JP3136091B2 - Transdermal formulation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a transdermal preparation (patch) constituted so that a drug can be absorbed into the body from the skin via a pressure-sensitive adhesive layer. And / or a transdermal preparation using a polyethylene naphthalate film as a release liner. The percutaneous absorption-type preparation of the present invention is excellent in storage stability because the support and the release liner do not easily absorb, adsorb, and permeate the drug or the additive, and the dosage of the drug is accurately controlled. Has advantages.

[0002]

2. Description of the Related Art Transdermal preparations in which a drug is administered from the skin can be applied to (1) a drug capable of avoiding the first-pass effect in the liver, and (2) a drug in which a side effect on the digestive tract is concerned. There are advantages such as (3) the dosage can be easily adjusted, and (4) the administration of the drug is easy and the administration can be easily stopped by peeling off. As such a transdermal absorption preparation, for example,
Patches in which nitroglycerin is dispersed as a drug in a pressure-sensitive adhesive layer have been used as a therapeutic or preventive drug for diseases such as angina pectoris, myocardial infarction and heart failure.

[0003] Transdermal preparations are generally required to be able to administer a predetermined amount of a drug over a long period of time. Conventionally, several methods have been proposed for controlling the dose of a drug in a transdermal absorption preparation. Typical examples thereof include (1) a support and a pressure-sensitive adhesive layer. A method has been proposed in which a drug storage layer comprising a capsule or a container containing a drug is provided between the outer layer and the outer surface (Japanese Patent Publication No. 54-16556).
The capsule or container is at least partially formed of a microporous substance that controls the rate of drug release. In addition, (2) a pressure-sensitive adhesive, which is a combination of a rubber-based pressure-sensitive adhesive and a tackifier resin having a polar group or a softener having a polar group, is used, and the holding stability of the drug in the pressure-sensitive adhesive is used. And a method for imparting sustained release properties have been proposed (JP-B-62-3811).

[0004] However, although such a method can control the sustained release and retention stability of the drug, the storage stability is still inadequate, and the precise control of the dose of the drug cannot be achieved. There was a problem that it became difficult. That is, a transdermal preparation generally has a support, a pressure-sensitive adhesive layer, and a release liner, and the drug dispersed in the pressure-sensitive adhesive or the drug in the drug storage layer is applied to the pressure-sensitive adhesive layer. It is configured to be absorbed into the body from the skin surface to which it is applied, but there is a problem that the drug migrates to the support or release liner during storage, and is absorbed, adsorbed, or permeated. there were. If the drug migrates to the support or release liner and is absorbed or adsorbed by it or permeates and volatilizes, it interferes with the control of the release of the drug, and secures the administration of a predetermined amount of the drug. Will not be.

[0005] Conventionally, as a support of a percutaneous absorption type preparation,
Polyester, nylon, polyvinylidene chloride, polyethylene, polypropylene, ethylene-vinyl acetate copolymer, polyvinyl chloride, ethylene-ethyl acrylate copolymer, polytetrafluoroethylene, films made of ionomer, etc., metal foil, etc. are used. (JP-A-5-65224). In addition to these, for example, a composite film composed of a polyester film having a thickness of 0.5 to 6 μm and a polyester nonwoven fabric (JP-A-5-30912)
No. 8), 20 to 45 mol% of vinyl alcohol unit
Ethylene-vinyl alcohol copolymer film (Japanese Patent Publication No. 6-696) and a linear low-density polyethylene film (US Pat. No. 5,264,219).
No.) has been proposed.

On the other hand, a release liner (release separator,
Examples of the release paper and the protective film) include a polyethylene terephthalate film that has been silicon-treated (Japanese Patent Laid-Open No. 6-256178), and a polyethylene alcohol-impregnated glassine paper having both surfaces laminated with a polyethylene film and further subjected to silicon treatment. (JP 6
No. 3-185919), a film obtained by evaporating aluminum on a polyethylene film and further subjecting it to silicon treatment (Transdermal Controlled)
Systemic Communications 198
7 Marcel Dekker, Inc. YIE
W. CHIEN p. 366) has been proposed.

