An oral suspension of an antitubercular drug and a method for preparing the same

Abstract

This invention discloses an oral suspension of an anti-tuberculosis drug and its preparation method. The oral suspension contains an anti-tuberculosis drug, a suspending agent, a surfactant, an antibacterial agent, an antioxidant, a flavoring agent, and a pH adjuster. It has technical advantages such as stable physical and chemical properties, uniform content, and easy long-term storage.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to an oral suspension of an anti-tuberculosis drug and its preparation method. Background Technology

[0002] Tuberculosis (TB), commonly known as consumption, is a chronic infectious disease caused by the Mycobacterium tuberculosis complex. Despite the availability of many anti-tuberculosis drugs in clinical practice, TB remains the leading cause of death from infectious diseases worldwide. Currently, approximately 8 to 10 million new cases of pulmonary TB are diagnosed annually, and about 2 to 3 million people die from it each year.

[0003] Tuberculosis is often treated with oral solid dosage forms or injections of drugs such as rifampin, isoniazid, pyrazinamide, and ethambutol. In clinical practice, especially for children, the elderly, or patients with swallowing difficulties, oral solid dosage forms (such as tablets and capsules) present problems such as poor compliance and inconvenient dosage adjustment. Oral suspensions, as a liquid preparation, offer advantages such as flexible dosing, convenient swallowing, and high bioavailability, making them an ideal dosage form for addressing these issues.

[0004] However, the development of oral suspensions of anti-tuberculosis drugs faces significant technical challenges. Taking rifampin as an example, it is highly degradable in aqueous solutions, especially unstable in acidic or alkaline environments, easily hydrolyzing to form impurities such as rifaquinone, leading to reduced efficacy and increased risk of adverse reactions. Simultaneously, rifampin and other drug particles are prone to aggregation, sedimentation, crystal transformation, and Ostwald ripening in liquid media, resulting in non-uniformity of content and drug crystallization during storage, seriously affecting the safety and effectiveness of medication.

[0005] CN201010254601.7 discloses a rifampicin nanosuspension and its preparation method. However, the encapsulation rate of the drug molecules using surfactants or directly using porous nanocarriers is low, resulting in insufficient drug loading, affecting the therapeutic effect, and the drug cannot remain stable for a long time. Patent US7195769 describes an oral anti-tuberculosis drug composition, but to overcome stability issues, it introduces a large number of functional excipients, bringing new safety risks, increasing formulation costs, quality control difficulties, and potential excipient interactions. In addition, some commercially available oral liquid anti-tuberculosis formulations need to be prepared immediately before use. Although this temporarily alleviates the stability problem, it causes inconvenience in clinical use and cannot ensure the accuracy of the dosage after dispersion.

[0006] Therefore, developing an oral suspension of anti-tuberculosis drugs that is stable in physicochemical properties, has uniform content, and is easy to store for a long time has important clinical value and commercial significance. Summary of the Invention

[0007] This invention provides an oral suspension of an anti-tuberculosis drug that is physically and chemically stable, has uniform content, and is easy to store for a long time.

[0008] In a first aspect, the present invention provides an oral suspension of an anti-tuberculosis drug, the oral suspension comprising or made from the following raw materials: an anti-tuberculosis drug, a suspending agent, a surfactant, an antibacterial agent, an antioxidant, a flavoring agent, and a pH adjuster.

[0009] In some embodiments, the anti-tuberculosis drug is one or more of rifampin, rifapentine, rifabutin, and rifaximin, preferably rifampin.

[0010] In some embodiments, the suspending agent is a mixture of low-molecular-weight compounds and high-molecular-weight compounds. The low-molecular-weight compounds include one or more of glycerol, sucrose, and sorbitol, preferably sucrose; the high-molecular-weight compounds include one or more of astragalus gum, gum arabic, sodium alginate, and agar.

[0011] In some embodiments, the surfactant is one or more of polysorbate 80, poloxamer 188, and poloxamer 407.

[0012] In some embodiments, the antibacterial agent is one or more of methylparaben, propylparaben, and potassium sorbate.

[0013] In some embodiments, the antioxidant is one or more of butylated hydroxytoluene, sodium metabisulfite, sodium bisulfite, vitamin C, and propyl gallate.

[0014] In some embodiments, the flavoring agent is one or more of o-benzoylsulfonylimide and fragrance.

[0015] In some embodiments, the pH adjuster is one or more of diethanolamine and triethanolamine.

[0016] In some embodiments, the oral suspension comprises or is made from the following raw materials: by weight, 1-3 parts of anti-tuberculosis drug, 1-3 parts of agar, 30-60 parts of sucrose, 0.05-0.15 parts of methylparaben, 0.01-0.05 parts of propylparaben, 0.05-0.15 parts of potassium sorbate, 0.05-0.2 parts of o-benzoylsulfonylimide, 0.05-0.15 parts of sodium metabisulfite, 0.01-0.02 parts of polysorbate 80, 0.1-0.3 parts of flavoring, 50-60 parts of purified water, and an appropriate amount of triethanolamine, wherein the appropriate amount means that the pH of the oral suspension can be adjusted to 4-5.

