JP2606255B2 - Drug dispenser - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a drug dispenser for sustained release of a vaporizable drug.

<Prior Art> As a drug dispenser of the type that releases a volatile drug slowly, a drug dispenser that releases a drug from the surface of a laminated film having a film containing a drug as an intermediate layer (JP-A-59-25)
No. 319) and those which release a drug from the side of a laminated sheet having a drug barrier layer on both sides of a layer containing the drug (Japanese Patent Application Laid-Open No. 58-11145) are known.

<Problems to be Solved by the Invention> However, the former drug dispenser has a large surface area for releasing the drug with respect to the volume of the intermediate layer composed of the drug-containing film, and thus it is difficult to maintain the drug effect for a long period of time. Further, in the latter drug dispenser, since the drug is released from the side surface of the laminated sheet, the initial release rate is large and the release rate is reduced within a very short period of time. That is, the release rate is not constant, and the drug efficacy is rapidly reduced.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a drug dispenser which exhibits a drug effect by releasing a vaporizable drug over a long period of time and at a release rate as constant as possible.

<Means for Solving the Problems> The present inventors have been intensively studying a drug dispenser that releases a vaporizable drug slowly. As a result, the present inventors have found out the relationship between the drug absorption amount of the resin constituting the drug dispenser and the efficacy of the drug dispenser, and have completed the present invention.

That is, the present invention provides a drug dispenser in which a resin (A) containing an amount of a drug (a) corresponding to 1 to 90% of a saturated absorption amount is coated with a resin (B).

Here, the drug (a) is liquid or waxy at 20 ° C. and has a vapor pressure of 0.00005 mmHg at 30 ° C.
The resin (A) is a resin having a saturated absorption amount of 4.0% by weight or more for the drug (A) at 20 ° C., and the resin (B) is a resin having a saturated absorption amount for the drug (A) at 20 ° C. It is a resin having an absorption amount of 0.1 to 2.0% by weight.

 The chemicals used in the present invention are insecticides, insect repellents, rust preventives, aroma
Agents and repellents, but inside resin A and resin B
That diffuses quickly and is easy to evaporate
Liquid or waxy at 20 ° C
And the vapor pressure at 30 ° C is 0.00005 (mmHg) or less.
The above agents are preferred. Chemicals with a vapor pressure of less than 0.00005 mmHg
In the case of the above, the surface layer of the molded body composed of the resin A and the chemical is
If the drug concentration is not high,
Suitable for long-term sustained-release drug dispensers
Not right. 1-ethynyl-2-methyl as insecticide
-2-pentenyl-chrisansmate (for example, Sumitomo Chemical
Vapor Surin manufactured by Kogyo Co., Ltd. ), The transpiration rate and
It is preferable because the speed at which the drug concentration becomes uniform inside the resin is fast.
No.

The saturated absorption amount of the resin A or the resin B for the drug is the maximum amount of the drug that the resin can absorb when the resin is immersed in the drug.

The resin A used in the present invention has a saturated absorption amount of the drug at 20 ° C. of 4.0% by weight or more, more preferably 5.0% by weight or more. 4.0% by weight of saturated absorption
It is not preferable to use a resin of less than 10% because the difference in the saturated absorption amount with the resin B described later is small.

Specific examples of the resin A include ethylene-vinyl acetate copolymer, ethylene-methyl (meth) acrylate copolymer, ethylene-ethyl from the viewpoints of saturation absorption, drug stability, drug diffusion rate, moldability, and the like. Copolymers of ethylene and a monomer having a polar group, such as an acrylate copolymer and an ethylene-vinyl acetate-methyl (meth) acrylate copolymer, among which 3 mol% of a monomer having a polar group Copolymers containing the above are preferred. Particularly preferred is an ethylene-vinyl acetate copolymer obtained by copolymerizing 3 mol% or more of vinyl acetate.

