A stable oral solution of isoniazid and a method for preparing the same

Abstract

The application discloses a stable isoniazid oral solution, which comprises isoniazid, hydroxybenzyl methyl ester, hydroxybenzyl propyl ester, a pH regulator and a solvent. The application prepares the isoniazid oral solution with good stability, improves the absorption and utilization rate of the medicament, and has good taste and market prospect.

Description

TECHNICAL FIELD

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

[0002] The anti-tuberculosis drug market has high concentration, and isoniazid is a first-line anti-tuberculosis drug, which has a large market capacity and ranks second only to rifampicin. In order to improve the drug properties, other raw materials are often added to the drug. Due to the different solubilities of the raw materials, the oral solution dosage form is unstable, and is prone to form a precipitate, which affects the absorption and effect of the drug. Therefore, the isoniazid oral preparation is mainly in the form of tablets, and there is no oral solution product on the market. SUMMARY

[0003] Therefore, the present application provides a stable isoniazid oral solution, which comprises isoniazid, hydroxybenzyl methyl ester, hydroxybenzyl propyl ester, a pH adjuster and a solvent.

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

[0005] Further, the oral solution further comprises 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 application also discloses a preparation method of the stable isoniazid oral solution.

[0007] (1) adding pure water into a liquid preparation tank, then starting stirring and heating, heating to 40-80℃ for preservation, then adding hydroxybenzyl methyl ester and hydroxybenzyl propyl ester, and constant temperature stirring after feeding;

[0008] (2) adding pure water into the liquid preparation tank, cooling the solution in the liquid preparation tank to below 50℃, then adding isoniazid, and stirring uniformly;

[0009] (3) adding a pH adjuster to adjust the pH value of the medicament, and adding pure water to the preparation amount to obtain an oral solution.

[0010] Further, in the oral solution, the content of isoniazid is 9.3mg / mL-10.7mg / mL, the content of hydroxybenzyl methyl ester is 1.17mg / mL-1.43mg / mL, and the content of hydroxybenzyl propyl ester is 0.15mg / mL-0.18mg / mL.

[0011] Further, the pH value of the oral solution is 4.5-5.5.

[0012] Further, in the step (1), the parahydroxybenzoic acid methyl ester and the parahydroxybenzoic acid propyl ester are replaced by a pretreatment solution, raw materials of the pretreatment solution including the parahydroxybenzoic acid methyl ester, the parahydroxybenzoic acid propyl ester, a soybean-blueberry extract and vitamin C.

[0013] Further, in the raw materials, the total mass of the parahydroxybenzoic acid methyl ester and the parahydroxybenzoic acid propyl ester and the mass ratio of the soybean-blueberry extract and vitamin C are as follows: the total mass of the parahydroxybenzoic acid methyl ester and the parahydroxybenzoic acid propyl ester: the mass of the soybean-blueberry extract: the mass of vitamin C = 1:0.1-0.3:0.05-0.08.

[0014] Further, the extraction method of the soybean-blueberry extract is as follows: soybean powder and blueberry fruit are added into a cellulase and neutral protease complex enzyme solution, and after the addition, water bath heating is performed to 60±3℃, and constant temperature enzyme hydrolysis is performed for 5-6h, then solid-liquid separation is performed, liquid phase enzyme inactivation treatment is performed, and reduced pressure concentration is performed to obtain the soybean-blueberry extract.

[0015] Further, the preparation method of the pretreatment solution is as follows: under stirring, the parahydroxybenzoic acid methyl ester, the parahydroxybenzoic acid propyl ester and vitamin C are added into the soybean-blueberry extract, and after the addition, water bath heating is performed to 50±5℃, and constant temperature stirring is performed for more than 5h to obtain the pretreatment solution.

[0016] The beneficial effects of the present application are as follows:

[0017] 1. At present, the oral solid preparation of isoniazid mainly takes tablets as the main form, there are many manufacturers, and the homogeneity is serious. There is no oral solution product on the market, the present application prepares an isoniazid oral solution with good stability, improves the absorption and utilization rate of the medicament, and has good taste and good market prospect.

