JP4454988B2 - Sustained release formulation - Google Patents

Description

  The present invention relates to a preparation that gradually releases a volatile drug.

  So far, as a technique for gradually releasing a volatile drug, for example, Patent Document 1 discloses a sustained release agent that kneads a resin that can be uniformly mixed with the volatile drug and gradually releases the volatile drug. Patent Document 2 discloses a narrowed part of the pores of the porous packaging substrate. Patent Document 3 discloses a fatty acid higher alcohol ester, paraffin, or fatty acid glycerin ester that is pasty or solid at room temperature.

JP 2000-186002 A WO95 / 12981 Japanese Patent No. 2796589

  However, examples of resins that suppress the volatilization of the volatile chemicals described in Patent Document 1 include rosin resins, shellac resins, ethylene-vinyl acetate copolymers, and the like. In the case of having a carbonyl group or a hydroxyl group of a free organic acid or alcohol, it reacts with the volatile chemical itself, and these resins or the volatile chemical are discolored or the odor is changed. was there. Furthermore, the rosin ester resin has a problem of discoloration due to oxidation of impurities contained therein.

  Further, in the method described in Patent Document 2, when the contents of the packaging material are liquid or when the liquid is impregnated into the carrier, the volatile chemical is easily oozed out of the container by a pinhole or the like. In some cases, volatilization control could not be performed.

  Furthermore, the fatty acid higher alcohol ester and paraffin which are used in Patent Document 3 and exhibit a paste or solid form at normal temperature are not preferable because they have a poor volatilization suppressing effect on the above volatilizing agents. When the fatty acid glycerin ester used in the same way becomes pasty or solid depending on the number of carbon atoms of the fatty acid constituting it, the affinity with the volatile agent is lowered, and the volatile agent cannot efficiently suppress volatilization. There was a case. Furthermore, when the fatty acid glycerin ester is a diglyceride or a monoglyceride, the fatty acid glycerin ester may react with the volatile drug itself because it has a hydroxyl group in the molecule.

  Therefore, an object of the present invention is to produce a sustained-release preparation that has a high affinity with a volatile drug and can efficiently suppress the volatile drug without reacting the volatile drug.

  This invention kneads a volatile drug, a fatty acid triglyceride that is liquid at normal temperature represented by the following chemical formula (1), and a hydrophobic substance that is solid at normal temperature to create a kneaded product. The above problem was solved by a sustained-release preparation filled in a permeable container.

  The fatty acid triglyceride that is liquid at room temperature represented by the chemical formula (1) has good affinity with the volatile drug, and can efficiently suppress the volatilization of the volatile drug. Further, by kneading with a solid hydrophobic substance at room temperature, the kneaded material can be handled as a solid material, and bleeding can be made difficult to occur.

  The sustained-release preparation according to the present invention has no fear of degeneration, uses liquid fatty acid triglycerides with good affinity with volatile drugs, does not cause reaction, prevents condensation during storage, and is efficient Volatilization is well suppressed and the effective period can be maintained. Furthermore, since the liquid or impervious container is filled with the solid or pasty material, exudation hardly occurs.

Hereinafter, the present invention will be described in detail.
This invention kneads a volatilizing agent, a fatty acid triglyceride having a fatty acid portion of C2 to C12 fatty acid at room temperature and a solid hydrophobic substance at room temperature to prepare a kneaded product. This is a sustained-release preparation filled in a liquid-impermeable container.