The content of the drug in the molded product composed of the composition containing the resin A and the drug is 1 to the saturated absorption amount of the resin A for the drug.
An amount corresponding to 90%, more preferably an amount corresponding to 5 to 80%. When the content of the drug is less than 1% of the saturated absorption amount, no drug effect is exhibited from the beginning because the absolute amount of the drug content is small. On the other hand, when the content exceeds 90% by weight, the transfer of the drug from the resin A to the resin B is performed rapidly, so that a long-term sustained release effect cannot be expected.

The resin B used in the present invention has a saturated absorption amount for a drug at 20 ° C. of 0.1 to 2.0% by weight, more preferably 0.2 to 1.5% by weight. If the amount is less than 0.1% by weight, the release amount does not reach the medicinal level, and 2.0% by weight
If it exceeds, a drug dispenser exhibiting a long-term sustained release effect cannot be obtained.

Examples of the resin B include low-density polyethylene, medium-density polyethylene, high-density polyethylene, polypropylene, and the like, and a copolymer of ethylene and a polar group-containing monomer containing 2 mol% or less of a polar group-containing monomer. And the like, ethylene-vinyl acetate copolymer as the copolymer,
Examples thereof include an ethylene-methyl (meth) acrylate copolymer, an ethylene-ethyl acrylate copolymer, and an ethylene-vinyl acetate-methyl (meth) acrylate copolymer. Particularly preferred as the resin B are low-density polyethylene, medium-density polyethylene, high-density polyethylene, and ethylene-vinyl acetate copolymer containing 2 mol% or less of vinyl acetate from the viewpoint of processability and flexibility.

In the present invention, for example, an antioxidant, an ultraviolet absorber, an anti-blocking agent, etc., within a range that does not impair the object of the present invention by, for example, greatly changing the saturated absorption amount of the resin A or the resin B for the drug. They can be used as appropriate.

The manufacturing method of the medicine dispenser of this invention is illustrated. First, the resin A is mixed with a drug and, if necessary, an antioxidant, an anti-blocking agent, and the like by a usual method such as a roll-type or Banbury-type mixer or an extruder, and a processing method of a synthetic resin from the obtained mixture. A molded article having a desired shape is obtained by a usual method known as, for example, injection processing, or a chip-shaped molded article is obtained by punching or the like from a sheet obtained by extrusion, calendering, or the like. On the other hand, the resin B and, if necessary, an antioxidant and an anti-blocking agent are kneaded by a usual method using a roll-type or Banbury-type mixer or an extruder, and the resulting mixture is processed into a synthetic resin. Into a film by a usual method known as, for example, inflation processing, calendar processing, T-die processing, or the like. Next, as a method of obtaining the medicine dispenser by coating the above-mentioned molded body composed of the resin A and the medicine with the above-mentioned film composed of the resin B and the like, the molded body is wrapped with a film, and then the film is heat-sealed. And a method in which the molded body is packaged with a film, the film is heat-shrinked, the molded body and the film are brought into close contact with each other, and then the film is sealed and coated.

In order for the drug dispenser thus obtained to achieve the object of the present invention satisfactorily, it is necessary to reduce the total surface area of the molded article.
Preferably, at least 60% is in contact with the surface of the film. Also, if the volume of the molded body is too small, it is not possible to expect long-term drug efficacy, so the minimum side length is 1 m
It is preferable that the formed body be a disk, a cylinder, a polygonal prism such as a triangular prism or a quadrangular prism having a length of at least m. Furthermore, the thickness of the film made of the resin B covering the molded body is preferably 100 μm or less in order to cover the molded body or the chip of the resin A containing the medicine and to control the amount of evaporation of the medicine. , 10 to 50 μm is a more preferred range.
If the film thickness of the resin B exceeds 100 μm, it is not preferable because the evaporation of the chemical becomes minute or it takes a long time before the evaporation starts.

The drug dispenser of the present invention exhibits a drug effect by releasing a vaporizable drug over a long period of time and at a release rate as constant as possible.Here, a long term means that the drug effect lasts for several months or more. Say.