However, among these films, the polyethylene film is difficult to absorb and adsorb the drug, but is easy to permeate. Solving this problem requires complex polymer blends of different density grades. The ethylene-vinyl alcohol copolymer film has a drawback that it is hard to absorb, adsorb and permeate a drug, but is susceptible to humidity and easily curls. Ethylene-vinyl acetate copolymer films are generally easy to absorb drugs and are not suitable as supports except in special cases. In the above examples, the polyester film does not absorb, adsorb, and transmit a relatively wide range of drugs. However, since the polyester film is a polycondensation product of a polyol and a dicarboxylic acid, the properties of the produced polymer differ depending on the combination of these monomers. Conventionally, among polyester films, polyethylene terephthalate film is particularly excellent in barrier properties.However, when a drug is added to the pressure-sensitive adhesive layer in an amount close to the saturation concentration, migration of the drug is recognized by the distribution. There is.

When aluminum is deposited on a plastic film, barrier properties are improved, but problems such as unavoidable generation of pinholes in the deposited layer, susceptibility to damage of the deposited layer at the time of silicon treatment, and increase in cost. is there. Polyvinyl alcohol-impregnated glassine paper laminated on both sides with a polyethylene film and then siliconized is a straight-chain compound often used as a softener because the manufacturing process is complicated and the surface layer is made of polyethylene. And swells, which may result in drug permeation. Therefore, in a transdermal preparation, a support or a release liner that hardly absorbs, adsorbs, and permeates a drug or an additive, etc., is required, but a material having a satisfactory material has not been found. It is the current situation.

[0009]

An object of the present invention is to provide a transdermal preparation having excellent storage stability and capable of accurately controlling the dose of a drug. More specifically, an object of the present invention is to provide a percutaneous absorption-type preparation using a support and / or a release liner that has extremely low absorption, adsorption and permeation of a drug. We have:
As a result of conducting research for overcoming the problems of the prior art, it has been found that polyethylene naphthalate film has extremely low absorption, adsorption and permeation of a transdermal drug, and a support and a release liner of a transdermal drug. Was found to be suitable. That is, in a transdermal preparation using a polyethylene naphthalate film as a support and / or a release liner, the amount of the drug held in the adhesive base or the drug storage layer transferred to the support or the release liner is extremely small, Therefore, there is almost no change in the drug content during storage, and a more precise formulation can be designed, and the stability of the formulation is improved. The present invention has been completed based on these findings.

[0010]

According to the present invention, there is provided a support having a support, a pressure-sensitive adhesive layer, and a release liner, wherein a drug dispersed in the pressure-sensitive adhesive or a drug in a drug storage layer is provided. A transdermal preparation, wherein the support and / or the release liner is a polyethylene naphthalate film, wherein the support and / or the release liner are configured to be absorbed into the body from the skin surface to which the adhesive is applied via a pressure-sensitive adhesive layer. An absorbent formulation is provided. The thickness of the polyethylene naphthalate film is
The range of 0.6 to 300 μm is preferred.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION A polyethylene naphthalate film used for a support and / or a release liner of a transdermal absorption preparation of the present invention is generally a polymer obtained by polycondensation of naphthalenedicarboxylic acid and ethylene glycol. Film. Polyethylene naphthalate usually contains 6 units of ethylene-2,6-naphthalate derived from ethylene glycol and 2,6-naphthalenedicarboxylic acid.
A thermoplastic polyester resin containing at least 0 mol%, preferably at least 90 mol%. Ethylene-2,
Structural units other than the 6-naphthalate unit include aromatic dicarboxylic acids such as terephthalic acid, isophthalic acid, 2,7-naphthalenedicarboxylic acid and 2,5-naphthalenedicarboxylic acid, and fats such as adipic acid, azelaic acid and sebacic acid. Dicarboxylic acid components such as alicyclic dicarboxylic acids such as aromatic dicarboxylic acid, 1,4-cyclohexanedicarboxylic acid and cyclopropanedicarboxylic acid, hydroxydicarboxylic acids such as p-hydroxybenzoic acid and p-hydroxyethoxybenzoic acid, and ethylene glycol And diol components such as propylene glycol, bisphenol A, polyalkylene glycol, diethylene glycol, 1,4-cyclohexanedimethanol, butanediol-1,4, and neopentyl glycol. In order to form a film, polyethylene naphthalate preferably has an intrinsic viscosity in the range of 0.2 to 1.1 dl / g usually measured at 25 ° C. in o-chlorophenol.

