JPH10330248A - Percutaneously absorbable formulation and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To prepare a percutaneously absorbable formulation, excellent in tack characteristics and capable of manifesting good percutaneous absorptivity. SOLUTION: This percutaneously absorbable formulation is prepared by adding a crosslinking agent to a solution of an acrylic copolymer obtained by copolymerizing an alkyl (meth)acrylate with a functional monomer, crosslinking a part of the acrylic copolymer, pulverizing a composition containing the crosslinked acrylic copolymer, preparing a tacky agent solution composed of the acrylic copolymer containing the crosslinked particles of the acrylic copolymer and adding a percutaneous absorbable drug or a percutaneous absorbefacient except buprenorphine and/or its salt to the resultant tacky agent solution.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a transdermal preparation and a method for producing the same. More specifically, the present invention relates to a percutaneous absorption preparation which is applied to a skin surface to continuously administer a drug from the skin to a living body, and a method for producing the same.

[0002]

2. Description of the Related Art In recent years, as a percutaneous absorption preparation for administering a drug into a living body through the skin, a transdermal absorption type external patch such as a poultice or a tape using a plaster or an adhesive has been proposed. Various agents have been developed.

[0003] As a method for effectively releasing a drug from these patch-type transdermal absorption preparations and efficiently absorbing it into the living body from the skin, a method of increasing the concentration of the drug or a transdermal absorption enhancer is used. A method for coexisting with the system has been proposed. Although these methods improve the transdermal absorbability of the drug, they often reduce the adhesiveness of the transdermally absorbable preparation, which causes a so-called stringing phenomenon and glue sticking to the skin surface.

As a means for solving these problems, a method of adding finely divided silica to a pressure-sensitive adhesive (JP-A-2-2955).
No. 65) and a method of controlling the adhesive properties by cross-linking the adhesive to make the plaster gel-like (Japanese Patent Laid-Open No.
Various methods have been proposed.

[0005] Of these, fine powder silica is generally known as a rheological agent to change the flow characteristics of the pressure-sensitive adhesive, and the method of adding the fine powder silica to the pressure-sensitive adhesive is used in various fields. ing.

However, the method of adding the finely divided silica may not be able to improve the adhesive properties depending on the composition and method of the adhesive. In particular, when a polar substance such as polyethylene glycol is added in a large amount as a transdermal absorption enhancer, a decrease in the viscosity of the pressure-sensitive adhesive cannot be suppressed.

On the other hand, the method of cross-linking the entire pressure-sensitive adhesive by external cross-linking to form a gel is very excellent in that the pressure-sensitive adhesive properties can be controlled even when a large amount of a transdermal absorption enhancer or other additives is used. I have.

[0008] However, this method also cannot sufficiently crosslink the pressure-sensitive adhesive when it contains a substance having a cross-linking inhibitory effect, so that this method cannot be used. In particular, when a polyfunctional isocyanate commonly used as a cross-linking agent is used, when a drug or an additive having a hydroxyl group, an amino group, a carboxyl group, or a mercapto group is added to the adhesive, cross-linking inhibition occurs. . Therefore, drugs and additives having these functional groups cannot be used.

[0009] Further, with respect to the technology of converting a pressure-sensitive adhesive into particles to obtain a transdermal absorption preparation, for example, Japanese Patent Publication No. 58-1225
No. 5 and Japanese Patent Publication No. 58-23367, it was difficult to obtain a suitable adhesive property when a large amount of a transdermal absorption enhancer or other additives was used.

Therefore, the inventors of the present invention have developed a skin-adhesive transdermal preparation which has excellent adhesive properties, does not exhibit skin irritation, and exhibits good transdermal absorbability.
As a result of intensive studies, it has been found that the above problems can be solved by blending the acrylic copolymer crosslinked particles obtained by crosslinking and crushing the acrylic copolymer into the adhesive, to complete the present invention. Reached.

In particular, it has been found that this adhesive is also effective for transdermal absorption drugs other than buprenorphine and / or its salts.

[0012]

The percutaneous absorption preparation of the present invention is intended to be applied to a drug for percutaneous absorption other than buprenorphine and / or a salt thereof. And / or a transdermal absorption preparation comprising a pressure-sensitive adhesive layer containing a drug for percutaneous absorption excluding its salt, wherein the pressure-sensitive adhesive layer comprises an acrylic copolymer,
It is characterized by containing crosslinked acrylic copolymer particles obtained by crosslinking and pulverizing an acrylic copolymer.

Further, the method for producing a percutaneously absorbable preparation of the present invention is a method for producing a percutaneously absorbable preparation of the present invention, wherein a crosslinking agent is added to a solution of an acrylic copolymer to carry out crosslinking.
By pulverizing to prepare an adhesive solution containing an acrylic copolymer and crosslinked acrylic copolymer particles, a drug for transdermal absorption excluding buprenorphine and / or a salt thereof, It is characterized by forming an adhesive layer by blending an absorption promoter or other additives.

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION As a support used in the present invention,
It is desirable that the drug for percutaneous absorption or the percutaneous absorption enhancer to be incorporated in the pressure-sensitive adhesive layer be passed through the support so as not to be lost from the back surface and not cause a decrease in the content thereof. In particular,
A single film such as polyester, nylon, Saran, polyethylene, polypropylene, polyvinyl chloride, ethylene-vinyl acetate copolymer, polytetrafluoroethylene, Surlyn, metal foil, or a laminated film thereof can be used.

In order to improve the adhesive force (anchoring force) between the support and the pressure-sensitive adhesive layer described later, the support is made of a non-porous film made of the above-mentioned material and a woven or non-woven fabric. It is preferable to use a laminated film with the above cloth.
In this case, the thickness of the laminated film is 10 μm to 20 μm.
It is preferable to use the one having a thickness of 0 μm.

Alternatively, if the characteristics of a single film are utilized, it is preferable that the single film be subjected to a so-called undercoating treatment and used as a support in order to improve the anchoring force. In this case, it is preferable to use a single film having a thickness of 1 μm to 100 μm.

