JP2007302653A - Sustained-release preparation included in foamed capillary - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a sustained-release preparation uniformly releasing a volatile medicament therein for a long period even if the liquid medicament in a tubular container including the preparation is decreased. <P>SOLUTION: The tubular container composed of outer and inner layers for the sustained-release preparation is provided, wherein the inner layer is 0.12-1.2 mm thick and of such foamed structure as to enable the liquid medicament to be sucked up by capillarity to a height of 25 mm or higher. A container unit for the sustained-release preparation, with a plurality of the above containers juxtaposed, is also provided. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a sustained-release preparation used for the purpose of releasing volatile drugs such as sex pheromones, repellents and insecticides and keeping the concentration in the atmosphere constant, and particularly releases sex pheromones. The present invention relates to a sustained-release preparation effective for a sustained-release preparation for controlling the occurrence of pests.

  The requirement to maintain the efficacy for a long time by gradually releasing volatile drugs is demanded by the communication disturbance method that releases sex pheromones at a constant concentration over a long period of time and suppresses the generation density of pests. Yes. The communication disruption method means that males and females cannot detect mating by locating the sex pheromone at a much higher concentration than the pests on the field, and the ability to detect individual sexes or reduce the communication ability to locate them. How to make it. In the communication disruption method, a sustained-release preparation containing a pest sex pheromone is used.

This sustained-release preparation has already been put into practical use and is commercially used, but due to its high performance stability, a plastic tubule filled with a sex pheromone has become the mainstream (Patent Document 1).
However, since the amount of residual liquid is reduced due to the discharge in the plastic thin tube, there is a problem that when the discharge area is lowered in the second half of the discharge, the discharge amount is lowered. In order to solve this problem, there has been proposed a plastic container having an inner layer which is a porous layer and each hole communicates with, and an outer layer having the same quality as the inner layer (Patent Document 2).
JP 57-156403 A JP-A-7-313035

  The inventors of the present invention have found that even if the porous layer has an inner layer having a continuous structure, the degree of liquid wetting on the inner surface of the container is different and does not necessarily result in uniform discharge. It was. Accordingly, an object of the present invention is to provide a sustained-release preparation capable of releasing a volatile drug uniformly for a long period of time even when the amount of the liquid drug inside the tubular container of the sustained-release preparation decreases. To do.

As a result of intensive studies to achieve the above object, the inner layer capable of sucking the liquid medicine up to a height exceeding 25 mm by capillary action is a tubular container having a foamed structure, and the inner layer has a thickness of 0. It has been found that a sustained-release preparation container having a size of 12 to 1.2 mm is useful for solving the above-mentioned problems, and has led to the present invention.
Specifically, it is a tubular container composed of two layers of an outer layer and an inner layer, the inner layer having a thickness of 0.12 to 1.2 mm, and sucking up a liquid medicine to a height exceeding 25 mm by capillary action. Provided is a sustained-release preparation container having a foam structure. Moreover, the container unit for sustained-release preparations provided with two or more this container for sustained-release preparations is provided. Furthermore, a sustained-release preparation comprising a sustained-release preparation container or a sustained-release preparation container unit and a liquid medicine accommodated in the container or the container unit is provided. In addition, a method for producing a container unit for sustained release preparation by extrusion molding comprising two layers of an outer layer and an inner layer, wherein the inner layer has two or more tubular containers having a thickness of 0.12 to 1.2 mm. And a dies having a flow path for the outer layer forming polymer so as to cover a plurality of flow paths for the inner layer forming polymer, and simultaneously extruding the inner layer forming polymer and the outer layer forming polymer. A method for producing a container unit for a releasable preparation is provided.

  ADVANTAGE OF THE INVENTION According to this invention, even if the quantity of the liquid chemical | medical agent inside the tubular container of a sustained release formulation decreases, the sustained release formulation which can release a volatile chemical | medical agent uniformly for a long period of time is obtained.