As the polyethylene naphthalate film, an unstretched sheet (film), a uniaxially stretched film, a biaxially stretched film and the like can be used. The thickness of the film, usually in the range of 0.6 to 300 μm. The polyethylene naphthalate film can be used alone as a support or a release liner, but when the film thickness is thin, it may be used by laminating it with another film, paper, cloth, nonwoven fabric or the like. When a polyethylene naphthalate film is used as a release liner, a release agent such as silicon or tetrafluoroethylene may be applied to one or both surfaces thereof as necessary.

In the transdermal preparation of the present invention, the drug dispersed in the pressure-sensitive adhesive or the drug in the drug storage layer is absorbed into the body from the attached skin surface via the pressure-sensitive adhesive layer. It is constituted as described above, and includes various types of patches known in the art. Such a transdermal preparation is often of the type in which a drug is dispersed in a pressure-sensitive adhesive layer, but the present invention is not limited to this, and has a drug storage layer as described above. A so-called reservoir type can also be used. As a transdermal preparation using a drug storage layer, a drug is contained in a capsule formed of a microporous substance, and the drug is dispersed in a pressure-sensitive adhesive layer, or at least one drug is provided on a support. There is a container in which a part is formed of a microporous substance, a drug is contained therein, and a pressure-sensitive adhesive layer is provided thereon.

Examples of the pressure-sensitive adhesive include rubber, acrylic, and silicone. In the case of a rubber-based pressure-sensitive adhesive, the tackifier resin is usually added to 100 parts by weight of the elastomer.
It is added in the range of 0 to 200 parts by weight, and if necessary, for example, a softening agent, an absorption promoter, a filler, an antioxidant and the like can be added. Examples of the elastomer include natural rubber, polyisoprene rubber, polyisobutylene rubber, butyl rubber, styrene / isoprene / styrene block copolymer, styrene / butadiene / styrene block copolymer, and the like. Examples of the tackifier resin include aromatic petroleum resins, aliphatic petroleum resins, alicyclic petroleum resins, petroleum resins such as ester gums, polyterpenes, and terpene phenols, and natural resins.
Examples of the softener include higher alcohols such as oleyl alcohol and lauryl alcohol, higher fatty acids such as oleic acid and lauric acid, higher fatty acid esters such as isopropyl myristate and isopropyl palmitate, liquid paraffin, olefin-based oil, and naphthenic oil. Lanolin, lanolin esters, various surfactants and the like. As the filler, for example, titanium oxide, zinc white,
Fine powder silica, inorganic filler such as clay, or polystyrene, polyethylene, polypropylene, nylon,
There is a polymer powder made of silicon or the like. Examples of the antioxidant include dibutylhydroxytoluene.

Examples of the acrylic pressure-sensitive adhesive include a copolymer of (meth) acrylic acid esters or a copolymer of (meth) acrylic acid with a monomer having a functional group and a polymerizable monomer having an effect of increasing cohesive strength. There are polymers. As the (meth) acrylate, the alkyl group usually has 1 to 18 carbon atoms. For example, methyl (meth) acrylate, ethyl (meth) acrylate, butyl (meth) acrylate, acrylic acid 2 -Ethylhexyl, n-octyl acrylate, isooctyl acrylate, nonyl acrylate, isononyl acrylate, dodecyl acrylate and the like. Examples of the polymer having a functional group include acrylic acid, acrylonitrile, 2-hydroxyethyl acrylate, acrylamide, diacetone acrylamide, ethylene glycol acrylate, propylene glycol acrylate, and the like. Examples of the polymerizable monomer include vinyl acetate and styrene. These monomers are used alone or in combination of two or more.

The acrylic pressure-sensitive adhesive can be obtained by a conventional method such as solution polymerization, suspension polymerization, and emulsion polymerization by radical polymerization. If necessary, a softening agent such as ethyl oleate or glyceryl monolaurate, or a crosslinking agent such as polyisocyanate, epoxy compound, ionic compound, or melamine can be added to the acrylic pressure-sensitive adhesive. Examples of the silicone-based pressure-sensitive adhesive include dimethylsiloxane alone or polysiloxane copolymerized with a silicon compound having a phenyl group. If necessary, a softening agent such as isopropyl myristate and isopropyl palmitate can be added to these at a concentration of 10% by weight or less.