  Said volatile chemical | medical agent means the thing which can volatilize at normal temperature and has a certain effect in a gaseous state, although it is solid or liquid at normal temperature. For example, bactericides, disinfectants, fragrances, pest repellents, insecticides, antiseptics, fungicides and the like. Specific examples of the volatile agent include pyrethroid, mint oil, terpineol, paradichlorobenzene, naphthalene, camphor and other insect repellents and repellents, pinene, limonene, camphene, terbinolene, linalool, geraniol, citronellol, citral, benzaldehyde, carvone, Menthone, coumarin, anisole, thymol, eugenol, anethole, cinnamic acid, phenylacetic acid, hydrocinnamic acid, ethyl acetate, geranyl acetate, isoamyl propionate, rose oxide, oxide ketone, cineole, indole, skatole, methylquinoline, musk, civet , Perfumes such as castrium, ambergris, lemon oil, rose oil, sandalwood oil, lavender oil, jasmine oil, allyl isothiocyanate, octylaldehyde, bromcinami Antibacterial and antifungal agents such as aldehydes, Hiba oil, Hinoki oil, Kiri oil, Buttercup oil extract, Camellia oil, Eucalyptus oil, Perilla oil, Wasabi extract oil, Mustard oil, Moon peach oil, etc. Can be mentioned.

  The fatty acid triglyceride that is liquid at normal temperature refers to a compound represented by the following chemical formula (1) among esters composed of one equivalent of glycerin and three equivalents of fatty acid. Here, p, q, and r are natural numbers from 1 to 11. That is, the carbon number of the fatty acid which comprises each ester part is a natural number of 2-12. If it is in the range of this numerical value, the aliphatic triglyceride from which each numerical value differs may be mixed. By kneading this compound, the vapor pressure of the volatile chemical can be reduced, and volatilization can be suppressed.

  On the other hand, fatty acid triglycerides whose fatty acid part is a fatty acid of C13 or higher and are solid at normal temperature have low affinity with the above volatile chemicals and have a small volatilization suppressing effect, and therefore, the meaning of kneading is poor.

  In addition, fatty acid monoglyceride and fatty acid diglyceride are not preferable because a hydroxyl group remains in the molecule and the hydroxyl group may react with the volatile agent to cause discoloration.

  The above-mentioned hydrophobic substance that is solid at room temperature is a substance that kneads the volatile chemical and the fatty acid triglyceride that is liquid at room temperature to solidify the liquid and suppress the seepage of the liquid. Substances that can be used as the hydrophobic substance include petroleum wax, rosin resin such as rosin ester resin, shellac resin, ethylene-vinyl acetate copolymer, polyamide, sugar ester, natural fatty acid containing alcohol group Examples thereof include waxes, higher fatty acids, higher alcohols, and synthetic polymer polymers such as polyesters, polystyrenes, polyolefins, and acrylic resins.

  However, when the volatile chemical is an unstable substance, it is particularly desirable to use petroleum wax as the hydrophobic substance. Of the above, rosin resins, shellac resins, ethylene-vinyl acetate copolymers, polyamides and the like contain carbonyl groups or hydroxyl groups by free organic acids or alcohols, so these and the above volatile chemicals. May cause discoloration or change in odor. Natural waxes, higher fatty acids, higher alcohols, sugar esters, and the like may similarly react with the volatile chemicals. Furthermore, in the synthetic polymer, since the softening point is high, the volatile chemical may be thermally decomposed when trying to knead, or the viscosity may be too high to finally fill the container. is there.

  The mixing ratio when kneading the volatile drug and the fatty acid triglyceride is such that the mixing weight ratio of the fatty acid triglyceride during the preparation of the kneaded product is 0.1 to 10 times the volatile drug. It is desirable that it is 0.25 to 5 times. If the mixing weight ratio is less than 0.1 times, the volatilization suppressing effect on the volatile drug is hardly exhibited, and the volatile drug is volatilized without restriction, and the effect cannot be expected to continue. Moreover, the container filled with the kneaded material after kneading may be condensed by the volatile chemical. On the other hand, when the mixing weight ratio exceeds 10 times, there is an effect of suppressing the volatilization of the volatile drug, but the effect of suppressing the volatility becomes too high with a decrease due to the volatilization of the volatile drug. In some cases, it is difficult to volatilize the volatile drug by an effective amount. Moreover, the amount may increase too much, and the size of the sustained-release preparation as a product may become larger than necessary. Moreover, the mixing weight ratio of the hydrophobic substance with respect to the total of the volatile drug and the fatty acid triglyceride is not particularly limited, but it is desirable to mix the mixture so as to be mixed and solidified in a ratio of 0.05 to 5 times. If it is less than 0.05 times, the kneaded product is difficult to form a paste, and if it exceeds 5 times, the product becomes solid, but the size may become larger than necessary.

