JPS6059208B2 - complex preparation - Google Patents

Description

[Detailed description of the invention] The present invention relates to a novel pressure-sensitive adhesive composite formulation.

More specifically, the present invention relates to a pressure-sensitive adhesive composite preparation that increases the amount of drug delivered to the skin per unit area and enables more efficient longitudinal absorption of the drug. Various pressure-sensitive adhesive composite preparations of the longitudinal absorption type have been proposed, which are made by incorporating a drug into a polymeric substance that exhibits pressure-sensitive adhesive properties at room temperature and forming this on a support.

Recently, attempts have been made to incorporate supersaturated active ingredients into pressure-sensitive adhesive polymer materials in order to ensure pharmacological effects or to increase the amount of drug per unit area. , when an excessive amount of the active ingredient is added in this way,
There is a problem in that the drug crystallizes on the surface of the polymeric material layer, resulting in a significant decrease in pressure-sensitive adhesion.

Therefore, attempts have been made to increase the amount of drug per unit area by lowering the amount of drug compounded to below the saturation solubility and increasing the thickness of the polymer material layer, but the amount of drug per unit area is There are problems such as insufficient medicinal efficacy cannot be expected due to the small amount, increased adhesion to the skin and pain when peeled off, and the polymeric substance protruding from the support.

Therefore, an object of the present invention is to increase the amount of drug that can be supplied per unit area by combining with an auxiliary agent contained in a polymer layer without increasing the thickness of the polymer layer, and to increase the amount of drug that can be supplied per unit area without increasing the thickness of the polymer layer. The object of the present invention is to provide a novel composite preparation that eliminates crystallization in the substance layer.

The second object of the present invention is to increase the amount of an auxiliary agent that increases longitudinal absorption that can be blended per unit area so that the axial absorption, diffusibility, and solubility of the drug are improved, and the auxiliary agent is crystallized. The purpose of the present invention is to provide a new composite preparation that eliminates the

A third object of the present invention is to provide a composite preparation whose drug efficacy rate, duration, etc. can be controlled relatively freely.

Other objects of the present invention will become clear from the description and examples below.

5. The present invention provides a medicinal active ingredient that can be absorbed longitudinally (hereinafter referred to as
A polymer material layer (also called an active ingredient) blended with it (however,
The polymer material layer has pressure-sensitive adhesive properties at room temperature, and the following auxiliary agents that come into contact with it may transfer), and the polymer material layer is in contact with the polymer material layer and has a pressure-sensitive adhesive property at room temperature, and is capable of transdermal absorption of the active ingredient. It is a pressure-sensitive adhesive composite preparation having a polymer layer containing an auxiliary agent to increase the amount of the active ingredient (provided that the polymer layer is one to which the above-mentioned active ingredient can be transferred upon contact).

Regarding the present invention, the polymer layer may satisfy the following conditions: it must have appropriate compatibility with the active ingredient and the auxiliary agent, the active ingredient may migrate upon contact with it, and it may be formed in the form of a film or sheet. Although there are no particular limitations, it is generally a polymer (or copolymer) having a glass transition temperature (Ty) of -50 to 120°C, preferably -40 to 75°C, or at least 1% by weight of the polymer. (The thickness is preferably about 10 to 1000 PTrL), such as a copolymer of polyvinyl acetate or a copolymer of vinyl acetate and a monomer copolymerizable with the vinyl, or a polymer containing an alkoxy acrylate. can be mentioned.

When the Tg is below -50°C, the physical strength is extremely reduced due to the addition of auxiliary agents, and when it is above 120°C, it lacks flexibility and irritates the skin, which is undesirable.

It is preferable to attach a film (or sheet) on one side of the polymer layer to which the active ingredient and the auxiliary agent do not substantially migrate, since this imparts self-supporting properties to the composite preparation. Such films include polyacrylate polyethylene, saponified ethylene-vinyl acetate copolymer, polyp. Examples include those made of pyrene, polyvinylidene chloride, polyester, polyamide, cellophane, metal foil, etc.

The polymer material must have pressure-sensitive adhesive properties at room temperature,
The preparation remains in close contact with the skin for a specified period of time.

