Stable isoniazide oral solution and preparation method thereof

Abstract

The invention discloses a stable isoniazide oral solution. The stable isoniazide oral solution comprises isoniazide, methylparaben, propylparaben, a pH regulator and a solvent. The isoniazide oral solution with good stability is prepared, the absorption and utilization rate of the medicament is improved, and the isoniazide oral solution tastes good and has a good market prospect.

Description

Technical Field

[0001] The present invention relates to the technical field of production and processing of isoniazid oral solution, in particular to a stable isoniazid oral solution and a preparation method thereof. Background Art

[0002] The anti-tuberculosis drug market is highly concentrated. Isoniazid is a first-line anti-tuberculosis treatment and has a large market share, ranking second only to rifampicin. To enhance its efficacy, other raw materials are often added to the drug. However, due to the varying solubility of these raw materials, oral liquid dosage forms are unstable and prone to precipitation, which can affect drug absorption and efficacy. Therefore, oral preparations for isoniazid are primarily tablets, with no oral solution products currently on the market. Summary of the Invention

[0003] To this end, the present invention provides a stable isoniazid oral solution comprising isoniazid, methylparaben, propylparaben, a pH regulator and a solvent.

[0004] Furthermore, the pH adjuster is a hydrochloric acid solution, and the solvent is pure water.

[0005] Furthermore, the oral solution also includes a flavoring agent for adjusting the taste of the oral solution; the flavoring agent is sucralose, and the added mass of sucralose is less than 1 / 10 of the mass of isoniazid in the oral solution.

[0006] The present invention also discloses a method for preparing the stable isoniazid oral solution, which comprises the following steps: (1) Add pure water to the liquid preparation tank, then start stirring, start heating, heat to 40-80°C and keep warm, then add methylparaben and propylparaben, and stir at constant temperature after adding; (2) Add pure water to the liquid preparation tank, cool the solution in the liquid preparation tank to below 50°C, then add isoniazid and stir evenly; (3) Add a pH adjuster to the preparation tank to adjust the pH value of the agent, and add pure water to the prepared amount to obtain an oral solution.

[0007] Furthermore, in the oral solution, the isoniazid content is 9.3 mg / mL to 10.7 mg / mL, the methylparaben content is 1.17 mg / mL to 1.43 mg / mL, and the propylparaben content is 0.15 mg / mL to 0.18 mg / mL.

[0008] Furthermore, the pH value of the oral solution is 4.5-5.5.

[0009] Further, in the step (1), methylparaben and propylparaben are replaced with a pretreatment solution, and the raw materials of the pretreatment solution include methylparaben, propylparaben, soybean-blueberry extract, and vitamin C.

[0010] Further, in the raw materials, the total mass ratio of methylparaben and propylparaben to the mixed mass of soybean-blueberry extract and vitamin C is methylparaben and propylparaben total mass: soybean-blueberry extract: vitamin C = 1: 0.1 - 0.3: 0.05 - 0.08.

[0011] Further, the extraction method of the soybean-blueberry extract is as follows: Add soybean powder and blueberry fruit dices into the complex enzyme solution of cellulase and neutral protease. After adding the materials, heat in a water bath to 60 ± 3 °C, keep the temperature constant for enzyme hydrolysis for 5 - 6 h, then separate the solid and liquid phases, perform enzyme inactivation treatment on the liquid phase, and concentrate under reduced pressure to obtain the soybean-blueberry extract.

[0012] Further, the preparation method of the pretreatment solution is as follows: Add methylparaben, propylparaben, and vitamin C to the soybean-blueberry extract under stirring. After adding the materials, heat in a water bath to 50 ± 5 °C, keep stirring at a constant temperature for more than 5 h to obtain the pretreatment solution.

[0013] The beneficial effects of the present invention are as follows: 1. Currently, domestic oral solid preparations of isoniazid mainly consist of tablets, with many manufacturers and serious homogenization. There is no oral solution product on the market. The present invention prepares an isoniazid oral solution with good stability, improves the absorption and utilization rate of the medicament, has a good taste, and has a good market prospect.

