JPS6258334B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention uses ionizing radiation irradiation to eliminate drug loss during the manufacturing process, and also uses post-polymerization to make the compound into a polymer, thereby eliminating unnecessary components that transfer to the body's outer skin or mucous membranes. The present invention also relates to a method for producing a novel pharmaceutical component that increases the durability of drugs. Methods for manufacturing pharmaceutical parts include a method in which drugs such as methyl salicylate, camphor, and menthol are mixed in solution into a drug-retaining matrix mainly made of natural rubber or synthetic rubber, and the mixture is coated on a support and dried; acrylic acid-acrylic A method in which the drug is added as a solution, emulsion or suspension to a solution or emulsion of acid ester copolymer or polyvinyl ester, etc., a crosslinking agent is added if necessary, and this is coated and dried on a support, in advance. A commonly used method is to coat, spray or immerse a solution or suspension of a drug onto the material surface of a support on which a material having pressure-sensitive adhesive properties at room temperature is formed, followed by drying. However, with these methods, there are problems such as scattering of the drug due to heating, decrease due to decomposition of the drug during production and over time due to the effects of compounding agents, and in the case of emulsion systems, there are limitations on the emulsifier used as a pharmaceutical component and polymerization stability. There are problems such as stability, stability over time, and uniform dispersion of drugs, and in solution systems, there are problems such as toxicity to workers during production, risk of fire, and air pollution. There is a problem in that a large capacity heat source is required. On the other hand, a method using ionizing radiation during the production of medical components has also been proposed (Japanese Patent Application Laid-open No. 49-55734). In the case of irradiation, there are problems in that the coating process is complicated and the fluidity is too high, making it difficult to obtain a uniform thickness. The present invention relates to a method for producing a novel pharmaceutical component that solves the various problems mentioned above at once.
A polymerizable monomer consisting of an acrylic ester or a vinyl alkyl ether alone, or at least one selected from the group of (meth)acrylic esters and vinyl esters that can be copolymerized with these and/or a vinyl monomer having functionality. The body was bulk polymerized using a polymerization initiator to achieve a polymerization rate of about 5 to 90% and a polymerization rate of about 10 to 90%.
It includes a first step of making a polymerizable adhesive composition having a viscosity of 1000 poise (30°C), and the first step includes bulk polymerizing the polymerizable monomer composition using a polymerization initiator and supporting the polymerizable composition. The polymerization rate and viscosity are adjusted to be convenient for applying, spraying, or dipping onto the body. The subsequent second step is to add and dissolve a predetermined amount of drug and an optional pharmaceutical auxiliary into the polymerizable composition prepared as described above, that is, having a residual monomer or in which an oligomer and a polymer coexist. By doing so, the decrease due to drug decomposition is eliminated. The drug-containing composition in which at least a drug is blended in this way can be made of a plastic film or sheet,
The formulation is coated onto a carrier such as paper, woven fabric, knitted fabric, non-woven fabric, foil, release liner, etc., and then irradiated with ionizing radiation at low temperatures to the extent that the formulation has pressure-sensitive adhesive properties. Therefore, we aim to polymerize the compound by crosslinking it simultaneously with post-polymerization without scattering the drug in the compound, thereby eliminating migratory components, and by encapsulating the drug in the polymer phase. A third step of increasing durability and sterilizing the medical component with radiation is performed to produce the medical component. The manufacturing method of the present invention provides a medicinal component suitable as a medicinal material by passing through each of the steps specified above. The characteristics of the manufacturing method of the present invention or the characteristics of the pharmaceutical components obtained as a result are that the polymerizable monomer composition is bulk polymerized using a polymerization initiator, and the reaction is quenched or inhibited according to the desired purpose. By stopping the reaction midway using a chemical agent or other means, the viscosity can be adjusted to a value suitable for coating, dipping, or spraying during manufacturing, and residual monomers, oligomers, and polymers coexist at low temperatures. By dissolving and dispersing a predetermined amount of a drug and irradiating it with radiation without causing decomposition or reduction of the drug, high molecular weight and high density crosslinking can be achieved. In addition, in order to carry out post-polymerization reaction at a low temperature without using a reaction reagent, a liquid chemical having a high vapor pressure can also be effectively contained. Furthermore, in conventional polymerization methods, depending on the type of drug, it was necessary to add comonomers to improve cohesiveness of reactive functional monomers and for grafting. Since high-density crosslinking is achieved, such addition is not necessary, and even a single polymer can serve the purpose, and is also good in terms of allergy to the human body. moreover,
