JP2002306584A - Drug sustained release formulation - Google Patents

Abstract

(57) [Summary] [PROBLEMS] To provide a constant sustained release of volatile agents such as fragrances over a long period of time. SOLUTION: Content containing volatile drug (14)
Is a gel having a slight fluidity of 30 mm in the liquid confirmation test in 90 seconds to 24 hours, preferably 90 seconds to 12 hours, more preferably 90 seconds to 30 minutes, preferably an oil gel.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a sustained-release drug preparation and a replaceable article, and more particularly to a preparation and a replaceable article for sustained release of a fragrance, an antibacterial agent and other similar volatile substances over a long period of time. About.

[0002]

2. Description of the Related Art Conventionally, in order to obtain sustained drug effects such as fragrance of fragrances, as a preparation for sustained release of volatile chemicals, a fibrous or porous substance such as pulp or silica gel has been used as a carrier. Known are those in which these are impregnated with a drug, those in which a drug is formed into a sol with silica or the like, and those in which a drug is gelled with a gelling agent.

[0003]

The impregnated and sol-type sustained-release drug preparations have a weaker drug-retaining effect than the gel-type preparations, so that the easily volatilizable components in the drug stand out in the early stage of use. It volatilizes, and the vaporization speed of the drug increases.
As a result, the drug cannot be gradually released over a long period of time, for example, the drug cannot be gradually released over a desired period, or the volatile component changes remarkably between the early and late stages of volatilization.

[0004] Conventional gel-type drug sustained-release preparations are formulated as gels having no fluidity in liquid confirmation tests, so that a larger amount of drug is volatilized than the volatilized surface in the early stage of use, and only the volatilized surface is used. Is dried and the volatilization surface is covered with the dried film, and a phenomenon occurs in which the volatilization ends with the drug retained inside. For this reason, in the conventional gel-type sustained-release drug preparation, the drug cannot be volatilized to the end, and it is difficult to release all the drugs constantly over a long period of time. It is extremely difficult to determine the end of the release.

The present invention has been made to solve the above-mentioned problems, and an object of the present invention is to provide a drug sustained-release preparation excellent in visibility of the remaining amount of a drug and a replaceable article.

[0006]

Means for Solving the Problems In order to achieve the above-mentioned object, a sustained-release preparation for a drug according to the present invention is characterized in that a content containing a volatile drug has a moving time of 30 mm for 90 seconds in a liquid confirmation test for 90 seconds. It has the form of a gel with a flowability of ２４24 hours.

According to the sustained-release drug preparation, the remaining amount of the drug can be easily visually recognized based on the level of the content containing the drug. Further, it is easy to determine the end of the sustained release of the drug. The sustained-release preparation for a drug preferably can maintain a constant sustained release amount of a volatile drug such as a fragrance for a long period of time.
More specifically, since the drug sustained-release preparation is a gel having fluidity, preferably, the volatilization surface moves with the sustained release of the drug, and the volatilization surface does not dry, and is preferably used over a long period of time. A certain amount of drug can be volatilized. This drug sustained release formulation, in the liquid confirmation test described below, 90 seconds to 12 hours,
More preferably, the gel has a slight fluidity of 90 seconds to 30 minutes. More preferably, the gel is an oil gel. This sustained-release drug preparation can be used as a heat-evaporating aroma deodorant.

[0008] The sustained-release drug preparation is preferably volatilized through a permeable polymer film. Thereby, the drug volatilization speed, the material, density,
It can be controlled by the film thickness. It is preferable that the drug sustained release preparation is volatilized by heating. This allows a sustained release for a long period (for example, 1.5 months or more). The reason why it is preferable to volatilize the drug by heating is to effectively volatilize components in the drug that are difficult to volatilize at room temperature, and to be able to volatilize the drug quickly and effectively in a space such as a room. No.

Further, in order to achieve the above-mentioned object, a replaceable article according to the present invention is a replaceable article in which the content containing a volatile agent is a gel having fluidity, and at least a part thereof is formed of a permeable polymer film. The contents are contained in the configured container.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The drug sustained-release preparation according to the present invention is obtained by converting a volatile drug into an oil gel having a slight fluidity by using a gelling agent. Any material may be used as long as it can prepare a gel having a fluidity of 90 seconds to 24 hours, preferably 90 seconds to 12 hours, more preferably 90 seconds to 30 minutes. The “oil gel” refers to one that satisfies the following two conditions. First, the substance is composed of two or more components, one of which is a liquid that is present in large quantities, the liquid being composed of an organic solvent. Second
In addition, the material is in a soft, solid, or solid-like shape.

