WO1990000472A1

WO1990000472A1 - Multilayer preparation which gradually releases liquid active agent

Info

Publication number: WO1990000472A1
Application number: PCT/JP1989/000685
Authority: WO
Inventors: Shinji Yamada; Yoshikazu Musa
Original assignee: Nitto Denko Corporation
Priority date: 1988-07-11
Filing date: 1989-07-06
Publication date: 1990-01-25

Abstract

The invention relates to a multilayer preparation (1) which gradually releases a liquid active agent, in which a release layer (3) composed of a polymer compatible with said liquid active agent is provided on at least one side of a liquid active agent-containing active layer (2) and barrier layers (4) are provided on both sides of the assembly of layer (2) and layer (3). This preparation releases the liquid active agent from the release layer (3) into the air at a substantially constant rate and, since barrier layers (4) are provided, it is not adversely affected by wind even when used outdoors.

Description

Specification

Liquid active substance sustained release multilayer formulation

Technical field

TECHNICAL FIELD The present invention relates to a sustained-release liquid active substance multilayer preparation, and more particularly to a sustained-release liquid active substance multilayer preparation capable of releasing a liquid active substance at a substantially constant rate for a long period of time. .

Background technology

Various types of sustained-release devices for controlling the release of the active substance into the surrounding environment are already known. For example, as described in U.S. Pat. No. 4,286,020 and U.S. Pat. No. 4,353,962, devices in which the active substance is encapsulated in microcapsules or Alternatively, as described in JP-A-52-55969 and JP-A-57-45101, or U.S. Pat. No. 4,017,030, the active substance is added to a tube or a capillary. Devices that are encapsulated are known. Further, as described in JP-A-59-13701, a device in which an active substance is impregnated in a porous resin molded body having continuous through holes, or U.S. Pat. As described in the specification, a device in which a release control layer is provided on an upper surface of an active substance storage layer is also known.

However, it is difficult for these formulations to reliably release the active substance over a long period of time at a substantially constant rate. For example, the release rate is too slow to release an effective amount, or the initial release rate is significantly higher.

Therefore, Japanese Patent Application Laid-Open No. 61-227031 discloses that the above-mentioned liquid active substance is applied to both surfaces of a porous polymer layer containing a liquid active substance in the form of droplets. A liquid active substance sustained-release multilayer preparation comprising one layer of a barrier that does not qualitatively diffuse and permeate has been proposed. According to such a formulation. Since the liquid active substance diffuses to the side surface of the porous polymer layer and reaches the side surface having a limited area exposed to the air, it is released into the air only after being used. In some cases, the release rate is too slow. In addition, the active substance present in the center of the surface of the porous polymer layer is not easily released even after a long period of time, and as a result, it is effective. It will remain in the drug product without being released to.

Disclosure of the invention

SUMMARY OF THE INVENTION The present invention has been made to solve the above-mentioned problem in a liquid active substance sustained-release multilayer preparation, and is intended to release a liquid active substance over a long period of time at a substantially constant relatively large rate. It is an object of the present invention to provide a liquid active substance sustained-release preparation which can be released and thus can effectively release the active substance contained in the preparation.

The liquid active substance sustained-release multilayer preparation according to the present invention is a liquid active substance sustained-release multi-layer preparation comprising an active layer comprising a polymer having the liquid active substance. A release layer composed of a united layer is laminated on at least one surface of the active layer, and a barrier layer that does not substantially diffuse and transmit the liquid active material is provided on both sides of the laminate of the active layer and the release layer. It is characterized by being laminated.

In particular, in the production according to the present invention, the active layer is preferably formed of a porous polymer layer having a large number of independent micropores. A liquid active substance having a limited solubility in the polymer at room temperature is enclosed in the pores as droplets in an amount exceeding this solubility.

Such an active layer preferably dissolves the polymer and the active substance which has a limited solubility in the polymer at room temperature and which is liquid at room temperature, and dissolves both the active substance and the polymer. At the same time as dissolving it in an organic solvent that is more volatile than the active substance, applying this solution to the surface of a suitable support, and evaporating the solvent to form a liquid active substance in the polymer layer. It can be obtained by dispersing and containing a substance in the form of fine droplets. In the above, the liquid active substance is dispersed as droplets in the polymer layer during preparation of the preparation, and is released from the polymer layer at a substantially constant rate after the preparation. It is blended in an amount exceeding the solubility in the polymer.