Being able to achieve high molecular weight and high density crosslinking at low temperatures means that there is less unnecessary migration of components to the human body.
In addition, there is less concern about the pharmacological effects of decomposed products of drugs that are unstable at high temperatures, and the active ingredients are more persistently absorbed into the human body than in the past. Furthermore, in the conventional method, there were practical problems such as adhesion with supports such as films, woven fabrics, and non-woven fabrics, and interlayer breakdown between different types of polymers.However, according to the production method of the present invention, the above supports, etc. Since the adhesion properties are significantly improved even with different types of polymers, it is possible to form multiple layers of different types of polymers. Compared to conventional methods, pre-polymerization and post-polymerization are carried out in a series, so there are fewer restrictions on the solubility and compatibility of polymers and monomers, and the range of use for combinations of drugs, polymers and monomers is significantly expanded. It has the feature that it can be sterilized as a medical component by radiation at the same time as it is manufactured, and the process can be simplified. (a) (meth)acrylic acid ester, (b) vinyl alkyl ether used in carrying out the present invention,
(c) Vinyl ester and (d) vinyl monomer having a functional group include the following. (a) (Meth)acrylic acid ester Types of esters include butyl, isobutyl, tertiarybutyl, propyl, isopropyl, amyl, isoamyl, octyl, isooctyl, 2-ethylhexyl, stearyl, tetrafurfuryl, 2-methoxyethyl, 2-ethoxyethyl, 2-butoxyethyl, ethoxyethylene glycol, ethoxydiethylene glycol, methoxyethylene glycol, methoxydiethylene glycol, 2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxybutyl, etc. (b) Vinyl alkyl ether, e.g. n-butyl (c) Vinyl esters such as vinyl acetate, vinyl propionate, etc. (d) Vinyl monomers with functionality ( meth)acrylic acid, itaconic acid, maleic acid, maleic anhydride, (meth)acrylamide,
Dimethylacrylamide, vinylpyrrolidone, acrylonitrile, 2-hydroxyethyl (meth)acrylate, 2-hydroxypropyl (meth)acrylate, 2-hydroxybutyl (meth)acrylate, dimethylaminoethyl (meth)acrylate, (meth) diethylaminoethyl acrylate,
(meth)acrylic acid t-butylaminomethyl, etc. In the present invention, the formulation for forming a drug-containing pressure-sensitive adhesive by irradiation with ionizing radiation is the above-mentioned (meth)acrylic ester or vinyl alkyl ether alone. Using a polymerization initiator, a polymerizable monomer consisting of at least one selected from the group of (meth)acrylic acid esters and vinyl esters copolymerizable with these and/or a vinyl monomer having functionality is used. The polymerization rate is about 5 to 90%, and the properties when coating on the carrier are about 5 to 90%.
Adjusted to a viscosity of 1000 poise (30°C), it is a polymerizable adhesive formulation that is easy to form. The polymerizable compound is a polymerizable monomer consisting of the above monomer alone or two or more of the above monomers, a polymerization initiator such as an azo type, a peroxide type, an organic redox type, etc., and a polymerizable monomer. Add 0.001 to 1 part by weight, preferably 0.01 to 0.5 part by weight per 100 parts by weight, stir at a temperature of about 40 to 100°C for 0.5 to 24 hours, polymerize in a non-solvent system, and cool if necessary. The polymerization rate is adjusted to about 5-90% and the viscosity is 10-1000 poise (30°C), preferably 20-350 poise (30°C), by adding a polymerization inhibitor or the like. . As the polymerization initiator used in the present invention, the above-mentioned ones can be used, but in particular, the use of azo polymerization initiators such as azobisisobutyronitrile, diazomethane, and diphenyldiazomethane is effective from the time of manufacturing the pharmaceutical component. This is preferable because the decrease due to drug decomposition up to the end of the period can be reduced compared to other polymerization initiators. A drug having the desired pharmacological activity is added to the polymerizable adhesive composition thus constituted at a low temperature (approximately 50 to -80°C) to produce a drug-containing composition. The amount of the drug to be added varies depending on the efficacy, degree of activity, etc. of the drug, but it can generally be added in the range of about 0.001 to 10 parts by weight per 100 parts by weight of the formulation. Such drug-containing formulations may optionally have the function of softening and/or swelling the body's outer skin to facilitate the absorption of the drug into the skin and/or the function of facilitating the release of the drug from the medicinal component. Appropriate amounts of pharmaceutical auxiliaries, other compounding agents such as drug stabilizers, pigments, and fillers can be added. Furthermore, monomers having compatibility with the same or different types of the formulation may be added as a softening component or a viscosity adjusting component. Examples of the drugs include corticosteroids such as hydrocortisone, prednisolone, betamethasone, and fluocinolone acetonide, analgesic anti-inflammatory agents such as indomethacin, methyl salicylate, glycol salicylate, and diclofenac, and hypnotic sedatives such as phenobarbital and amobarbital. , diazepam, tranquilizers such as fluphenazine, other antihypertensive agents, antibiotics, vitamins, antibacterial substances, etc. In addition, substances used as medicinal auxiliaries either have no radiation blocking effect at all, or even if they do have a relatively weak blocking effect, such as glycerin, ethylene glycol, proprene glycol, polyethylene glycol, butanediol,