  Such a volatile chemical, the liquid fatty acid triglyceride and the hydrophobic substance are kneaded to prepare a kneaded product. The kneading means that a highly viscous mixture is uniformly mixed and dispersed using a strong shearing force. As a kneading method, a general kneading method may be used, and there is a method using a mixer, a kneader or the like. However, kneading under a high temperature condition where the volatile chemical is decomposed is not desirable because the volatile chemical may be denatured and excessively evaporated during the kneading.

  Moreover, you may add antioxidant, a light stabilizer, etc. to the said kneaded material other than these as a stabilizer which stabilizes the said volatile chemical | medical agent. Examples of the antioxidant include dibutylhydroxytoluene and dibutylhydroxyanisole. Examples of the light stabilizer include 2-hydroxy-4-methoxybenzophenone and 2- (2'-hydroxy-5'-methylphenyl) benzotriazole.

  The kneaded product is filled in a liquid-impermeable container to obtain the sustained-release preparation. If it is liquid permeable, the contents may leak during storage or use, and volatilization control may not be possible. Moreover, in order to volatilize a volatile chemical | medical agent, it is desirable for a part or all of the said container to have gas permeability. Examples of materials that are liquid impermeable and gas permeable include polyethylene, polypropylene, polystyrene, and polyethylene terephthalate.

  Hereinafter, the present invention will be described more specifically with reference to examples.

[Cineol volatilization suppression effect and stability]
(Experimental example 1)
[Volatilization concentration measurement]
In a 50 ml extraction bottle (manufactured by Maruemu Co., Ltd.), 2.0 g of cineol (manufactured by Ogawa Fragrance Co., Ltd.) and liquid fatty acid triglyceride (manufactured by Kao Corp .: Coconut ML containing carbon number of fatty acids: 8, 10, 12) 0 g and 2.0 g of petroleum wax (manufactured by Nippon Seiki Co., Ltd .: HNP-9) are sealed, heat-kneaded at 85 ° C., dissolved, and left at room temperature (about 25 ° C.). did.
After 5 days, the cineol concentration in the space in the extraction bottle was measured by gas chromatography (Hewlett Packard, HP 6890). The number of tests was N = 2, and the average value obtained is shown in Table 1.

[Measurement of odor and color change]
In a 50 ml extraction bottle (same as above), 2.0 g of cineol and 8.0 g of liquid fatty acid triglyceride (same as above) are sealed, heat-kneaded in a water bath at 85 ° C. The container was filled. The material of the container was a laminate having a thickness of 70 μm obtained by applying polyethylene laminate to stretched polypropylene (manufactured by Toyobo Co., Ltd .: thickness 20 μm). This container was put in an airtight aluminum bag and left in a 60 ° C. environment for one month. After one month, whether the sineol smelled in the container or whether there was a color change was confirmed by smell and vision. The results are shown in Table 1. Note that “the odor does not change” means that the odor of cineole remains as it is. The case where no change in both the odor and the color is felt is indicated as “◯”, and the case where a change is felt is indicated as “X”.

(Experimental example 2)
In Experimental Example 1, instead of liquid fatty acid triglyceride (manufactured by Kao Corporation: Coconut ML-containing fatty acid carbon number: 8, 10, 12), fatty acid triglyceride (manufactured by Wako Pure Chemical Industries, Ltd .: triacetin-containing fatty acid carbon number 2) ) Was used in the same manner as in Experimental Example 1 to measure changes in cineol concentration, odor, and color in the container. The results are shown in Table 1.

(Comparative Example 1)
In Experimental Example 1, liquid fatty acid triglyceride was not added at the time of kneading, and the changes in cineol concentration, odor, and color in the container were measured in the same manner as in Experimental Example 1 except that. The results are shown in Table 1.

