Sustained-release formulation, gelling agent for forming sustained-release formulation, and sustained-release formulation production method

Abstract

[Problem] To provide a sustained-release formulation which has little impact on the environment and with which the dissolution rate of a drug can be adjusted easily, and to provide a gelling agent for forming a sustained-release formulation and a sustained-release formulation production method. [Solution] This sustained-release formulation includes a drug and a gel-like carrier which carries the drug and slowly releases the drug. The carrier contains P2O5, an alkaline earth metal oxide, Al2O3, and water. This gelling agent for forming a sustained-release formulation contains P2O5, an alkaline earth metal oxide, and Al2O3. This sustained-release formulation production method includes: a mixing step for obtaining a mixture which contains a drug, a gelling agent containing P2O5, an alkaline earth metal oxide, and Al2O3, and water; and a heat treatment step for obtaining a gel-like sustained-release formulation by heating the mixture, in a sealed state, at 50-90°C, inclusive, for 24-72 hours, inclusive.

Description

Sustained-release preparation, gelling agent for forming the sustained-release preparation, and method for producing the sustained-release preparation

[0001] The present invention relates to a sustained release formulation, a gelling agent for forming the sustained release formulation, and a method for producing the sustained release formulation.

[0002] Patent Document 1 discloses a sustained release carrier for sustained release of a drug. The sustained release carrier is made of engineering plastic and has a plurality of pores in its surface layer. The sustained release carrier is immersed in a solution containing the drug, so that the drug is carried on the surface within the pores.

[0003] Patent No. 5469872

[0004] The sustained-release carriers described above are made of plastic, which poses the problem of environmental pollution due to microplastics when used in the natural environment. Furthermore, the drug release rate varies depending on the size of the pores, making it difficult to control the drug release rate.

[0005] In view of the above background, an object of the present invention is to provide a sustained-release preparation that has little impact on the environment and allows easy control of the drug dissolution rate. Another object of the present invention is to provide a gelling agent for forming the sustained-release preparation and a method for producing the sustained-release preparation.

[0006] In order to solve the above problems, one aspect of the present invention is a sustained-release preparation, which comprises a drug and a gel-like carrier that supports the drug and sustainably releases the drug, and the carrier comprises P ２ O ５ and alkaline earth metal oxides and Al ２ O ３ and water. The alkaline earth metal oxide may be at least one selected from the group including MgO, CaO, SrO, and BaO.

[0007] In the case of substances such as glass, elements are bonded via oxygen to form something like a giant molecule. In addition, substances such as gel and metaphosphate may contain water, carbonates, hydroxides, etc., and cannot be expressed by a specific chemical formula. In other words, P, alkaline earth metals such as Mg and Ca, and Al do not exist as simple elements in glass and gel. Therefore, P, alkaline earth metals, and Al that make up glass and gel are expressed as oxides, and P ２ O ５ , alkaline earth metal oxides, Al ２ O ３ For the same reason, when specifying the ratio of each component in glass or gel, each component is expressed in terms of oxide.

[0008] According to this embodiment, since the carrier does not contain plastic, it is possible to provide a sustained-release preparation that has little impact on the environment. ２ O ５ , alkaline earth metal oxides, and Al ２ O ３ The release rate of the drug can be changed by adjusting the composition and water content of the above. As a result, it is possible to provide a sustained-release preparation that has little impact on the environment and allows easy adjustment of the release rate of the drug.

[0009] In the above aspect, the support contains P in terms of oxide. ２ O ５ , alkaline earth metal oxides, and Al ２ O ３ P for the sum of ２ O ５ The molar ratio may be 20% or more and 55% or less.

[0010] According to this embodiment, the sustained-release preparation can be easily formed, and the sustained-release preparation can be provided with appropriate sustained-release properties.

[0011] In the above aspect, the support contains P in terms of oxide. ２ O ５ , alkaline earth metal oxides, and Al ２ O ３The molar ratio of the alkaline earth metal oxide to the total of the above may be 35% or more and 70% or less.

[0012] According to this embodiment, it is possible to impart appropriate sustained release properties to the sustained release preparation. By increasing the content of alkaline earth metal oxide, the dissolution rate of the drug decreases.

