methylhexane, 2,3-dimethylhexane, 2-methylnonane, 2,6-dimethyloctane, Hydrogenation of 2,2,4,4,6,8,8-heptamethylnonane, pristane, squalane, light liquid paraffin, paraffin, limonene, limonene dimer,
Examples thereof include cyclohexane, 1,3-dimethylcyclohexane, cyclooctane, isobutylcyclohexane, cyclododecane, methyldecalin, decalin, octyl bromide, decyl bromide, dodecyl bromide, hexadecyl bromide, dodecyl bromide and dibromidedecane.

Alcohol ester of aliphatic carboxylic acid having total carbon number of 11 to 26: As alcohol part, methyl alcohol, ethyl alcohol, n-propyl alcohol, iso-propyl alcohol, n-butyl alcohol, iso-butyl alcohol, sec- Butyl alcohol, t-butyl alcohol, n-amyl alcohol,
Monohydric alcohols having 1 to 6 carbon atoms such as iso-amyl alcohol and n-hexyl alcohol are exemplified as preferable ones. The carboxylic acid moiety has 10 carbon atoms.
.About.20 fatty acids, especially saturated fatty acids having 12 to 18 carbon atoms are preferred. Specific examples of the ester include methyl laurate, ethyl laurate, hexyl laurate, isopropyl myristate, isopropyl palmitate,
Examples include methyl stearate and butyl stearate.

C10-C24 mono- or diethers: specifically dibutyl ether, dihexyl ether, dioctyl ether, didodecyl ether, methoxydodecane, ethoxydodecane, and other alkyl monoethers; 1,8-cineole and other alicyclic rings And an alkyl diether such as ethylene glycol dibutyl ether and ethylene glycol dioctyl ether.

C11-C15 ketones: Aliphatic ketones are preferred, such as 2-undecanone, 3-undecanone, 4-undecanone, 5-undecanone, 6-undecanone, 3-dodecanone, 4-dodecanone, 5-dodecanone, 2-tridecanone, 3-tridecanone, 7-tridecanone, 8-pentadecanone, 3-hexadecanone and the like can be mentioned.

Other transdermal absorption enhancers include azone, pyrrolidonecarboxylic acid lauryl ester, nicotinic acid lauryl ester, proline lauryl ester and the like.

The above-mentioned percutaneous absorption enhancer can be added alone or in combination of two or more, if necessary, and the amount of the adhesive is taken into consideration in consideration of the balance between the adhesive force and cohesive force of the adhesive layer. 0.5 to 50% by weight of the layer weight, especially 5 to 30% by weight
It is desirable to set the range to.

If desired, various additives such as a filler, an antioxidant and a softening agent can be appropriately added to the drug-containing pressure-sensitive adhesive layer in an arbitrary amount. In the transdermal preparation of the present invention, the sticking surface is usually covered with a release liner to protect the pressure-sensitive adhesive layer. Examples of the release liner include release paper treated with silicone resin or fluororesin, metal foil, aluminum foil, plastic film and the like.

The transdermal preparation of the present invention can be produced, for example, by the following method. One or more elastomers are kneaded with a kneader at room temperature or under heating. Pilocarpine free base, 1
One kind or two or more kinds of water absorbing substances and other optional components are added, and the mixture is further kneaded at room temperature or under heating.
The pressure-sensitive adhesive composition thus obtained is press-molded or extrusion-molded to a desired thickness to form a pressure-sensitive adhesive layer. A release liner is attached to one surface of the pressure-sensitive adhesive layer and a support is attached to the other surface of the pressure-sensitive adhesive layer to obtain a transdermal preparation. The formation of the pressure-sensitive adhesive layer can also be carried out by dissolving the components of the pressure-sensitive adhesive layer in a suitable solvent, coating the obtained pressure-sensitive adhesive solution on a support, and drying to remove the solvent.

[0028]

EXAMPLES The percutaneous absorption-type pharmaceutical preparation of the present invention will be described in more detail below with reference to Examples and Test Examples. Needless to say, various applications can be made without departing from the technical idea of the present invention. In the following text,% means% by weight.

Example 1 Polyisobutylene 60% Gelatin 9.32% Pectin 9.32% Sodium carboxymethyl cellulose 9.32% Aluminum hydroxide gel 1.54% Alum 0.77% Pilocarpine 10.0%

After kneading the high molecular weight polyisobutylene (viscosity average molecular weight 990000) and the low molecular weight polyisobutylene (viscosity average molecular weight 1260) at a ratio of 1: 3 at 80 ° C. for 20 minutes, other components were added and further at 80 ° C. Kneaded for 20 minutes. Press molding at 80 ° C for 2 minutes (thickness 20
0 μm) was performed and the support was bonded to obtain a sample.

Example 2 Polyisobutylene 30.0% Gelatin 15.39% Pectin 15.39% Sodium carboxymethyl cellulose 15.39% Aluminum hydroxide gel 2.54% Alum 1.27% Pilocarpine 20.0%

After kneading high molecular weight polyisobutylene (viscosity average molecular weight 990000) and low molecular weight polyisobutylene (viscosity average molecular weight 1260) at a ratio of 1: 1 at 80 ° C. for 20 minutes, other components were added, and further at 80 ° C. Kneaded for 20 minutes. Press molding at 80 ° C for 2 minutes (thickness 20
0 μm) was performed and the support was bonded to obtain a sample.