According to the present invention, a tubular container comprising two layers of an outer layer and an inner layer, the inner layer having a thickness of 0.12 to 1.2 mm, and sucking up a liquid medicine to a height exceeding 25 mm by capillary action A sustained-release preparation comprising a tubular container having a foamed structure and a liquid medicine accommodated in the tubular container can be provided.
The container for sustained-release preparation of the present invention is a tubular container in which an inner layer capable of sucking a liquid drug up to a height exceeding 25 mm by capillary action has a foamed structure, and the inner layer has a thickness of 0.12-1. 2 mm.
Whether or not the inner layer capable of sucking the liquid medicine up to a height exceeding 25 mm by capillary action is a capillary having a foamed structure is determined by placing one of the capillaries 11 on the colored liquid medicine 12 as shown in FIG. This can be done by immersing and examining if the liquid drug is sucked up to a predetermined height.
Specifically, the thin tube (inner layer) 11 to be used is inserted into a bottle 101 having a diameter of 3 cm and a height of 6 cm containing 1 cm of the liquid drug 12 to be used at room temperature (25 ° C.). A thin tube is inserted up to 5 mm from the liquid drug surface. The thin tube is fixed vertically using a wire 102. The difference between the position where the narrow tube is in contact with the liquid level of the liquid drug in the bottle and the position of the liquid level where the liquid level is elevated in the narrow tube after the liquid drug in the bottle is prevented from evaporating and left for 24 hours. Let the height be sucked up. If this height exceeds 25 mm, the said thin tube can be used as an inner layer.
The thin tube (inner layer) 11 to be used may be a thin tube including only the inner layer before forming the outer layer, or may be a thin tube including both the inner layer and the outer layer. Moreover, it is not limited to the capillary to be used, and any form that has a correlation with the capillary to be used and can confirm that the liquid medicine can be sucked up to a height exceeding 25 mm by capillary action during use can be used. The liquid drug is preferably a liquid drug scheduled to be used, but may be another liquid drug having a correlation with the liquid drug scheduled to be used.

It is known that the rising height (h) of the liquid in capillary action is given by the following equation.
h = 2γcosθ / rρg… (1)
Here, γ is the surface tension of the liquid, θ is the contact angle, r is the radius of the tube, ρ is the density of the liquid, and g is the acceleration of gravity. As can be seen from the equation (1), if the liquid and the material are determined, it can be seen that h depends only on r, but in the case of a foam structure, it is general that r is not constant and has a certain distribution. . Therefore, not all capillaries having a foamed structure are suitable as sustained-release preparations.
Therefore, in the sustained-release preparation of the present invention, the distance by which the tubule having a foamed structure sucks up the target liquid medicine was measured, and the height thereof exceeded 25 mm, preferably 30 mm or more. When this height is 25 mm or less, liquid wetting is insufficient and the uniformity of discharge cannot be obtained.

  The thickness of the inner layer of the tubular container having a foam structure is 0.12 to 1.2 mm, preferably 0.2 to 1.0 mm. If the thickness of the inner layer is less than 0.12 mm, the amount of the liquid drug that permeates and is retained is insufficient, and the release uniformity cannot be obtained. In particular, in the case of a container having a large inner diameter with an increased filling amount of a liquid drug, the uniformity of release cannot be obtained. If it exceeds 1.2 mm, the amount of the liquid drug adsorbed on the polymer forming the foamed layer increases, and the amount of the drug remaining without being released increases.

The foam diameter of the inner layer of the tubular container is preferably 0.2 to 700 μm, more preferably 0.3 to 500 μm. A more preferable foam diameter is 50 to 95% (number average) for 0.2 to 100 μm, and 5 to 50% (number average) for 100 to 700 μm. The foam diameter is obtained by observing the structure of the tubular container with a magnifier and measuring the pore diameter.
As shown in FIG. 2, the portion A having a small foam diameter in the tubular container serves to suck up the liquid far from the liquid surface, and the portion B having a large foam diameter serves to hold a large amount of liquid. It is thought that the liquid rises. On the other hand, as shown in FIG. 3, the tubule whose suction height remains at 20 mm is porous and has the same diameter even if the holes are continuous with each other.

  The container for sustained-release preparation of the present invention is a tube in which a first layer (inner layer) having a foamed structure as shown in FIG. 4 is coated with a second layer (outer layer) C of a polymer that controls the penetration rate of a liquid drug. Container. The polymer for controlling the penetration rate of the liquid drug is preferably a polyolefin, an olefin copolymer (olefin-olefin copolymer, olefin-ester copolymer, etc.), aliphatic polyester, or aliphatic ester copolymer ( Aliphatic ester-aliphatic ester copolymer, etc.). Specifically, high density polyethylene, polypropylene, ethylene-vinyl acetate copolymer, blend polymer of ethylene-vinyl acetate copolymer and aliphatic polyester, aliphatic polyester (biodegradable polymer), butylene succinate and butylene Examples include a copolymer with adipate (biodegradable polymer), a copolymer of butylene succinate and ethylene terephthalate (biodegradable polymer), and the like.