[0018] 2. The present application uses isoniazid, parahydroxybenzoic acid methyl ester and parahydroxybenzoic acid propyl ester for compounding, on the one hand, the drug efficacy of the oral solution is improved, and certain bactericidal and anti-inflammatory effects are achieved, on the other hand, the stability of isoniazid is improved, the decomposition of the effective component is reduced, and the impurity content is reduced; in addition, by adding the soybean-blueberry extract and vitamin C for compounding and embedding, the stability of the effective component can be further improved, the generation of impurities is reduced, and the shelf life of the medicament is improved. DETAILED DESCRIPTION

[0019] The present application is further described below in combination with examples.

[0020] Example 1

[0021] A preparation method of a stable isoniazid oral solution, steps including:

[0022] (1) Weighing: Ensure that all containers are clean and disinfected before preparation. Check the quality before production. Take the raw and auxiliary materials from the temporary storage according to the production sequence. Accurately weigh each material in the weighing room, and use it after another person reviews it and finds no errors.

[0023] (2) Preparation of 1 mol / L hydrochloric acid solution: Take 84 mL of concentrated hydrochloric acid and add it to a volumetric flask. Then add purified water to make up to 1000 mL. Shake until uniform to prepare a 1 mol / L hydrochloric acid solution. Use as needed.

[0024] (3) Add 60% (300 kg) of the total preparation amount of purified water to a 3000 L preparation tank. Set the stirring speed to 200 rpm and start the magnetic stirring. Then turn on the heating and control the purified water temperature to 70±5°C. Add the prescribed amount of hydroxybenzyl and hydroxybenzyl propyl to the preparation tank. Take 1 L of purified water to rinse the feeding container, and add the rinse solution to the preparation tank. Stir at 70±5°C for 20 minutes.

[0025] (4) Turn off the magnetic stirring and add purified water to 90% (450 kg) of the prescribed amount. Set the magnetic stirring speed to 200 rpm and start the magnetic stirring. Then turn on the refrigerated water and cool the solution to 40°C. Add the prescribed amount of isoniazid, take 1 L of purified water to rinse the feeding container, and add the rinse solution to the preparation tank. Stir for 10 minutes.

[0026] (5) Add the 1 mol / L hydrochloric acid solution that has been diluted in advance to adjust the pH value.

[0027] (6) Turn off the magnetic stirring and add purified water to the preparation amount (total weight reaches 500.5 kg). Set the magnetic stirring speed to 200 rpm and start the magnetic stirring. Stir for 15 minutes to obtain the stable isoniazid oral solution, which contains 10.1 mg / mL of isoniazid, 1.31 mg / mL of hydroxybenzyl, 0.16 mg / mL of hydroxybenzyl propyl, and the final pH value is 5.1.

[0028] After stirring for 15 minutes, test the uniformity of the oral solution. The results are shown in Table 1. Then perform a freeze-thaw test to detect the change in impurity content. The results are shown in Table 2, where the percentages are mass percentages.

[0029] Table 1

[0030]

[0031] Table 2

[0032]

[0033] Example 2

[0034] A preparation method of a stable isoniazid oral solution, comprising the following steps:

[0035] (1) Weighing: Ensure that all containers are cleaned and disinfected before preparation, and only after passing the pre-production inspection can the preparation be carried out; take the raw and auxiliary materials from the temporary storage room according to the production sequence, accurately weigh each material in the weighing room, and then use it after another person reviews it without error;

[0036] (2) 1 mol / L hydrochloric acid solution preparation: take 84 mL of concentrated hydrochloric acid, add it to a volumetric flask, then add purified water to make up to 1000 mL, then shake until uniform, prepare a 1 mol / L hydrochloric acid solution, and wait for use;

[0037] (3) Add 60% (300 kg) of the total amount of purified water to a 3000 L liquid preparation tank; set the stirring speed to 200 rpm and start the magnetic stirring, then start heating, control the purified water temperature to 70±5℃, add the pretreatment solution to the liquid preparation tank, take 1 L of purified water to rinse the feeding container, and add the rinse liquid to the liquid preparation tank., 70±5℃ constant temperature stirring for 20 min;