[0017] In some embodiments, the oral suspension comprises or is made from the following ingredients: by weight, 1.5-2.5 parts rifampin, 1.5-2.8 parts agar, 35-45 parts sucrose, 0.08-0.15 parts methylparaben, 0.02-0.04 parts propylparaben, 0.08-0.12 parts potassium sorbate, 0.08-0.12 parts o-benzoylsulfonylimide, 0.08-0.12 parts sodium metabisulfite, 0.012-0.018 parts polysorbate 80, 0.15-0.25 parts flavoring, 52-58 parts purified water, and an appropriate amount of triethanolamine, wherein the appropriate amount means that the pH of the oral suspension can be adjusted to 4-5.

[0018] In some embodiments, the oral suspension comprises or is made from the following ingredients: by weight, 2 parts rifampin, 2 parts agar, 40 parts sucrose, 0.12 parts methylparaben, 0.03 parts propylparaben, 0.1 parts potassium sorbate, 0.11 parts o-benzoylsulfonylimide, 0.1 parts sodium metabisulfite, 0.015 parts polysorbate 80, 0.2 parts flavoring, 55.325 parts purified water, and an appropriate amount of triethanolamine, wherein the appropriate amount means that the pH of the oral suspension can be adjusted to 4-5.

[0019] In a second aspect, the present invention provides a method for preparing the oral suspension of the anti-tuberculosis drug described in the first aspect, comprising the following steps:

[0020] S01: Preparation of suspension matrix: Take 50%-80% of the prescribed amount of water, uniformly disperse the polymer compound in the water at room temperature, turn on the low speed stirring at 30-70 RPM, place it in an oil bath glass reactor, set the oil bath heating to 110-150℃, keep the solution boiling for more than 10 minutes, cool the solution to 60-90℃, add sucrose and dissolve it completely, and continue stirring for 5-15 minutes;

[0021] S02: Add methylparaben, propylparaben and potassium sorbate to the solution and stir for 20-40 minutes until completely dissolved;

[0022] S03: Add o-benzoylsulfonylimide to the solution, stir for 10-30 minutes to dissolve completely, and then cool to 35-45℃;

[0023] S04: Add antioxidants and surfactants to the solution and stir for 5-15 minutes to dissolve completely;

[0024] S05: Continue cooling to 20-30℃, add anti-tuberculosis drugs to the solution, stir for 5-15 minutes to mix evenly, add fragrance and stir for 5-15 minutes, adjust the pH to 4.0-5.0 using pH adjuster, and continue stirring for 5-15 minutes;

[0025] S06: Discharge the material and replenish the remaining water, then fill with nitrogen to obtain the final product.

[0026] In some embodiments, the method for preparing the oral suspension of the anti-tuberculosis drug includes the following steps:

[0027] S01: Preparation of suspension matrix: Take 70% of the prescribed amount of water, uniformly disperse the polymer compound in the water at room temperature, turn on the low speed of 50 RPM, place it in an oil bath glass reactor, set the oil bath to heat to 130℃, keep the solution boiling for more than 15 minutes, cool the solution to 80℃, add sucrose and dissolve it completely, and continue stirring for 10 minutes.

[0028] S02: Add methylparaben, propylparaben and potassium sorbate to the solution and stir for 30 minutes to dissolve completely.

[0029] S03: Add o-benzoylsulfonylimide to the solution, stir for 20 minutes to dissolve completely, and then cool to 40°C.

[0030] S04: Add antioxidant and surfactant to the solution and stir for 10 minutes to dissolve completely.

[0031] S05: Continue cooling to 25℃, add anti-tuberculosis drugs to the solution, stir for 10 minutes to mix evenly, add fragrance and stir for 10 minutes, adjust the pH to 4.0~5.0 using pH adjuster, and continue stirring for 10 minutes.

[0032] S06: Discharge the material and replenish the remaining water, then fill with nitrogen to obtain the final product.

[0033] Thirdly, the present invention provides the use of the oral suspension of anti-tuberculosis drugs described in the first aspect or the oral suspension of anti-tuberculosis drugs prepared according to the preparation method described in the second aspect in the preparation of drugs for treating tuberculosis.

[0034] Beneficial effects:

[0035] 1. This invention addresses the problems of poor stability, easy crystallization, and poor content uniformity in oral liquid formulations of anti-tuberculosis drugs in the prior art by providing an innovative preparation method. By optimizing the preparation process and dispersion system, the drug particles exist in a stable and uniform state in the medium, which significantly improves the long-term storage stability and medication safety of the formulation.

[0036] 2. This invention involves boiling a polymer compound at high temperature to cause the polysaccharide chain to form a double helix in the regular sequence region. Then, low-molecular-weight compounds such as sucrose are added to the solution to form stable hydrogen bonds with water. This interrupts the sequence, prevents the helix from extending, and prevents the polysaccharide chain from weaving a three-dimensional network and forming a gel, thus constructing a stable suspension system.