Examples of the gelling agent satisfying the above requirements include waxes such as caster wax, carnauba wax, and hardened fats and oils, and fatty acid derivatives and metal soaps such as sodium stearate, aluminum stearate, and 2-ethyl ester. In polymers such as aluminum hexanoate and 12-hydroxystearic acid, styrene-
Butadiene block copolymer, styrene polymer, divinylbenzene polymer, poly-1,2-butadiene,
Examples of amino acid derivatives such as silicone resin include dibutylamide N-lauroylglutamate, examples of clay minerals include smectite and montmorillonite, and examples of other gelling agents include dibenzylidene sorbitol and aluminum dialkyl phosphate. Among them, aluminum 2-ethylhexanoate is preferred.

Further, by covering the volatilization surface with a permeable polymer film, the volatilization speed of the drug can be freely adjusted. The material of the polymer film is preferably polyethylene or polypropylene. This polymer film does not necessarily need to be formed in one layer, but may be formed in a plurality of layers. Further, in order to adjust the volatilization rate, a layer of aluminum, polyethylene terephthalate, or the like having low permeability of a drug may be laminated. The total thickness of the polymer film is preferably about 10 to 300 μm.

[0013] Further, by putting the gelled drug into an impermeable container having an open volatilization surface, the volatilization direction can be adjusted. As the material of the impermeable container, polyethylene terephthalate, ethylene vinyl alcohol copolymer, ethylene vinyl acetate copolymer, aluminum and the like are preferable. The impermeable container does not necessarily need to be formed in one layer, and may be formed in a plurality of layers.

Further, by heating the contents of the preparation,
It is also possible to adjust the rate of volatilization to volatilize drugs that are difficult to volatilize at room temperature. The heating temperature is 35 ° C to 7 ° C.
About 0 ° C. is preferred.

The above-mentioned chemicals include fragrances, plant essential oils, volatile deodorants, antibacterial chemicals and the like, and any chemicals can be used as long as they are volatile at normal temperature and when heated. Further, a solvent or water may be added for the purpose of controlling the rate of volatilization or adjusting the concentration of a volatile drug. More specifically, it is as follows.

The fragrance may be a simple fragrance or a compound fragrance. Specifically, α-pinene, β-pinene, limonene, linalool, geraniol, α-farnesene, β-
Farnesene, α-guaien, d-guaien, α-caryophyllene, β-caryophyllene, d-cadinene, g-cadinene, α-visabolene, β-visabolene, g-visabolene,
α-Cedren, β-Cedren, Valensen, Tuyobsen,
Farnesol, nerolidol, α-visabolol, β
-Caryophyllene alcohol, α-santa roll, β-
There are santalol, vetiverol, cedrol, ethylhexanoate, lactone C-10 gamma, cis-3-hexenol, alcohol C-6, linalool, linalyl acetate, geraniol, benzyl alcohol, terpineol, methylyonone and the like. In plant essential oils,
Sage oil, peppermint oil, spearmint oil, lemon oil, lemongrass oil, orange oil, rosemary oil, lavender oil, basil oil, bergamot oil, citronella oil, clove oil, coriander oil, eucalyptus oil, geranium oil, ginger oil, Grapefruit oil, hiba oil, hinoki oil, lavandin oil,
There are thyme oil, ylang-ylang oil, lime oil, cinnamon leaf oil, peppermint oil, anise oil, petitgren oil, laurel oil, pine oil and the like.

As the volatile deodorant, JP-A-6-12182
2. Pyruvate such as ethyl pyruvate and phenylethyl pyruvate described in 2. Antibacterial agents include hinokitiol, allylthioisocyanate and the like.

The organic solvent includes kerosene, light oil, paraffinic hydrocarbon, isoparaffinic hydrocarbon, aromatic hydrocarbon, aromatic alcohol, silicone oil, salad oil, soybean oil, normal decane, normal tridecane, normal hexadecane, Isooctane, isododecane, cyclohexane, toluene, xylene, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, oleyl alcohol, benzyl alcohol,
Examples thereof include dipropylene glycol monomethyl ether, 3-methyl-3-methoxybutanol, and linoleic acid.