(Comparative Example 2)
In Experimental Example 1, rosin ester (manufactured by Arakawa Chemical Industries, Ltd .: A-18) was used instead of liquid fatty acid triglyceride (manufactured by Kao Corporation: Coconut ML-containing fatty acid carbon number: 8, 10, 12). Except for the above, in the same manner as in Experimental Example 1, the cineol concentration, odor and color change in the container were measured. The results are shown in Table 1.

(Comparative Example 3)
In Experimental Example 1, instead of liquid fatty acid triglyceride (manufactured by Kao Corporation: Coconut ML-containing fatty acid carbon number: 8, 10, 12), solid fatty acid triglyceride (manufactured by Kanto Chemical Co., Ltd .: Tristearin-containing fatty acid carbon number: Except for using 18), the cineol concentration, odor, and color change in the container were measured in the same manner as in Experimental Example 1. The results are shown in Table 1.

(result)
When liquid fatty acid triglycerides were used, the cineol concentration was 1000 ppm or more lower than when nothing was added, and even lower than when using solid fatty acid triglycerides. Thus, it was found that the effect of suppressing volatilization was sufficiently exhibited since the concentration of cineole was kept low. Moreover, there was no change in odor and color as in the case of using rosin ester, and it was stable.

[Efficacy and stability of allyl isothiocyanate]
(Experimental example 3)
[Volatilization concentration measurement]
In a 50 ml extraction bottle (manufactured by Maruemu Co., Ltd.), 5.0 g of allyl isothiocyanate (manufactured by Nippon Terpene Co., Ltd., hereinafter referred to as “AIT”) and liquid fatty acid triglyceride (manufactured by Kao Co., Ltd .: Coconut ML containing fatty acid carbon number : 8, 10, 12) After 2.3 g of petroleum wax (manufactured by Nippon Seisaku Co., Ltd .: HNP-9) was sealed, sealed, heated and kneaded at 85 ° C., and dissolved. And left at room temperature (about 25 ° C.).
After 5 days, the AIT concentration in the space in the extraction bottle was measured by gas chromatography (Hulet Packard: HP6890). The number of tests was N = 2, and the average value obtained is shown in Table 2.

[Measurement of odor and color change]
In a 50 ml extraction bottle (same as above), 5.0 g of AIT and 2.3 g of liquid fatty acid triglyceride (same as above) are sealed and heat-kneaded in a water bath at 85 ° C. to dissolve them. The container was filled. The material of the container was a laminate having a thickness of 70 μm obtained by applying polyethylene laminate to stretched polypropylene (manufactured by Toyobo Co., Ltd .: thickness 20 μm). This container was put in an airtight aluminum bag and left in a 60 ° C. environment for one month. After one month, whether or not there was an AIT odor in the container and whether there was a color change was confirmed by smell and vision. The results are shown in Table 2. In addition, the odor does not change means that the odor of the AIT remains as it is. A case where no change in both the odor and the color is felt is indicated as ◯, and a case where a change is felt is indicated as x.

(Experimental example 4)
In Experimental Example 3, instead of liquid fatty acid triglyceride (Kao Co., Ltd .: Coconut ML-containing fatty acid carbon number: 8, 10, 12), fatty acid triglyceride (Wako Pure Chemical Industries, Ltd .: Triacetin-containing fatty acid carbon number: The changes in AIT concentration, odor, and color in the container were measured in the same manner as in Experimental Example 3 except that 2) was used. The results are shown in Table 2.

(Comparative Example 4)
In Experimental Example 3, the liquid fatty acid triglyceride was not added at the time of kneading, and the changes in AIT concentration, odor, and color in the container were measured in the same manner as in Experimental Example 3 except that. The results are shown in Table 2.

(Comparative Example 5)
In Experimental Example 3, rosin ester (manufactured by Arakawa Chemical Industries, Ltd .: A-18) was used instead of liquid fatty acid triglyceride (manufactured by Kao Corporation: Coconut ML-containing fatty acid carbon number: 8, 10, 12). Except for the above, the AIT concentration, odor, and color change in the container were measured in the same manner as in Experimental Example 3. The results are shown in Table 2.