In the present invention, the liquid active substance refers to a substance which is liquid at normal temperature and has a chemical or physiological activity such as an attractant activity, an agrochemical activity, a repellent activity, an aroma activity, and the like. When used as an insecticide pi-mon, for example, Z—11—tetradecenyl acetate, Z—9—tetradecenyl acetate, E-11—tetradecenyl acetate , Z—9-dodecenyl acetate, 10—methyl dodecyl acetate, 11—dodecenyl acetate, Z—ί—Tetradecena, Ζ—9—Tetradecena ,

Ζ — 1 1—Tetradecenal, Ζ — 7 ^ Kisadesenal, Ζ-

9 · Xadecenal, Ζ — 1 1 1 ^ Xadecenal, 4,8-dimethyltildecanal, η — Dodecanol, Ζ — 1 1 1 hexadecene, Ζ — 8 — Dodecenol , Or — Reno Reitsk Aldehid, — Linolenic aldehyde, (R, Z) -5— (1—decenyl) dihydro-1 2 (3H) —Furanon, (Z, Z) -3,6- (9S, 10R) —Epoxy cat feline, (B) —10—Methyl 2—Tridecane, Methyl (Z) —5—Tetradecenoate, (E) —6— ( 1 — pentenyl) 1 2 H — pyran 1 2 — on, invertide, dihydroactinidelide, suspenseolide, anastrefin, epiphanerefrey , 3 — methyl 1 6 — isopropenyl 9-decyl 1-yl acetate, periplanone 1 A, periplananone — B, 3 — N, N-dimethyl 1 2 —Methizole 2 —Pronoz'nor, 2-methyl-1 (7R, 8S) —Epoxy-octadecane, etc. are preferably used. Specific examples of other active substances include, for example, pesticide active substances such as insecticides such as Naled, Di-azinon, and Sumithione, and sterilization such as ^ -propiolactone. Agents, triethylene glycol monohexyl ether, N, N-ethylethyl, m-toluamide and other repellents, limonene, benzyl alcohol, carbon number 6-16 And aromatic active substances such as esters, ethers, and aldehydes derived from hydrocarbons.

As described above, the polymer for forming the active layer has a limited solubility in the liquid active substance to be used, and usually a polymer that dissolves the liquid active substance only in a range of 20 parts by weight or less. A polymer which is dissolved in the range of 0.01 to 5 parts by weight is preferably used. Such a polymer is appropriately selected depending on the liquid active substance to be used. Examples thereof include, for example, polysulfone, thermoplastic polyester, polycarbonate, polystyrene, and polystyrene. Poly (meth) acrylic acid ester containing polymethyl methacrylate Amide, polyvinylidene polychloride, vinylidene polyfluoride, cellulose ester, regenerated cellulose, polyurethane, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate And one or a mixture of two or more of ethylene vinyl acetate copolymer, vinyl chloride-vinyl acetate copolymer, and polystyrene-polybutadiene block copolymer. You.

The organic solvent used in producing the preparation according to the present invention must be capable of dissolving both the active substance and the polymer used, and must be more volatile and have a lower boiling point than the active substance. It is appropriately selected according to the types of the active substance and the polymer, and specifically, for example, lower aliphatic halogenated hydrocarbons such as methylene chloride, macropore form, carbon tetrachloride, etc. Lower aliphatic alcohols such as ethanol and ethanol, and their acetates, as well as acetonitril, acetone, ethyl ether, tetrahydrofuran, etc. One or more mixtures are used. In particular, lower aliphatic hachigenated hydrocarbons such as methylene chloride are preferably used. The total concentration of these in a solution containing the liquid active substance and the polymer is usually from 10 to 60% by weight, preferably from 15 to 50% by weight. This solution is usually applied onto a suitable support that forms a barrier layer, for example, a resin film, a metal foil or a thin sheet, or a laminate of these, and then the organic solvent is evaporated off. Is done. Thus, a laminate in which the active layer is laminated on one barrier layer can be obtained.

The temperature at which the organic solvent is evaporated is usually from 0 to 100, preferably from 15 to 70, and not higher than the boiling point of the solvent. Degrees. Normally, room temperature is sufficient, but heating may be performed if necessary. Moreover, you may evaporate under reduced pressure. In this way, as the organic solvent evaporates, the liquid active substance has a limited solubility in the polymer, and the liquid active substance is in excess of the solubility in the polymer. Phase separation occurs between the particles and fine droplets of the active substance are evenly dispersed in the polymer matrix, so that the polymer forms a porous layer with a large number of independent micropores. A liquid active substance is sealed in the micropores.

Micropores formed in the active layer by such a method are usually independent pores defined by partition walls having a thickness of 0.1 to 5; rai, and the pore diameter is about 0.5 to 10 lord. Also, since the active layer has a porosity of about 30 to 80%, it can contain up to about 70% by weight of a liquid active substance, but in practice, it should be up to about 50% by weight. Appropriate. The thickness of the active layer is not limited at all, but is usually in the range of 10 to 500.