The coating layer (outer layer) that controls the penetration rate of the liquid drug regulates the rate of dissolution, diffusion, and evaporation from the outer surface of the liquid drug in the coating polymer. Therefore, the liquid drug and the polymer have moderate compatibility.
Moreover, since the thickness of the outer layer greatly affects the penetration rate of the liquid drug, it is necessary to select an appropriate thickness. The dimensions of the tubular container are not particularly limited, but an inner diameter of 0.5 to 3 mm and an outer diameter of 1.5 to 8 mm are preferable from the viewpoint of manufacturing and handling, and the thickness of the outer layer is such a size. It is preferable to combine with the inner layer so as to form a tubular container. The length of the tubular container is preferably 50 to 2,000 mm, more preferably 100 to 400 mm.

The inner layer of the tubular container of the sustained-release preparation of the present invention can be obtained by molding a polymer containing a foaming agent at or above the decomposition temperature of the foaming agent.
Although it does not specifically limit as a polymer which adds a foaming agent, Preferably, a high density polyethylene, a low density polyethylene, a crosslinking type polyethylene, an ethylene-vinyl acetate copolymer, an aliphatic polyester, the blend polymer of polyolefin and an aliphatic polyester, Polylactic acid is mentioned.
As the foaming agent, organic foaming agents such as azodicarbonamide, p, p′-oxybisbenzenesulfonylhydrazide, and inorganic foaming agents such as sodium hydrogen carbonate are used. Since the degree of foaming varies greatly depending on the concentration of the foaming agent and the processing temperature, it is necessary to study the concentration and processing temperature to obtain the desired foamed thin tube.
In order to obtain a foamed structure capable of sucking up a liquid medicine to a height exceeding 25 mm by capillary action, the foaming rate is preferably 15% by volume or more, more preferably 40% by volume or more.
Specifically, low-density polyethylene containing 2% by mass of azodicarbonamide is foamed at 190 to 200 ° C., and polylactic acid of 2.4% by mass of p, p′-oxybisbenzenesulfonylhydrazide is 160 to 170. Examples thereof include those foamed at ℃.

For the inner layer, a foaming agent may be added to the inner layer polymer to which a filler has been added.
Examples of the filler include talc, silica powder, titanium oxide, carbon black, magnesium silicate, calcium carbonate, magnesium carbonate, barium sulfate, aluminum sulfate, and calcium sulfate. When a filler is used, the dispersion of bubbles becomes dense, and an inner layer having a large distribution with a foam diameter of 0.2 to 100 μm is obtained.
The filler is preferably 4 to 60 parts by mass with respect to 100 parts by mass of the polymer for the inner layer, and 10 to 50 parts by mass is particularly preferable considering the distribution diameter of the bubbles and the strength of the inner layer.

In the inner layer, 1 to 5 parts by mass of silica powder can be preferably added to 100 parts by mass of the inner layer polymer. By adding silica powder, the foaming processing temperature can be lowered, and a foamed inner layer having a structure in which bubbles are densely dispersed can be obtained.
The silica powder preferably has an average particle size of 7 to 40 μm and has been subjected to a hydrophobic surface treatment with methyl group, trimethylsilyl group, dimethyl silicone oil, octylsilane, or the like. Specifically, Aerosil R972, Aerosil 200, Aerosil R202, Aerosil R805, Aerosil R812, Aerosil RX200, Aerosil RY200 (manufactured by Toshin Kasei), SS-30P, SS-70, SS-50 (manufactured by Tosoh Silica) ) And the like.

The sustained-release preparation container comprising the tubular container enclosing the foamed layer of the present invention is preferably produced by extrusion molding. More preferably, when extruding the molten polymer for the outer layer through the die, It extrudes while passing the above-mentioned foamed thin tube through the mandrel in the center.
Furthermore, two extruders are prepared, foamed resin is inserted into one extruder, the polymer for the outer layer that controls the penetration rate of the liquid drug is inserted into the other, and extrusion is performed while coating the outside of the foam tubule A method is also illustrated.

Further, in the sustained release preparation container unit in which a plurality of tubular containers are provided, the inner layer and the outer layer are formed using a die provided with an outer layer flow path so as to separately cover the plurality of polymer flow paths constituting the inner layer. There is a manufacturing method to extrude the two simultaneously.
For example, in the molding in which the inner layer and the outer layer are extruded at the same time by using a die processed into a shape capable of extruding a plurality of tubes using two extruders, the inner layers of the respective tubes are combined. Therefore, as shown in FIG. 5, there is a method of extruding using a die having a shape in which an outer layer flow path F2 is provided so as to separately cover the inner layer flow path F1 divided so as to extrude a plurality of tubes. It is done.

