JPS5984812A - Pharmaceutical for prolonged release of chemical - Google Patents

Abstract

PURPOSE:The titled excellent pharmaceutical prepared by dispersing a carrier powder in which a chemical is impregnated and absorbed in a porous layer, filling pores of the porous layer with a solvent capable of dissolving the chemical, and laminating the resultant porous layer to a backing member, and capable of controlling the release rate of the chemical. CONSTITUTION:A pharmaceutical for prolonged release of a chemical prepared by dispersing a powder 3, containing the chemical, e.g. an antiangina pectoris agent or anticonvulsant agent, and obtained by impregnating and absorbing the chemical uniformly in a powdery carrier layer 2, e.g. a silicone resin, polyvinyl acetate or collagen, filling pores of the porous layer 2 with a solvent 5, e.g. mineral oil or silicone oil, and laminating the resultant porous layer 2 to one surface of a backing member 1, e.g. cellulose acetate or polyamide. The resultant pharmaceutical has improved prolonged release properties of releasing the chemical at substantially a constant rate for a long term and keeping the concentration in blood of the chemical to be absorbed from the applied surface into the body substantially at a constant value.

Description

[Detailed description of the invention] The present invention long-awaited a drug with pharmacological activity.

The present invention relates to sustained release drug formulations that release at a controlled rate.

To achieve the desired therapeutic effect by administering a drug, it is desirable to maintain the drug at an effective concentration or higher in the diseased area or the circulatory system for a long period of time, and for this reason it is conventional to release the drug at a controlled rate. Various sustained release drugs have been proposed. Typically, as described in Japanese Patent Publication No. 54-16566, a backing member forming the outer surface, a pressure-sensitive adhesive layer forming the adhesive surface to the skin or mucous membrane, and these backing members and adhesive. It is a laminate consisting of a drug storage layer containing a drug between the layers. The storage layer consists of a resin layer that is permeable to the drug and controls its release rate, and a drug that is dispersed, for example, simply or as microcapsules, in such a resin layer. It diffuses through the adhesive layer, is released from the surface at a controlled rate, and is absorbed into the body through the skin or mucous membrane at the adhesive surface. In some cases, a control layer in which the diffusion rate of the drug is lower than that of the storage layer may be interposed between the storage layer and the adhesive layer.

However, even in sustained-release preparations such as Heko, the sustained-release property of releasing the drug at a substantially constant rate over a long period of time is not fully satisfactory, and furthermore, the release rate varies depending on the type of drug. The rate of release is often limited because it is difficult to vary and control the rate.

The present invention has been made to solve the above-mentioned problems, and the present invention is aimed at reducing the blood concentration of the drug absorbed into the body 6 from the application surface by releasing the drug at a substantially constant rate over a long period of time. It is an object of the present invention to provide a sustained release preparation that has excellent sustained release properties that are maintained substantially constant, and furthermore allows the release rate of a drug to be controlled over a wide range.

The sustained release preparation of the present invention comprises a lining member, a porous layer laminated on the lining member, a drug-containing powder obtained by impregnating and absorbing a drug into a carrier powder and dispersing it in the porous layer.
It is characterized by comprising a drug-soluble solvent filled into the pores of the porous layer.

The present invention will be described below based on drawings showing examples.

The backing member 1 may be either non-flexible or flexible, but is preferably flexible and drug-impermeable because many sustained-release preparations are applied on the skin or mucous membranes by adhesion. Preferred specific examples include resin sheets or films of cellulose acetate, ethyl cellulose, cellophane, polyethylene terephthalate, plasticized vinyl acetate-vinyl chloride copolymer, polyamide, polyethylene, polyvinylidene chloride, aluminum foil, etc. metal foil,
and a laminate of two or more of these.

In the sustained release preparation of the present invention, a porous layer M2 is deposited on one surface of the backing member 1, and a drug-containing powder 3 obtained by impregnating and absorbing a drug into a powder carrier is placed in this porous layer. Evenly distributed.