There are no particular restrictions on the material as long as it satisfies the following conditions: compatibility with the active ingredient and the auxiliary agent, and not inhibiting the release of the active ingredient and the auxiliary agent.
Preferably, it is a synthetic resin and/or a polymeric substance having a Ty of -70 to -10°C. A polymer substance with a Tg of -70°C or lower is undesirable because it reduces the shape retention of the base, leaves a residue on the skin, and causes physical irritation to the skin when peeled off. The above-mentioned polymeric substances are undesirable because the diffusion and movement ability of the active ingredient and auxiliary agent in the substance is reduced, resulting in poor release properties and poor adhesion to the skin.

The most preferred Ty is -55°C to 25°C.

The polymer material having pressure-sensitive adhesive properties at room temperature with Ty of -70C to -10C is made from a system selected from the following synthetic resin and/or rubber group. Synthetic resins include polyvinyl alkyl ether, poly(meth)acrylate, polyurethane, polyester, polyamide, ethylene-vinyl acetate copolymer, etc. Rubbers include styrene-isoprene-styrene block copolymer rubber, styrene -butadiene rubber, polybutene rubber,
Examples include polyisoprene rubber, butyl rubber, silicone rubber, and natural rubber.

However, in these systems, the required Ty
If the Tg cannot be obtained, the required Tg can be adjusted by combining with other systems or adding commonly known compounding agents.

According to the inventor's experiments, the polymer material that can most reliably satisfy the requirements of adhesion, compatibility, solubility, and release properties with relatively simple manufacturing operations is acrylic polymer. It turned out to be a thing.

A preferred acrylic copolymer has the following composition. That is, the average C number of the alkyl group is 4 or more (
It is an acrylic copolymer containing at least 50% by weight of alkyl meth)acrylate.

The copolymer has good adhesion to the skin and good solubility of the active ingredient and auxiliary agent, is less irritating to the skin, and stably retains the active ingredient and auxiliary agent.

The copolymer includes a copolymer of a (meth)acrylic acid alkyl ester and another copolymerizable functional monomer, and the monomer contains O to 20% by weight, preferably 0.5 to 15% by weight. It is blended in a range of % by weight. The monomer can change the cohesiveness of the copolymer depending on the number of parts added, so the release rate or amount of the active ingredient and auxiliary agent from the base can be controlled, and the type of monomer can be selected. The hydrophilic ability of the copolymer can be increased by

Furthermore, the above-mentioned copolymer also includes a copolymer of (meth)acrylic acid alkyl ester and other copolymerizable vinyl ester monomer, and the monomer has a weight of 0 to 4%, preferably 10%. It is blended in a range of 3% to 3% by heel weight.
A copolymer containing the monomer has a high solubility of the active ingredient and the auxiliary agent. Therefore, at least 5% by weight of (meth)acrylic acid alkyl ester and 0 to 2% by weight
a functional monomer copolymerizable with the esters, and 0
It is understood that an acrylic copolymer mainly composed of ~4% by volume of the above-mentioned esters and a copolymerizable vinyl ester monomer is suitable as a polymer material supporting an auxiliary agent and an active ingredient. There will be.

In addition, the polymer material layer and the polymer layer may be crosslinked by chemical crosslinking, ultraviolet irradiation, electron beam irradiation, etc. in order to prevent insufficient shape retention, control of release of active ingredients, and improvement of adhesion. You can leave it there.

Auxiliary agents refer to substances that directly or indirectly increase the amount of transdermal absorption of active ingredients, and examples of substances that directly increase transdermal absorption include the water-retaining function of the stratum corneum (skin). , absorption enhancers that have the function of promoting swelling or hardening of the stratum corneum, the function of improving the wettability of the stratum corneum, and the function of opening pores, and these multiple functions can often be obtained from one substance. In addition, substances that increase the diffusion of active ingredients in each layer can indirectly promote transdermal absorption;
Examples include substances that improve the solubility of active ingredients in each layer.

Examples of substances that indirectly increase transdermal absorption include liquid paraffin, petrolatum, lanolin, olive oil, glycerin, benzyl alcohol, butyl benzoate,
Other alcohols and surfactants such as isopropyl myristate, octanol, 1,3-butanediol, (poly)propylene glycol, (poly)ethylene glycol, and low molecular weight (number average molecular weight = 30,000 or less) polyacrylate, polymethacrylate , oligomers such as polyvinyl ether, etc. Examples of substances that directly increase transdermal absorption include the following.