The acrylic copolymer used in the pressure-sensitive adhesive layer of the present invention is, for example, an alkyl (meth) acrylate used for a general acrylic pressure-sensitive adhesive as a main component monomer, and a functional monomer. It can be obtained by copolymerizing a monomer.

Examples of the alkyl (meth) acrylate include carbon atoms such as butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and tridecyl. Number 4
It is possible to use (meth) acrylic acid alkyl esters having from 13 to 13 linear alkyl groups or branched alkyl groups, and it is possible to use one or two or more (meth) acrylic acid alkyl esters.

The alkyl (meth) acrylate is not limited to those described above, but may be a straight-chain alkyl group having 1 to 3 carbon atoms or a branched alkyl group as long as the properties of the present invention are not changed. (Meth) acrylic acid alkyl ester having an alkyl group or (meth) having a linear or branched alkyl group having 14 or more carbon atoms
The alkyl acrylate may be used in combination with the alkyl (meth) acrylate having 4 to 13 carbon atoms.

As the functional monomer copolymerizable with the alkyl (meth) acrylate, a polar monomer or a vinyl monomer can be used.

Examples of the copolymerizable polar monomer include carboxyl group-containing monomers such as (meth) acrylic acid, itaconic acid, maleic acid, maleic anhydride, crotonic acid, styrene sulfonic acid, and allyl sulfone. Acid, sulfoxypropyl (meth) acrylate, (meth) acryloyloxynaphthalenesulfonic acid, sulfoxyl group-containing monomers such as acrylamidomethylpropanesulfonic acid,
Hydroxy group-containing monomers such as (meth) acrylic acid hydroxyethyl ester, (meth) acrylic acid hydroxypropyl ester, (meth) acrylamide, dimethyl (meth) acrylamide, N-butylacrylamide, N-methylol (meth) acrylamide, Amide group-containing monomers such as N-methylolpropane (meth) acrylamide, and alkyls such as (meth) acrylic acid aminoethyl ester, (meth) acrylic acid dimethylaminoethyl ester, and (meth) acrylic acid tert-butylaminoethyl ester Aminoalkyl group-containing monomers, methoxyethyl (meth) acrylate, ethoxyethyl (meth) acrylate, alkoxyalkyl (meth) acrylates, tetrahydrofurfuryl (meth) acrylate (Meth) acrylic acid esters containing an alkoxy group (or an oxidic bond in the side chain) such as methoxyethylene glycol (meth) acrylate, methoxydiethylene glycol (meth) acrylate, and methoxypolyethylene glycol (meth) acrylate; (Meth) acrylonitrile and the like, and these monomers can be copolymerized by one kind or in combination of two or more kinds.

Further, as the vinyl monomer, for example,
Vinyl acetate, vinyl esters such as vinyl propionate, N-vinyl-2-pyrrolidone, methylvinylpyrrolidone, vinylpyridine, vinylpiperidone, vinylpyrimidine, vinylpiperazine, vinylpyrazine, vinylpyrrole, vinylimidazole, vinylcaprolactam,
Examples include vinyl monomers having a nitrogen-containing heterocycle such as vinyl oxazole, and these monomers also include
One type or a combination of two or more types can be copolymerized.

The above polar monomer and vinyl monomer are
One or two or more of these monomers can be copolymerized with the above-mentioned alkyl (meth) acrylate. Among these copolymerizable monomers, a functional group serving as a crosslinking point when a crosslinking treatment is performed And carboxyl group-containing monomer, hydroxy group-containing monomer, amide group-containing monomer, and (meth) It is desirable to polymerize an alkoxyalkyl acrylate or a (meth) acrylate containing an alkoxy group (or an oxide bond in a side chain) as a copolymerization component. Further, from the viewpoint of improving cohesion and improving drug solubility when a drug is contained, it is preferable to copolymerize a vinyl ester or a vinyl monomer having a nitrogen-containing heterocycle.

The amount of the copolymerizable polar monomer and / or vinyl monomer can be adjusted by adjusting the cohesive force of the pressure-sensitive adhesive layer based on the acrylic copolymer or by containing a drug. Can be arbitrarily set by adjusting the solubility in the case of, but is usually 50% by weight or less as a copolymerization amount,
Preferably, it is in the range of 2 to 40% by weight.

The crosslinked acrylic copolymer particles of the present invention prevent the percutaneous absorption enhancer described below from flowing out, impart cohesive force to the pressure-sensitive adhesive layer, prevent the stringing phenomenon, and improve the pressure-sensitive adhesive layer. It plays a role of giving shape-retaining property to the material. It also plays a role in controlling the release characteristics of the contained drug.

As the acrylic copolymer used for the crosslinked acrylic copolymer particles, the same acrylic copolymer used for the pressure-sensitive adhesive layer can be used as described above.

The cross-linking reaction for preparing cross-linked acrylic copolymer particles includes physical cross-linking treatment by irradiating radiation such as ultraviolet rays and electron beams, multifunctional isocyanates, organic peroxides, and organic metal salts. , Metal alcoholate,
Chemical cross-linking treatment using a cross-linking agent such as a metal chelate compound, a divinyl compound, an epoxy compound, melamine and other polyfunctional compounds can be applied.

In terms of its reactivity and its handling,
In particular, it is preferable to carry out a chemical crosslinking treatment using a trifunctional isocyanate, a metal alcoholate composed of titanium or aluminum, or a metal chelate compound. The amount of the crosslinking agent used for performing the chemical crosslinking is 0.1 to 100 parts by weight of the acrylic copolymer.
It is preferable to use from 0.01 to 2.0 parts by weight. Furthermore, when using these crosslinking agents, from the viewpoint of crosslinking reactivity,
It is desirable to use (meth) acrylic acid as the functional monomer.

More specifically, as a method for producing crosslinked acrylic copolymer particles, the above acrylic copolymer and the above crosslinking agent are uniformly stirred in the presence of a suitable solvent such as an organic solvent, and then directly stirred for 50 minutes. Either store at a temperature of from 80 ° C. to 80 ° C. while cross-linking into a gel and solidify, or form an acrylic copolymer solution with a cross-linking agent using a coating machine for general adhesive tape production. Then, it is cross-linked and solidified by heat aging.