[0013] In the above aspect, the support contains P in terms of oxide. ２ O ５ , alkaline earth metal oxides, and Al ２ O ３ Al to the sum of ２ O ３ The molar ratio may be greater than 0% and not greater than 15%.

[0014] According to this embodiment, it is possible to impart appropriate sustained release properties to the sustained release formulation. ２ O ３ As the content increases, the dissolution rate of the drug decreases.

[0015] Another aspect of the present invention is a gelling agent for forming a gel-like sustained-release preparation that sustainably releases a drug carried therein, comprising: ２ O ５ and alkaline earth metal oxides and Al ２ O ３ The alkaline earth metal oxide may be at least one selected from the group including MgO, CaO, SrO, and BaO.

[0016] According to this embodiment, it is possible to provide a gelling agent for forming a sustained-release preparation that has little impact on the environment and allows easy control of the drug dissolution rate.

[0017] In the above embodiment, P is 45 mol % or more and 55 mol % or less in terms of oxide. ２ O ５ and 35 mol% or more and 45 mol% or less of an alkaline earth metal oxide, and more than 0 mol% and 15 mol% or less of Al. ２ O ３ The glass powder may include

[0018] According to this embodiment, the gelling agent can impart appropriate sustained release properties to the sustained release preparation.

[0019] In the above embodiment, P is 20 mol % or more and 45 mol % or less in terms of oxide. ２ O ５ and 40 mol% or more and 70 mol% or less of an alkaline earth metal oxide, and more than 0 mol% and 15 mol% or less of Al. ２ O ３ The metaphosphate may be a metaphosphate containing

[0020] According to this embodiment, it is possible to impart appropriate sustained-release properties to the sustained-release preparation. Furthermore, the step of vitrifying the raw material can be omitted in the production process of the gelling agent. This makes it possible to produce the gelling agent with less energy and at lower cost.

[0021] Another aspect of the present invention is a method for preparing a sustained release formulation, comprising: ２ O ５ , alkaline earth metal oxides, and Al ２ O ３ and a heat treatment step of heating the mixture in a sealed state at 50° C. to 90° C. for 24 hours to 72 hours to obtain a gel-like sustained-release preparation. The alkaline earth metal oxide is preferably at least one selected from the group consisting of MgO, CaO, SrO, and BaO.

[0022] According to this embodiment, it is possible to produce a sustained-release preparation that has little impact on the environment and allows easy control of the drug dissolution rate.

[0023] In the above aspect, the gelling agent contains 45 mol % or more and 55 mol % or less of P in terms of oxide. ２ O ５ and 35 mol% or more and 45 mol% or less of an alkaline earth metal oxide, and more than 0 mol% and 15 mol% or less of Al. ２ O ３ The glass powder may include

[0024] According to this embodiment, it is possible to impart appropriate sustained release properties to the sustained release preparation.

[0025] In the above aspect, in the mixing step, at least one of an aluminum salt in an amount of 1 mol % or more and 4 mol % or less, calculated as an oxide, and an alkaline earth metal salt in an amount of 1 mol % or more and 4 mol % or less, may be added to the drug, the gelling agent, and the water.

[0026] According to this embodiment, it becomes possible to adjust the elution rate of the drug.

[0027] In the above aspect, the gelling agent contains 20 mol % or more and 45 mol % or less of P in terms of oxide. ２ O ５ and 40 mol% or more and 70 mol% or less of an alkaline earth metal oxide, and more than 0 mol% and 15 mol% or less of Al. ２ O ３ The metaphosphate may be a metaphosphate containing

[0028] According to this embodiment, the gelling agent can be obtained inexpensively and simply.

[0029] According to the above aspects, it is possible to provide a sustained-release formulation that has little impact on the environment and can increase the amount of drug carried, a gelling agent for forming the sustained-release formulation, and a method for producing the sustained-release formulation.

[0030] Photographs of sustained-release formulations Photographs of samples A1 to A5 Graph showing the sustained-release performance of each of samples A1 to A5 Photographs of each of samples A1 to A5 after 8 days in water Photographs of each of samples B1 to B7 in their initial state and after 3 days in water Graph showing the sustained-release performance of each of samples B1 to B7 Graph showing the sustained-release performance of each of samples C1 to C7 Photographs of each of samples D1 to D11 in their initial state Graph showing the sustained-release performance of each of samples D1 to D17 Graph showing the sustained-release performance of each of samples D1, D7, D12 Graph showing the sustained-release performance of each of samples D10 and D11 Graph showing the sustained-release performance of each of samples D6 and D17 Graph showing the sustained-release performance of each of samples D2, D4, D6, D8 to D11, and D13 to D16 Graph showing the sustained-release performance of each of samples D2, D18 to D20

[0031] Hereinafter, embodiments of the sustained-release preparation, the gelling agent for forming the sustained-release preparation, and the method for producing the sustained-release preparation according to the present invention will be described.