Dimethyl sulfoxide, dodecyl sulfoxide, methyl octyl sulfoxide, dimethyl decyl phosphooxide, mono- or diethylacetamide, N-hydroxyethyl lactamide, dimethyl acetamide, N●N-dimethyl dodecamide, dimethyl formamide, Toluic acid diethylamide, tetrahydrofurfuryl alcohol,
Tetrahydrofuran, sorbitol, dodecylpyrrolidone, methylpyrrolidone, urea, diethyl adipate, squalene, squalane, acetylated lanolin, cetyl lactate, dioctyl sebacate, ethoxylated stearyl alcohol, lanolic acid, lanolin alcohol, higher fatty acid alcohol, salicylic acid, liquid Paraffin, petrolatum, amino acids, protease, methyl nicotinate, l
- menthol, camphor, salokol, sodium lauryl sulfate, sodium lauryl acid, steering lycerin stearate, higher fatty acid triglycerides, polyoxyalkylene glycol, fatty acid mono(or di)ethanolamide, ethylene glycol monoethyl ether, polyoxypropylene alkyl ether, These include higher alkyl sulfones.

The active ingredient is not particularly limited as long as it can be absorbed through the skin to a therapeutically effective concentration, either alone or with the aid of a transdermal absorption enhancer, and examples include the following: . (a) Corticosteroids: For example, hydrocortisone, prednisolone, paramethasone, beclomethasone propionate, flumethasone, betamethasone, beclomethasone propionate, dexamethasone, triamcinolone, triamcinolone acetonide, fluocinolone, fluocinolone acetonide, fluocinolone acetonide acetate, Oral pain relievers, such as clobetasol propionate: e.g. acetaminophen,
Mefenamic acid, indomethacin flufenamic acid, diclofenac, alclofenamate, oxyphenbutazone, phenylbutazone, ibuprofen, flurbuprofen, salicylic acid, 1-menthol, camphor and combinations thereof, etc. (c) Hypnosedatives: e.g. Barbitals, such as barbital, amobarbital, and cyclobarbital; 2. Tranquilizers, such as fluphenazine, thioridazine, benzodiazepines (e.g., diazepam, lorazepam, flunitrazepam), and chlorpromazine. Antihypertensive agents, such as clonidine, cyclobarbital, etc. Antihypertensive diuretics: For example, hydrothiazide, bendroflumethiazide, etc. Antibiotics: For example, β-lactam antibiotics (penicillins, cephalosporins), oxytetracycline, fradiomycin sulfate, erythromycin, chloramphenicol, etc. Anesthesia Antibacterial agents: such as nitrofurazone, nystatin, acetosulfamine, etc.
Antifungal substances: such as pentamycin, amphotericin B1 pyrrolnitrine, clotrimazole, etc. Vitamins: such as vitamin A
1. Ergocalciferol, cholecalciferol, octothiamine, riboflavin butyrate, etc. Antiepileptic drugs: e.g. nitrazepam, meprobamate, etc. Coronary vasodilators: e.g. nitroglycerin, difedipine, dipyridamole, isosorbitinitrate Antihistamines: e.g. diphenhydramine hydrochloride, chlorpheniramine, siphenylimidazole, etc. These drugs may be used as needed.
More than one species can be used together.

As other optional components, a filler can be added to maintain the shape retention of the polymer layer.

Further, a small amount of compounding agents such as general adhesion-imparting resins and softeners may be added to the layer. Examples of the filler include finely powdered silica, titanium white, calcium carbonate, etc., and can be added in an amount of 3 filtration percent or less based on the formulation.

In the formulation of the present invention, the amount of active ingredient blended varies depending on the type of active ingredient, its solubility in high molecular substances and polymers, the thickness of each layer, etc., but is usually about 0.1% based on the total weight of both layers. ~20% by weight, preferably 0.5-1
5% by weight, and the amount of the auxiliary agent is usually 1.0 to 3.
The saliva amount % is preferably 3.0 to 2 saliva amount %.

The thickness of the polymer material layer is usually 5 to 500 pm, preferably 20 to 200 μm, and the thickness of the polymer layer is usually 1.
The thickness is 0 to 1000 μm, preferably 30 to 500 μm.

The polymeric material layer is formed entirely or partially on the polymeric material layer.

The formulation of the present invention can be prepared, for example, by directly applying a polymeric substance/layer composition to a polymer layer, or by forming a polymeric substance layer on a release liner in advance and transferring this to the polymeric layer. It is prepared by layering.