An appropriate solvent is further added to the crosslinked and solidified acrylic copolymer composition to dilute it to a desired concentration. Thereafter, the acrylic copolymer composition is pulverized with a pulverizer to produce crosslinked acrylic copolymer particles. At this time, as a pulverizer, for example, Golator (trade name) manufactured by Nippon Steel Mining Co., Ltd., Disintegrator (trade name) manufactured by Komatsu Zenoa Co., Ltd., T.K. K. A pulverizer such as a cut ruder (trade name) can be used. Other than these crushers,
For example, an emulsifying and dispersing device such as TK homomixer (trade name) manufactured by Tokushu Kika Kogyo Co., Ltd. can be used. Of these, Golator, Disintegrator, T.P. K. It is preferable to use a cut ruder.

The particle size of the crosslinked acrylic copolymer particles is as follows:
Depending on the dilution solvent, for example, when ethyl acetate is used and the concentration of the crosslinked particles is 1% by weight, 0.5%
μm to 50 μm, particularly 1 μm to 20 μm
It is preferred that If the particle size is smaller than this, the effect of adding the crosslinked particles is lost, the cohesive force of the pressure-sensitive adhesive layer is reduced, and a stringing phenomenon occurs. Also, if it is larger than this, the coatability to the support will be worse, and it will be streaked, or the unevenness of the coated surface after coating and drying will be large, the coating thickness will be uneven and the appearance will be poor, I can't stand it.

The crosslinked acrylic copolymer particles thus obtained can be taken out by an appropriate method and mixed with another acrylic copolymer solution.

The content of the crosslinked acrylic copolymer particles in the pressure-sensitive adhesive layer is preferably mixed so as to be 70 to 400 parts by weight with respect to 100 parts by weight of the acrylic copolymer. 100 to 300 parts by weight. If the content is less than this, the effect of adding the crosslinked particles is reduced, the cohesive force is reduced, and a stringing phenomenon occurs. On the other hand, if the amount is more than this, the adhesive strength of the pressure-sensitive adhesive layer is reduced, so that the sticking property to the skin surface is deteriorated and the anchoring force between the support and the support is reduced, which is not preferable.

Further, as described above, the above-mentioned crosslinking agent is added to the solution of the acrylic copolymer, a part of the acrylic copolymer is subjected to a crosslinking treatment, and this is pulverized to obtain an acrylic copolymer. Since the crosslinked acrylic copolymer particles can be contained in the combined solution, it can be used as it is in the pressure-sensitive adhesive layer of the present invention. In this way, from the preparation of the acrylic copolymer, the pressure-sensitive adhesive layer containing the acrylic copolymer crosslinked particles can be obtained by a continuous process, and the production process can be simplified, which is convenient. .

At this time, the crosslinking ratio (gel fraction) at the time when the crosslinking reaction is completed becomes equal to the content of the acrylic copolymer crosslinked particles in the pressure-sensitive adhesive layer. Therefore, by adjusting the amount of the cross-linking agent added, the time of the cross-linking reaction, and the like, and adjusting the gel fraction of the acrylic copolymer, the above preferable content ratio can be obtained. For example, the gel fraction is 50 to 60% by weight.
If it is made to become, the remaining unreacted acrylic copolymer will be 40 to 50 weight%, and the thing of the said content ratio can be obtained easily.

In the pressure-sensitive adhesive layer of the transdermal absorption preparation of the present invention,
Various additives can be added, and not only drugs for percutaneous absorption but also percutaneous absorption enhancers and other additives such as antioxidants can be used. These additives are preferably blended in a solution of the acrylic copolymer containing the crosslinked acrylic copolymer particles obtained above.

As the transdermal absorption enhancer, a compound having a function of improving the solubility and diffusibility of a drug in the pressure-sensitive adhesive layer,
In addition, functions to improve percutaneous absorption such as water retention of keratin, keratin softening, keratin penetrating (loose), function as penetration aid and pore opening agent, and function to change skin interface state Compounds having the above-mentioned functions, compounds having the above-mentioned functions, and compounds having a drug-effect promoting function for further increasing the drug-effect of a drug, in addition to these functions, are widely used.

Specific examples of such a transdermal absorption enhancer include the following compounds. For example,
Glycols such as diethylene glycol, propylene glycol and polyethylene glycol as compounds that mainly enhance drug solubility, oils and fats such as olive oil, squalene, and lanolin as compounds that mainly increase drug diffusibility, and mainly improve the water retention of keratin Compounds such as urea, urea derivatives such as allantoin, and compounds that mainly enhance keratin permeability include dimethyldecylphosphoxide, methyloctylsulfoxide, dimethyllauramide, dodecylpyrrolidone, isosorbitol, dimethylacetamide, dimethylsulfoxide, and dimethylformamide. Polar solvents, mainly salicylic acid, which enhances keratin softening properties, mainly amino acids as penetration aids, mainly benzyl nicotinate as pore-opening agents, and lauryl sulfate, which has the function of mainly changing the interface state of the skin Sodium, percutaneous absorbability like Sarokoru used in combination with good drug.

Other plasticizers such as diisopropyl adipate, phthalate and diethyl sebacate, hydrocarbons such as liquid paraffin, various emulsifiers, ethoxylated stearyl alcohol, oleic acid monoglyceride,
Glycerin monoesters such as caprylic acid monoglyceride and lauric acid monoglyceride, or glycerin diester, glycerin triester or mixtures thereof, higher fatty acid esters such as isopropyl myristate and octyl palmitate, and higher grades such as oleic acid and caprylic acid Fatty acids and the like can be mentioned.