In a multilayered formulations according to the invention, as _e the release layer emitting layer made of the porous even without less of the polymer layer excellent in compatibility with the liquid祅活material on a surface polymer is laminated, For example, it is preferable that the adhesive polymer be composed of an adhesive polymer. Examples of such an adhesive polymer include an acrylic adhesive and a sulfuric acid which are well known in the technical field of adhesives. Vinyl-based adhesives, rubber-based adhesives and the like are preferably used. In this way, by using the adhesive as the release layer, the active layer and the barrier layer can be easily adhered and laminated via the protruding layer while forming the release layer. As described above, when an active layer is formed on one layer of the barrier, a solution of the above-mentioned adhesive is applied on this active layer and dried, or a solid hot-melt adhesive is applied by melting. By doing so, an emission layer can be formed on the active layer. If a barrier layer is laminated on this release layer, the formulation according to the invention is obtained.

In the present invention, for example, an adhesive tape comprising a polyester film as a base material and an adhesive applied thereto is a laminate having a barrier layer and a release layer formed in advance. Can be used. Therefore, for example, if the active layer is formed on the polyester film and the adhesive tape of the polyester film substrate is laminated and bonded with the adhesive side facing the active layer, the preparation according to the present invention is obtained. be able to.

FIG. 1 shows a preparation 1 according to the present invention thus obtained, in which an active layer 2 is laminated with a release layer 3, and barrier layers 4 are laminated on both sides of the laminate.

However, in the preparation according to the present invention, as shown in FIG. 2, the active layer 2 has a release layer 3 on both sides thereof and a barrier layer 4 on the outside of the release layer. Is also good. Such a preparation can be obtained, for example, by laminating a release layer above the barrier layer, an active layer, a release layer and a barrier layer in this order. That is, the preparation according to the present invention only needs to have a release layer composed of a liquid active substance and a polymer having citrus solubility laminated on at least one surface of the active layer. On both sides of the laminate with the release layer, a barrier layer that does not substantially diffuse and transmit the liquid active substance is laminated. In the present invention, the barrier layer that is substantially impermeable to the liquid active substance is appropriately selected depending on the liquid active substance to be used, and is usually a metal foil such as an aluminum foil, or polyethylene terephthalate. A resin film made of, for example, is preferably used. Further, in the present invention, it is preferable that the barrier layer has a light-shielding property in order to exclude a change in the release rate of the liquid active substance from the preparation under the influence of solar radiation. Foil—colored resin layer, especially the former is preferably used.

As described above, in the preparation according to the present invention, the release layer composed of a polymer compatible with the liquid active substance is laminated on the active layer composed of the polymer layer containing the liquid active substance. The liquid active substance is diffused and transmitted on both sides of the body, and a ^: ぃ barrier layer is laminated.

Therefore, according to the multilayer preparation of the present invention, the liquid active substance diffuses and permeates from the active layer to the release layer, and is mainly released from the release layer to the atmosphere. Is exposed to the atmosphere, and the liquid active substance is released only from this side, so that it is released with high accuracy and at a relatively high speed at a substantially constant rate. In particular, according to the preparation of the present invention, since the laminate composed of the active layer and the release layer is covered with the barrier layer, the preparation is substantially free from the influence of wind even if it is applied outdoors. In addition, in accordance with the present invention, in this pore of the porous polymer layer having a large number of independent micropores, a liquid / active substance having a limited solubility in the polymer at room temperature is contained in this pore. If the active layer is formed by encapsulating the droplets in an amount exceeding Since the liquid active substance encapsulated in the micropores has limited solubility in the polymer, the liquid active substance in the micropores is suppressed from diffusing into the carrier polymer, and as a result, Through diffusion through the carrier polymer, the rate of release into the ambient atmosphere is maintained substantially constant and sustained release.

Further, as described above, when the layer has a light-shielding property, it is substantially unaffected by the solar radiation, and thus is slowly released from the preparation at a substantially constant rate over a long period of time. Further, the barrier layer having a light-shielding property has an effect of preventing the liquid active substance from being deteriorated or deteriorated by the solar radiation.

BRIEF DESCRIPTION OF THE FIGURES

Fig. 1 is a cross-sectional view showing one embodiment of the multilayer preparation according to the present invention. Fig. 2 is a cross-sectional view showing another embodiment of the multilayer preparation according to the present invention. Fig. 3 is the present invention and a comparative example. 4 is a graph showing an example of the change over time in the release amount of a liquid active substance from a preparation according to the invention.