In the preparation of the present invention, since the active ingredient and the auxiliary agent are blended in separate layers, it is possible to incorporate a larger amount of the active ingredient and the auxiliary agent than when both are blended in one layer. .

Furthermore, if an active ingredient with a saturation solubility or higher is blended into the polymeric material layer, the excess amount of the active ingredient will migrate into the polymeric material layer before it crystallizes. Of course, this transition also occurs when an active ingredient with a saturation solubility or less is blended. On the contrary, not only those having a saturation solubility or more but also those having a saturation solubility or less migrate from the polymer layer to the polymer material layer.

Therefore, the preparation of the present invention is a composite preparation in which the active ingredient and the auxiliary agent do not crystallize over time.

By applying the composite preparation of the present invention to the application site on the skin surface, the active ingredient in the polymer substance is gradually absorbed transdermally, and at the same time, the auxiliary agent is also partially absorbed and transferred. A change occurs in the abundance ratio of the auxiliary agent and the active ingredient, and the active ingredient and auxiliary agent are supplied from the polymeric film to the polymer material layer by the amount of drug and auxiliary agent that have been reduced through transdermal absorption. The amount of active ingredient and auxiliary agent per unit area of the formulation is substantially increased to achieve the same effect.

Therefore, by satisfying the relationship between the solubility of the drug in the polymeric substance, the solubility of the drug in the polymeric film, and the thickness of the polymeric substance layer and the thickness of the polymeric film, rapid-acting composite preparations can be obtained. However, the solubility of drugs in polymeric substances, the solubility of drugs in polymeric films,
By satisfying the relationship between the thickness of the polymer layer and the thickness of the polymer film, the slow-acting composite preparation can further saturate the amount of drug in the polymer layer and the polymer film. The solubility (where the solubility of the drug in the substance is greater than the solubility of the drug in the film), and the thickness of the polymeric substance layer is
By satisfying the relationship between the thickness of the polymer film, a fast-acting and long-lasting composite preparation can be obtained.
Furthermore, an auxiliary agent? By combining the degree of solubility in the polymer material layer and the polymer layer, and the resulting equilibrium, and the solubility of the auxiliary agent in the active ingredient, it is possible to control the release of the active ingredient more precisely to suit the purpose. It will be understood. Hereinafter, the present invention will be made clearer with reference to Examples, and in the text, 1 part means parts by weight.

Example 1 96f of isooctyl acrylate and 4g of acrylic acid were charged into a three-necked flask, and 25y of ethyl acetate containing 0.2y of azobisisobutyronitrile was added, and the mixture was replaced under an inert gas atmosphere. Then, the temperature was raised to 60°C to start the reaction, and ethyl acetate was added dropwise to 60°C.
React for 5 hours at 2-65°C and further at 75-77°C.
The copolymer solution was aged for 2 hours at 195 poise (30°C) to obtain a copolymer solution with a solid content of 30% by weight.

50y of flunitrazebam is added to 100 parts of the solid content of this solution, and the mixture is coated and dried on a release liner to a thickness of 60P70 after drying to obtain a base film.

On the other hand, on one side of the 12.7 μm thick corona-treated polyester film, a 50 μm thick acrylic film was applied as a film layer made of a drug-transferable polymer containing 4% by weight of diethyl sebacate. A laminated film having an ethyl acrylate-vinyl acetate copolymer film (ethyl acrylate/vinyl acetate in a weight ratio of 2:1) is prepared.

The base film was laminated and pressed onto the copolymer film layer surface of this film to obtain a composite preparation.Example 2
The mixture was coated on a release liner to a thickness of 40 μm after drying, and dried to obtain a base film.

On the other hand, 1 part by weight of ethylene-vinyl acetate copolymer olive oil containing 40% by weight of vinyl acetate was coextruded with polyethylene to form a 100 PTrL laminated film (EV
The thickness of the film layer made by A is 40 pm). The base film is laminated and pressed onto the copolymer film layer surface of this film to obtain a composite preparation.

Example 3 A blend consisting of 45 parts of polyisoprene rubber, 15 parts of liquid paraffin, 1 part of lanolin and 1 part of aliphatic petroleum resin was dissolved under inert gas for 5 hours (110-125°C),
After cooling to 80° C., 5 parts of indomethacin dispersed in 7 parts of propylene glycol is added and coated on the release liner to a thickness of 100 PTL to obtain a base film.