The obtained tubule is filled with a liquid medicine, both ends are sealed, and it can be used as a sustained-release preparation comprising the liquid medicine in a tubular container. Moreover, you may use with the sustained-release formulation unit of the shape which provided the tubular container side by side. This form of formulation can enclose separate liquid medicaments and can be used for multiple purposes. For example, FIG. 6 (A) shows a sustained-release preparation 20 in which plastic capillaries (tubular containers) 22a and 22b are combined at the fused end 23. FIG. If necessary, the tubular containers 22a and 22b can be separated and used as shown in FIG. 6 (B).
In addition, it is easy to suspend by separating the tubular container and the tubular container that are provided side by side, especially when used for sustained-release preparations that release sex pheromones and suppress the generation of pests. Is significantly improved.

Examples of liquid drugs include volatile liquids such as sex pheromones, repellents, and insecticides, and are particularly effective for sustained-release preparations that control the generation of pests by releasing sex pheromones.
Further, the liquid drug may be diluted with a solvent. In this case, the diluted product needs to be sucked up to a height exceeding 25 mm by capillary action.

EXAMPLES Hereinafter, although an Example is shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example.
[Example 1]
A high-density polyethylene to which 1 part by mass of sodium bicarbonate was added as a foaming agent was extruded at 190 ° C. to obtain a foamed capillary having an inner diameter of 1.22 mm and a thickness of 0.40 mm. FIG. 7 shows an enlarged photograph of the cross section of the thin tube. Based on the obtained cross-sectional enlarged photograph, the diameter of the formed bubbles was measured, and the distribution of the diameters of the bubbles was obtained. As a result, the distribution was 0.2% to 100 μm, 73% (number average), and 100% to 700 μm, 27% (number average).
The capillary tube was cut to 150 mm, and one end was immersed in a solution of Z8-dodecenyl acetate, which is a red-colored Nashihimeshinki sex pheromone. When this capillary tube was observed after being left for 24 hours, it was colored red over the entire length and was sucked up to a height of 150 mm by capillary action.
Next, a tube in which high-density polyethylene was coated so as to form a coating layer (outer layer) having a thickness of 0.50 mm was formed on the outside of the foamed thin tube by extrusion molding. FIG. 4 shows an enlarged photograph of the cross section of the thin tube. This tube was filled with Z8-dodecadienyl acetate, a sex pheromone of Nashihimeshinki, welded at a length of 200 mm, cut, and 240 mg of sex pheromone was enclosed to prepare a sustained-release preparation.
This formulation was exposed to a constant condition of a temperature of 30 ° C. and a wind speed of 0.7 m / s, and the change with time in the amount of sex pheromone released is shown in FIG. As can be seen from FIG. 8, there is a uniform release over 40 days. Further, the remaining amount of sex pheromone after 40 days was 10% of the initial filling amount.

[Example 2]
The foamed tubule molded in Example 1 was cut to 150 mm, and one end was immersed in a solution of Z11-tetradecenyl acetate, which is one component of the red-colored Chahamaki sex pheromone. When this capillary was observed after being left for 24 hours, it was sucked up to a height of 125 mm from the liquid surface.
Next, a tube in which high-density polyethylene was coated so as to form a coating layer (outer layer) having a thickness of 0.50 mm was formed on the outside of the foamed thin tube by extrusion molding. FIG. 4 shows an enlarged photograph of the cross section of the thin tube. This tube was filled with Z11-tetradecadienyl acetate, which is one component of Chahamaki's sex pheromone, welded with a length of 200 mm, and then cut to prepare a sustained-release preparation in which 240 mg of sex pheromone was enclosed.
This formulation was exposed to a constant condition of a temperature of 30 ° C. and a wind speed of 0.7 m / s, and the change with time in the amount of sex pheromone released is shown in FIG. As can be seen from FIG. 9, there is a uniform release over 60 days. Further, the remaining amount of sex pheromone after 60 days was 15% of the initial filling amount.