[0014] 2. The present invention uses a compound of isoniazid, methylparaben, and propylparaben. On the one hand, it improves the efficacy of the oral liquid, plays a certain role in sterilization and anti-inflammation, and on the other hand, it improves the stability of isoniazid, reduces the decomposition of the active ingredient, and reduces the impurity content. In addition, by adding a compound embedding of soybean-blueberry extract and vitamin C, the stability of the active ingredient can be further improved, the generation of impurities can be reduced, and the shelf life of the drug can be extended. Specific Embodiments

[0015] The following further illustrates the present invention in conjunction with embodiments.

[0016] Example 1 A preparation method of a stable isoniazid oral solution, the steps include: (1) Weighing: Ensure that all containers and utensils have been cleaned and disinfected before preparation, and can be prepared only after passing the inspection before production; Take out the raw and auxiliary materials from the raw and auxiliary material temporary storage room in the production order, accurately weigh each material in the weighing room in turn, and use it after being checked and verified by another person. (2) Preparation of 1 mol / L hydrochloric acid solution: Measure 84 mL of concentrated hydrochloric acid, add it to a volumetric flask, then add purified water to make up the volume to 1000 mL, and then shake until uniform to prepare a hydrochloric acid solution with a concentration of 1 mol / L for standby; (3) Add 60% (300 kg) of the total preparation amount of purified water to a 3000 L liquid preparation tank; Set the rotation speed to 200 rpm and start magnetic stirring, then start heating, control the temperature of the purified water to 70 ± 5 °C, add the prescribed amounts of methylparaben and propylparaben to the liquid preparation tank, measure 1 L of purified water to rinse the feeding container, and add the rinsing solution to the liquid preparation tank, and stir at a constant temperature of 70 ± 5 °C for 20 min; (4) Turn off the magnetic stirring, add purified water to 90% (450 kg) of the prescribed amount; Set the rotation speed of the magnetic stirring to 200 rpm, start magnetic stirring, then start chilled water, and cool the temperature of the liquid medicine to 40 °C; Add the prescribed amounts of isoniazid in sequence, measure 1 L of purified water to rinse the feeding container, and add the rinsing solution to the liquid preparation tank, and stir for 10 min; (5) Add the pre-diluted 1 mol / L hydrochloric acid solution to adjust the pH value; (6) Turn off the magnetic stirring, add purified water to the preparation amount (the total weight reaches 500.5 kg); Set the rotation speed of the magnetic stirring to 200 rpm, start magnetic stirring, and stir for 15 min to obtain the stable isoniazid oral solution, in which the isoniazid content is 10.1 mg / mL, the methylparaben content is 1.31 mg / mL, the propylparaben content is 0.16 mg / mL, and the final pH value is 5.1.

[0017] After stirring for 15 min, test the uniformity of the oral solution, and the results are shown in Table 1. Then conduct a freeze-thaw test to detect the change in impurity content, and the results are shown in Table 2. The percentages in the table are all mass percentages.