Alcohols such as octanol, hexanol, cyclohexanol, benzyl alcohol,
diethyl sebacate, ethyl laurate, cetyl lactate, ethylene glycol stearate,
Drug release enhancers such as propylene glycol stearate, diisopropyl adipate, salicylic acid, urea, allantoin, dimethyl sulfoxide, dimethyl acetamide, and dimethyl formamide, as well as olive oil, liquid paraffin, and sorbitol surfactants, are included. The drug-containing formulation is uniformly coated, sprayed or dipped onto a carrier such as a plastic film or sheet, paper, woven fabric, knitted fabric, non-woven fabric, foil, release liner. Then, the polymerizable compound for adhesives, which is adjusted to a specific polymerization rate and viscosity by bulk polymerizing the polymerizable monomer, which is the base material of the compound, using a polymerization initiator, becomes a semi-solid without curing. at low temperatures (approximately 30
By irradiating the material with ionizing radiation at a temperature of -100° C.), crosslinking is generated simultaneously with post-polymerization, and a completely sterilized medicinal component is obtained. In this way, in order to provide a drug-containing paste on a carrier with a well-balanced pressure-sensitive adhesive force and cohesive force, without any migrating components, and to exhibit persistence for the contained drug. It is necessary to adjust the dose of ionizing radiation to an appropriate amount depending on the type of multipolymerizable monomer and drug constituting the polymerizable compound, the coating thickness on the carrier, etc. To achieve the above objectives, the dose should be 1~
It can be irradiated in the range of 100 Mrad, but preferably 2~
It is best to irradiate within a range of 30. As a source of ionizing radiation, high-energy electron beams generated from electron accelerators are desirable because they can easily obtain large doses and greatly improve processing speed, but gamma rays, x-rays, and beta The use of lines is also possible. In the present invention, a drug-containing formulation is prepared by bulk polymerizing a specific polymerizable monomer using a polymerization initiator to obtain a specific property, and a drug is added to a polymerizable formulation with good coating workability, on a carrier. By forming the drug and irradiating it with ionizing radiation, a completely sterilized pharmaceutical component with no loss of drug, less migrating components, and good persistence of the drug can be produced. A drug-containing paste that can eliminate the decomposition of drugs due to the use of organic solvents and the instability of pharmaceutical components due to the influence of emulsifiers, and has good pressure-sensitive adhesive strength and cohesive strength without causing various problems caused by the use of organic solvents. It can form a body. In addition, as a carrier, a film made of a resin with low adhesiveness such as polyethylene or polypropylene,
Even if sheets, synthetic paper, cloth, etc. are used, when the compound is polymerized by irradiation with ionizing radiation, grafting occurs at the same time, creating an anchoring force and creating a strong adhesive state between the carrier and the plaster. It is something that can be done. Even if a drug-free polymerizable monomer or copolymer layer is formed on a carrier by utilizing this phenomenon, a drug-containing formulation is formed thereon, and then ionizing radiation is irradiated, each It is also possible to obtain a multilayered medical component in which interfacial peeling does not occur between layers. The present invention will be explained below with reference to Examples. The words "part of the text" indicate parts by weight. Example 1 100 parts of 2-ethylhexyl acrylate and 0.05 part of azobisisobutyronitrile were charged into a three-necked flask, and after displacing dissolved oxygen with inert gas, the temperature was raised to 80°C to start the reaction. After a period of time, the mixture is cooled on ice to obtain a polymerizable adhesive composition having a polymerization rate of 35% and a viscosity of 65 poise (at 30°C). Next, 100 parts of the above formulation is cooled to 0°C and 0.25 parts of fluocinolone acetonide is added thereto to obtain a drug-containing formulation. This was applied to a polyethylene film to a thickness of 40μ, placed in an inert gas atmosphere with the above compound side facing upward, and 7000 cuys of Co-60γ rays were applied at -10°C. A medical component is obtained by irradiating the product with 20 Mrad. Example 2 20 parts of 2-ethylhexyl vinyl ether, 78 parts of butyl acrylate, 2 parts of methacrylic acid, and 0.05 part of benzoyl peroxide were charged and polymerized at 80°C for 2 hours, resulting in a polymerization rate of 44% and a viscosity of 110 poise (at 30°C). A polymerizable adhesive formulation is obtained. Next, 100 parts of the above formulation is cooled to 0°C and 3 parts of indomethacin are added thereto to obtain a drug-containing formulation. This is made of soft polyvinyl chloride film with a thickness of 40 mm.
Co-60 gamma rays of 7000 cuys were applied under an inert gas atmosphere with the above compound side facing upward.
A medical component is obtained by irradiating with 15 Mrad. Table 1 shows the test results of Examples 1 and 2, in which the drug content was measured at the initial stage and after the passage of time. The drug content is determined by extracting the drug from the plaster layer of a certain area of the medical device with methanol (3 times at 40°C), concentrating the extract at low temperature, and eluating this with an ethanol:hexane (3:1) mixture. Quantitate as a liquid using high performance liquid chromatography and measure the ratio to the set amount of drug. However, glycol salicylate is determined by gas chromatography of the extract.