[Example 3]
The foamed thin tube formed in Example 1 was cut to 150 mm, and one end was immersed in a solution of Z13-icosen-10-one, which is a red-colored peach sink moth sex pheromone. When this capillary was observed after being left for 24 hours, it was sucked up to a height of 95 mm from the liquid level.
Next, a tube in which high-density polyethylene was coated so as to form a coating layer (outer layer) having a thickness of 0.50 mm was formed on the outside of the foamed thin tube by extrusion molding. FIG. 4 shows an enlarged photograph of the cross section of the thin tube. The tube was filled with Z13-icosen-10-one, a sex pheromone of peach sink moth, welded at a length of 200 mm, and then cut to prepare a sustained-release preparation in which 240 mg of sex pheromone was enclosed.
This formulation was exposed to a constant condition of a temperature of 30 ° C. and a wind speed of 0.7 m / s, and the change with time of the amount of sex pheromone released is shown in FIG. As can be seen from FIG. 10, there is a uniform release over 120 days. Further, the remaining amount of sex pheromone after 120 days was 18% of the initial filling amount.

[Example 4]
Polylactic acid added with 2.4 parts by mass of p, p′-oxybisbenzenesulfonylhydrazide as a foaming agent was extruded at 168 ° C. to obtain a foamed capillary having an inner diameter of 1.2 mm and a thickness of 0.30 mm. An enlarged photograph of the cross section of the thin tube is shown in FIG.
The capillary tube was cut to 150 mm, and one end was immersed in a solution of Z8-dodecenyl acetate, which is a red-colored Nashihimeshinki sex pheromone. When this capillary tube was observed after being left for 24 hours, it was colored red over the entire length and was sucked up to a height of 70 mm by capillary action.
Next, a copolymer of butylene succinate and butylene adipate (copolymer mass ratio succinate 80 / adipate 20) is formed on the outer side of the foamed thin tube by extrusion so as to form a coating layer (outer layer) having a thickness of 0.25 mm. The coated tube was molded. This tube was filled with Z8-dodecadienyl acetate, a sex pheromone of Nashihimeshinki, welded at a length of 200 mm, and then cut to prepare a sustained-release preparation in which 180 mg of sex pheromone was enclosed.
This formulation was exposed to a constant condition of a temperature of 30 ° C. and a wind speed of 0.7 m / s, and the change with time in the amount of sex pheromone released is shown in FIG. As can be seen from FIG. 12, there is a uniform release over 60 days. Further, the remaining amount of pheromone after 60 days was 15% of the initial filling amount.

[Example 5]
A high-density polyethylene to which 1.5 parts by mass of azodicarbonamide was added as a foaming agent was extruded at 190 ° C. to obtain a foamed capillary having an inner diameter of 1.52 mm and a thickness of 0.15 mm.
The capillary tube was cut to 150 mm, and one end was dipped in a solution of Z8-dodecadienyl acetate, which is a red-colored Nashihimeshinki sex pheromone. When this capillary tube was observed after being left for 24 hours, it was colored red over the entire length and was sucked up to a height of 150 mm by capillary action.
Next, a tube in which high-density polyethylene was coated so as to form a coating layer (outer layer) having a thickness of 0.60 mm on the outside of the foamed thin tube was formed by extrusion molding. The tube was filled with Z8-dodecenyl acetate, a sex pheromone of Nashihimeshinki, welded with a length of 200 mm, cut, and 280 mg of sex pheromone was enclosed to prepare a sustained release preparation.
This formulation was exposed to a constant condition of a temperature of 30 ° C. and a wind speed of 0.7 m / s, and the change over time in the release amount of sex pheromone is shown in FIG. As can be seen from FIG. 13, there was a uniform release over 60 days. Moreover, the remaining amount of pheromone after 40 days was 10% of the initial filling amount.

[Example 6]
A high density polyethylene to which 1.5 parts by mass of azodicarbonamide was added as a foaming agent was extruded at 190 ° C. to obtain a foamed capillary having an inner diameter of 1.52 mm and a thickness of 1.1 mm.
The capillary tube was cut to 150 mm, and one end was dipped in a solution of Z8-dodecadienyl acetate, which is a red-colored Nashihimeshinki sex pheromone. When this capillary tube was observed after being left for 24 hours, it was colored red over the entire length, and was sucked up to a height of 130 mm by capillary action.
Next, a tube in which high-density polyethylene was coated so as to form a coating layer (outer layer) having a thickness of 0.60 mm on the outside of the foamed thin tube was formed by extrusion molding. This tube was filled with Z8-dodecenyl acetate, a sex pheromone of Nashihimeshinki, welded at a length of 200 mm, and then cut to prepare a sustained-release preparation containing 280 mg of sex pheromone.
This formulation was exposed to a constant condition of a temperature of 30 ° C. and a wind speed of 0.7 m / s, and the change over time in the release amount of sex pheromone is shown in FIG. As can be seen from FIG. 13, there was a uniform release over 55 days. Further, the remaining amount of pheromone after 40 days was 15% of the initial filling amount.