[0018] Table 1 Table 2 Example 2 A preparation method of a stable isoniazid oral solution, the steps include: (1) Weighing: Ensure that all containers and utensils have been cleaned and disinfected before preparation, and can be prepared only after passing the inspection before production; Take out the raw and auxiliary materials from the raw and auxiliary material temporary storage room in the production order, accurately weigh each material in the weighing room in turn, and use it after being checked and verified by another person; (2) Preparation of 1 mol / L hydrochloric acid solution: Measure 84 mL of concentrated hydrochloric acid, add it to a volumetric flask, then add purified water to make up the volume to 1000 mL, and then shake until uniform to prepare a hydrochloric acid solution with a concentration of 1 mol / L for standby; (3) Add 60% (300 kg) of the total formulated amount of purified water to a 3000 L liquid preparation tank; set the rotation speed to 200 rpm to start magnetic stirring, then start heating, control the temperature of the purified water to 70 ± 5 °C, add the pretreatment solution to the liquid preparation tank, measure 1 L of purified water to rinse the feeding container, add the rinsing solution to the liquid preparation tank, and stir at a constant temperature of 70 ± 5 °C for 20 min; The raw materials of the pretreatment solution include methylparaben, propylparaben, soybean-blueberry extract, and vitamin C. The total mass ratio of methylparaben and propylparaben to the mixed mass of soybean-blueberry extract and vitamin C is methylparaben and propylparaben total mass: soybean-blueberry extract: vitamin C = 1:0.2:0.06; the extraction method of the soybean-blueberry extract is: add soybean powder and blueberry fruit dices to the complex enzymatic hydrolysate of cellulase and neutral protease, and the mixed mass ratio of soybean powder to blueberry fruit dices is soybean powder: blueberry fruit dices = 1:2; during the enzymatic hydrolysis process, the total enzyme addition amount of cellulase and neutral protease is 2 wt%, and the mass ratio of cellulase to neutral protease is cellulase: neutral protease = 1:1; the mass ratio of the material to the liquid during enzymatic hydrolysis is material: liquid = 1:10; after adding materials, heat in a water bath to 60 °C, carry out enzymatic hydrolysis at a constant temperature for 5 h, then carry out solid-liquid separation, heat the liquid phase in a water bath to 95 °C and keep it warm for 10 min for enzyme inactivation treatment, and concentrate under reduced pressure to half of the volume before concentration to obtain the soybean-blueberry extract. Add methylparaben, propylparaben, and vitamin C to the soybean-blueberry extract under stirring state, heat in a water bath to 50 °C after adding materials, and stir at a constant temperature for 5 h to obtain the pretreatment solution; (4) Turn off the magnetic stirring, add purified water to 90% (450 kg) of the prescription amount; set the magnetic stirring speed to 200 rpm, start magnetic stirring, then start the chilled water, and cool the temperature of the medicinal liquid to 40 °C; sequentially add the prescription amount of isoniazid, measure 1 L of purified water to rinse the feeding container, add the rinsing solution to the liquid preparation tank, and stir for 10 min; (5) Add the pre-diluted 1 mol / L hydrochloric acid solution to adjust the pH value; (6) Turn off the magnetic stirring, add purified water to the formulated amount (the total weight reaches 500.5 kg); set the magnetic stirring speed to 200 rpm, start magnetic stirring, and stir for 15 min to obtain the stable isoniazid oral solution, where the isoniazid content is 10.1 mg / mL, the methylparaben content is 1.31 mg / mL, the propylparaben content is 0.16 mg / mL, and the final pH value is 5.1.

[0019] The oral liquid obtained in this example was subjected to freeze-thaw tests to detect the change in impurity content, and the results are shown in Table 3. The percentages in the table are all mass percentages.

[0020] Table 3 Example 3 A preparation method of a stable isoniazid oral solution, the steps include: (1) Weighing: Ensure that all containers have been cleaned and disinfected before preparation, and can be prepared only after passing the inspection before production; Take the raw and auxiliary materials from the raw and auxiliary material temporary storage room in the production order, accurately weigh each material in turn in the weighing room, and use it after being checked and verified by another person; (2) Preparation of 1mol / L hydrochloric acid solution: Measure 84 mL of concentrated hydrochloric acid, add it to a volumetric flask, then add purified water to make up to 1000 mL, and then shake until uniform to prepare a hydrochloric acid solution with a concentration of 1mol / L for standby; (3) Add 60% (300 kg) of the total preparation amount of purified water to a 3000L liquid preparation tank; Set the rotation speed to 200 rpm and turn on the magnetic stirrer, then turn on the heating, control the temperature of the purified water to 70±5°C, add the pretreatment solution to the liquid preparation tank, measure 1L of purified water to rinse the feeding container, add the rinsing solution to the liquid preparation tank, and stir at a constant temperature of 70±5°C for 20 min; Wherein the raw materials of the pretreatment solution include methylparaben, propylparaben, soybean extract and vitamin C, and the total mass ratio of methylparaben and propylparaben to the mixed mass of soybean extract and vitamin C is methylparaben and propylparaben total mass: soybean extract: vitamin C = 1:0.2:0.06; The extraction method of the soybean extract is: add soybean powder to the composite enzymatic hydrolysis solution of cellulase and neutral protease; During the enzymatic hydrolysis process, the total enzyme addition amount of cellulase and neutral protease is 2wt%, and the mass ratio of cellulase to neutral protease is cellulase: neutral protease = 1:1; The mass ratio of the material to the liquid during enzymatic hydrolysis is material: liquid = 1:10; After adding the material, heat it in a water bath to 60°C, carry out enzymatic hydrolysis at a constant temperature for 5 h, then carry out solid-liquid separation, heat the liquid phase in a water bath to 95°C and keep it warm for 10 min for enzyme inactivation treatment, and concentrate it under reduced pressure to half of the volume before concentration to obtain the soybean extract. Add methylparaben, propylparaben and vitamin C to the soybean extract under stirring, heat it in a water bath to 50°C after adding the material, and stir at a constant temperature for 5 h to obtain the pretreatment solution; (4) Turn off the magnetic stirrer, add purified water to 90% (450 kg) of the prescription amount; Set the rotation speed of the magnetic stirrer to 200 rpm, turn on the magnetic stirrer, then turn on the chilled water, and cool the temperature of the medicinal liquid to 40°C; Add the isoniazid of the prescription amount in turn, measure 1L of purified water to rinse the feeding container, add the rinsing solution to the liquid preparation tank, and stir for 10 min; (5) Add the pre-diluted 1mol / L hydrochloric acid solution to adjust the pH value; (6) Turn off the magnetic stirring, add purified water to the formulated volume (the total weight reaches 500.5 kg); set the magnetic stirring speed to 200 rpm, turn on the magnetic stirring, and stir for 15 min to obtain the stable isoniazid oral solution, wherein the isoniazid content is 10.1 mg / mL, the methylparaben content is 1.31 mg / mL, the propylparaben content is 0.16 mg / mL, and the final pH value is 5.1.