In the present invention, through the above-mentioned adhesive,
Alternatively, by adding a drug to the adhesive, a percutaneous absorption-type preparation in which the drug is administered from the skin can be obtained.
The drug to be used can be arbitrarily selected depending on the purpose of the treatment. Specific examples of the drug used in the present invention include, for example, antiphlogistic analgesics, corticosteroids, tranquilizers, antibiotics, anesthetics, antihypertensives, coronary vasodilators, antihistamines, antitussives, antiemetics, antiemetic drugs, There are depression, hormones, sedatives, antihypertensive diuretics, antibacterials, antifungals, vitamins, cerebral circulation improvers, antitumor agents, muscle relaxants, immunosuppressants, etc. Drugs can be used. Each of these drugs can be used alone, but if necessary, two or more of them may be used in combination. The amount of the drug to be added can be determined in consideration of the permeability of the drug itself, the effective concentration in blood, the solubility in the preparation, and the like.On the basis of the pressure-sensitive adhesive, generally,
It is about 1 to 50% by weight, preferably about 2 to 30% by weight.

The transdermal preparation of the present invention can be produced by a conventional method. For example, in the case of a type in which a drug is dispersed in a pressure-sensitive adhesive, a predetermined amount of a rubber-based, acrylic, or silicone-based adhesive dissolved in an organic solvent such as n-hexane, toluene, and ethyl acetate is used. Add the drug and stir to homogeneity. Using a coating machine such as a knife coater, a comma coater, a reverse coater, and a lip coater, the obtained solution is uniformly applied on a release liner obtained by applying a silicone release agent to a polyethylene naphthalate film. Then, at elevated temperatures (eg, 60
(120 ° C. to 120 ° C.) for a certain time (eg, 2 to 5 minutes) to evaporate the organic solvent. Appropriate coating and drying conditions are selected and adopted depending on the type of the organic solvent used and the thickness of the adhesive base to be set. On the coated pressure-sensitive adhesive layer, a polyethylene naphthalate film or a support obtained by laminating a polyethylene naphthalate film with another film or non-woven fabric is laminated, wound up, cut into a predetermined size to prepare a preparation. . Of course, the transdermal preparation of the present invention is not limited to the above-mentioned production method, and various modified production methods are possible. For example, after a solution of the pressure-sensitive adhesive composition is applied on a support, a release liner may be stuck on the pressure-sensitive adhesive layer. The percutaneous absorption-type preparation obtained in this way has almost no transfer of the drug to the support and the release liner, so that the drug content in the pressure-sensitive adhesive base can be kept constant, and the storage stability is excellent. ing. Further, the transdermal absorption preparation of the present invention,
Since the dissipation of the drug is extremely small, the dose of the drug can be accurately controlled.

[0019]

The present invention will be described more specifically below with reference to examples and comparative examples. In the following examples, parts and percentages are by weight unless otherwise specified.

Example 1 98 parts of 2-ethylhexyl acrylate, 2 parts of acrylic acid and 400 parts of ethyl acetate were placed in a flask, and the atmosphere was replaced with nitrogen for about 1 hour. To this, 0.5 parts of azobisisobutylnitrile previously dissolved in a small amount of ethyl acetate was added, and the mixture was heated to about 70 ° C.
Stirred for hours. Thereafter, the temperature was raised to 85 ° C. and the mixture was stirred for 2 hours to obtain a solution of an acrylic pressure-sensitive adhesive having an average molecular weight of about 350,000. After the temperature of the pressure-sensitive adhesive solution was lowered to room temperature, 5 parts of nitroglycerin was added to 100 parts of the pressure-sensitive adhesive solution (solid content concentration: 20%) and stirred for about 30 minutes. The obtained mixture was applied on a polyethylene naphthalate film having a thickness of 25 μm using an applicator.
Evaporate the ethyl acetate for 5 minutes in an atmosphere of
An adhesive layer having a dry thickness of μm was formed. On this adhesive layer, a silicon-treated surface of a release liner made of a 75 μm-thick polyethylene naphthalate film in which a release agent, polydimethylsiloxane was previously applied to one surface of the film, was bonded, and then cut into a size of 20 cm ^2. Was used as a sample.