[0032] (Sustained-release formulation) A sustained-release formulation comprises a drug and a gel-like carrier (sustained-release carrier) that supports the drug and slowly releases the drug. Here, sustained release refers to the ability to gradually release the drug over a long period of time. The period over which the sustained release lasts may be selected depending on the intended use, and may be, for example, one day, one month, three months, six months, one year, or three years. The drug may be any compound or composition, such as an insecticide, insect repellent, horticultural agent, fertilizer, or pharmaceutical. The sustained-release formulation may be sprayed outdoors or placed in a predetermined location outdoors or indoors. The sustained-release formulation may also be administered orally. For example, the drug may be pyriproxyfen, which suppresses the growth of insects such as mosquito larvae, and the sustained-release formulation may be an insecticide with long-lasting insecticidal activity.

[0033] The carrier is P ２ O ５ and alkaline earth metal oxides (RO), and Al ２ O ３ and water. The carrier is a phosphate glass or a metaphosphate hydrogel. The carrier contains P in terms of oxide. ２ O ５ , alkaline earth metal oxides, and Al ２ O ３ P for the sum of ２ O ５ The molar ratio of P in terms of oxide is preferably 20% or more and 55% or less. ２ O ５ , alkaline earth metal oxides, and Al ２ O ３ P for the sum of ２ O ５ The molar ratio of P may be 30% or more and 40% or less in terms of oxide. ２ O ５ , alkaline earth metal oxides, and Al ２ O ３ The molar ratio of the alkaline earth metal oxide to the total of the above is preferably 35% or more and 70% or less. ２ O ５, alkaline earth metal oxides, and Al ２ O ３ Al to the sum of ２ O ３ The alkaline earth metal oxide is preferably at least one selected from the group consisting of MgO, CaO, SrO, and BaO.

[0034] In the carrier, P ２ O ５ As the content of alkaline earth metal oxides and Al increases, the structure of the carrier weakens and the release rate of the drug increases. ２ O ３ When the content of increases, the structure of the carrier becomes strong and the dissolution rate of the drug decreases.

[0035] (Method of producing gelling agent: 1) The gelling agent used to form the carrier is P ２ O ５ and alkaline earth metal oxides and Al ２ O ３ The gelling agent contains 45 mol % or more and 55 mol % or less of P in terms of oxide. ２ O ５ and 35 mol% or more and 45 mol% or less of an alkaline earth metal oxide, and more than 0 mol% and 15 mol% or less of Al. ２ O ３ The alkaline earth metal oxide may be at least one selected from the group including MgO, CaO, SrO, and BaO.

[0036] A method for producing the first gelling agent, which is glass powder, will be described. First, powdered aluminum hydroxide (Al(OH) ３ ) and powdered magnesium carbonate (MgCO ３) are mixed. Next, water and liquid orthophosphoric acid are mixed with the mixture of aluminum hydroxide and magnesium carbonate to carry out a wet reaction. The wet reaction is preferably carried out at a temperature of 100°C or higher and 200°C or lower for 1 to 5 hours, for example, at 150°C for 2 hours. During this time, water vapor generated from the mixture is condensed and returned to the mixture. The mixture is then dried. Drying is preferably carried out at a temperature of 200°C or higher and 300°C or lower for 5 to 15 hours, for example, at 230°C for 8 hours. This produces metaphosphate.

[0037] The resulting metaphosphate is melted to produce glass. The melting is preferably carried out at a temperature of 1200 to 1500°C for 1 to 5 hours, for example, at 1250°C for 2 hours. The resulting glass is pulverized into powder to produce the first gelling agent.

[0038] The proportions of aluminum hydroxide, magnesium carbonate, water, and orthophosphoric acid (100%) may be set to any desired proportions, for example, the proportion of aluminum hydroxide to the total amount excluding water may be 5% to 25%, the proportion of magnesium carbonate to the total amount excluding water may be 10% to 60%, and the proportion of orthophosphoric acid to the total amount excluding water may be 25% to 75%.