<Operation> The drug dispenser of the present invention utilizes the absorption performance of a resin for a drug, and a resin A having a different absorption performance is used.
The effect is exhibited by contacting the resin B with the resin B.

In general, it is said that liquid small molecules in a matrix are rapidly diffused in a direction in which no concentration gradient is formed according to Fick's law and stabilized as a system. The diffusion behavior of the liquid small molecule in the resin diffuses in a direction that does not create a concentration gradient and stabilizes when mixed at about 90% or less of the saturated absorption amount. However, before and after the saturated absorption, it behaves completely differently, and if liquid low-molecules are mixed in excess of the saturation absorption, it will be released from the inside of the resin at a high speed up to about 90% of the saturated absorption, at which point the release will be Stop. Since this phenomenon occurs due to the movement of resin molecules, etc., it is very difficult to suppress the release, and at the same time, the phenomenon of reabsorption of the bleed material into the resin due to the contact between the surface of the drug dispenser and an external object is determined. Therefore, it does not become a drug dispenser having stable performance. In addition, since the release behavior is performed from the time of manufacture, the expected effect is not always exhibited during use.

Therefore, in order to stably provide a drug effect and to give a sustained release effect, a drug dispenser which exerts its effect by evaporation from a resin in a saturated system is considered. However, when considering the evaporation of the drug from the same resin, the amount of evaporation is greatly affected by the concentration of the drug present in the surface layer of the resin. The amount was so large that it quickly became a drug dispenser whose transpiration decreased, and a long-term sustained release effect could not be expected.

However, the saturated absorption amount of the resin differs depending on the type of resin, and the concentration in the system below the saturated absorption amount when different resins are brought into contact by selecting the resin and the chemical does not become uniform, and the saturated absorption amount of the contact resin Stabilize as a system with the concentration difference corresponding to the amount.

Therefore, depending on the selection of the resin and the small molecule, when a resin having a high saturation absorption is mixed with a liquid medicine having a saturation absorption or less and a resin having a low saturation absorption is brought into contact with the resin, the inside of the resin having a high saturation absorption is reduced. The drug concentration in the resin having a high drug concentration and a low saturated absorption amount is stabilized in a low state.

In the present invention, the saturation absorption at 20 ° C. of the resin mixed with the drug is set to 4.0% by weight or more because the difference in the saturation absorption between the resin used for coating and the resin used for coating becomes small when the resin used is less than 4.0% by weight. The reason is that mixing the drug in an amount corresponding to 1 to 90% or less of the saturated absorption does not cause a rapid release from the resin inside at the saturation absorption or more. It is to make a system.

Further, the saturated absorption amount at 20 ° C. of the coating resin is 0.1%.
The content of not more than 2.0% by weight is necessary in order to suppress the amount of evaporation from the resin surface and to exert a long-term sustained release effect. In particular, at 20 ° C., the resin A of the molded body and the resin B of the film to be coated are formed at 20 ° C. It is more preferable that the difference between the saturated absorption amounts is 4.0% by weight or more from the viewpoint of exhibiting a long-term sustained release effect.

The chemicals used in the present invention need to have instantaneous concentration uniformity inside the resin and have the ability to evaporate to some extent at the use temperature, and the vapor pressure at 30 ° C. is 0.
[00005] It is preferable to select a vaporizable agent that is liquid or waxy at 20 ° C. or higher at 20 ° C. (mmHg) or more in view of evaporation from the inside of the film and instantaneous concentration uniformity within the same resin. In general, a drug having a vapor pressure of less than 0.00005 (mmHg) cannot be expected to exert its efficacy unless the concentration of the resin surface layer is increased, and is not suitable as a drug dispenser having a long-term sustained release.

<Examples> Hereinafter, examples of the present invention will be described, but the present invention is not limited thereto. In addition, the measuring method of the physical quantity in an Example is as follows.