FIGS. 1 and 2 show an embodiment in which a replaceable article of a volatile agent (also called a cartridge or a refill) according to the present invention is applied as a replaceable article of a heated and volatile aroma deodorant. I have. Replaceable goods 10
Is a deep dish-shaped container body 11 made of an impermeable resin such as polyethylene terephthalate (PET), and a permeable polymer film 12 adhered to the container body 11 so as to cover the opening of the container body 11. And an impermeable protective sheet 13 such as an aluminum thin film that is releasably attached to the outer surface of the polymer film 12, and a volatile chemical ( The gel composition 14 having fluidity and containing a mixed flavoring agent is filled and contained.

As the gel composition 14 as a heat-evaporating fragrance deodorant, the composition (% by weight) was 40.0% of fragrance,
An isoparaffinic hydrocarbon (solvent) of 54.0% and aluminum 2-ethylhexanoate (gelling agent) of 6.0% can be used.

The gel composition 14 comes into contact with the polymer film 12, and the polymer film 12 serves as a volatile surface of the gel composition 14. When the impermeable protective sheet 13 attached to the outer surface of the polymer film 12 is peeled off, the replaceable article 10 enters a volatilization start state.

The polymer film 12 is made of a linear low-density polyethylene (LLDPE) or the like, and is a transparent or translucent film so that a residue of the contents can be visually recognized from the outside in a use process in which the protective sheet 13 is peeled off. Preferably, there is. The container main body 11 has a bottom shape such as a spherical shape that is resistant to decompression deformation.

The above gel composition 14 and the gel composition 14
In combination with the polymer film 12 forming a volatile surface, a long-term sustained release of 1 to 2 months becomes possible, and since the gel composition 14 has fluidity, It can stably volatilize without a change in incense tone, and the residue can be visually recognized accurately. In addition, as a condition for sustained release, 5 g of the gel composition was placed in a container molded of polyethylene terephthalate (PET), and the volatile surface (area 1
0 cm ² ) was covered with a 100 μm thick linear low density polyethylene (LLDPE) film and the container was heated to 50 ° C.

The gel composition 14 may optionally contain
Heating can cause convection in the container. This convection facilitates movement of the gel composition 14 within the container,
Long-term uniform volatility can be guaranteed.

FIG. 3 shows an example of the configuration of a plug-in type heating fragrance using a heat-vaporizable fragrance deodorant replaceable article 10. The plug-in type heating fragrance device 20 includes an appliance case 22 and a front cover 23 which define a container accommodating chamber 21 for accommodating the replaceable article 10 in an upright posture and exchangeably.
And the exchangeable article 1 attached to the instrument case 22
PTC heater 24 for heating the PTC heater 24 from the container bottom side, and an outlet plug 26 attached to the appliance case 22 and electrically connected to the electrode of the PTC heater 24 by a conductor 25 or the like.
And is directly attached to the outlet by the outlet plug 26.

An opening 27 is formed in the front cover 23 so that the surface of the polymer film 12 of the replaceable article 10 in the container accommodating chamber 21 can be seen from the outside (front). This allows the gel composition 14 in the replaceable article 10 to pass through the transparent polymer film 12 while the plug-in type heating fragrance 20 is connected to the outlet.
Can be visually checked.

[0027]

EXAMPLES A sustained-release preparation of the present invention was formed as follows.

<Preparation of sustained-release drug preparation> (Example 1) 20.0 g of perfume A and IP solvent 20
28 and 26.5 g to form a homogeneous solution.
3.5 g of FA (aluminum 2-ethylhexanoate) was added little by little with stirring. After standing overnight, 50.0 g of a fluid gel was obtained (result of liquid confirmation test: 300).
Sec / 30 mm). 5 g of this was placed in a PET molded container, and the volatile surface (area 10 cm ² ) was 100 μm thick.
And the container was heated to 50 ° C. and the change in weight was measured. Further, changes in odor intensity and fragrance were confirmed by sensory evaluation. The results are shown in Tables 1 to 3 (see below).

Example 2 20.0 g of perfume A and 26.5 g of IP Solvent 2028 were mixed to form a uniform solution, and then DAP (aluminum dialkyl phosphate) was obtained.
3.5 g was added little by little with stirring. The mixture was left overnight to obtain 50.0 g of a fluid gel (result of liquid confirmation test: 150 seconds / 30 mm). 5 g of this was used in Example 1.
And a change in weight was measured under the same conditions as in Example 1. Further, changes in odor intensity and fragrance were confirmed by sensory evaluation. The results are shown in Tables 1 to 3 (see below).