The drug used in the present invention is not particularly limited as long as it is absorbed into the body through the skin or mucous membrane and exerts the desired pharmacological effect. Cardiac agents, anticonvulsants such as atropine and scopolamine, antibiotics such as penicillin, tetracycline, chlorotetracycline, oxytetracycline, and sulfonamides, barbiturates, phenobarbicur, bendoparbital, α-bromoinovaleryl urea, Analgesic hypnotics such as Codin, anti-inflammatory analgesics such as indomethacin, mefenamic acid, diclofenac, alclofenac, phenylbutacin, tranquilizers such as chloropromacine, thioridazine, diacepam, reserpine, haloperidol, 3-(2-amino butyl)
Psychoactive agents such as indole acetate, prednisolone, hydrocortisone, fluocinolone acetonide, triamcinolone acetonide, methyltestosterone, megesterol acetate, fluoximusterone, esterone, estradiol, ethinyl estradiol, 1,7α-hydroxyprogesterone acetate, 1
Contains steroid hormones such as 9-norprogesterone and methoxyprogesterone acetate, and antipyretic agents such as acetylsalicylic acid and tylamide-poor sodium salicylate. In addition, when these drugs are difficult to absorb through the skin or mucous membranes, they may be prepared as a pharmaceutically acceptable solution.
Moreover, it may be made into a pharmaceutically acceptable derivative if necessary.

In the present invention, the drug is impregnated and absorbed into a powder carrier,
It is uniformly dispersed in a porous layer that is permeable to drugs.

As the carrier powder, resin powder having a diameter of several tens of micrometers is usually preferably used. The drug can be impregnated and absorbed into the carrier as it is or by mixing it with carrier powder as an appropriate solution or dispersion if necessary.

Preferably, the porous layer is made of a drug-permeable resin,
For example, silicone resins such as polydimethylsiloxane, poly(meth)acrylic esters such as polyhydroxylethyl (meth)acrylate, polymethyl acrylate, polybutyl acrylate, polyacrylic acid, its salts, polyvinyl alcohol, polyacetic acid. vinyl,
Polyethylene wax, polyethylene oxide, polyvinylpyrrolidone, hydroxyethyl cellulose, carboxymethyl cellulose, plasticized polyvinyl chloride, plasticized polyamide, polyurethane, polyisobutylene, styrene-butadiene rubber, egulene-carbon oxide copolymer, collagen, gelatin, gum acacia, gum tragacanth, etc. Synthetic or natural resins and rubbers are preferably used.

In the sustained release preparation of the present invention, the pores 4 of the porous layer are filled with a drug-soluble solvent 5.

This solvent bi is appropriately selected from solvents that dissolve the drug among solvents that do not dissolve the porous layer, but in general, in addition to mineral oil, silicone oil, glycols such as diethylene glycol, propylene glycol, and polyethylene glycol, olive oil , oils and fats such as squalene and lanolin, polar organic solvents such as dimethyldecyl phosphooxide, methyloctyl sulfoxide, dimethyl laurylamide, dodecylpyrrolidone, isosorbitol, dimethylacetamide, dimethyl sulfoxide, dimethylformamide, water, or these A mixed solvent of two or more of these is used. By selecting this solvent, it is possible not only to make the release rate of the drug in the sustained release preparation substantially constant, but also to control it to a desired rate depending on the drug.

The sustained release preparation of the present invention is usually provided with a pressure-sensitive adhesive layer 6 on the surface of the porous layer for adhesive application to the skin or mucous membrane. This adhesive may be any adhesive as long as it is dermatologically and mucosologically acceptable and is permeable to the drug used, but specific examples include acrylic resin adhesives, silicone resin adhesives, and other adhesives. , natural rubber, polyurethane,
Rubber adhesives such as polyisoprene, polyisobutylene, and polybutadiene, vinyl MJ&-4F agents such as polyvinylpyrrolidone and polyvinyl acetate, and cellulose adhesives such as ethylcellulose and methylcellulose are used. If necessary, a release sheet 7 made of a resin film coated with silicone resin, paper, or the like is adhered to the surface of the adhesive layer.

An example of the method for producing the sustained release preparation of the present invention will be given below.

For example, by adsorbing and impregnating a drug into resin powder with a diameter of several tens of μm,
After uniformly mixing this with a drug-permeable resin and a foaming agent such as azodicarbonamide, azobisisobutyronitrile, or sulfonyl hydrazide, it is formed into a sheet and foamed to contain the drug within the porous layer. Uniformly disperse the resin powder. Next, this porous layer is impregnated with a solvent to fill the pores with the solvent, and then a backing member is laminated on one side of the porous layer, and a pressure-sensitive adhesive layer is laminated on the other side. Note that the porous layer in which the resin powder containing the drug is dispersed is not limited to the method using the above-mentioned foaming agent, but may be formed by conventionally known methods for making resin porous, such as so-called solvent substitution, stretching, and extraction. can be adopted as appropriate.