[0039] (Method for producing gelling agent: 2) The metaphosphate obtained in the process of producing the first gelling agent may be used as the second gelling agent. The conditions for producing the second gelling agent may be the same as the conditions for obtaining the metaphosphate in the method for producing the first gelling agent from glass powder. The second gelling agent contains 20 mol % or more and 45 mol % or less of P in terms of oxide. ２ O ５ and 40 mol% or more and 70 mol% or less of an alkaline earth metal oxide, and more than 0 mol% and 15 mol% or less of Al. ２ O ３ The alkaline earth metal oxide may be at least one selected from the group including MgO, CaO, SrO, and BaO.

[0040] (Method for producing sustained-release preparation) A method for producing a sustained-release preparation comprises mixing a drug and P ２ O５ , alkaline earth metal oxides, and Al ２ O ３ and a heat treatment step of heating the mixture in a sealed state at 50° C. to 90° C. for 24 hours to 72 hours to obtain a gel-like sustained-release preparation. The alkaline earth metal oxide is preferably at least one selected from the group consisting of MgO, CaO, SrO, and BaO.

[0041] The gelling agent may be a first gelling agent or a second gelling agent. When a first gelling agent is used, the weight ratio of water to the first gelling agent may be, for example, 15% to 60%. When a second gelling agent is used, the weight ratio of water to the second gelling agent may be, for example, 15% to 60%. When the weight ratio of water to the first gelling agent is less than 15%, the fluidity of the mixture decreases, making it difficult to stir and mold the mixture. Similarly, when the weight ratio of water to the second gelling agent is less than 15%, the fluidity of the mixture decreases, making it difficult to stir and mold the mixture.

[0042] In the mixing step when the first gelling agent is used, at least one of an aluminum salt in an amount of 1 mol % to 4 mol % in terms of oxide and an alkaline earth metal salt in an amount of 1 mol % to 4 mol % in terms of MgO may be added to the drug, gelling agent, and water. The alkaline earth metal salt may be at least one selected from the group including magnesium salts and calcium salts.

[0043] The mixture is made into a slurry. Next, the slurry mixture is molded into a predetermined shape. The molding of the mixture is preferably performed using a mold.

[0044] In the heat treatment step, the molded mixture is heat-treated in a sealed container without allowing moisture to escape from the container. The heat treatment is carried out at a temperature of 50°C to 90°C, preferably 60°C to 80°C, for 24 to 90 hours, preferably 36 to 60 hours. This causes the mixture to undergo a hydration reaction and become gel-like. The mixture before the heat treatment is cloudy, whereas the gel-like mixture after the heat treatment becomes translucent. This produces a sustained-release formulation. A sustained-release formulation is one that retains the ability to sustain the release of the drug after heat treatment by mixing a gelling agent, a drug, and water.

[0045] As shown in Figure 1, the mixture before heat treatment (Figure 1A) is cloudy white and absorbs water and disintegrates when immersed in water (Figure 1B). On the other hand, the phosphate glass gel, which is the mixture after heat treatment, is translucent (Figure 1B) and does not disintegrate even when immersed in water. This shows that the formation of phosphate glass gel has a significant impact on water resistance.

[0046] When the phosphate glass gel, which is the mixture after heat treatment, is dried at 70°C, the phosphate glass gel changes from translucent to a cloudy white state (Fig. 1D). When the dried phosphate glass gel is immersed in water, it absorbs water and disintegrates (Fig. 1B). This suggests that the water in the phosphate glass gel has a significant effect on bonding.

[0047] (Effect of Water Proportion in Mixing Process) The effect of the water proportion in the mixing process on the sustained-release performance of the sustained-release formulation was confirmed. The composition of the first gelling agent used is as shown in Table 1. The drug was a colorant containing 15% Food Red No. 102 (New Coccine) and 85% dextrin. Using the first gelling agent, water, and drug, sustained-release formulations were produced based on the above-mentioned sustained-release formulation manufacturing method. Table 1 shows the composition of the first gelling agent, the weight percentage of water relative to the first gelling agent, and the weight percentage of colorant relative to the entire sustained-release formulation for each of Samples A1 to A5. Each of Samples A1 to A5 was molded into a cylindrical tablet. Heat treatment was performed at 70°C for 48 hours.