Comparative Example Acrylic adhesive 90.0% Pilocarpine 10.0%

Pilocarpine was added to an ethyl acetate solution of an acrylic adhesive in an amount of 10.0% by weight of the plaster,
This pressure-sensitive adhesive solution was applied onto release paper so that the thickness after drying was 20 μm, and after drying, a support was attached to form a sample.

Control Example Polyisobutylene 52.87% Gelatin 14.51% Pectin 14.51% Sodium carboxymethyl cellulose 14.51% Aluminum hydroxide gel 2.40% Alum 1.20%

After kneading the high molecular weight polyisobutylene (viscosity average molecular weight 990000) and the low molecular weight polyisobutylene (viscosity average molecular weight 1260) at a ratio of 1:10 at 80 ° C. for 20 minutes, other components were added, and further at 80 ° C. Kneaded for 20 minutes. Further press-molding at 80 ° C for 2 minutes (thickness 2
00 μm) was performed and the support was bonded to obtain a sample.

Test Example 1 The samples of Comparative Example, Control Example and Examples 1 and 2 obtained above were punched out into 3 × 5 cm and the total weight was measured. The release paper is removed, the plaster is attached to the skin, and after a certain period of time, the plaster is peeled off and the weight of the plaster is immediately measured. The weight of the release paper was measured and the amount of water absorption, that is, the amount of perspiration was measured from the increase in the weight of the plaster, and at the same time, the presence or absence of peeling due to perspiration was observed. The results are shown in Table 1.

[0038]

[Table 1]

In the preparation of the present invention, the water content of perspiration generated by the percutaneous administration of pilocarpine was absorbed by the hygroscopic substance in the adhesive layer, and the peeling during application was prevented. In the preparation of Comparative Example containing no hygroscopic substance, peeling was observed 30 minutes after application.

Test Example 2 The saliva secretion promoting effect of the transdermal preparation of the present invention was tested. The sample of Example 1 (2.5 × 5 cm) was attached to the left and right lower ears of four healthy adults (male), one on each side, and a total of two sheets were attached, and the total saliva secretion amount for 5 minutes was measured over time. did. Two samples (5 x 5 cm) of the above comparative example were attached to the left and right lower ears of five healthy adults (male), one in total,
The total salivary secretion for 5 minutes was measured over time. In the group to which the sample of Example 1 was applied, an increase in salivary secretion of 1.3 to 2.1 times was observed in 3 out of 4 people compared with before application. The peak of saliva secretion increase was 60 to 120 minutes after application. No exfoliation of the formulation was observed. In the group to which the sample of Comparative Example was applied, 4 out of 5 persons had 1.3 to 1.
A 5-fold increase in salivary secretion was observed. The peak of increased salivary secretion was 90 to 105 minutes after application. Peeling of the preparation was observed 30 minutes after application.

[0041]

EFFECTS OF THE INVENTION The percutaneous absorption type pilocarpine preparation of the present invention absorbs perspiration generated as a side effect of pilocarpine by the hygroscopic substance contained in the pressure-sensitive adhesive layer, resulting in the adhesiveness of the drug-containing pressure-sensitive adhesive layer and pilocarpine. The percutaneous absorption type preparation is capable of being applied for a long time while preventing peeling off against perspiration without impairing the percutaneous absorption of. Pilocarpine, which has a salivation-promoting action, can be transdermally administered over a long period of time, and thus is preferably used for the treatment of xerostomia.

Claims (12)

[Claims] 1. A transdermal preparation comprising a drug-containing pressure-sensitive adhesive layer formed on one surface of a support, wherein the pressure-sensitive adhesive layer comprises pilocarpine free base as a drug and one or more moisture-absorbing agents. A percutaneous absorption type preparation containing an active substance. 2. The transdermal preparation according to claim 1, wherein the adhesive layer contains 0.1 to 60% by weight of pilocarpine free base. 3. The transdermal preparation according to claim 2, wherein the adhesive layer contains 1 to 20% by weight of pilocarpine free base. 4. The transdermal preparation according to claim 1, wherein the adhesive layer contains 30 to 90% by weight of one or more elastomers. 5. The transdermal preparation according to claim 4, wherein the elastomer is at least one selected from polyisobutylene, acrylic polymers and styrene-isoprene-styrene block copolymers. 6. The transdermal preparation according to claim 1, wherein the hygroscopic substance is at least one selected from sodium carboxymethyl cellulose, pectin and gelatin. 7. The transdermal preparation according to claim 1, wherein the adhesive layer contains a hygroscopic substance in an amount of 5 to 60% by weight. 8. The transdermal preparation according to claim 7, wherein the adhesive layer contains a hygroscopic substance in an amount of 10 to 50% by weight. 9. The transdermal preparation according to claim 1, wherein the adhesive layer further contains a polyvalent metal salt. 10. The polyvalent metal salt is selected from alum, aluminum hydroxide, zinc oxide, calcium oxide, aluminum oxide, calcium oxalate, potassium alum, calcium citrate, aluminum alum, calcium chloride, calcium hydroxide and calcium carbonate. The transdermal preparation according to claim 9, which is at least one of the following: 11. The transdermal preparation according to claim 1, wherein the adhesive layer further contains a tackifier. 12. The transdermal preparation according to claim 1, wherein the adhesive layer further contains a transdermal absorption enhancer.