Example 2 An acrylic pressure-sensitive adhesive solution was prepared in the same manner as in Example 1, and a 35 μm-thick dry pressure-sensitive adhesive layer was formed on a 25 μm-thick polyethylene naphthalate film. A film having a thickness of 50 μm in which a release agent, polydimethylsiloxane, was previously applied to one side of the film.
m, a silicone-treated surface of a release liner made of a polyethylene naphthalate film,
The sample was cut into a size of m ² to obtain a sample.

[Comparative Example 1] An acrylic pressure-sensitive adhesive solution was prepared in the same manner as in Example 1, a 35 µm-thick dry pressure-sensitive adhesive layer was formed on a 25 µm-thick polyethylene naphthalate film, and then a Having a thickness of 7 in which polydimethylsiloxane as a release agent was previously applied to one side of the film.
The silicone-treated surface of a release liner made of a polyethylene terephthalate film of 5 μm was stuck and 20 cm
^The sample was cut into ² pieces.

[Comparative Example 2] An acrylic pressure-sensitive adhesive solution was prepared in the same manner as in Example 1, and a pressure-sensitive adhesive layer having a dry thickness of 35 µm was formed on a polyethylene naphthalate film having a thickness of 25 µm. A silicon-treated surface of a release liner made of a 75 μm-thick polyethylene terephthalate aluminum vapor-deposited film in which a release agent, polydimethylsiloxane was previously applied to the aluminum vapor-deposited surface of the film, was bonded, and then cut into a size of 20 cm ² to obtain a sample. did.

Comparative Example 3 An acrylic pressure-sensitive adhesive solution was prepared in the same manner as in Example 1, a 35 μm-thick pressure-sensitive adhesive layer was formed on a 25 μm-thick polyethylene naphthalate film, and then a , the laminated polyethylene film on both sides of the glassine paper impregnated with polyvinyl alcohol, further polydimethylsiloxane film both sides release agent bonded to silicon treated surface of the coated composite release liner, then the size of 20 cm ² It was cut and used as a sample. <Experiment 1> Each of the samples obtained in Examples 1 and 2 and Comparative Examples 1 to 3 was placed in an atmosphere at 40 ° C., and the amounts of nitroglycerin contained in the release liner after 2 weeks and 4 weeks were measured. Table 1 shows the results.

[0025]

[Table 1] From the results in Table 1, the absorption rate of nitroglycerin into a release liner using a polyethylene naphthalate film is:
1 / of the aluminum-deposited product that was the least in the comparative examples
It can be seen that the number is as small as about 4.

Example 3 Isooctyl acrylate 6
5 parts, 30 parts of butyl acrylate, 5 parts of acrylic acid, and 300 parts of ethyl acetate were placed in a flask, and the atmosphere was replaced with nitrogen by flowing nitrogen for about 1 hour. To this, azobisisobutylnitrile 0.5 previously dissolved in a small amount of ethyl acetate was added.
Then, the mixture was heated to about 70 ° C. and stirred for 3 hours. Thereafter, the temperature was raised to 85 ° C., and the mixture was stirred for 2 hours.
Ten thousand acrylic adhesive solutions were prepared. After the temperature of the pressure-sensitive adhesive solution was lowered to room temperature, 5 parts of nitroglycerin was added to 100 parts of the pressure-sensitive adhesive solution (solid content concentration: 20%), followed by stirring for about 30 minutes. This solution was applied on a polyethylene naphthalate film having a thickness of 25 μm using an applicator, and then ethyl acetate was volatilized in an atmosphere at 80 ° C. for 5 minutes to form an adhesive layer having a dry thickness of 35 μm. On this pressure-sensitive adhesive layer, a film having a thickness of 7 in which polydimethylsiloxane as a release agent was previously applied to one surface of the film.
A silicon-treated surface of a release liner made of a 5 μm polyethylene naphthalate film is attached to
It was cut into a size of 0 cm ² to obtain a sample.