[0048] Figure 2 shows photographs of the prepared samples A1 to A5. It can be seen from Figure 2 that the surface of sample A1, which was mixed with 0.6 g of water, is more wet than the surfaces of samples A2, A4, and A5, which were mixed with 0.4 to 0.5 g of water. It was also confirmed that the surfaces of samples A1, A3 to A5, which were mixed with 25 wt% or more of water relative to the first gelling agent, were glossy, whereas the surface of sample A3, which was mixed with 20 wt% of water relative to the first gelling agent, lacked gloss. It is believed that gelation in sample A3 was insufficient due to a lack of water.

[0049] The sustained-release performance of Samples A1 to A5 was confirmed by absorption spectrometry. Each sample was placed in 500 g of water at room temperature (24°C), and the absorbance of the medium at 400 nm was measured at predetermined intervals. When the colorant elutes from the sustained-release formulation into the medium, the absorbance of the medium at 400 nm increases. Therefore, by measuring the absorbance of the medium at 400 nm, the dissolution rate of the colorant eluted from the sustained-release formulation into the medium can be measured. The dissolution rate of the colorant varies between 0 and 100%. Note that due to measurement error, the dissolution rate may exceed 100%.

[0050] Figure 3 is a graph showing the sustained release performance of each of Samples A1 to A5. Figure 4 is a photograph of each of Samples A1 to A5 after 8 days in water. From Figure 3, it was confirmed that Sample A2 maintained sustained release for the longest period. The sustained release duration of Sample A2 was approximately 60 days. It was confirmed that the dissolution rate of Sample A2 increased almost linearly with the elapsed time. Since the sustained release duration of Sample A1 was slightly shorter than that of Sample A2, it is inferred that there is an appropriate range for the water content.

[0051] Furthermore, the results of Sample A3 confirmed that the sustained-release duration was significantly reduced when the moisture content was lower than the appropriate range. The photograph of Sample A3 in Figure 4 confirmed that Sample A3 swelled and collapsed. This is thought to be due to insufficient gelation due to the low moisture content.

[0052] In addition, from the results of sample A5 in FIG. 3, it is clear that P in the first gelling agent ２ O５ It was confirmed that the sustained release duration was significantly reduced when the content was high. From the photograph of sample A5 in Figure 4, it was confirmed that sample A5 was deformed. This is due to the P in the first gelling agent. ２ O ５ This is thought to be due to the fact that the water resistance of the gel of the sustained-release formulation decreased due to the high drug content. In addition, the sustained-release duration of Sample A4 was slightly shorter than that of Sample A2, which indicates that the dissolution rate changes depending on the drug content.

[0053] (Effect of Heat Treatment Conditions) The effect of the heating temperature and heating time in the heat treatment process on the sustained-release performance of the sustained-release formulation was confirmed. The composition of each of Samples B1 to B7 was the same as that of Sample A2 above. Each of Samples B1 to B7 was molded into a cylindrical tablet. Table 2 shows the heat treatment conditions for each of Samples B1 to B7. The dissolution rate of each of the prepared Samples B1 to B7 was measured using the absorbance analysis described above.

[0054] Figure 5 shows photographs of each sample B1 to B7 in its initial state and after 3 days in water. Figure 6 is a graph showing the sustained release performance of each sample (B1 to B7). The initial state of each sample refers to the state immediately after production, before immersion in water. Figure 5 confirms that samples B3 to B5 in their initial state were glossy, while samples B1, B2, B6, and B7 were not glossy. It was also confirmed that samples B1 and B2 expanded and collapsed in water. It is believed that gelation by hydration reaction was insufficient in samples B1 and B2 due to the low heating temperature of 50°C. It was also confirmed that samples B6 and B7 in their initial state discolored blacker than samples B1 to B5.

[0055] 6 shows that, among samples B1 to B7, the dissolution rates of samples B4 and B5, which were heated at 70°C, were relatively low. This suggests that the sustained-release duration is longer when the heating temperature is 70°C than when the heating temperature is 50°C or 90°C. This is thought to be because when the heating temperature is 70°C, the gelation of the carrier, i.e., the hydration reaction, is sufficient. On the other hand, when the heating temperature is 50°C, the gelation of the carrier, i.e., the hydration reaction, is thought to be insufficient. Furthermore, when the heating temperature is 90°C, the high temperature reduces the amount of water in the carrier gel, which is thought to make the gel more susceptible to collapse.