Saturated absorption amount: After immersing a sheet-like resin having a size of 40 × 10 × 0.5 thickness (unit: mm) in a drug at 20 ° C. until saturation, it was calculated by the following equation.

｛(X ₁ −X ₂ ) / X ₁ ｝ × 100 (%) (where X ₁ represents the weight of the sheet resin after immersion, and X ₂ represents the weight of the sheet resin before immersion) The amount of the transpiration of the drug shown in the comparative example was determined by extracting the drug concentration (remaining amount) inside the drug dispenser after a certain period of time with a Soxhlet extractor using acetone as a solvent, followed by gas chromatography (manufactured by Shimadzu Corporation). GC
-7A, liquid phase DEGS 2%, carrier ChromosorbW AW, DMCS treatment, using a 100-120 mesh 1 m long column) and calculated from the residual amount.

Example 1 1-ethynyl-2-methyl-2- as a drug has a vapor pressure of 0.00162 (mmHg) at 30 ° C. and is liquid at 20 ° C.
Using pentenyl-chrysanth mate (trade name: Vapor Surin, manufactured by Sumitomo Chemical Co., Ltd.), an ethylene-vinyl acetate copolymer (trade name: Evatate H2020, manufactured by Sumitomo Chemical Co., Ltd., 5.4 mol of vinyl acetate) as resin A %, 20% of the drug
99.1 parts by weight)
0.9 parts by weight was kneaded with a Banbury-type kneader, and the obtained kneaded product was formed into a disk having a diameter of 30 mm and a thickness of 6 mm.

Low-density polyethylene as resin B (Sumikasen F208-O, trade name, manufactured by Sumitomo Chemical Co., Ltd., saturated absorption of 0.38% by weight of the drug at 20 ° C.) was formed into a 50 μm thick film by inflation.

After the disc-shaped molded body was covered with a film made of resin B, the opening was sealed by heat sealing to obtain a medicine dispenser.

The drug dispenser was left in an atmosphere at 20 ° C., and the amount of transpiration was measured over time. The remaining amount of drug (mg) per time is the first
As shown in the table, the drug dispenser had a long-term sustained release effect.

Example 2 As a resin B, an ethylene-vinyl acetate copolymer (trade name: Evatate D2011, manufactured by Sumitomo Chemical Co., Ltd .; vinyl acetate 1.7)
Mol%, saturation absorption of the drug at 20 ° C. 1.90% by weight)
A drug dispenser was obtained in the same manner as in Example 1 except that

The dispenser was left in a 20 ° C. atmosphere and the amount of transpiration was measured over time. As a result, as shown in Table 1, the dispenser improved the release rate, and had a sustained release effect over a longer period, although shorter than that of Example 1.

Comparative Example 1 A method similar to that of Example 2 was used except that low-density polyethylene (Sumikasen F208-0, trade name, manufactured by Sumitomo Chemical Co., Ltd., saturated absorption amount of the drug at 20 ° C. 0.38% by weight) was used as resin A. To obtain a drug dispenser. However, in this drug dispenser, the drug bleeds out during the molding process, and the sustained release effect was not preferable as shown in Table 1.

Comparative Example 2 A dispenser was obtained in the same manner as in Example 1, except that the dispenser was not coated with the resin B. This dispenser at 20 ℃
It was left in the atmosphere and the amount of transpiration was measured over time. The result is first
As shown in the table, the amount of transpiration resulted in an extremely reduced drug dispenser over time.

Claims (1)

(57) [Claims] 1. A drug dispenser comprising a resin (A) containing a drug (a) in an amount corresponding to 1 to 90% of the saturated absorption amount, coated with the resin (B). Here, the drug (a) is a liquid or wax-like drug at 20 ° C. and has a vapor pressure of 0.00005 mmHg or more at 30 ° C., and the resin (A) is saturated with the drug (a) at 20 ° C. It is a resin having an absorption of 4.0% by weight or more, and the resin (B) is a resin having a saturated absorption of 0.1 to 2.0% by weight with respect to the drug (A) at 20 ° C.