[0038] The raw materials of the pretreatment solution include hydroxybenzyl methyl ester, hydroxybenzyl propyl ester, soybean-blueberry extract and vitamin C, and the total mass of hydroxybenzyl methyl ester and hydroxybenzyl propyl ester is mixed with the mass ratio of soybean-blueberry extract, vitamin C, which is hydroxybenzyl methyl ester and hydroxybenzyl propyl ester total mass:soybean-blueberry extract: vitamin C = 1:0.2:0.06; The extraction method of the soybean-blueberry extract is: adding soybean powder and blueberry fruit into a cellulase and neutral protease complex enzyme solution, and the mixed mass ratio of the soybean powder and the blueberry fruit is soybean powder:blueberry fruit = 1:2; The total enzyme amount of cellulase and neutral protease in the enzyme hydrolysis process is 2wt%, and the mass ratio of cellulase and neutral protease is cellulase:neutral protease = 1:1; The solid-liquid mass ratio of enzyme hydrolysis is solid:liquid = 1:10; After feeding, heat the water bath to 60℃, and keep the temperature constant for 5h, then solid-liquid separation, liquid phase water bath heating to 95℃ for 10min enzyme inactivation treatment, reduced pressure concentration to half of the volume before concentration, to obtain the soybean-blueberry extract. Under stirring, add the hydroxybenzyl methyl ester, hydroxybenzyl propyl ester and vitamin C to the soybean-blueberry extract, heat the water bath to 50℃ after feeding, and keep the temperature constant for 5h, to obtain the pretreatment solution;

[0039] (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 the magnetic stirring, then start the refrigerated water, cool the liquid temperature to 40℃, then add the prescription amount of isoniazid, take 1 L of purified water to rinse the feeding container, add the rinse liquid to the liquid preparation tank, and stir for 10 min;

[0040] (5) Add 1 mol / L hydrochloric acid solution which has been diluted in advance to adjust the pH value;

[0041] (6) Close the magnetic stirring, add purified water to the preparation amount (the total weight reaches 500.5 kg); set the magnetic stirring speed to 200 rpm, open the magnetic stirring, stir for 15 min, and obtain the stable isoniazid oral solution, wherein the isoniazid content is 10.1 mg / mL, the hydroxybenzyl acetate content is 1.31 mg / mL, the hydroxybenzyl propylate content is 0.16 mg / mL, and the final pH value is 5.1.

[0042] The oral solution obtained in the example is subjected to freeze-thaw test, and the impurity content change is detected, and the results are shown in Table 3. The percentages in the table are mass percentages.

[0043] Table 3

[0044]

[0045] Example 3

[0046] A preparation method of a stable isoniazid oral solution, comprising the following steps:

[0047] (1) Weighing: Before preparation, ensure that all containers are cleaned and disinfected, and can be prepared only after passing the pre-production inspection; take the raw and auxiliary materials from the raw and auxiliary material temporary storage according to the production order, accurately weigh each material in the weighing room in turn, and use it after being rechecked by another person without error;

[0048] (2) Preparation of 1 mol / L hydrochloric acid solution: take 84 mL of concentrated hydrochloric acid, add it to a volumetric flask, then add purified water to make up to 1000 mL, then shake until uniform, to prepare a 1 mol / L hydrochloric acid solution, and wait for use;

[0049] (3) Add 60% (300 kg) of the total preparation amount of purified water to a 3000 L preparation tank; set the stirring speed to 200 rpm, open the magnetic stirring, then open the heating, control the purified water temperature to 70±5℃, add the pretreated solution to the preparation tank, take 1 L of purified water to rinse the feeding container, add the rinse solution to the preparation tank, and stir at 70±5℃ for 20 min;