On the other hand, a vinyl acetate-butyl acrylate-methoxyedyl acrylate (40:30:3 saliva weight ratio) copolymer film (thickness: 40 pTrL) containing 4% by weight of monoethylene glycol salicylate (Salocol) and a polyvinylidene chloride film (thickness: A laminated film produced by heating and pressurizing 50P7T1.) is prepared.

The drug-containing base film described above is laminated and pressed onto the copolymer film layer surface of this film to obtain a composite preparation.

Tables 1 to 3 show the test results for the composite preparations of Examples 1 to 3. Table 1 shows the time until the drug crystallizes, and Table 2 shows the adhesion to the skin. The graphs show the adhesion and holding power to the Bakelite plate, respectively.

FIG. 3 shows the change in blood concentration over time when each sample was applied. Comparative Examples 1 to 3 in Tables 1 to 2 correspond to Examples 1 to 3, in which the base film was a polyester film without a polymer layer, respectively.
It is laminated and pressure-bonded to polyethylene film and polyvinylidene chloride film. Measurement method vs. Bakelite board adhesive strength in Table 2 A sample with a width of 12Tsn was pasted on a Bakelite board, pressed back and forth once with a 2.0k9 rubber roller, and after 3 days of storage, the sample was peeled off from one end and bonded. The force was determined (peeling angle: 180 degrees, peeling speed: 300 m/min, conditions were 20°C and 65% R.
H. ).

Holding force: Paste one end of two samples (width 1CM, length 100Tfn) by 20wn to the end of the Bakelite board.
After storage, a load of 300y was applied to the other end, and the time until the sample peeled off from the Bakelite plate was measured (measured in an atmosphere of 40'C).

Note that 1 failure in Table 2 means interlayer failure between the base and the film or interfacial failure from the Bakelite plate. Blood concentration measurement method Each pharmaceutical preparation (6 cm x 6 cm) was placed in a rabbit (body weight 2
Remove the hair from the back of k9) and paste it, and remove it for 3m at specified intervals.
1 blood sample was taken.

To 1 ml of flunitrazepam blood, add 2 ml of saturated ammonium chloride and 6 ml of toluene-niheptani 8:2 mixed solvent, mix the powder, shake it once, centrifuge it, take the organic layer, and add HC-HC.
e, and further centrifuged to collect the extracted fraction,
While cooling with ice? The organic layer was evaporated, the residue was dissolved in 250 Pe ethanol, and analyzed by gas chromatography using prazepam as an internal standard.

Propatyl nitrate blood was collected in 3 mι portions, plasma was separated, extracted with 2 mt(1) n-hexane, centrifuged, and 0.577% of the blood was collected under inert gas. Concentrate to l.

The mixture was further extracted with 1 mι of acetonitrile, and the acetonitrile layer was dried under an inert gas, dissolved in 100 μl of benzene, and measured by gas chromatography.
Indomethacin plasma 177! 2 mι of 0.5M citrate buffer (PH5.O) was added to the solution, and the mixture was extracted with 10 mι of 1.2 dichloroethane.

After adding 2,4,6-triphenylnitrobenzene as an internal standard to the organic layer and distilling off the solvent, diazomethane was added and indomethacin was analyzed as a methyl ester by gas chromatography.

The composite preparation thus obtained by the production method of the present invention is
Despite the large amount of active ingredients and auxiliary agents per unit area as a whole, there is no crystallization of the drug on the layer surface of the polymer material layer (base layer), and it adheres reliably to the skin surface. The drug can be absorbed transdermally well, and the drug efficacy can be controlled more freely by using a pressure-sensitive adhesive polymer material that contains an auxiliary agent in the polymer layer or an auxiliary agent that has migrated from the polymer layer. It has the characteristic of being able to

Claims (1)

[Claims] 1. A polymeric material layer containing a medicinal active ingredient that can be absorbed transdermally (provided that the polymeric material layer has pressure-sensitive adhesive properties at room temperature and that the following auxiliary agents that come into contact with it are transferable)
and a polymer layer that is in contact with the polymer material layer and contains an auxiliary agent that increases the amount of transdermal absorption of the active ingredient (
However, the polymer layer is one to which the above-mentioned pharmaceutically active ingredient that comes into contact can migrate).