(Comparative Example 1) 20.0 g of perfume A and 30.0 g of IP Solvent 2028 were mixed to form a uniform solution 5.
0.0 g was obtained (result of liquid confirmation test: determined to be liquid). 5 g of the formulation was formulated in the same manner as in Example 1, and the weight change was measured under the same conditions as in Example 1. Further, changes in odor intensity and fragrance were confirmed by sensory evaluation. The results are shown in Tables 1 to 3 (see below).

Comparative Example 2 IP Solvent 2028-2
4.0 g of 12-HSA (12-hydroxystearic acid) was added to 6.0 g, and heated to 70 ° C. to dissolve 12-HSA, thereby preparing a uniform solution. There fragrance A2
0.0g was added to obtain 50.0g of gel (result of liquid confirmation test: no fluidity). 5 g of the formulation was formulated in the same manner as in Example 1, and the weight change was measured under the same conditions as in Example 1. Further, changes in odor intensity and fragrance were confirmed by sensory evaluation. The results are shown in Tables 1 to 3 (see below). <Components used in sustained release drug formulation> Fragrance A is a mixture of 60 parts by weight of the prepared flavor 1 and 40 parts by weight of limonene shown in the following table.

Details of the TFA and the like are as follows. TFA: The name of a product manufactured by Taiyo Perfume Co., Ltd. Aluminum 2-ethylhexanoate. DAP: aluminum dialkyl phosphate having 16 carbon chains in the alkyl group. 12HSA: 12-hydroxystearic acid (manufactured by Tokyo Chemical Industry Co., Ltd.). IP Solvent 2028: Name of a product manufactured by Idemitsu Petrochemical Co., Ltd. Isoparaffinic hydrocarbons.

<Polymer film and container used in sustained-release drug preparation> LLDPE: colorless and transparent linear low-density polyethylene. PET: colorless and transparent polyethylene terephthalate.

<Liquid Confirmation Test Method> The liquid confirmation method described above is in accordance with the method described in "Fire Defense Law: Regulations on Dangerous Goods Regulation, Article 69-2". In particular,
An article is placed in a vertical test tube (made of flat-bottom cylindrical glass having an inner diameter of 30 mm and a height of 120 mm; hereinafter, referred to as a "test tube") until the height from the bottom of the test tube becomes 55 mm. When the test tube is horizontal, the time is measured and recorded until the tip of the moving surface of the article passes through a portion having a distance from the bottom of the test tube of 85 mm. If the measurement result is within 90 seconds, it is determined as "liquid". The measurement temperature is set at 20 ° C ± 0.1 ° C.

<Evaluation of Smell Intensity> The drug sustained-release preparation to be evaluated is placed in the center of a space 1.5 m wide, 2 m long and 2.5 m high, which can be evacuated and is fully air-conditioned. A warming holder with a heater (see FIG. 3) was installed.

The intensity of the odor at regular intervals is directly smelled by five male and five female panelists in their thirties. Then, how to feel the intensity at that time is used as an evaluation scale for setting the reference value in the Odor Control Law. The six-step odor intensity scale shown below ("The 3rd Edition Handbook Odor Control Law" (Odor Law Research) Edited by the Society; see page 48 of Gyosei Co., Ltd.), and the average score was calculated. Six-stage odor intensity display method 0: Odorless 1: Smell that can be detected at last (detection threshold density) 2: Smell to know what smell is (cognitive threshold density) 3: Smell that can be easily detected 4: Strong smell 5: Intense What smell

<Effect of fragrance> At the same time as the evaluation of the odor intensity, the change of odor was also evaluated. More specifically, a standard drug sustained-release preparation was prepared for each evaluation for the evaluation of incense tone. In addition, 1.5 m in width, 2 m in length, and 2.
A warming holder with a heater containing a standard drug sustained-release preparation was installed in the center of a space of 5 m, and compared with the preparation to be evaluated.

Table 1 shows the residual amount (%) as the weight change data of the sustained release drug preparation when the sustained release test of the sustained release drug preparation was performed at a heating surface temperature of 50 ° C.

[Table 1]

Table 2 shows the change in odor intensity (of the drug sustained release preparation) in the sustained release test.

[Table 2]

Table 3 shows the change in fragrance tone (of the drug sustained release preparation) in the sustained release test. In addition, ○ mark does not change,
The △ mark shows a slight change, the X mark shows a change, and the − mark shows that the odor intensity is low and cannot be confirmed.

