JPS6254401B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a patch that is applied to the body for treating diseased areas of the body or for administering medicine to the circulatory system.

Conventionally, this type of adhesive patch has a structure in which a polymer composition containing a drug, usually in the form of a solution, is coated on a support such as a plastic film and dried to form a drug-containing polymer layer. For pasting purposes, if the polymer layer is adhesive, it can be applied directly to the body using its adhesiveness, or if it is not adhesive, it can be attached to the body by other means such as adhesive tape. By pasting it on a surface, it can treat diseased areas of the body or administer drugs to the circulatory system. However, such patches generally have the disadvantage that they have poor sustained drug release properties and their medicinal efficacy disappears in a short period of time.

The present invention aims to provide a method for producing a patch that eliminates the above-mentioned drawbacks, and will be described below with reference to the drawings.

Figures 1 and 2 show an example of a patch manufactured by the method of the present invention, in which 1 is a patch made of plastic film, nonwoven fabric, woven fabric, composite film of metal and plastic, and discontinuous foam sheet. The support 2 is composed of a continuous phase 2A made of a cross-linked lipophilic polymer and a dispersed phase 2B made of water in which a water-soluble polymer is dissolved, and the drug is mainly uniformly distributed in the continuous phase 2A. This is a drug-containing polymer layer that is dissolved or partially dispersed.

In the present invention, in forming the drug-containing polymer layer 2, W / O-type emulsion is prepared and a composition containing a drug is applied directly to the support 1, or it is once applied to a release liner and then transferred to the support 1, and then the above-mentioned direct coating is applied. Alternatively, after or before transfer, ionizing radiation is irradiated to polymerize and crosslink. Through this polymerization and crosslinking treatment, the oil phase component is polymerized in a state containing the drug and constitutes a continuous phase 2A in which the polymers are mutually crosslinked.
An aqueous phase component in which a water-soluble polymer is dissolved in A is stably held as a dispersed phase 2B.

The monomer used here as an oil phase component or the mixed system of this and a polymer may be one that exhibits tackiness when it is polymerized and crosslinked to form the continuous layer 2A, or may not show tackiness. It can be something. The key is to dissolve the drug and this drug becomes layer 2.
It can be widely applied as long as it diffuses inside A and is transferred to or absorbed by the body surface.

In addition, the water-soluble polymer dissolved in water as an aqueous phase component has the function of stably retaining water particles in the continuous phase 2A, and conventionally known water-soluble polymers include polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, and hydroxyethyl cellulose. ,
Hydroxypropyl cellulose, a copolymer of methyl vinyl ether and maleic anhydride, etc. can be widely applied. These polymers are approximately 0.2
It is used in a range of ~10% by weight.

When preparing a W/O emulsion from both of the above components, a nonionic emulsifier such as polyoxyethylene sorbitan monolaurate or sorbitan monolaurate is used as an emulsifier, and generally 100 parts by weight of the oil phase component is used. water phase components 10-200%
Both parts are stirred at a rotation speed of 1100~ by weight.
Mixing may be carried out using a disper at 1300 rpm, an ajihomo mixer, or the like.

The drug added to this W/O emulsion is 80% or more soluble in the oil phase component, and when the continuous phase 2A is formed, it diffuses within this phase 2A and is transferred or absorbed onto the body surface. It is something that can be done. For example, corticosteroids, anesthetics, antihistamines, antibacterial substances, antifungals, analgesic anti-inflammatory agents, keratin emollients, vitamins, antispasmodics, and systemic drugs such as antihypertensives, antibiotics, and central nervous system agents. , vasodilators, antispasmodics, sedatives, sex hormones, and antidiabetics. An appropriate amount of these drugs is selected to obtain the desired treatment or administration effect depending on the type of drug.

Examples of corticosteroids include prezonisolone acetate, presonisolone, hydrocortide acetate, hydrocortide, dexamethasone, fluocinolone acetonide, betamethasone, beclomethasone propionate, fludroxycortide, fluocinonide, and the like. Anesthetics include benzocaine, lidocaine, and ethyl aminobenzoate.
Antihistamines include diphenhydramine hydrochloride, isocypenzyl hydrochloride, and diphenylimidazole, antibacterial agents include benzalkonium chloride and nitrofurazone, antifungal agents include nystatin and undecylenic acid, and analgesic and antiinflammatory agents include Indomethamine, methyl salicylate, glycol salicylate, salicylic acid amide,
Examples include sodium salicylate.

In addition, salicylic acid, vitamin A, atropine,
Examples include methscopolamine bromide. In addition, systemic drugs such as antihypertensive agents such as reserpine and clonidine, antibiotics such as erythromycin, chloramphenicol, cephalexin, tetracycline, neomycin sulfate, oxytetracycline, and penicillin, and central nervous system agents such as barbiturates, diazepam, nitrazepam, and chlorpromazine and vasodilators such as nitroglycerin and isosorbide dinitrate.

