Isoniazide oral solution and preparation method thereof

Abstract

The invention provides an isoniazide oral solution and a preparation method thereof. According to the isoniazide oral solution, the degradation rate of the product is obviously reduced by controlling the pH value of the finished product to be 5.4-5.9 and the dissolved oxygen to be less than 1mg / L, so that the stability of the product is improved.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an isoniazid oral solution and a preparation method thereof. Background Art

[0002] Isoniazid (INH) is the first-line anti-tuberculosis drug recommended by WHO. Invented in 1952, the discovery of isoniazid brought another great leap forward in the treatment of tuberculosis. The sterilization properties of isoniazid are: it can inhibit the synthesis of mycolic acid components of the tuberculosis bacterial wall, thereby causing the tuberculosis bacillus to lose multiple abilities (such as acid-fast staining, proliferation, hydrophobicity, etc.) and die. Isoniazid can also bind to the coenzyme of tuberculosis bacteria to interfere with the synthesis of deoxyribonucleic acid and ribonucleic acid, thereby achieving the purpose of killing tuberculosis bacteria.

[0003] Isoniazid has a good antibacterial effect on Mycobacterium tuberculosis, good efficacy, small dosage, relatively low toxicity, and is easily accepted by patients. The oral absorption rate of isoniazid is 90%.

[0004] The metabolism of isoniazid in the human body is mainly acetylation in the liver, and the metabolites are acetylisoniazid, isonicotinic acid, etc. There are obvious racial and individual differences in the speed of isoniazid acetylation in the human body. People with fast metabolizers have more acetylisoniazid in their blood, and people with slow metabolizers have more free isoniazid prototype in their blood. Because acetylisoniazid is highly toxic to the liver and can easily damage liver cells, people with fast metabolizers of isoniazid are prone to liver damage; and the isoniazid prototype can compete with vitamin B6 for the same enzyme or the two can combine to form hydrazone compounds and then be excreted in the urine, leading to vitamin B6 deficiency, so people with slow metabolizers are prone to neurological toxicity. There are isoniazid vitamin B6 tablets on the market that are mainly for patients with slow metabolism, but there are no very effective preparations for patients with fast metabolism.

[0005] Compared with the richer types of preparations available abroad, the isoniazid currently approved in China are all oral solid preparations. For children with tuberculosis, from birth to 16 years old, their physiological conditions vary greatly, and their acceptance of oral solid preparations varies. Young children have incomplete swallowing abilities and find it difficult to accept tablets and capsules designed for adults, and it is also difficult to meet the requirements for dosage accuracy and compliance.

[0006] Currently, isoniazid oral solution is an antibacterial drug developed by Cmp Pharma Inc. in the United States. It was approved for marketing in the United States on November 11, 1983. ® Stability studies revealed that the pH value was not well controlled, and the unknown impurities D, E, H and total impurities increased significantly during the test, and the stability needs to be improved. Summary of the invention

[0007] The technical problem solved by the present invention is to provide an isoniazid oral solution and a preparation process thereof, thereby improving the stability of the isoniazid oral solution.

[0008] In order to achieve the above object, in a first aspect, the present invention provides an isoniazid oral solution, wherein the isoniazid oral solution comprises an anhydrous citric acid and sodium citrate buffer system, so that the pH value of the solution is 5.4-5.9.

[0009] Specifically, the raw materials and auxiliary materials of the isoniazid oral solution include isoniazid, sorbitol solution, potassium sorbate, anhydrous citric acid and sodium citrate buffer system, orange flavor and purified water.

[0010] Specifically, in the isoniazid oral solution, the buffer is anhydrous citric acid or sodium citrate, or a buffer system of a mixture of the two.

[0011] Specifically, the pH value of the isoniazid oral solution is controlled at 5.4-5.9 by an anhydrous citric acid and sodium citrate buffer system.

[0012] In a second aspect, the present invention provides an isoniazid oral solution, characterized in that it includes the steps of weighing, liquid preparation, filtering and filling.

[0013] Specifically, the preparation process includes: preparing the buffer system into a solution, adding it to a sorbitol solution, cooling it to 20°C~30°C, adding potassium sorbate and isoniazid to dissolve, and the pH value of the detection solution should reach 5.4~5.9.

[0014] Specifically, in the process of liquid preparation and filling, nitrogen is charged until the dissolved oxygen content is less than 1 mg / L.

[0015] Compared with the prior art, the advantages of the present invention are as follows.

[0016] 1. The present invention controls the pH value of the drug solution between 5.4 and 5.9 by adding anhydrous citric acid and sodium citrate as the buffer system, and the pH value has good stability.

[0017] 2. The method for preparing the isoniazid oral solution provided by the present invention performs nitrogen filling during the liquid preparation and filling process to control the dissolved oxygen to less than 1 mg / L, which is beneficial to the growth rate of impurities during the stability period.

[0018] During the stability process of the isoniazid oral solution prepared by the above technology, the pH value is stabilized at 5.4~5.9; the increases in isonicotinic acid, unknown impurity D, unknown impurity E, unknown impurity H and total impurities are significantly reduced, which significantly improves the stability of the product. DETAILED DESCRIPTION

[0019] In the following examples, unless otherwise specified, the test machines and instruments used are reagents and instruments commonly used in the art, and the methods used are conventional methods in the art. Those skilled in the art can know how to specifically implement the methods and achieve corresponding results based on the contents of the examples. Example

[0020] An isoniazid oral solution, the prescription is as follows: Isoniazid 5g Sorbitol solution 500g Potassium Sorbate 1g Anhydrous citric acid 0.5g Orange flavor 0.25g Purified water Make up to 500ml .