(Comparative Example 6)
In Experimental Example 3, instead of liquid fatty acid triglyceride (manufactured by Kao Corporation: Coconut ML-containing fatty acid carbon number: 8, 10, 12), solid fatty acid triglyceride (manufactured by Wako Pure Chemical Industries, Ltd .: Tristearin-containing fatty acid carbon) The change in AIT concentration, odor, and color in the container was measured in the same manner as in Experimental Example 3 except that the number: 18) was used. The results are shown in Table 2.

(Comparative Example 7)
In Experimental Example 3, glycerin (manufactured by Wako Pure Chemical Industries, Ltd .: carbon number of contained fatty acid: 0) instead of liquid fatty acid triglyceride (manufactured by Kao Corporation: coconut ML-containing fatty acid carbon number: 8, 10, 12) In the same manner as in Experimental Example 3 except that was used, changes in the AIT concentration, odor, and color in the container were measured. The results are shown in Table 2.

(result)
When liquid fatty acid triglycerides were used, the AIT concentration was 1000 ppm or more lower than when nothing was added, and even lower than when solid fatty acid triglycerides were used. Thus, since the density | concentration of AIT was suppressed low, it turned out that the effect which suppresses volatilization fully appears. Moreover, there was no change in odor and color as in the case of using rosin ester, and it was stable.

[Comparison of mixing ratio of volatile drug and fatty acid triglyceride]
In a 50 ml extraction bottle (manufactured by Marem Co., Ltd.), 2.0 g of limonene (manufactured by Ogawa Fragrance Co., Ltd.), a predetermined amount of fatty acid triglyceride (same as above) and 2.0 g of petroleum wax (same as above) are sealed. The mixture was heat-kneaded at 85 ° C. and dissolved, and then filled into a container made of a laminate having a thickness of 60 μm laminated to a nonwoven fabric with polyethylene. The container after filling was put in an airtight aluminum bag and left in a 40 ° C. environment for one month. One month later, the state of condensation on the container surface was observed.
Further, the container after filling was left in an environment at 25 ° C., and over the course of one month, the presence or absence of the smell of limonene was confirmed over time, and the stability of volatilization was examined. In addition, the thing in which the scent of limonene is felt is described as “◯”, and the object in which the scent is not felt is denoted as “X”.

(Experimental Examples 5-8)
The amount of fatty acid triglyceride was 0.1 g, 0.5 g, 10.0 g, 25.0 g, respectively, and the weight ratios with respect to limonene at the time of preparing the kneaded product were 0.05 times, 0.25 times, 5.0 times, respectively. The state of condensation and the stability of volatilization were examined under the condition of 12.5 times. Each was made into Experimental Examples 5-8, and those results are shown in Table 3.

(Comparative Example 8)
The state of condensation and the stability of volatilization were investigated without adding fatty acid triglycerides. The results are shown in Table 3.

(result)
In Experimental Example 5, dew condensation was observed, but the volatilization for 10 days could be continued. In Experimental Examples 6 and 7, there was no condensation and the volatilization continued for 30 days or more. In Experimental Example 8, the volatilization for 5 days could be continued. On the other hand, dew condensation was observed in Comparative Example 8, and volatilization was finished after 5 days.

Claims (4)

A volatile chemical, a fatty acid triglyceride that is liquid at normal temperature represented by the following chemical formula (1), and petroleum wax that is solid at normal temperature are kneaded to create a kneaded product, and the kneaded product is placed in a liquid-impermeable container. Filled sustained release formulation.

  The sustained-release preparation according to claim 1, wherein the kneaded product is in a paste form or a solid form at room temperature.   The sustained-release preparation according to claim 1 or 2, wherein the mixing weight ratio of the fatty acid triglyceride is 0.1 to 10 times that of the volatile drug at the time of preparing the kneaded product. The sustained-release preparation according to any one of claims 1 to 3 , wherein the volatile drug is allyl isothiocyanate.