As described above, according to the sustained-release preparation of the present invention, the drug impregnated and absorbed into the resin powder is contained in a drug-permeable porous layer and a solvent formed continuously or discontinuously in this layer. It diffuses to the surface in contact with the skin or mucous membranes, and is released at a substantially constant and controlled rate, so that its blood concentration remains approximately constant. In addition, when a porous layer has pores that are continuous in the thickness direction, drug release depends on the type and thickness of the resin forming the porous layer, its porosity, and the type of solvent filled in the pores. Speeds can be selected and controlled within a wide range.

Example 1 100 g of 2-hydroxyethyl methacrylate and 0.2 g of ethylene glycol dimecrylate were added to 100 g of water.
Among them, t-butyl peroxide 0.2 as a polymerization initiator
The resulting polymer was separated, dried, and ground into a powder of about 25 μm.

10 g of this resin powder is mixed with an acetone solution containing 1 g of isosorbide nitrate and impregnated until the resin absorbs the drug to saturation, then 50 g of dimethyl silicone rubber and 5 g of azodicarbonamide blowing agent are added and mixed uniformly. After forming into a sheet, it was heated and foamed to obtain a porous layer.

After impregnating this porous layer with diethylene glycol,
Laminated on the surface of aluminum foil to a thickness of 200 μm, further, on this porous layer, 50 parts by weight of 2-ethylhexyl methacrylate, 50 parts by weight of butyl acrylate, and 1.
Coating a 20% by weight ethyl acetate solution of a copolymer consisting of 0.02 parts by weight of 6-hexanethiol dimethacrylate,
It was dried to form an adhesive layer with a thickness of about 50 μm.

This preparation was cut into a circle with a diameter of 3cITl, and the weight was 3.7cm.
The blood concentration of isosorbide nitrate was measured by pasting it on the depilated back of an ITG rabbit. The results are shown in the table.

The unit of blood concentration is ng/ml. The method for measuring blood concentration is as follows. After applying the preparation as described above, 3 ml of blood was collected at predetermined intervals, plasma was separated, and extracted with 4 ml of hexane. Next, this was evaporated to dryness in an inert gas, dissolved in 100 μl of ethyl acetate, and measured using ECD-gas chromatography.

Example 2 10 g of resin powder impregnated with insorbide nitrate in the same manner as in Example 1 was uniformly mixed with 100 g of a 10 M% polyvinyl alcohol aqueous solution and 10 g of calcium carbonate, coated on an appropriate base material, dried, and formed into a film. After this film is biaxially stretched at a temperature of 100°C, the average pore size is 6.
A porous layer having pores of 2 μm, a porosity of 50%, and a thickness of 200 μm was obtained.

This porous layer was impregnated with polyethylene glycol in the same manner as in Example 1, and a room temperature curable silicone resin adhesive was applied to both surfaces, and then aluminum foil was coated on one side to form a sustained release preparation of the present invention. I got it.

Regarding this preparation, 1. Cut into a circle with a diameter of 5 cm,
In the same manner as in Example 1, the sustained release properties were measured from the rabbit blood concentration. The results are shown in the table.

From the above, it is understood that the sustained release preparation of the present invention has excellent sustained drug release properties and maintains the blood concentration of the drug constant over a long period of time.

[Brief explanation of drawings]

The drawing shows a sectional view of essential parts of the sustained release preparation of the present invention. DESCRIPTION OF SYMBOLS 1... Backing member, 2... Porous layer, 3... Drug-containing powder, 4... Holes, 5... Solvent, 6... Adhesive layer, 7... Release sheet . Patent applicant Mototoshi Fujinuma, representative of Sekisui Chemical Co., Ltd.

Claims (1)

[Claims] (1) A backing member, a porous layer laminated on the backing member, a drug-containing powder obtained by impregnating and absorbing a drug into a carrier powder and dispersing it in the porous layer, and the voids in the porous layer. A drug sustained release preparation comprising a drug-soluble solvent filled in the pores.