[Table] Examples 3 to 6 The polymerizable monomers shown in Table 2 were bulk polymerized using 0.1 part of azobisisobutyronitrile to obtain a polymerizable composition for adhesive. Next, 100 parts of the formulation is cooled to 0°C, and a prescribed amount of the drug listed in Table 2 is added thereto to obtain a drug-containing formulation. This was applied to a polyethylene film to a thickness of 40μ, placed in an inert gas atmosphere with the compound side facing upward, and 7000 cuy
Co-60 gamma rays are irradiated at 20 Mrad in an atmosphere of -10°C to obtain a medical component.

【table】

[Table] In Comparative Examples 1 to 4 in Table 2, the formulations were polymerized in ethyl acetate in a conventional manner (65°C for 12 hours), and a predetermined amount of each drug was added at room temperature. The film was coated and dried to a thickness of 40 μm after drying, and dried at 80° C. for 8 minutes to obtain a medical component. In addition, in the lower row of Comparative Example 1 in Table 2, 0.2 parts of benzoyl peroxide was used, and 150°C x 5
The lower rows of 2 and 4 contain an adduct of hexamethylene diisocyanate and trimethylolpropane to the above polymer in ethyl acetate.
0.5 part was added as a crosslinking agent. Table 3 shows the results of the sterility test of the medical components obtained in Example 3 and Comparative Example 3, and the test method was based on the sterility test method of the Japanese Pharmacopoeia.

[Table] In Table 3, + indicates that bacterial growth was observed, and - indicates that no bacterial growth was observed. Table 4 shows the test results for durability of drug efficacy.

[Table] According to the method of Christie and Moore-Robinson, samples were cut into 10 x 10 cm pieces and pasted on the flexor side of the forearm. The pasting time was 3, 6, 9, 12, 24, 36, and 48 hours. Judgments were made after the tape was removed. , 2 hours. Judgment criteria: 0 points: No change from the untreated area 1 point: Slight whitish appearance 2 points: Two corners can be relatively clearly distinguished 3 points: All corners can be clearly distinguished

Claims (1)

[Claims] 1 Consists of (meth)acrylic acid ester or vinyl alkyl ether alone or at least one selected from the group of (meth)acrylic acid ester and vinyl ester copolymerizable with these and/or a functional vinyl monomer A first step of bulk polymerizing a polymerizable monomer using a polymerization initiator to produce a polymerizable adhesive composition having a polymerization rate of about 5 to 90% and a viscosity of 10 to 1000 poise (30°C); A second step of adding a drug and optional pharmaceutical auxiliaries to the formulation to form a drug-containing formulation, and coating the drug-containing formulation on a carrier and sensitizing the formulation at a low temperature. 1. A method for producing a pharmaceutical component, comprising a third step of irradiating ionizing radiation in an area that has pressure-adhesive properties to effect post-polymerization and simultaneous crosslinking, and radiation sterilization.