[Example 7]
High-density polyethylene containing 2.0 parts by weight of azodicarbonamide as a foaming agent and 35 parts by weight of talc as a filler is extruded by one extruder, extruded at 190 ° C., and then from the second extruder. Extruded a high-density polyethylene at 190 ° C. to obtain a thin tube having an outer layer coating layer having a thickness of 0.60 mm on the outside of a foam layer having an inner diameter of 1.52 mm and a thickness of 1.1 mm.
The capillary tube was cut to 150 mm, and one end was immersed in a solution of Z8-dodecenyl acetate, which is a red-colored Nashihimeshinki sex pheromone. When this capillary tube was observed after being left for 24 hours, it was colored red over the entire length, and was sucked up to a height of 130 mm by capillary action.
In addition, this foamed thin tube was cut into rounds, photographed on a cross-sectional enlarged photograph (FIG. 14), the diameter of the formed bubbles was measured, and the distribution of the diameters of the bubbles was obtained. As a result, 0.2 to 100 μm had a distribution of 90% (number average), and 100 to 700 μm had a distribution of 10% (number average).
This tube was filled with Z8-dodecadienyl acetate, a sex pheromone of Nashihimeshinki, welded with a length of 200 mm, and then cut to prepare a sustained-release preparation containing 280 mg of sex pheromone.
This preparation was exposed to a constant condition of a temperature of 30 ° C. and a wind speed of 0.7 m / s, and the change over time in the amount of sex pheromone released was measured.
As a result, a uniform release was obtained over about 60 days. Further, the remaining amount of pheromone after 60 days was 10% of the initial filling amount.

[Example 8]
A copolymer of butylene succinate and butylene adipate containing 2.0 parts by weight of sodium hydrogen carbonate as a foaming agent and 35 parts by weight of talc as a filler was extruded at 165 ° C. with a first extruder, and 2 While extruding two tubes at the same time, a copolymer of butylene succinate and butylene adipate is extruded from the second extruder at 165 ° C., so that the outside of the foam layer having an inner diameter of 1.42 mm and a thickness of 0.3 mm is obtained. A two-tube parallel thin tube having an outer coating layer having a thickness of 0.60 mm was obtained.
The capillary tube was cut to 150 mm, and one end was immersed in a 1: 1 mixed solution of Z11-hexadecenyl acetate and Z11-hexadecenal, a red-colored diamondback pheromone. When this capillary was observed after being left for 24 hours, it was colored red over the entire length, and was sucked up to a height of 100 mm by capillary action.
In addition, this foamed thin tube was cut into rounds, photographed in a cross-sectional enlarged photograph (FIG. 15), the diameter of the formed bubbles was measured, and the distribution of the diameters of the bubbles was obtained. As a result, 0.2 to 100 μm had a distribution of 60% (number average), and 100 to 700 μm had a distribution of 40% (number average).
This tube is filled with a 1: 1 mixed solution of Z11-hexadecenyl acetate and Z11-hexadecenal, which is the sexipheral sex pheromone, and is cut after welding at a length of 200 mm. A sustained-release preparation encapsulating 460 mg of pheromone was prepared.
This preparation was exposed to a constant condition of a temperature of 30 ° C. and a wind speed of 0.7 m / s, and the change over time in the amount of sex pheromone released was measured.
As a result, a uniform release was obtained over about 60 days. Further, the remaining amount of pheromone after 60 days was 20% of the initial filling amount.