[0050] The raw materials of the pretreatment solution include hydroxybenzoic acid methyl ester, hydroxybenzoic acid propyl ester, soybean extract, and vitamin C, the total mass of hydroxybenzoic acid methyl ester and hydroxybenzoic acid propyl ester is mixed with the mass of soybean extract and vitamin C in a mass ratio of hydroxybenzoic acid methyl ester and hydroxybenzoic acid propyl ester:soybean extract:vitamin C = 1:0.2:0.06; the extraction method of the soybean extract is as follows: soybean powder is added into a cellulase and neutral protease complex enzyme solution; the total enzyme amount of the cellulase and the neutral protease in the enzyme hydrolysis process is 2 wt%, the mass ratio of the cellulase and the neutral protease is cellulase:neutral protease = 1:1; the solid-liquid mass ratio of the enzyme hydrolysis is solid:liquid = 1:10; after the addition, the water bath is heated to 60℃, and the constant temperature enzyme hydrolysis is performed for 5 h, then solid-liquid separation is performed, the liquid phase is heated to 95℃ in a water bath for 10 min for enzyme inactivation treatment, and the pressure is reduced to concentrate to half of the volume before concentration, to obtain the soybean extract; the hydroxybenzoic acid methyl ester, the hydroxybenzoic acid propyl ester, and the vitamin C are added to the soybean extract in a stirring state, the water bath is heated to 50℃ after the addition, and the constant temperature stirring is performed for 5 h, to obtain the pretreatment solution;

[0051] (4) Close the magnetic stirring, add purified water to 90% of the prescription amount (450 kg); set the magnetic stirring speed to 200 rpm, open the magnetic stirring, then open the refrigerated water, and cool the liquid temperature to 40℃; add the prescription amount of isoniazid in sequence, measure 1 L of purified water to rinse the addition container, and add the rinse liquid to the solution preparation tank and stir for 10 min;

[0052] (5) Add the 1 mol / L hydrochloric acid solution diluted in advance to adjust the pH value;

[0053] (6) Close the magnetic stirring, add purified water to the preparation amount (the total weight reaches 500.5 kg); set the magnetic stirring speed to 200 rpm, open 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 hydroxybenzoic acid methyl ester content is 1.31 mg / mL, the hydroxybenzoic acid propyl ester content is 0.16 mg / mL, and the final pH value is 5.1.

[0054] The oral solution obtained in the example is subjected to freeze-thaw test, and the impurity content change is detected, and the results are shown in Table 4. The percentages in the table are mass percentages.

[0055] Table 4

[0056]

[0057] Example 4

[0058] A preparation method of a stable isoniazid oral solution, comprising the following steps:

[0059] (1) Weighing: Ensure that all containers are clean and disinfected before preparation. Check the quality before production. Take the raw and auxiliary materials from the temporary storage room according to the production sequence. Accurately weigh each material in the weighing room, and another person should check it before use.

[0060] (2) Preparation of 1 mol / L hydrochloric acid solution: Take 84 mL of concentrated hydrochloric acid and add it to a volumetric flask. Then add purified water to make up to 1000 mL. Shake until uniform to prepare a 1 mol / L hydrochloric acid solution. Wait for use.

[0061] (3) Add 60% (300 kg) of the total amount of purified water to the 3000 L liquid preparation tank. Set the stirring speed to 200 rpm and start the magnetic stirring. Then turn on the heating and control the purified water temperature to 70±5℃. Add the pretreatment solution to the liquid preparation tank. Rinse the feeding container with 1 L of purified water and add the rinse liquid to the liquid preparation tank. Stir at 70±5℃ for 20 minutes.

[0062] The raw materials of the pretreatment solution include hydroxybenzyl alcohol, hydroxybenzyl propyl, blueberry extract and vitamin C. The total mass of hydroxybenzyl alcohol and hydroxybenzyl propyl is mixed with the mass ratio of blueberry extract and vitamin C as follows: hydroxybenzyl alcohol and hydroxybenzyl propyl total mass: blueberry extract: vitamin C = 1:0.2:0.06. The extraction method of the blueberry extract is as follows: add blueberry fruit to a cellulase and neutral protease complex enzyme solution. The total enzyme amount of cellulase and neutral protease during enzyme hydrolysis is 2wt%, and the mass ratio of cellulase to neutral protease is 1:1. The solid-liquid mass ratio of enzyme hydrolysis is 1:10. After adding the material, heat the water bath to 60℃, and keep the temperature constant for 5 hours. Then separate the solid and liquid phases. Heat the liquid phase in a water bath to 95℃ for 10 minutes for enzyme inactivation treatment. Concentrate under reduced pressure to half the original volume to obtain the blueberry extract. Add the hydroxybenzyl alcohol, hydroxybenzyl propyl and vitamin C to the blueberry extract under stirring. After adding the material, heat the water bath to 50℃, and keep the temperature constant for 5 hours to obtain the pretreatment solution.