Further, two or more of these transdermal absorption enhancers may be mixed, and a particularly preferred transdermal acceleration enhancer is a combination of isopropyl myristate and caprylic monoglyceride. The amount of these additives is 1
The total amount of the seed or two or more transdermal absorption enhancers is 150 to 400 parts by weight, more preferably 200 to 300 parts by weight, based on 100 parts by weight of the acrylic copolymer. If the amount is less than this, the effect as a percutaneous absorption enhancer cannot be sufficiently exerted. If the amount is more than this, the pressure-sensitive adhesive layer is plasticized, which causes stringing and glue residue. Also, even if added more than necessary, the effect as a transdermal absorption enhancer often does not increase in proportion to the amount added, which is economically undesirable.

It is desirable that these percutaneous absorption enhancers be well compatible with the acrylic copolymer and the crosslinked acrylic copolymer particles. A soft feeling can be imparted, the adhesiveness can be improved, and transdermal absorbability can be improved, and skin irritation can be reduced.

The drug for transdermal absorption which can be incorporated in the above-mentioned pressure-sensitive adhesive layer is not particularly limited as long as it has transdermal absorbability, and is widely used for drugs other than buprenorphine and / or its salts. Can be used. Specifically, general anesthetics, hypnotics and sedatives, antiepileptic drugs, antipyretic analgesics and anti-inflammatory drugs, analgesics, drugs for psychiatric nerves, drugs for skeletal muscle relaxants, drugs for autonomic nerves, antispasmodics, antiparkinson drugs, antihistamines Drugs, inotropics, arrhythmias, diuretics, antihypertensives, vasoconstrictors, coronary vasodilators, peripheral vasodilators, arteriosclerotics,
Cardiovascular drugs, respiratory stimulants, antitussive expectorants, hormonal drugs, topical drugs for suppurative diseases, drugs for analgesia, pruritus, astringency, anti-inflammatory, drugs for parasitic skin diseases, drugs for hemostasis, drugs for gout, drugs for diabetes Drugs, antineoplastic drugs, antibiotics, chemotherapeutics, narcotics and the like can be used.

The content of the drug for transdermal absorption can be appropriately set according to the drug species and the purpose of administration. Preferably, it is added to the pressure-sensitive adhesive layer in a range of about 1 to 60% by weight, more preferably about 5 to 30% by weight. If the content is less than 1% by weight, release of a therapeutically effective amount of the drug may not be expected. If it exceeds 60% by weight, the effect of increasing the amount of the drug may not be expected in many cases. Not only is this disadvantageous, but also the adhesion to the skin may be reduced. In the present invention, the drug for percutaneous absorption does not need to be completely dissolved in the pressure-sensitive adhesive layer, and contains a drug amount not less than the solubility in the pressure-sensitive adhesive layer, and the drug is dispersed in an undissolved state. It may be in the state of being done.

The present invention is an effective means especially when a crosslinking inhibitor is present in the pressure-sensitive adhesive layer. That is, in a conventional transdermal absorption preparation, a trifunctional isocyanate, by using a chemical cross-linking agent such as a metal alcoholate or a metal chelate compound composed of titanium or aluminum, by cross-linking the entire pressure-sensitive adhesive layer, a so-called Optimum adhesive properties were obtained by making the gel state. However, in this method, when a crosslinking inhibitor is present in the pressure-sensitive adhesive layer, the crosslinking reaction is inhibited, and sufficient adhesive properties cannot be obtained. In such a case, by including the crosslinked acrylic copolymer particles in the pressure-sensitive adhesive layer, optimum pressure-sensitive adhesive properties can be created.

For example, a compound having a hydroxyl group, an amino group, a carboxyl group, or a mercapto group corresponds to a crosslinking inhibitor for a polyfunctional isocyanate. Examples of those having a hydroxyl group include alcohols such as methanol and ethanol, glycols such as diethylene glycol, propylene glycol and polyethylene glycol, glycerin monoesters such as oleic acid monoglyceride, caprylic acid monoglyceride, and lauric acid monoglyceride, and glycerin diesters. Examples include silica such as hydrated silicon dioxide and light silicic anhydride, polyhydric alcohols such as glycerin, and water. Examples of those having an amino group include amino acids. Examples of those having a carboxyl group include fatty acids.

Water, alcohols, diketones, ketoesters, diesters, fatty acids, acid anhydrides, various esters, hydrogen chloride, amino acids and the like, as crosslinking inhibitors for metal alcoholates and metal chelate compounds composed of titanium and aluminum. And a wide variety of compounds.

The percutaneous absorption enhancer and the drug for percutaneous absorption contained in the percutaneous absorption preparation of the present invention sometimes function as a crosslinking inhibitor. The amount acting as a cross-linking inhibitor varies depending on the substance and other additives, but when the content is 10% by weight or more in the pressure-sensitive adhesive layer, the cross-linking inhibitory effect often appears strongly. When it is contained in an amount of 70% by weight or more, it acts not only as a cross-linking inhibitory effect but also as a plasticizing effect, deteriorating adhesiveness, losing shape retention, and causing stringing and glue residue. In particular, when a fatty acid monoglyceride such as caprylic acid monoglyceride is blended in the pressure-sensitive adhesive layer, the fatty acid monoglyceride migrates into the separator, and the peelability of the pressure-sensitive adhesive layer from the separator deteriorates.

That is, according to the present invention, by including crosslinked acrylic copolymer particles in the pressure-sensitive adhesive layer,
These problems can be solved, and the release of the drug can be easily controlled by adding various transdermal absorption enhancers.

[0049]

EXAMPLES Next, transdermal preparations as examples of the present invention were prepared as shown below, and the effects of the present invention were confirmed. It should be noted that all “parts” in the text below indicate parts by weight, and “%” means% by weight.

(Example 1) <Preparation of Acrylic Copolymer Solution> First, an acrylic copolymer necessary for forming an adhesive layer and an acrylic copolymer for producing acrylic copolymer crosslinked particles were prepared. A polymer solution was prepared.

Under an atmosphere of an inert gas such as nitrogen gas, 95 parts of 2-ethylhexyl acrylate and 5 parts of acrylic acid are copolymerized in ethyl acetate according to a conventional method to obtain an acrylic copolymer containing an acrylic copolymer. A polymer solution was prepared.