[Example 9]
High-density polyethylene containing 2.0 parts by mass of azodicarbonamide as a foaming agent, 35 parts by mass of talc as a filler, and 2.0 parts by mass of R972 (manufactured by Toshin Kasei Co., Ltd.) as an airgel is extruded by the first extruder. By extruding at 160 ° C., and extruding high-density polyethylene from the second extruder at 160 ° C., to the outside of the foam layer having an inner diameter of 1.52 mm and a thickness of 1.1 mm, having a thickness of 0.60 mm. A capillary with an outer coating layer was obtained.
The capillary tube was cut to 150 mm, and one end was immersed in a solution of Z8-dodecenyl acetate, which is a red-colored Nashihimeshinki sex pheromone. When this capillary tube was observed after being left for 24 hours, it was colored red over the entire length, and was sucked up to a height of 130 mm by capillary action.
In addition, this foamed thin tube was cut into rounds, photographed on a cross-sectional enlarged photograph (FIG. 16), the diameter of the formed bubbles was measured, and the distribution of the diameters of the bubbles was obtained. As a result, 0.2 to 100 μm had a distribution of 95% (number average), and 100 to 700 μm had a distribution of 5% (number average).
This tube was filled with Z8-dodecenyl acetate, a sex pheromone of Nashihimeshinki, welded at a length of 200 mm, and then cut to prepare a sustained-release preparation containing 280 mg of sex pheromone.
This preparation was exposed to a constant condition of a temperature of 30 ° C. and a wind speed of 0.7 m / s, and the change over time in the amount of sex pheromone released was measured.
As a result, a uniform release was obtained over about 60 days. Further, the remaining amount of pheromone after 60 days was 10% of the initial filling amount.

[Comparative Example 1]
A high-density polyethylene to which 1 part by mass of sodium bicarbonate was added as a foaming agent was extruded at 155 ° C. to obtain a foamed capillary having an inner diameter of 1.22 mm and a thickness of 0.40 mm. A cross-sectional enlarged photograph of the thin tube is shown in FIG.
The capillary tube was cut to 150 mm, and one end was immersed in a solution of Z8-dodecenyl acetate, which is a red-colored Nashihimeshinki sex pheromone. When this capillary was observed after being left for 24 hours, it was sucked up to a height of 25 mm from the liquid level.
Next, a tube coated with high-density polyethylene was formed by extrusion molding so that a coating layer (outer layer) having a thickness of 0.25 mm was formed on the outside of the foamed thin tube. The tube was filled with Z8-dodecadienyl acetate, a sex pheromone of Nashihimeshinki, welded at a length of 200 mm, and then cut to prepare a sustained-release preparation in which 240 mg of sex pheromone was enclosed.
This formulation was exposed to a constant condition of a temperature of 30 ° C. and a wind speed of 0.7 m / s, and the time-dependent change in the amount of pheromone released is shown in FIG. As can be seen from FIG. 8, this sustained release formulation has a uniform release over 30 days and then the release rate gradually decreases. Further, the remaining amount of sex pheromone after 30 days was 35% of the initial filling amount.

[Comparative Example 2]
A high-density polyethylene to which 1 part by mass of sodium bicarbonate was added as a foaming agent was extruded at 190 ° C. to obtain a foamed capillary having an inner diameter of 1.22 mm and a thickness of 0.1 mm.
The capillary tube was cut to 150 mm, and one end was immersed in a solution of Z8-dodecenyl acetate, which is a red-colored Nashihimeshinki sex pheromone. When this capillary tube was observed after being left for 24 hours, it was colored red over the entire length and was sucked up to a height of 150 mm by capillary action.
Next, a tube in which high-density polyethylene was coated so as to form a coating layer (outer layer) having a thickness of 0.50 mm was formed on the outside of the foamed thin tube by extrusion molding. This tube was filled with Z8-dodecadienyl acetate, a sex pheromone of Nashihimeshinki, welded with a length of 200 mm, cut, and 240 mg of sex pheromone was enclosed to prepare a sustained-release preparation.
This formulation was exposed to a constant condition of a temperature of 30 ° C. and a wind speed of 0.7 m / s, and the change with time in the amount of sex pheromone released is shown in FIG. As can be seen from FIG. 8, this sustained release formulation has a uniform release over 40 days, after which the release rate gradually decreases. Further, the remaining amount of sex pheromone after 40 days was 40% of the initial filling amount.

[Comparative Example 3]
A high density polyethylene to which 1.5 parts by mass of azodicarbonamide was added as a foaming agent was extruded at 190 ° C. to obtain a foamed capillary having an inner diameter of 1.52 mm and a thickness of 1.3 mm.
The capillary tube was cut to 150 mm, and one end was immersed in a solution of Z8-dodecenyl acetate, which is a red-colored Nashihimeshinki sex pheromone. When this capillary was observed after being left for 24 hours, it was colored red over the entire length, and was sucked up to a height of 100 mm by capillary action.
Next, a tube in which high-density polyethylene was coated so as to form a coating layer (outer layer) having a thickness of 0.60 mm on the outside of the foamed thin tube was formed by extrusion molding. This tube was filled with Z8-dodecadienyl acetate, a sex pheromone of Nashihimeshinki, welded at a length of 200 mm, cut, and 280 mg of sex pheromone was enclosed to prepare a sustained release preparation.
This formulation was exposed to a constant condition of a temperature of 30 ° C. and a wind speed of 0.7 m / s, and the change over time in the release amount of sex pheromone is shown in FIG. As can be seen from FIG. 13, this sustained release formulation had a uniform release over 40 days, after which the release rate decreased significantly. Further, the remaining amount of the sex pheromone after 40 days was 40% of the initial filling amount, and it was found that most of it was dissolved in the foamed layer polymer of the tube.