[0021] The freeze-thaw test was carried out on the oral liquid obtained in this example to detect the change in impurity content. The results are shown in Table 4, and the percentages in the table are all mass percentages.

[0022] Table 4 Example 4 A preparation method of a stable isoniazid oral solution, the steps include: (1) Weighing: Ensure that all containers are clean and disinfected before preparation, and can only be prepared after passing the pre-production inspection; take out the raw and auxiliary materials from the raw and auxiliary material temporary storage room in the production order, accurately weigh each material in the weighing room in turn, and use it after being checked and verified by another person. (2) Preparation of 1 mol / L hydrochloric acid solution: Measure 84 mL of concentrated hydrochloric acid, add it to a volumetric flask, then add purified water to make up to 1000 mL, and then shake evenly to prepare a hydrochloric acid solution with a concentration of 1 mol / L for use. (3) Add 60% (300 kg) of the total formulated volume of purified water to a 3000 L liquid preparation tank; set the speed to 200 rpm and turn on the magnetic stirring, then turn on the heating, control the temperature of the purified water to 70 ± 5 °C, add the pretreatment solution to the liquid preparation tank, measure 1 L of purified water to rinse the feeding container, add the rinsing solution to the liquid preparation tank, and stir at a constant temperature of 70 ± 5 °C for 20 min. The raw materials of the pretreatment solution include methylparaben, propylparaben, blueberry extract, and vitamin C. The total mass ratio of methylparaben and propylparaben to the combined mass of blueberry extract and vitamin C is methylparaben + propylparaben:blueberry extract:vitamin C = 1:0.2:0.06. The extraction method of the blueberry extract is as follows: Add crushed blueberry fruits to a composite enzyme solution of cellulase and neutral protease. During the enzymatic hydrolysis process, the total enzyme dosage of cellulase and neutral protease is 2 wt%, and the mass ratio of cellulase to neutral protease is cellulase:neutral protease = 1:1. The mass ratio of solid to liquid during enzymatic hydrolysis is solid:liquid = 1:10. After adding the materials, heat in a water bath to 60 °C and keep the temperature constant for enzymatic hydrolysis for 5 h. Then, perform solid-liquid separation. Heat the liquid phase in a water bath to 95 °C and keep it warm for 10 min for enzyme inactivation treatment. Concentrate under reduced pressure to half of the original volume to obtain the blueberry extract. Add methylparaben, propylparaben, and vitamin C to the blueberry extract under stirring. After adding the materials, heat in a water bath to 50 °C and keep stirring at a constant temperature for 5 h to obtain the pretreatment solution; (4) Turn off the magnetic stirring, add purified water to 90% of the prescription amount (450 kg); set the magnetic stirring speed to 200 rpm, turn on the magnetic stirring, and then turn on the chilled water to cool the temperature of the medicinal solution to 40 °C; sequentially add the prescribed amount of isoniazid, measure 1 L of purified water to rinse the feeding container, and add the rinsing solution to the mixing tank and stir for 10 min; (5) Add the pre-diluted 1 mol / L hydrochloric acid solution to adjust the pH value; (6) Turn off the magnetic stirring, add purified water to the prepared amount (the total weight reaches 500.5 kg); set the magnetic stirring speed to 200 rpm, turn on the magnetic stirring, and stir for 15 min to obtain the stable isoniazid oral solution, where the isoniazid content is 10.1 mg / mL, the methylparaben content is 1.31 mg / mL, the propylparaben content is 0.16 mg / mL, and the final pH value is 5.1.