In addition to the above-mentioned drug, a release auxiliary substance that promotes the release of the drug may be mixed into the oil phase of the emulsion, and various additives that do not impede the stability of the emulsion may also be added.

The above-mentioned release aid substance can be simply defined as one that promotes the release of the drug to the body surface, but it also includes substances that have the function of improving the solubility and diffusibility of the drug within the polymer layer, and Items that have functions that improve transdermal absorption, such as water retention capacity of the stratum corneum, keratin softening properties, permeability (loosening) of the stratum corneum, functions as penetration aids and pore openers, and functions that change the skin interface condition. , and further includes a wide range of drugs that have both of the above-mentioned functions or, in addition to these functions, also have a drug efficacy promotion function that increases the drug efficacy.

Specific examples of these release auxiliary substances include glycols (mainly drug-soluble) such as diethylene glycol, propylene glycol, and polyethylene glycol, oils and fats (mainly drug-diffusing) such as olive oil, squalene, and lanolin, urea,
Urea derivatives such as allantoin (mainly for the water retention capacity of stratum corneum), dimethyldecyl phosphooxide, methyloctyl sulfoxide, dimethyl laurylamide, dodecylpyrrolidone, isosorbitol, dimethylacetamide, dimethyl sulfoxide,
Polar solvents such as dimethylformamide (mainly keratin permeability), salicylic acid (mainly keratin softening), amino acids (mainly penetration aid), benzyl nicotinate (mainly pore opening agent), sodium lauryl sulfate (mainly (function that changes the skin interface condition), Sarokol (used in combination with drugs that have good transdermal absorption), etc. Others diisopropyl adipate, phthalate ester,
Examples include plasticizers such as diethyl sebacate, hydrocarbons such as liquid paraffin, various emulsifiers, ethoxylated stearyl alcohol, higher ester ethers of glycerin, isopropyl myristate, and ethyl laurate.

Drug-containing polymer layer 2 formed by the above method
According to , when this is attached to the body surface, the drug in the continuous layer 2A diffuses inside this layer 2A and is transferred to or absorbed by the body surface. At this time layer 2
There is a dispersed phase 2B in which the drug is difficult to diffuse and move, and the continuous layer 2A itself is a denser layer that is crosslinked as a whole, so that an appropriate diffusion rate can be obtained and the drug efficacy can be improved. Sustainability brings good results.

In the above example, the drug-containing polymer layer 2 is composed of a continuous phase 2A made of a lipophilic polymer and a dispersed phase 2B in which a water-soluble polymer is dissolved. Dispersed phase 2B
In addition to this, a dispersed phase 2C made of a lipophilic polymer stably retained in the dispersed phase 2B may be formed. In order for the drug contained in the dispersed phase 2C to be absorbed into the body surface, it must first pass through the dispersed phase 2B, but this usually takes a very long time. That is, creating an extreme difference in the release properties of the drug between the continuous phase 2A and the dispersed phase 2C as described above has a favorable effect on the sustainability of drug efficacy.

When forming the polymer layer 2 having such a configuration,
(O/
A W)/O type emulsion is prepared, a drug is impregnated therein, and after or before direct coating or transfer to a support, ionizing radiation may be irradiated to polymerize and crosslink the emulsion.

The above (O/W)/O emulsion can be prepared by first using the oil phase component and aqueous phase component as described above, and using sorbitan monooleate, polyoxyethylene sorbitan trioleate, or polyoxyethylene stearate as an emulsifier. By using a nonionic material such as Rate, the aqueous phase component is added and mixed in 5 to 15 portions while stirring the oil phase component at a stirring speed of 1100 to 1300 rpm, and then the phase is inverted using a known method. to make an O/W type emulsion.

Next, this emulsion is added to a new oil phase component, and at this time, the ratio of the water phase component to 100 parts by weight of the oil phase component is generally set to be 10 to 100 parts by weight, and sorbitan monolaurate is added as an emulsifier. By using nonionic materials such as sorbitan monostearate and polyoxyethylene sorbitan monolaurate, the desired (O/W)/O type emulsion can be obtained by mixing with a disper at a stirring speed of 200 to 500 rpm. can get.

Drugs and other additives to be added to this (O/W)/O type emulsion may be added in advance to each oil phase component constituting the dispersed phase and continuous phase, or they may be added to the oil phase components constituting the dispersed phase in advance. Alternatively, the remaining amount may be added after preparing the (O/W)/O type emulsion.

As detailed above, in forming a drug-containing polymer layer on a support, the present invention uses an oil phase component consisting of a lipophilic monomer alone or a mixture of this monomer and a polymer, and a water-soluble polymer formed by dissolving a water-soluble polymer. Depending on the phase components, W/O type to (O/
W)/O-type emulsion is formed, and is characterized by polymerization and crosslinking by irradiating ionizing radiation with a drug impregnated in it, and the patch obtained from this has a high medicinal efficacy. It is possible to improve sustainability. In addition, when a volatile drug such as nitroglycerin or methyl salicylate or one that is liquid at room temperature is used as a drug, the presence of an aqueous or dispersed phase makes it difficult to handle the patch during manufacture or storage. Good results can be obtained.