[0063] (4) Turn off the magnetic stirring, add purified water to 90% (450 kg) of the prescription amount, and set the stirring speed to 200 rpm. Turn on the magnetic stirring, then turn on the refrigerated water, and cool the liquid temperature to 40℃. Add the prescribed amount of isoniazid, rinse the feeding container with 1 L of purified water, and add the rinse liquid to the liquid preparation tank. Stir for 10 minutes.

[0064] (5) Add the 1 mol / L hydrochloric acid solution that has been diluted in advance to adjust the pH value.

[0065] (6) turn off the magnetic stirring, add purified water to the preparation amount (total weight reaches 500.5 kg); set the magnetic stirring speed to 200 rpm, turn on the magnetic stirring, stir for 15 min, and obtain the stable isoniazid oral solution, wherein the isoniazid content is 10.1 mg / mL, the hydroxybenzyl methyl ester content is 1.31 mg / mL, the hydroxybenzyl propyl ester content is 0.16 mg / mL, and the final pH value is 5.1.

[0066] The oral solution obtained in the example is subjected to freeze-thaw test, and the impurity content change is detected, and the results are shown in Table 5. The percentages in the table are mass percentages.

[0067] Table 5

[0068]

[0069] As shown in Tables 2-5, the isoniazid oral solution prepared by the present application has good stability, the obtained solution is a colorless and clear liquid, the solubility of the drug ingredient in water is improved, which is beneficial to the absorption and utilization of patients. After the freeze-thaw test, the impurity content of the oral solution increases less, and the results meet the requirements, and the product quality is stable. And the effect of adding the soybean-blueberry compound extract is obviously better than that of adding the soybean or blueberry extract alone.

[0070] The above describes the technical solutions provided by the present application in detail. For those skilled in the art, according to the idea of the examples of the present application, the specific implementation manner and application range can be changed. In summary, the content of the present application should not be understood as a limitation.

Claims

1. A stable oral solution of isoniazid, characterized in that, The stable isoniazid oral solution comprises isoniazid, a pretreatment solution, a pH regulator and a solvent; raw materials of the pretreatment solution comprise methylparaben, propylparaben, soybean-blueberry extract and vitamin C; and the preparation steps comprise: (1) adding pure water into a solution preparation tank, then starting stirring, heating and keeping the temperature at 40-80°C, and then adding the pretreatment solution, wherein raw materials of the pretreatment solution comprise methylparaben, propylparaben, soybean-blueberry extract and vitamin C, the total mass of methylparaben and propylparaben and the mass ratio of the soybean-blueberry extract and vitamin C are as follows: total mass of methylparaben and propylparaben: soybean-blueberry extract: vitamin C = 1:0.1-0.3:0.05-0.08; the extraction method of the soybean-blueberry extract is as follows: adding soybean powder and blueberry pieces into a cellulase and neutral protease compound enzyme solution, heating to 60±3°C in a water bath after adding the materials, and then performing enzyme hydrolysis for 5-6h, followed by solid-liquid separation, liquid-phase enzyme inactivation treatment and vacuum concentration to obtain the soybean-blueberry extract; the preparation method of the pretreatment solution is as follows: adding the methylparaben, propylparaben and vitamin C into the soybean-blueberry extract under stirring, heating to 50±5°C in a water bath after adding the materials, and then stirring for more than 5h to obtain the pretreatment solution; and the solution in the solution preparation tank is cooled to below 50°C after adding pure water, and then the isoniazid is added and stirred uniformly; (2) adding pure water into the solution preparation tank, cooling the solution in the solution preparation tank to below 50°C, and then adding the isoniazid and stirring uniformly; (3) adding the pH regulator into the solution preparation tank to adjust the pH value of the medicament, adding pure water to the preparation amount, and obtaining the oral solution.

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

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

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

5.

5. The stable oral solution of isoniazid according to claim 3, wherein The stable isoniazid oral solution further comprises 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.

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