[0056] 6, the results for Samples B3 to B5 show that Samples B4 and B5, which were heated for 48 and 72 hours, had lower dissolution rates than Sample B3, which was heated for 24 hours. Furthermore, no significant difference in dissolution rate was observed between Sample B4, which was heated for 48 hours, and Sample B5, which was heated for 72 hours. These results suggest that a heating time longer than 24 hours is preferable to slow down the rate of increase in dissolution rate.

[0057] (Effect of Addition of Al or Mg on Sustained-Release Duration) In the mixing step, it was confirmed whether the sustained-release duration would change by adding Al or Mg to the first gelling agent and water. In the mixing step, a predetermined amount of the first gelling agent and a predetermined amount of Al(OH) ３ or MgCO ３ Acetone was added to the mixture, and after mixing, the acetone was evaporated. ２ O ５ , MgO, and Al ２ O ３ For the sum of ２ O ５ The molar ratio of MgO is 40%, and the molar ratio of Al is 50%. ２ O ３ The molar ratio of the first gelling agent and Al(OH) is 10%. ３ or MgCO ３Water and a colorant were added to the mixture, mixed, and then formed into cylindrical tablets. The colorant contained 15% Food Red No. 102 (New Coccin) and 85% dextrin. The tablets were then heat-treated in a sealed state to produce sustained-release formulations. The heat treatment was carried out at 70°C for 48 hours. Table 3 shows the compositions of sustained-release formulation samples C1 to C7. The dissolution rates of each of the prepared samples C1 to C7 were measured using the absorbance analysis described above.

[0058] Figure 7 is a graph showing the sustained-release performance of each sample C1 to C7. It was confirmed from Figure 7 that the dissolution rate of the sustained-release formulation decreased as the content of Al or Mg increased. Furthermore, the results of samples C4 and C7 confirmed that Mg was more effective than Al in reducing the dissolution rate of the sustained-release formulation. This indicates that the sustained-release duration can be adjusted by adjusting the content of Al and Mg in the sustained-release formulation.

[0059] (Sustained-release formulations using a metaphosphate-based second gelling agent) Samples D1 to D17 of sustained-release formulations were prepared using a metaphosphate-based second gelling agent, and the sustained-release performance of the sustained-release formulations was confirmed. Samples D1 to D17 were prepared using the second gelling agent, water, and a drug according to the sustained-release formulation manufacturing method described above. Table 4 shows the composition and evaluation of Samples D1 to D17. The drug was a colorant containing 15% Food Red No. 102 (New Coccin) and 85% dextrin. Each of Samples D1 to D17 was molded into a cylindrical tablet. Heat treatment was performed at 70°C for 48 hours. The dissolution rate of each of the prepared Samples D1 to D17 was measured using the absorbance analysis described above.

[0060] Figure 8 is a photograph of the initial state of each sample D1 to D11. The initial state of each sample refers to the state immediately after production, before immersion in water. Sample D6 has a low viscosity, and is deformed after molding, resulting in a decrease in height. However, it can be evaluated that sample D6 can also be molded into a cylindrical shape. From the above, it was possible to mold samples D1 to D11 into a cylindrical shape. P ２ O ５As the content of P increases, the viscosity of the sustained-release preparation decreases. ２ O ５ , MgO, and Al ２ O ３ P for the sum of ２ O ５ The molar ratio of is less than 45 mol %, preferably 40 mol % or less. Although photographs of samples D12 to D17 are omitted, they could be molded into a cylindrical shape in the same manner as D1 to D11.

[0061] 9 to 13 are graphs showing the sustained release performance of each of Samples D1 to D17 obtained by absorbance analysis. From FIG. 9, it was confirmed that the dissolution rate of Samples D1 to D17 increased with time. In other words, it was found that Samples D1 to D17 have sustained release properties.