It is a figure which shows the method of measuring siphoning height. It is sectional drawing (40 times) which shows the foam structure of the inner layer of a sustained release formulation. It is sectional drawing (40 times) which shows the foaming structure of the thin tube where the height which sucks up remains at 20 mm. It is sectional drawing (40 times) of an example of the sustained release formulation which coat | covered the polymer which controls the osmosis | permeation rate of a liquid chemical | medical agent on the outer side of the foaming layer inner tube in Examples 1-3. It is a figure which shows the manufacturing apparatus of the container unit for sustained release preparations. (A) shows a sustained-release preparation with a thin tube (tubular container), and (B) shows the separation of the thin tube. It is sectional drawing (40 times) which shows the foam structure of the inner layer of the sustained release formulation in Example 1. FIG. It is a figure which shows a time-dependent change of the release of the sex pheromone of Nashihimeshinki in Example 1, Comparative Example 1 and Comparative Example 2. It is a figure which shows the time-dependent change of the release of the chahamaki sex pheromone in Example 2. It is a figure which shows the time-dependent change of the release of the sex pheromone of the peach moth in Example 3. It is sectional drawing (40 times) which shows the foaming structure of the inner layer of the sustained release formulation in Example 4. FIG. It is a figure which shows the time-dependent change of the release of the sex pheromone of Nashihimeshinki in Example 4. It is a figure which shows the time-dependent change of the release of the sex pheromone of Nashihimeshinki in Example 5, Example 6, and Comparative Example 3. It is sectional drawing (40 times) which shows the foam structure of the inner layer of the sustained release formulation in Example 7. It is sectional drawing (40 times) which shows the foam structure of the inner layer of the sustained release formulation in Example 8. It is sectional drawing (40 times) which shows the foaming structure of the inner layer of the sustained release formulation in Example 9. FIG.

Explanation of symbols

DESCRIPTION OF SYMBOLS 11 Fine tube 12 Liquid medicine 20 Sustained release preparation 22a, 22b Plastic thin tube 23 Fusion end 101 Bottle 102 Wire F1 Inner layer flow path F2 Outer layer flow path

Claims (10)

  A tubular container composed of two layers of an outer layer and an inner layer, the inner layer having a thickness of 0.12 to 1.2 mm, and having a foamed structure capable of sucking up a liquid medicine to a height exceeding 25 mm by capillary action A container for a sustained-release preparation.   The container for sustained release preparation according to claim 1, wherein the foam diameter of the inner layer has a distribution of 0.2 to 700 µm.   The container for sustained-release preparation according to claim 1 or 2, wherein the outer layer is a polymer that controls the penetration rate of the liquid drug.   The container for sustained-release preparation according to claim 3, wherein the polymer for controlling the penetration rate of the liquid drug is a polyolefin, an olefin copolymer, an aliphatic polyester, or an aliphatic ester copolymer.   The container for sustained release preparation according to any one of claims 1 to 4, wherein the liquid drug is a sex pheromone.   The container for sustained release preparation according to any one of claims 1 to 5, wherein the inner layer contains a filler.   The sustained-release preparation container according to any one of claims 1 to 6, wherein the inner layer contains silica powder.   A container unit for sustained-release preparation comprising a plurality of containers for sustained-release preparation according to any one of claims 1 to 7.   A sustained-release preparation container according to any one of claims 1 to 7, or a sustained-release preparation container unit according to claim 8, and a liquid medicine accommodated in the container or the container unit. A sustained-release preparation.   A method for producing a container unit for sustained release preparation by extrusion molding comprising two layers of an outer layer and an inner layer, wherein the inner layer has two or more tubular containers having a thickness of 0.12 to 1.2 mm. The controlled release property is characterized in that the inner layer forming polymer and the outer layer forming polymer are extruded simultaneously using a die provided with a flow path of the outer layer forming polymer so as to cover a plurality of flow paths of the inner layer forming polymer. A method for producing a pharmaceutical container unit.