[Table 3]

FIGS. 4 and 5 are graphs of Tables 1 and 2. As shown in FIG. 4, in the sustained-release gel drug preparations having slight fluidity of Examples 1 and 2, the change in weight is almost constant, and it can be seen that the incense tone which is a volatile component is sustainedly released ( Example 1: O, Example 2: Δ).

As shown in FIG. 5, in the sustained-release preparations of Examples 1 and 2, the odor intensity gradually decreased with the number of days of sustained release, but the scent was sufficiently recognized even after 50 days. it can. Further, as shown in Table 3, the change in the fragrance during the sustained release period was small.

On the other hand, as shown in FIG. 4, in the case of the sustained-release liquid drug preparation of Comparative Example 1 (marked with *), the volatilization rate during the above-mentioned sustained release test was higher than that of Examples 1 and 2, and was longer. Can not have a scent for a period. Further, as shown in FIG. 5, in the case of the same preparation, the strength at the initial stage of sustained release is strong, but the strength is extremely reduced after 10 days. As shown in Table 3, the fragrance during the sustained release period is also significantly changed.

Further, as shown in FIG. 4, the gel drug sustained-release preparation having no fluidity described in Comparative Example 2 (marked with ×) had a
The rate of weight loss slows down from around the day. However, despite the presence of the sustained release formulation, as shown in FIG. 5, the odor intensity decreases after 30 days. This is because the drug is volatilized and dried only from the volatilization surface, so that the drug incorporated in the sustained-release preparation cannot be completely volatilized. In the case of such a preparation, the end point of volatilization cannot be visually recognized. As described above, according to the drug sustained-release preparation of this example, since the gel has fluidity, the compounded drug can be gradually released to the end, and the remaining amount can be visually recognized. Further, according to the sustained-release drug preparation of this example, the change in the fragrance between the initial stage and the final stage of volatilization can be reduced due to the specific composition and the composition of the polymer film. Further, according to the drug sustained-release preparation of this example, a volatile drug can be sustainably released over a long period of time. More specifically, according to the drug sustained-release preparation of this example, a long-term (1.5 months or more) sustained release can be achieved by a combination of its unique compounding composition, polymer film configuration, and heat volatilization. can do.

[0045]

As will be understood from the above description, according to the present invention, it is possible to provide a sustained-release drug preparation and a replaceable article excellent in visibility of the remaining amount of the drug.

[Brief description of the drawings]

FIG. 1 is a perspective view showing one embodiment of a replaceable article according to the present invention.

FIG. 2 is a sectional view showing one embodiment of the replaceable article according to the present invention.

FIG. 3 is a sectional view showing a configuration example of a plug-in type heating fragrance using a replaceable article according to the present invention.

FIG. 4 is a graph showing a change in weight of a sustained-release drug preparation.

FIG. 5 is a graph showing a change in odor intensity of a sustained-release drug preparation.

[Explanation of symbols]

 DESCRIPTION OF SYMBOLS 10 Replaceable article 11 Container main body 12 Polymer film 13 Protective sheet 14 Gel composition 20 Plug-in type heating fragrance 21 Container accommodation room 24 PTC heater

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A01N 35/06 A01N 35/06 47/46 47/46 A61L 9/02 A61L 9/02 (72) Inventor Atsushi Katayama 2-3-1, Bunka, Sumida-ku, Tokyo, Japan Kao Co., Ltd. (72) Inventor Takashi Yamada 2-3-1, Bunka, Sumida-ku, Tokyo Kao Co., Ltd. F-term (reference) 4C080 AA04 BB03 HH06 JJ01 JJ09 KK03 KK04 LL06 MM12 MM13 NN01 NN14 NN18 NN27 NN29 QQ12 QQ16 4H011 AA02 BA01 BB05 BB11 BC01 BC06 BC19 BC20 DA17 DD05 DH02 DH16

Claims (4)

[Claims] 1. A drug sustained-release preparation containing a volatile drug in a gel having a flowability of 30 seconds to 24 hours in a liquid confirmation test for a moving time of 90 seconds to 24 hours. 2. The sustained-release drug preparation according to claim 1, wherein the drug is volatilized through a permeable polymer film. 3. The sustained-release drug preparation according to claim 1, wherein the drug is heated and volatilized. 4. A replaceable article in which a fluid gel containing a volatile drug is contained in a container at least partially composed of a permeable polymer film.