<Preparation of PSA Solution Containing Crosslinked Acrylic Copolymer Particles> Trifunctional isocyanate (Coronate, manufactured by Nippon Polyurethane Co., Ltd.) was used in an amount of 0.13 part with respect to 100 parts of the acrylic copolymer. HL, hereinafter the same)
Was added to the acrylic copolymer solution obtained above, and ethyl acetate was further added to adjust the concentration of the acrylic copolymer to 2
It was adjusted to be 5%. Then put in an airtight container,
Heat aging was performed at 60 ° C. for 96 hours to prepare a pressure-sensitive adhesive solution containing a crosslinked acrylic copolymer. The gel fraction at this time was measured by the following method, and was found to be 59%. (Hereinafter, the gel fraction shows the result measured by the same method.) The weight ratio of the acrylic copolymer and the acrylic copolymer cross-linked particles in this adhesive solution is the acrylic copolymer weight. Acrylic copolymer crosslinked particles were 144 parts by weight with respect to 100 parts by weight of the combined.

The pressure-sensitive adhesive solution containing the crosslinked acrylic copolymer thus obtained was fed with a high-viscosity pump, and the particle size was 1 to 3 using Golator manufactured by Nittetsu Mining Co., Ltd. Crushed to 2 mm. Further, the mixture was diluted with ethyl acetate so that the concentration of the acrylic copolymer crosslinked particles became 10%, and pulverized with a TK homomixer manufactured by Tokushu Kika Kogyo Co., Ltd. so that the particle size became 1 to 10 μm. did.

Next, 50% of prilocaine and 10% of isopropyl myristate were added to the pressure-sensitive adhesive solution containing the crosslinked acrylic copolymer particles, and the mixture was uniformly stirred and dissolved. This adhesive solution was placed on a polyester separator (thickness: 75 μm) and the adhesive weight after drying was 2 m.
g / cm < ² > and dried to form an adhesive layer. Next, a polyester film (thickness: 12 μm) was adhered as a support on the pressure-sensitive adhesive layer to obtain a transdermal preparation of Example 1.

(Example 2) In the adhesive solution containing the acrylic copolymer crosslinked particles obtained in Example 1, 5% of indeloxazine hydrochloride, 30% of caprylic acid monoglyceride, 10% of isopropyl myristate, 10% of hydrous silica An acid (Carplex # 80, manufactured by Shionogi & Co., Ltd.) was added so as to have a concentration of 10%, and the mixture was uniformly stirred and dispersed. This adhesive solution was applied to a polyester nonwoven fabric (a basis weight of 12
g / m ² ) and a polyester film (thickness: 2 μm), on the nonwoven fabric side, the weight of the adhesive after drying is 4 m.
g / cm < ² > and dried to form an adhesive layer. Next, a polyester film (thickness: 12 μm) was laminated on the pressure-sensitive adhesive layer as a separator to obtain a transdermal preparation of Example 2.

(Example 3) The procedure of Example 2 was repeated, except that the trifunctional isocyanate was added in an amount of 0.06 part based on 100 parts by weight of the acrylic copolymer. Thus, a percutaneous absorption preparation of Example 3 was obtained. At this time, the gel fraction of the pressure-sensitive adhesive solution was 41%, and the crosslinked acrylic copolymer particles were 70 parts with respect to 100 parts of the acrylic copolymer.

Example 4 The procedure of Example 2 was repeated, except that the trifunctional isocyanate was added in an amount of 0.17 parts by weight based on 100 parts by weight of the acrylic copolymer. Thus, a percutaneous absorption preparation of Example 4 was obtained. At this time, the gel fraction of the pressure-sensitive adhesive solution was 75%, and the acrylic copolymer crosslinked particles were 300 parts with respect to 100 parts of the acrylic copolymer.

Comparative Example 1 A three-necked flask equipped with a stirrer and a reflux condenser was charged with 600 parts of ion-exchanged water and polyvinyl alcohol as a dispersant (saponification degree of 78.5% to 8%).
(1.5%) and 0.5 part of the mixture were sufficiently mixed and stirred. To this aqueous solution was added a monomer mixture consisting of 200 parts of 2-ethylhexyl acrylate, 10 parts of acrylic acid and 0.2 parts of benzoyl peroxide. The solution was stirred for 1 hour (at a temperature of 25 ° C. and a rotation speed of 300 rpm) under an atmosphere of an inert gas such as nitrogen gas.
The resulting mixture was heated to 4 ° C. and heated and stirred for 4 to 5 hours for copolymerization.
Further, the temperature was raised to 80 ° C. and the mixture was stirred for 2 hours to complete the copolymerization, thereby obtaining a pressure-sensitive adhesive solution containing non-crosslinked acrylic copolymer particles. The content of the acrylic copolymer particles in the adhesive solution was 25%. To this adhesive solution, 600 parts of methanol was added to precipitate and collect the acrylic copolymer particles, and then the acrylic copolymer particles were dispersed in ethyl acetate to a concentration of 10%. . The particle size of the acrylic copolymer particles at this time was 5 to 80 μm. Prilocaine in this solution,
Transdermally absorbable preparation of Comparative Example 1 was prepared in the same manner as in Example 1 except that isopropyl myristate was added.

(Comparative Example 2) In the acrylic copolymer solution obtained in Example 1, the content in the final preparation was made equal to the content in the percutaneous absorption preparation obtained in Example 1. , Prilocaine and isopropyl myristate were added. Then, a trifunctional isocyanate was added so as to be 0.052% (corresponding to 0.13 part with respect to 100 parts of the acrylic copolymer) to prepare a pressure-sensitive adhesive solution.
In the same manner as in 1, a transdermal absorption preparation containing prilocaine and the like was prepared. Thereafter, the mixture was further heated and aged at 70 ° C. for 60 hours to obtain a transdermal absorption preparation of Comparative Example 2. At this time, the gel fraction of the pressure-sensitive adhesive solution was 20%, and the content of the crosslinked acrylic copolymer was about 8% of the whole pressure-sensitive adhesive.