[0021] The preparation method of the isoniazid oral solution comprises the following steps.

[0022] ① Weighing: Weigh the batch prescription amount of isoniazid and excipients and set aside.

[0023] ② Liquid preparation: Add sorbitol solution to the liquid preparation tank at a temperature of 25℃~35℃, add the prescribed amount of potassium sorbate and anhydrous citric acid in sequence, set the stirring frequency to 200rpm, and start stirring for 20min respectively; add the prescribed amount of isoniazid to the liquid preparation tank and stir until completely dissolved; add the prescribed amount of orange flavor and stir until completely dissolved; detect the pH value to be 5.20, and add purified water to the full amount.

[0024] ③Filtration: The liquid medicine is pressurized by compressed air and filtered through a 1μm filter element into the filling buffer tank.

[0025] ④Filling: Use a filling machine for filling, the filling volume range is controlled within 50ml~54ml, and the filling speed is adjusted to 20 bottles / min.

[0026] ⑤Leak detection and packaging. Example

[0027] An isoniazid oral solution, the prescription is as follows: Isoniazid 5g Sorbitol solution 500g Potassium Sorbate 1g Anhydrous citric acid 0.5g Sodium Citrate Orange Flavor 0.1g0.25g Purified water Make up to 500ml .

[0028] The preparation method of the isoniazid oral solution comprises the following steps.

[0029] ① Weighing: Weigh the batch prescription amount of isoniazid and excipients and set aside.

[0030] ② Liquid preparation: Add sorbitol solution to the liquid preparation tank at a temperature of 25℃~35℃, add the prescribed amount of potassium sorbate, anhydrous citric acid and sodium citrate solution in sequence, set the stirring frequency to 200rpm, and start stirring for 20min respectively; add the prescribed amount of isoniazid to the liquid preparation tank and stir until completely dissolved; add the prescribed amount of orange flavor and stir until completely dissolved; detect the pH value to be 5.47, and add purified water to the full amount.

[0031] ③Filtration: The drug liquid is pressurized with nitrogen and filtered through a 1μm filter element into the filling buffer tank.

[0032] ④Filling: Use a filling machine for filling, the filling volume range is controlled within 50ml~54ml, and the filling speed is adjusted to 20 bottles / min.

[0033] ⑤Leak detection and packaging. Example

[0034] An isoniazid oral solution, the prescription is as follows: Isoniazid 5.0g Sorbitol solution 500g Potassium Sorbate 1g Anhydrous citric acid 0.5g Sodium Citrate Orange Flavor 0.15g0.25 Water for injection Make up to 500ml .

[0035] The preparation method of the isoniazid oral solution comprises the following steps.

[0036] ① Weighing: Weigh the batch prescription amount of isoniazid and excipients and set aside.

[0037] ② Liquid preparation: Add sorbitol solution to the liquid preparation tank at a temperature of 25℃~35℃, add the prescribed amount of potassium sorbate, anhydrous citric acid and sodium citrate solution in sequence, set the stirring frequency to 200rpm, and start stirring for 20min respectively; add the prescribed amount of isoniazid to the liquid preparation tank and stir until completely dissolved; add the prescribed amount of orange flavor and stir until completely dissolved; detect the pH value to be 5.92, and add purified water to the full amount.

[0038] ③Filtration: The drug liquid is pressurized with nitrogen and filtered through a 1μm filter element into the filling buffer tank.

[0039] ④Filling: Use a filling machine for filling, the filling volume range is controlled within 50ml~54ml, and the filling speed is adjusted to 20 bottles / min.

[0040] ⑤Leak detection and packaging. Example

[0041] An isoniazid oral solution, which differs from Example 2 in that no front and back nitrogen filling operations are performed during the liquid preparation process and the filling process, and the pH value is controlled at 5.4-5.9.

[0042] Although the present invention has described the above-mentioned implementation cases, it does not limit the patent protection scope of the present invention. Therefore, changes and modifications made to the implementation cases described herein, or equivalent structure or equivalent process transformations made using the contents of the present invention specification, directly or indirectly applying the above technical solutions to other related technical fields, are all included in the patent protection scope of the present invention.

Claims

1. An isoniazid oral solution, characterized in that: The prescription composition of the isoniazid oral solution comprises isoniazid, sorbitol solution, preservatives, pH regulators, flavors and purified water.

2. The isoniazid oral solution according to claim 1, characterized in that The preservative is potassium sorbate.

3. The isoniazid oral solution according to claim 1, characterized in that The pH regulator is anhydrous citric acid, sodium citrate or a combination thereof.

4. The isoniazid oral solution according to claim 3, characterized in that The pH value of the isoniazid oral solution is 5.4-5.

9.

5. The isoniazid oral solution according to claim 1, characterized in that: The production process includes weighing, liquid preparation, filtration and filling steps.

6. The isoniazid oral solution according to claim 5, characterized in that: The production process includes: weighing a prescribed amount of sorbitol solution, cooling it to 20°C-30°C, adding a preservative, isoniazid, and flavor in sequence to completely dissolve them, adjusting the pH value to 5.4-5.9 with a pH adjuster, filtering, and filling the finished product.

7. The isoniazid oral solution according to claim 6, characterized in that: During the production process, the preparation and filling procedures adopt nitrogen protection technology, so that the dissolved oxygen of the finished product is less than 1mg / L.