Comparative Example 4 An acrylic pressure-sensitive adhesive solution was prepared in the same manner as in Example 3, and a 35 μm-thick pressure-sensitive adhesive layer was formed on a 6 μm-thick polyethylene terephthalate film. A film having a thickness of 75 μm in which a release agent, polydimethylsiloxane, was previously applied to one side of the film.
m, a silicone-treated surface of a release liner made of a polyethylene naphthalate film,
The sample was cut into a size of m ² to obtain a sample.

[Comparative Example 5] An acrylic pressure-sensitive adhesive solution was prepared in the same manner as in Example 3, and a 35-μm-thick dry pressure-sensitive adhesive layer was formed on a 60-μm-thick polyethylene film. A silicone-treated surface of a release liner made of a polyethylene naphthalate film having a thickness of 75 μm to which a release agent, polydimethylsiloxane was previously applied, was bonded, and then cut into a size of 20 cm ² to obtain a sample.

Comparative Example 6 An acrylic pressure-sensitive adhesive solution was prepared in the same manner as in Example 3, and a pressure-sensitive adhesive layer having a dry thickness of 35 μm was formed on a polypropylene film having a thickness of 40 μm. A silicon-treated surface of a 75 μm-thick polyethylene naphthalate film, to which a release agent, polydimethylsiloxane was previously applied, was attached.
It was cut into a size of 0 cm ² to obtain a sample. <Experiment 2> The samples obtained in Example 3 and Comparative Examples 4 to 6 were placed in a 40 ° C. atmosphere for a predetermined period. Thereafter, the support was peeled off from the preparation, and the amount of nitroglycerin contained in the support was quantified. Table 2 shows the results.

[0030]

[Table 2]

From the results shown in Table 2, when the polyethylene naphthalate film was used for the support, the adsorption and absorption of nitroglycerin on the support were small. On the other hand, when a polyethylene terephthalate film, a polyethylene film and a polypropylene film were used as a support, the adsorption / absorption of nitroglycerin to these films was recognized to a considerable extent. From the above results, it is apparent that the polyethylene naphthalate film exhibits remarkably excellent properties as a support of the transdermal absorption type preparation. <Experiment 3> The release liner of the sample (nitroglycerin amount 12.63 mg / sheet) prepared in Example 1 was peeled off,
Instead, various films cut out to a size of 30 cm ² were attached to each other, left in an atmosphere at 32 ° C. for 5 days, and then the preparation and the film were peeled off, and the amount of nitroglycerin contained in each was measured. Table 3 shows the types of the films used and the results.

[0032]

[Table 3]

From the results shown in Table 3, when the polyethylene naphthalate film was used as the release liner,
, The nitroglycerin from the preparation did not volatilize, and almost no transfer to the release liner was observed. In contrast, when the polyethylene terephthalate film and the polypropylene film were used as the release liner, the nitroglycerin content in the preparation was slightly reduced, and the transfer to the release liner was also observed. In each of the polyethylene, polybutadiene, and polyurethane films, the nitroglycerin content in the preparation was significantly reduced, and transfer to the release liner was also observed.

[0034]

According to the present invention, there is provided a transdermal preparation having excellent storage stability and capable of accurately controlling the dose of a drug. Since the transdermal preparation of the present invention uses a support and / or a release liner that has extremely low absorption, adsorption and permeation of a drug, the drug and additives are transferred to the support and the release liner. Since absorption, adsorption, and permeation are suppressed, there is an advantage that storage stability is excellent and the dose of the drug is accurately controlled.

────────────────────────────────────────────────── ─── Continuing the front page (72) Inventor Masanori Yamamoto 2-3-3 Sekiguchi, Bunkyo-ku, Tokyo Nichiban Co., Ltd. (58) Field surveyed (Int. Cl. ⁷ , DB name) A61K 9/70

Claims (1)

(57) [Claims] 1. A pressure-sensitive adhesive layer comprising a support, a pressure-sensitive adhesive layer, and a release liner, wherein a drug dispersed in the pressure-sensitive adhesive or a drug in a drug storage layer is adhered via the pressure-sensitive adhesive layer. A percutaneous absorption preparation which is configured to be absorbed into the body from the skin surface, wherein the support and / or the release liner is a polyethylene naphthalate film.