Comparative Example 3 A percutaneously absorbable preparation of Comparative Example 3 was obtained in the same manner as in Comparative Example 2 except that heat aging was performed without adding a trifunctional isocyanate. At this time, the gel fraction of the pressure-sensitive adhesive solution was 18%.

Comparative Example 4 An emulsion of a copolymer obtained in an aqueous solution of methacrylic acid and n-butyl acrylate in aminoacetic acid (Nippon Acrylic Chemical Co., Ltd., Primal N-580 (NF) -1)), the same weight of ethanol was added thereto, and copolymer particles of methacrylic acid and n-butyl acrylate were sedimented and collected.
%, And re-dispersed in ethanol to give a% concentration. The particle size of the copolymer particles was about 250 to 550 nm. To this solution, indeloxazine hydrochloride, caprylic acid monoglyceride, isopropyl myristate, and hydrous silicic acid were added, and a percutaneous absorption preparation of Comparative Example 4 was obtained in the same manner as in Example 2.

(Comparative Example 5) In the acrylic copolymer solution obtained in Example 1, the content in the final preparation was adjusted to be equal to the content in the transdermal preparation obtained in Example 2. , Indeloxazine hydrochloride, caprylic acid monoglyceride, isopropyl myristate, and hydrous silicic acid were added. Then 3
After adding a functional isocyanate so as to be 0.0585% (corresponding to 0.13 part with respect to 100 parts of the acrylic copolymer) to prepare an adhesive solution, the same procedure as in Example 2 was carried out. A transdermal preparation containing indeloxazine hydrochloride and the like was prepared. Thereafter, the mixture was further heated and aged at 70 ° C. for 60 hours to obtain a transdermal absorption preparation of Comparative Example 5. At this time, the gel fraction of the pressure-sensitive adhesive solution was 25%, and the content of the crosslinked acrylic copolymer was about 11.25% of the whole pressure-sensitive adhesive.
Met.

Comparative Example 6 A percutaneously absorbable preparation of Comparative Example 6 was obtained in the same manner as in Comparative Example 5 except that trifunctional isocyanate was not added and heat aging was performed. At this time, the gel fraction of the pressure-sensitive adhesive solution was 18%.

Comparative Example 7 The procedure of Example 2 was repeated, except that the trifunctional isocyanate was added in an amount of 0.03 part based on 100 parts by weight of the acrylic copolymer. Thus, a transdermal preparation of Comparative Example 7 was obtained. At this time, the gel fraction of the pressure-sensitive adhesive solution was 29%, and the weight ratio of the acrylic copolymer crosslinked particles after pulverization was 40 parts per 100 parts of the acrylic copolymer. Department.

Comparative Example 8 Example 2 was repeated except that the trifunctional isocyanate was added in an amount of 0.5 part based on 100 parts by weight of the acrylic copolymer.
In the same manner as in the above, a percutaneous absorption preparation of Comparative Example 8 was obtained. In addition,
At this time, the gel fraction of the pressure-sensitive adhesive solution was 83%, and the weight ratio of the acrylic copolymer crosslinked particles after crushing was 500 parts for the acrylic copolymer crosslinked particles with respect to 100 parts of the acrylic copolymer. there were.

<Measurement of Gel Fraction> In measuring the gel fraction, the pressure-sensitive adhesive solution of the acrylic copolymer used in each of the above Examples and Comparative Examples was used to prepare a general pressure-sensitive adhesive tape. Under the conditions, a sample was prepared which was applied and dried on a support so that the thickness of the pressure-sensitive adhesive layer after drying was about 40 μm, and a test was performed by the following method.

A porous membrane made of tetrafluoroethylene resin (thickness: 30 μm to 100 μm, average pore size: 0.1 to 1.0 μm)
Is cut into a width of 100 mm and a length of 200 mm, and the cut porous membrane is provided with 40 cm ² (adhesive weight of 60 to
Equivalent to 200 mg. Paste the sample punched in). Next, the porous membrane is folded into two so that the samples do not overlap, and the three ear ends are bent twice each so that the crosslinked acrylic copolymer particles leaking from the sample do not leak. Make a bag of porous membrane. This bag is immersed in a solvent capable of dissolving the acrylic copolymer, for example, 100 ml of ethyl acetate for 24 hours. Further, this dipping operation is repeated twice. Thereafter, after the solvent is evaporated, the following weights are measured, and the gel fraction is calculated by the following equation. Gel fraction (%) = [(BCDF) / (ACD)
-E)] × 100 A: Weight (g) of porous membrane bag (including sample) before immersion B: Weight (g) of porous membrane bag (including sample) after immersion C: Weight of porous membrane (including sample) g) D: weight of the support (g) E: weight of the additive (g) F: weight of the additive that cannot be removed 100% by the solvent and remains in the bag of the porous membrane after immersion

The weight C of the porous membrane and the weight D of the support
When changes before and after immersion, the weight change is measured in advance for each of the porous membrane and the support, and the weight change is converted to correct the gel fraction. In addition, when the additive was contained in the pressure-sensitive adhesive solution from which the sample was prepared (Comparative Examples 2, 3, 5, and 6), the weight E of the additive,
As F, a value converted from the mixing ratio of the additive was used.

<Comparative Test> Each test (measurement) was performed for the following items with respect to the percutaneously absorbable preparations obtained in Examples 1 to 4 and Comparative Examples 1 to 8, and the results were shown in Tables 1 and 2.
The results are shown in Table 3.

[0070]

[Table 1]

[0071]

[Table 2]

(Adhesion test) Each sample in the form of a strip obtained by cutting a percutaneously absorbable preparation to a width of 12 mm was adhered to a bakelite plate, and a roller with a load of 850 g was reciprocated once to make close contact with each other. . H. Under the conditions described above, peeling was performed at a rate of 300 mm / min in a 180 ° direction using a Tensilon tensile tester, and the peeling force (g) at that time was measured.

(Holding force test) Transdermal absorption preparation was 10 m wide
m, one end of each sample cut into a size of 50 mm in length is attached to the end of the bakelite plate at a length of 20 mm, a load of 150 g is applied to the other end, stored at 40 ° C., and subjected to cohesive failure. Was caused and the time (minutes) until each sample dropped was measured.