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described below with reference to examples, but the present invention is not limited to these examples.

Example 1

Polycarbonate resin (Molelon, manufactured by Mopay Chemical Co., Ltd.) δ g and 3 g of Z—11-tetradecenyl acetate, a kind of insect phlomone, were added to methyl chloride. And dissolved in 10 g of a solution to obtain a homogeneous solution.

This solution was applied on a 50 ^ -thick polyethylene terephthalate (PET) film at room temperature with a coating of 70, and then 50 and 3 minutes It was dried and the methylene chloride was evaporated to prepare an active layer having a thickness of about 30 and having about 35% by weight of the above attractant on a PET film as a barrier layer.

Next, a pressure-sensitive adhesive tape having a PET film as a base was laminated on the exposed surface of the active layer with the pressure-sensitive adhesive layer side facing the active layer to prepare a multilayer preparation according to the present invention.

The solubility in the pheromone polycarbonate resin is about 5% by weight at room temperature.

Example 2

5 g of saturated polyester resin (Toyobo Co., Ltd. vial 200) and Z

—11—Tetradecenyl acetate (3 g) and tocopherol (0.3 g) as an antioxidant were dissolved in methylene chloride (10 g) to obtain a homogeneous solution.

Is this solution thick at room temperature on a PET film of thickness 50? And then dried with 50 parts for 3 minutes, and the methylene chloride is evaporated to obtain about 35% by weight of the above attractant on a PET film as a barrier layer. An active layer was prepared.

In addition, the solubility of the above chromone in the polyester resin is about 5% by weight at room temperature.

Example 3

5 g of a saturated polyester resin (manufactured by Nippon Synthetic Chemical Industry Co., Ltd .; Polyester-TP236) and (R, Z) 5 — (ί), a kind of insect pheromone 5-decenyl) dihydro_2 (3H) -furanone (5 g) and 2,6-di-t-butyl-14-methylphenol (0.5 g) as an antioxidant in methyl chloride And dissolved in 10 g of a solution to obtain a homogeneous solution.

This solution is applied on a 50 / mi-thick PET film at room temperature to a thickness of 50%, dried at 50'C for 3 minutes, and the methylene chloride is evaporated to form a PET layer as a barrier layer. An active layer having a thickness of about 25% and containing about 50% by weight of the above attractant was prepared on the film.

Next, a pressure-sensitive adhesive tape having a PET film as a base was laminated on the exposed surface of the active layer with the pressure-sensitive adhesive layer side facing the active layer to prepare a multilayer preparation according to the present invention. From gas chromatographic analysis, the release rate of pheromone from this product was 1 g '/ of · day. Comparative Example 1

5 g of saturated polyester resin (Vin 200 manufactured by Toyobo Co., Ltd.), 3 g of Z—11-tetradecenyl acetate, and 0.3 g of tocopherol as an antioxidant are mixed with methylene chloride. It was dissolved in 10 g to obtain a homogeneous solution.

This solution is applied on a PET film with a thickness of 70 ATII at room temperature, dried at 50 ° C for 3 minutes, the methylene chloride is evaporated, and the attractant is placed on the PET film. An active layer having a thickness of about 30 and a thickness of about 35% by weight was prepared.

A 50-layer thick PET film was directly thermo-compressed to the exposed surface of this active layer.

Each of the preparations obtained as described above was left in an open atmosphere at 30 ° C, and the amount of the liquid active substance remaining in the preparation was quantified over time by gas chromatography to determine the liquid activity. From the preparation of the substance The sustained release was examined. The results are shown in FIG. According to the preparation of the present invention, substantially all of the liquid active substance contained in the preparation is sustained-released at a relatively large constant rate. According to the preparation of Comparative Example, the release rate of the active substance is low. It is evident that it is small and practically no longer released over time, and that the amount remaining in the formulation is large.

Claims

If request range

(1) In a liquid active substance sustained-release multilayer preparation having an active layer composed of a polymer having a liquid active substance, the release layer composed of a polymer compatible with the liquid active substance is less than the active layer. And a barrier layer that substantially diffuses and permeates the liquid active material on both sides of the laminate of the active layer and the emission layer. Liquid active substance sustained release multi-layer formulation.

(2) In the pores of the porous polymer layer having a large number of independent pores, a liquid active material having a limited solubility in the polymer at room temperature exceeds the solubility. The sustained-release liquid active substance multilayer preparation according to claim 1, wherein the active layer is formed by being encapsulated as droplets.

(3) The liquid active substance sustained-release multilayer preparation according to claim 1 or 2, wherein the liquid active substance is an insect pheromone.