[0062] 10 is a graph showing the sustained release performance of Samples D1, D7, and D12. In Samples D1, D7, and D12, the second gelling agent P ２ O ５ The content of P was 20 mol%. It was confirmed that the dissolution rate of samples D1, D7, and D12 reached saturation relatively early. ２ O ５ This is thought to be because the content of the second gelling agent P is low at 20 mol%, making the structure of the carrier strong and the carrier less likely to decompose. ２ O ５ The content is preferably greater than 20 mol %, or 30 mol % or more.

[0063] 11 is a graph showing the sustained release performance of Samples D10 and D11. In Samples D10 and D11, the Al second gelling agent ２ O ３ The only difference is the content of MgO in sample D11 compared to the composition of sample D10. ２ O ３ From FIG. 11, it can be seen that the elution rate of sample D10 is lower than that of sample D11. ２ O ３It can be seen that MgO has a greater effect of reducing the elution rate than ZnO.

[0064] 12 is a graph showing the sustained release performance of Samples D6 and D17. In Samples D6 and D17, the second gelling agent P ２ O ５ The content of P was 45 mol%. It was confirmed that the dissolution rate of samples D6 and D17 increased with time, reaching 80%. ２ O ５ As the content of is increased, the structure of the carrier is weakened, and therefore the dissolution rate can be increased.

[0065] Figure 13 is a graph showing the sustained-release performance of Samples D2, D4, D6, D8 to D11, and D13 to D16. Samples D2, D4, D6, D8 to D11, and D13 to D16 differ in the composition of the second gelling agent or the water content. As can be seen from Figure 13, the increase in the amount of elution continued for 30 days or more in each sample. In other words, the sustained-release property was maintained for 30 days or more. It can be seen that the amount of elution, i.e., the sustained-release duration, of each sample can be adjusted by adjusting the composition and water content of the second gelling agent.

[0066] From the above results, when focusing on moldability, it is clear that P ２ O ５ , MgO, and Al ２ O ３ P for the sum of ２ O ５ The molar ratio of P is 45% or less, preferably less than 45%, more preferably 40% or less. ２ O ５ , MgO, and Al ２ O ３ P for the sum of ２ O ５ The molar ratio of is greater than 20%, preferably 30% or more.

[0067] (Sustained-release formulations using a second gelling agent containing another alkaline earth metal) Samples D18 to D20 of sustained-release formulations were prepared using a second gelling agent containing one of Ca, Sr, or Ba as the alkaline earth metal, and the sustained-release performance of the sustained-release formulations was confirmed. Samples D18 to D20 were prepared using the second gelling agent, water, and a drug according to the sustained-release formulation manufacturing method described above. Table 5 shows the composition and evaluation of Samples D1 to D17. The drug was a colorant containing 15% Food Red No. 102 (New Coccin) and 85% dextrin. Each of Samples D18 to D20 was molded into a cylindrical tablet. Heat treatment was performed at 70°C for 48 hours. The dissolution rate of each of the prepared Samples D18 to D20 was measured using the absorbance analysis described above.

[0068] Figure 14 is a graph showing the sustained-release performance of samples D2 and D18 to D20. It was confirmed from Figure 14 that the dissolution rate increased over time for samples D18 to D20. This indicates that samples D18 to D20 have sustained-release properties. It was also found that sustained-release properties continued for approximately seven days for samples D19 and D20. These results demonstrate that the formulations have sustained-release properties even when CaO, SrO, or BaO is used as the alkaline earth metal instead of MgO.

[0069] (Sustained-release formulation using a drug containing pyriproxyfen) Sample E1 of a sustained-release formulation was produced using a drug containing pyriproxyfen, and the sustained-release performance of the sustained-release formulation was confirmed. Sample E1 was produced using a first gelling agent, water, and a drug containing pyriproxyfen based on the above-mentioned sustained-release formulation manufacturing method. Table 6 shows the composition and measurement results of Sample E1. The drug used was Fumakilla Sumirab Granules F from Fumakilla Co., Ltd. Fumakilla Sumirab Granules F contains 0.5 wt% pyriproxyfen as an active ingredient. Sample E1 was molded into a cylindrical tablet. Heat treatment was performed at 70°C for 48 hours.