[0023] The oral liquid obtained in this example was subjected to freeze-thaw tests to detect changes in impurity content. The results are shown in Table 5, where the percentages in the table are all mass percentages.

[0024] Table 5 As can be seen from Tables 2 - 5, the isoniazid oral solution prepared by the present invention has good stability. The obtained solutions are all colorless and clear liquids, which improve the solubility of drug components in water and are beneficial for patients to absorb and utilize. Moreover, after the freeze-thaw test of the oral liquid, the increase in impurity content is relatively small, and the results all meet the requirements, and the product quality is stable. And the effect of adding the soybean-blueberry composite extract is obviously better than the addition of soybean or blueberry extract alone.

[0025] The above has introduced the technical solution provided by the present invention in detail. For those of ordinary skill in the art, according to the idea of the embodiments of the present invention, there will be changes in the specific implementation manners and application scopes. In summary, the content of this specification should not be construed as a limitation to the present invention.

Claims

1. A stable isoniazid oral solution, characterized in that, It includes isoniazid, methylparaben, propylparaben, a pH regulator and a solvent.

2. The stable isoniazid oral solution according to claim 1, wherein In the oral solution, the content of isoniazid is 9.3 mg / mL to 10.7 mg / mL, the content of methylparaben is 1.17 mg / mL to 1.43 mg / mL, and the content of propylparaben is 0.15 mg / mL to 0.18 mg / mL.

3. The stable isoniazid oral solution according to claim 2, characterized in that, The pH regulator is hydrochloric acid solution and the solvent is pure water.

4. A stable isoniazid oral solution according to claim 3, characterized in that, The pH value of the oral solution is 4.5 to 5.

5.

5. A stable isoniazid oral solution according to claim 3, characterized in that, The oral liquid further includes a flavoring agent for adjusting the taste of the oral solution; the flavoring agent is sucralose, and the added mass of sucralose is less than 1 / 10 of the mass of isoniazid in the oral solution.

6. The preparation method of the stable isoniazid oral solution according to claim 4, characterized in that the step It includes: (1) Add pure water to the liquid preparation tank, then start stirring and heating, heat to 40 - 80 °C for insulation, then add methylparaben and propylparaben, and stir constantly at a constant temperature after feeding. (2) Add pure water to the liquid preparation tank again, cool the solution in the liquid preparation tank to below 50 °C, then add isoniazid and stir evenly. (3) Add a pH regulator to the liquid preparation tank to adjust the pH value of the medicament, and add pure water to the configured amount to obtain the oral solution.

7. The preparation method according to claim 6, characterized in that, In the step (1), replace methylparaben and propylparaben with a pretreatment solution, and the raw materials of the pretreatment solution include methylparaben, propylparaben, soybean - blueberry extract and vitamin C.

8. A preparation method according to claim 7, characterized in that, In the raw materials, the mass ratio of the total mass of methylparaben and propylparaben to the mixed mass of soybean - blueberry extract and vitamin C is methylparaben and propylparaben total mass:soybean - blueberry extract:vitamin C = 1:0.1 - 0.3:0.05 - 0.

08.

9. A preparation method according to claim 7, characterized in that, The extraction method of the soybean - blueberry extract is: add soybean powder and blueberry fruit dices into the complex enzyme solution of cellulase and neutral protease, heat in a water bath to 60 ± 3 °C after feeding, carry out constant - temperature enzymatic hydrolysis for 5 - 6 h, then carry out solid - liquid separation, inactivate the enzyme in the liquid phase, and concentrate under reduced pressure to obtain the soybean - blueberry extract.

10. A preparation method according to claim 7, characterized in that, The preparation method of the pretreatment solution is: add methylparaben, propylparaben and vitamin C to the soybean - blueberry extract under stirring, heat in a water bath to 50 ± 5 °C after feeding, and stir constantly at a constant temperature for more than 5 h to obtain the pretreatment solution.

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