(Anchoring force test) Width 13 mm, length 100 m
The support surface of a placebo tape (a tape prepared without adding a drug and an additive from the percutaneous absorption preparation prepared in each of Examples, Comparative Examples, etc.) cut to 25 m was coated with a double-sided tape at 25 × 1.
The transdermal preparation was fixed to a 00 mm bakelite plate, and the percutaneous absorption preparation was 12 mm wide and 70 m long on the adhesive layer surface of the placebo tape.
m, the adhesive layers were stuck to each other using a roller with a load of 850 g, and
3 ° C, 60% R. H. Under the conditions described above, peeling was performed at a speed of 300 mm / min in a 90 ° direction using a Tensilon tensile tester, and the applied stress (g) at that time was measured.

<Determination of Anchoring Force> At the time of measurement, the applied stress when the support and the adhesive layer of the transdermal absorption preparation prepared in each of Examples and Comparative Examples were peeled off cleanly was defined as the anchoring force on the support. . At this time, a case where the pressure-sensitive adhesive layer remained on the support and a destruction phenomenon of the pressure-sensitive adhesive layer such as stringing was observed during the measurement was regarded as cohesive failure. In the above intermediate phenomenon, a case where the pressure-sensitive adhesive layer partially remains on the support was regarded as a partial anchorage failure. Furthermore, the case where the adhesive layer of the transdermal absorption preparation and the adhesive layer of the placebo tape prepared in each of Examples and Comparative Examples were cleanly peeled was defined as interfacial peeling. When interfacial peeling or anchorage breakage with a placebo tape occurs, it is considered that the percutaneous absorption preparations prepared in Examples and Comparative Examples have sufficient anchoring power and cohesiveness.

(Human Skin Adhesion Test)
Each sample cut to a size of 0 mm and a length of 50 mm was adhered to the inside of the forearm of a healthy volunteer for 1 hour, peeled off, observed the state of anchor breakage at that time, and evaluated according to the following criteria. did. ○: No anchor breakage and no glue residue. Δ: Anchor breakage or cohesive breakage occurs slightly at the edge portion, and the adhesive remains on the skin. ×: Anchor breakage or cohesive breakage occurs on the entire surface, and the adhesive remains on the skin.

(Coatability and Appearance Test) The coatability at the time of coating and the appearance of the prepared transdermal absorption preparation were evaluated according to the following criteria. : Smooth coated surface, no abnormal appearance. Δ: The coating surface is slightly uneven, and there is no problem in appearance. ×: The streak coating was severe, and the coated surface was uneven, and the appearance was poor, making it unsuitable as a preparation.

<Test Results> As is apparent from Table 1, when the transdermal preparation of Example 1 and the transdermal preparations of Comparative Examples 1 to 3 were compared, almost the same adhesive strength was obtained. Although obtained, the percutaneous absorption preparation of Example 1 contains acrylic copolymer cross-linked particles in which the acrylic copolymer has been cross-linked in advance. The transdermal preparation of Example 1 was the most excellent, and was improved about 10 times as compared with the comparative example.

Further, unexpectedly, the anchoring property to the support is also good.
Surprisingly, more than twice the anchoring force was obtained as compared with the comparative example. Furthermore, in the human skin sticking test, Example 1 was used.
Was practical without glue residue. In addition, since the crosslinked product of the acrylic copolymer was pulverized into fine particles in terms of coatability, no problem occurred and it was confirmed that the preparation was an excellent transdermal preparation.

On the other hand, in the percutaneously absorbable preparation using the particulate pressure-sensitive adhesive of Comparative Example 1, the coating properties were unstable with a solvent other than an aqueous solvent, and the external appearance was not practical. Further, in the transdermal preparations of Comparative Examples 2 and 3, there was no problem in coatability and appearance, but since the prilocaine acts as a cross-linking inhibitor of trifunctional isocyanate, the acrylic copolymer was cross-linked. It is considered that excellent holding power and the like were not obtained.

As can be seen from Table 2, the adhesive strength of the percutaneously absorbable preparation of Example 2 was significantly lower than that of the corresponding transdermally absorbable preparations of Comparative Examples 4 to 6 due to the effect of caprylic acid monoglyceride. , But almost the same adhesive strength was obtained. In addition, excellent results were obtained in the holding force test, and the result of the human skin sticking test was practical without glue residue. In the anchoring force test, since a laminated film of a polyester nonwoven fabric and a polyester film was used for the support, the anchoring force was all very strong and could not be measured as complete anchorage destruction. In the percutaneously absorbable preparation No. 2, a large amount of stringing due to cohesive failure as in Comparative Examples 5 and 6 was not observed, and the value was about 3.5 times the anchoring force of Comparative Example 4,
It was confirmed to be an excellent transdermal preparation.

This large amount of stringing phenomenon was observed in Comparative Examples 5 and 6.
It is considered that the composition of the percutaneously absorbable preparation of the above indicates that caprylic acid monoglyceride and hydrous silicic acid inhibit the crosslinking of the acrylic copolymer. In particular, the transdermal preparation using the particulate pressure-sensitive adhesive of Comparative Example 4 has excellent coatability but low cohesive strength (holding power) compared to the transdermal preparation of Comparative Example 1, and the human In the skin sticking test, glue was generated at the edge.

[0083]

[Table 3]

Table 3 shows a comparison of transdermal preparations having different contents of crosslinked acrylic copolymer particles. In Table 3, the content of the crosslinked particles indicates the content (parts by weight) based on 100 parts by weight of the acrylic copolymer. As a result, as can be seen from Table 3, Example 2
It can be said that each of the percutaneously absorbable preparations Nos. To 4 has a higher cohesive force than the corresponding percutaneously absorbable preparation of Comparative Example 7 because of its higher holding power. In addition, when compared with the corresponding transdermal absorption preparation of Comparative Example 8, it can be said that the adhesive strength, anchoring strength, and coatability are excellent. Furthermore, in a human skin sticking test, it is excellent in terms of stringiness and anchoring properties, and can be said to be a practical transdermal absorption preparation.