[0070] The sustained release properties of Sample E1 were confirmed by the following dissolution experiment. In the dissolution experiment, Sample E1 was left to stand in 250 mL of water (dissolution medium) at 30°C for a predetermined dissolution period, and the dissolution medium was measured to determine the amount of pyriproxyfen dissolved in the dissolution medium. The dissolution medium was then replaced with fresh water, and the same measurement was repeated. To measure the amount of pyriproxyfen dissolved, 100 mL of the dissolution medium was filtered through a 0.2 μm filter, and pyriproxyfen was adsorbed by solid-phase extraction. The adsorbed pyriproxyfen was eluted with acetone and concentrated using a rotary evaporator. The concentrated pyriproxyfen was dissolved in acetone to a volume of 5 mL, filtered through a 0.2 μm PTFE filter, and then analyzed by liquid chromatography. The results of the dissolution test revealed that pyriproxyfen continued to be dissolved at approximately 0.05 ppm even in the water after the third water change.

Claims

1. A sustained-release preparation comprising a drug and a gel-like carrier that supports the drug and sustains its release, the carrier being P ２ O ５ and an alkaline earth metal oxide, and Al ２ O ３ and water.

2. In the support, P is calculated as an oxide. ２ O ５ , alkaline earth metal oxides, and Al ２ O ３ P for the sum of ２ O ５ 2. The sustained release formulation according to claim 1, wherein the molar ratio of is 20% or more and 55% or less.

3. In the support, P is calculated as an oxide. ２ O ５ , alkaline earth metal oxides, and Al ２ O ３ 3. The sustained release preparation according to claim 2, wherein the molar ratio of the alkaline earth metal oxide to the total of the above is 35% or more and 70% or less.

4. In the support, P is calculated as an oxide. ２ O ５ , alkaline earth metal oxides, and Al ２ O ３ Al to the sum of ２ O ３ The sustained release formulation according to claim 2, wherein the molar ratio of is greater than 0% and not greater than 15%.

5. The sustained release preparation according to claim 1, wherein the alkaline earth metal oxide is at least one selected from the group consisting of MgO, CaO, SrO and BaO.

6. A gelling agent for forming a gel-like sustained-release preparation that sustains the release of a loaded drug, comprising: ２ O ５ and an alkaline earth metal oxide, and Al ２ O ３ and a gelling agent comprising:

7. P of 45 mol% or more and 55 mol% or less in terms of oxide ２ O ５ and 35 mol % or more and 45 mol % or less of an alkaline earth metal oxide, and 0 mol % or more and 15 mol % or less of Al. ２ O ３ The gelling agent according to claim 6, which is a glass powder comprising:

8. P of 20 mol% or more and 45 mol% or less in terms of oxide ２ O ５ and 40 mol % or more and 70 mol % or less of an alkaline earth metal oxide, and 0 mol % or more and 15 mol % or less of Al. ２ O ３ The gelling agent according to claim 6, which is a metaphosphate comprising:

9. The gelling agent according to claim 6, wherein the alkaline earth metal oxide is at least one selected from the group consisting of MgO, CaO, SrO, and BaO.

10. A method for producing a sustained release formulation comprising: ２ O ５ , alkaline earth metal oxides, and Al ２ O ３ and a heat treatment step of heating the mixture in a sealed state at 50° C. or higher and 90° C. or lower for 24 hours or longer and 72 hours or shorter to obtain a gel-like sustained-release formulation.

11. The gelling agent contains 45 mol % or more and 55 mol % or less of P, calculated as an oxide. ２ O ５ and 35 mol % or more and 45 mol % or less of an alkaline earth metal oxide, and 0 mol % or more and 15 mol % or less of Al. ２ O ３ The method for producing a sustained release preparation according to claim 10, wherein the glass powder comprises 12. A method for producing a sustained-release formulation as described in claim 10, wherein in the mixing process, at least one of an aluminum salt in an amount of 1 mol% to 4 mol% and an alkaline earth metal salt in an amount of 1 mol% to 4 mol% in terms of oxide is added to the drug, the gelling agent, and the water.

13. The gelling agent contains 20 mol % or more and 45 mol % or less of P, calculated as an oxide. ２ O ５ and 40 mol % or more and 70 mol % or less of an alkaline earth metal oxide, and 0 mol % or more and 15 mol % or less of Al. ２ O ３ The method for producing a sustained release formulation according to claim 10, wherein the metaphosphate comprises 14. The method for producing a sustained release preparation according to claim 10, wherein the alkaline earth metal oxide is at least one selected from the group consisting of MgO, CaO, SrO and BaO.

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