Examples of this invention will be described below. In the following, parts and % mean parts by weight and % by weight, respectively.

Example 1 20 parts of water in which 1% polyvinyl alcohol was dissolved, 70 parts of a monomer mixture consisting of 90% isooctyl acrylate, 6% isobornyl acrylate, and 4% methacrylic acid, and 3.5 parts of sorbitan monolaurate as an emulsifier. Used and 1100 ~
Stir and mix with an Ajihomo mixer at 1300 rpm.
I made an O-type emulsion. After adding 3 parts of isosorbide dinitrate to this emulsion and stirring and mixing, it was coated on a 80μ thick film of ethylene-vinyl acetate copolymer (vinyl acetate content 28%) to a thickness of 50μ. ionizing radiation
The adhesive patch of the present invention was prepared by irradiating with 10 Mrad to polymerize and crosslink.

Example 2 Isoamyl acrylate 75%, vinyl acetate 23%
A monomer mixture consisting of 2% and hydroxyethyl methacrylate was reacted at 60° C. in a nitrogen stream using azobisisobutyronitrile as a polymerization initiator, and after about 10 minutes, the reaction was stopped by rapid cooling. This reaction product contained a portion of unreacted monomer.

0.8 parts of fluocinolone acetonide was dissolved in 50 parts of the above reactant, heated to 50°C in a nitrogen gas stream, and mixed with vinyl methyl ether and maleic anhydride while stirring with a disper at a stirring speed of 1100 rpm. An aqueous solution prepared by adding 5 parts of polyoxyethylene stearate as an emulsifier to 40 parts of water in which 2% of the polymer was dissolved was added in 10 portions over 1 hour and mixed. Thereafter, the phase was inverted by a known method to produce an O/W emulsion.

On the other hand, 0.2 parts of fluocinolone acetonide was dissolved in 80 parts of the above reactant, and 6 parts of a 1:1 mixture of sorbitan monolaurate and sorbitan monostearate was added as an emulsifier, and the mixture was heated at 60°C in a nitrogen gas stream. The above O/W emulsion was added all at once while stirring at 300 rpm, and the stirring was continued for 3 hours until the temperature dropped to 20°C or less, thereby creating an (O/W)/O emulsion. .

The drug-containing (O/W)/O obtained in this way
The adhesive patch of the present invention was prepared by coating the mold emulsion to a thickness of 60 μm on a polyethylene-aluminum foil sheet having a thickness of 80 μm, and then irradiating it with ionizing radiation of 15 Mrad to cause polymerization and crosslinking.

In order to examine the sustained drug release properties of the patches of Examples 1 and 2 above, the following water release test was conducted.

<Water release test> A 4 x 4 cm test piece was prepared from each patch, immersed in 200 ml of water (30°C), and the amount of drug released was examined at predetermined intervals. In addition, 1 ml of the released aqueous solution of the isosorbide dinitrate of Example 1 was collected at each time point, and the drug was extracted with 5 ml of hexane and quantified using a gas chromatography device. Further, fluocinolone acetonide in Example 2 was quantified using a high performance liquid chromatography apparatus after water was distilled off under reduced pressure from the discharged liquid sampled at each time point as an ethanol solution at a constant concentration.

4 and 5 respectively show the above test results. Curve 1a in FIG. 4 is the result of Example 1, and curve 2a in FIG. 5 is the result of Example 2. Curve 1b in FIG. 4 is a composition obtained by adding 2.5 parts of the drug described in Example 1 to 100 parts of the polymer to a polymer prepared from the monomer mixture described in Example 1 by a conventional method. These are the results of a conventional adhesive patch prepared by coating the following on the support described in Example 1. Similarly, curve-2b in FIG.
The agent described in Example 2 was added to a polymer prepared by a conventional method from the monomer mixture described in Example 2.
These are the results of a conventional adhesive patch prepared by applying a composition of 0.55 parts to 100 parts onto the support described in Example 2.

As is clear from both of the above, in the conventional patches (1b, 2b), the amount of drug released reaches saturation in a relatively short period of time and the sustainability of the drug effect is poor, whereas the patch according to the present invention The drug shows a gradual change in the amount of drug released, and the durability of the drug's efficacy has been greatly improved, with drug release still being observed even after 40 hours.

[Brief explanation of the drawing]

FIG. 1 is a sectional view showing an example of a patch according to the invention method, FIG. 2 is an enlarged view of the part shown in FIG. 1, and FIG.
The figure is an enlarged sectional view of a main part showing another example of the patch according to the method of the present invention, and FIGS. 4 and 5 are characteristic diagrams showing the drug release characteristics of the patch, respectively. 1...Support, 2...Drug-containing polymer layer.

Claims (1)

[Claims] 1. When forming a drug-containing polymer layer on a support, W /O
A method for producing a patch, which comprises forming a (O/W)/O type emulsion and irradiating the emulsion with a drug and polymerizing and crosslinking it with ionizing radiation.