FIG. 1 shows the content ratio of crosslinked acrylic copolymer particles in the transdermal preparations of Examples 2 to 4 and the transdermal preparations of Comparative Examples 7 and 8, and the content of each transdermal preparation. The relationship with various physical properties was shown. In the figure,-○-indicates the adhesive strength, and-
×-indicates a holding force, and-△-indicates a ratio of the holding force to the adhesive force (holding force / adhesive force). According to this, the value of the holding force / adhesion force of 0.5 or more, in which both are balanced, is 100 parts by weight of the acrylic copolymer,
It contains at least 100 parts by weight of acrylic copolymer crosslinked particles.

[0086]

FIG.

FIG. 2 shows the relationship between the added amount of the added cross-linking agent and the gel fraction of the pressure-sensitive adhesive solution containing the crosslinked acrylic copolymer particles. If the amount exceeds 0.17 parts by weight (corresponding to 300 parts by weight of the crosslinked acrylic copolymer particles) with respect to 100 parts by weight of the acrylic copolymer, even if the addition amount of the crosslinking agent is further increased, the acrylic resin will not increase. It can be seen that the production rate of the copolymer crosslinked particles did not improve and was not efficient.

[0088]

FIG. 2

From these results, it is found that a preparation having a value of holding force to an adhesion value of 0.5 or more, preferably a preparation close to 1, has a good balance between adhesive force and cohesive force. It can be said that it is an excellent patch-type transdermal absorption preparation which does not cause stringing or glue residue. Furthermore, in a practical level in a human skin sticking test, the crosslinked acrylic copolymer particles contained 7%.
0 parts by weight or more is required, and it can be said that 400 parts by weight or less is preferable from the viewpoint of coatability.

As described above, the percutaneous absorption preparations of Examples 1 to 4, which are examples of the present invention, have an excellent balance between adhesion and cohesion, and contain a percutaneous absorption enhancer to provide a soft feeling. In other words, it is a practically excellent transdermal preparation having practically excellent irritation, that is, it has little irritation to the skin and has high pharmacological activity due to its absorption promoting effect.

[0091]

The pressure-sensitive adhesive layer of the percutaneously absorbable preparation of the present invention contains acrylic copolymer cross-linked particles obtained by cross-linking and grinding an acrylic copolymer in an acrylic copolymer. It is possible to increase the cohesive force of the agent layer and to provide a transdermal drug with excellent coating properties and appearance. In particular, this pressure-sensitive adhesive layer is an excellent pressure-sensitive adhesive layer in that it can be applied to transdermal absorption drugs other than buprenorphine and / or its salt.

Further, a percutaneous absorption preparation having excellent anchoring power can be obtained, and stringing phenomenon and glue residue can be reduced.

In particular, it is effective when the percutaneous absorption drug or percutaneous absorption enhancer to be contained exhibits a crosslinking inhibiting effect.
Adhesive properties can be controlled without being affected by crosslinking inhibitors. For example, it is convenient to add a fatty acid monoglyceride as a transdermal absorption enhancer. Therefore,
Unaffected by the type of transdermal drug or transdermal absorption enhancer,
It can be applied to various drugs, and by using various transdermal absorption enhancers, it becomes easy to control the release of the drug,
The application range of the transdermal absorption preparation can be expanded.

According to the method for producing a percutaneously absorbable preparation of the present invention, a crosslinking agent is added to a solution of an acrylic copolymer, and the solution is crosslinked and pulverized to prepare an adhesive solution containing crosslinked particles of an acrylic copolymer. Therefore, the pressure-sensitive adhesive solution in which the crosslinked particles are formed can be used as it is without taking out the acrylic copolymer crosslinked particles. Thereafter, a drug for transdermal absorption other than buprenorphine and / or a salt thereof, other necessary additives, and the like are added to the pressure-sensitive adhesive solution, and the mixture is applied to form a pressure-sensitive adhesive layer. Therefore, it can be produced consistently from the preparation of the acrylic copolymer,
The formulation process is not complicated.

[Brief description of the drawings]

FIG. 1 is a graph showing the relationship between the content ratio of crosslinked acrylic copolymer particles and various physical properties of each transdermal absorption preparation.

FIG. 2 is a graph showing the relationship between the amount of a crosslinking agent added to an acrylic copolymer and the gel fraction of an adhesive solution containing acrylic copolymer crosslinked particles.

Claims (5)

[Claims] 1. A buprenorphine and / or buprenorphine on one surface of a support.
Or in a transdermal absorption preparation comprising a pressure-sensitive adhesive layer containing a drug for transdermal absorption excluding its salt, wherein the pressure-sensitive adhesive layer is obtained by crosslinking and pulverizing the acrylic copolymer into an acrylic copolymer. A transdermal absorption preparation characterized by containing crosslinked acrylic copolymer particles. 2. The acrylic copolymer crosslinked particles are used in an amount of 70 to 40 parts by weight based on 100 parts by weight of the acrylic copolymer.
The percutaneous absorption preparation according to claim 1, comprising 0 parts by weight. 3. The transdermal absorption preparation according to claim 1, wherein the pressure-sensitive adhesive layer further contains a transdermal absorption enhancer. 4. The percutaneous absorption preparation according to claim 1, wherein the pressure-sensitive adhesive layer contains a fatty acid monoglyceride as a percutaneous absorption enhancer. 5. The method for producing a percutaneously absorbable preparation according to claim 1, wherein a cross-linking agent is added to a solution of the acrylic copolymer to carry out cross-linking, followed by pulverization to obtain an acrylic copolymer. A pressure-sensitive adhesive solution containing a polymer and an acrylic copolymer crosslinked particle is prepared, and a drug for transdermal absorption excluding buprenorphine and / or a salt thereof, and further, a percutaneous absorption enhancer or other additives are added to the pressure-sensitive adhesive solution. A method for producing a transdermally absorbable preparation, characterized by forming an adhesive layer by mixing an agent.