[0037] 3. This invention utilizes the hydrogen bonding between low-molecular-weight compounds such as sucrose and water to construct a "water competition-structure interference" model between sucrose and high-molecular-weight compounds. This reduces the hydration of high-molecular-weight compounds, decreases their hydration layer, and hinders their double helix formation and orderly aggregation. This results in smoother high-molecular-weight particles, reduced surface "hairs," and the formation of large, loose aggregates. Through a stepped cooling process, the active ingredient is embedded within the high-molecular-weight aggregates, reducing the contact between the active ingredient and water, thereby improving formulation stability and producing an oral suspension of anti-tuberculosis drugs that is physically and chemically stable, has uniform content, and is suitable for long-term storage.

[0038] 4. The present invention provides a preparation method that directly adds active ingredients to a suspension system without wetting, thereby avoiding the dissolution of active ingredients during the wetting process and preventing the active ingredients in the formulation from coming into contact with water more during storage, which would cause the active ingredients to mature and recrystallize, affecting the stability of the formulation.

[0039] 5. The oral suspension of anti-tuberculosis drug prepared by the method described in this invention was tested under accelerated, high temperature and light conditions. It was found that the main component did not recrystallize during the stability test, the content of the main component was uniformly distributed, and the stability was excellent. Detailed Implementation

[0040] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.

[0041] Example 1

[0042]

[0043] Preparation process:

[0044] S01: Preparation of suspension matrix: Take 60% of the prescribed amount of water, and uniformly disperse the agar in the water at room temperature. Turn on the stirring at a low speed of 50 RPM, place it in an oil bath glass reactor, set the oil bath heating to 130℃, keep the solution boiling for more than 15 minutes, cool the solution to about 80℃, add sucrose and dissolve it completely, and continue stirring for about 10 minutes.

[0045] S02: Add methylparaben, propylparaben, and potassium sorbate to the solution and stir for about 30 minutes until completely dissolved.

[0046] S03: Add o-benzoylsulfonylimide to the solution, stir for about 20 minutes to dissolve completely, and then cool to 40°C.

[0047] S04: Add sodium metabisulfite and polysorbate 80 to the solution and stir for 10 minutes to dissolve completely.

[0048] S05: Continue cooling to 25℃, add rifampicin to the solution, stir for about 10 minutes to mix evenly, then add fragrance and stir for 10 minutes. Adjust the pH to 4.0~5.0 using a pH adjuster, and continue stirring for about 10 minutes.

[0049] S06: Discharge the material and replenish the remaining water to obtain the final product.

[0050] Example 2

[0051]

[0052] Preparation process:

[0053] S01: Preparation of suspension matrix: Take 70% of the prescribed amount of water, uniformly disperse agar in the water at room temperature, turn on the low speed of 50 RPM, place it in an oil bath glass reactor, set the oil bath heating to 130℃, keep the solution boiling for more than 15 minutes, cool the solution to about 80℃, add sucrose and dissolve it completely, and continue stirring for about 10 minutes.

[0054] S02: Add methylparaben, propylparaben, and potassium sorbate to the solution and stir for about 30 minutes until completely dissolved.

[0055] S03: Add o-benzoylsulfonylimide to the solution, stir for about 20 minutes to dissolve completely, and then cool to 40°C.

[0056] S04: Add sodium metabisulfite and polysorbate 80 to the solution and stir for 10 minutes to dissolve completely.

[0057] S05: Continue cooling to 25℃, add rifampicin to the solution, stir for about 10 minutes to mix evenly, then add fragrance and stir for 10 minutes. Adjust the pH to 4.0~5.0 using a pH adjuster, and continue stirring for about 10 minutes.

[0058] S06: Discharge the material and replenish the remaining water, then fill with nitrogen to obtain the final product.

[0059] Example 3

[0060]

[0061] Preparation process:

[0062] S01: Preparation of suspension matrix: Take 70% of the prescribed amount of water, uniformly disperse agar in the water at room temperature, turn on the low speed of 50 RPM, place it in an oil bath glass reactor, set the oil bath heating to 130℃, keep the solution boiling for more than 15 minutes, cool the solution to about 80℃, add sucrose and dissolve it completely, and continue stirring for about 10 minutes.

[0063] S02: Add methylparaben, propylparaben, and potassium sorbate to the solution and stir for about 30 minutes until completely dissolved.

[0064] S03: Add o-benzoylsulfonylimide to the solution, stir for about 20 minutes to dissolve completely, and then cool to 40°C.

[0065] S04: Add sodium metabisulfite and polysorbate 80 to the solution and stir for 10 minutes to dissolve completely.

[0066] S05: Continue cooling to 25℃, add rifampicin to the solution, stir for about 10 minutes to mix evenly, then add fragrance and stir for 10 minutes. Adjust the pH to 4.0~5.0 using a pH adjuster, and continue stirring for about 10 minutes.

[0067] S06: Discharge the material and replenish the remaining water to obtain the final product.

[0068] Example 4

[0069]

[0070] Preparation process:

[0071] S01: Preparation of suspension matrix: Take 70% of the prescribed amount of water, uniformly disperse agar in the water at room temperature, turn on the low speed of 50 RPM, place it in an oil bath glass reactor, set the oil bath heating to 130℃, keep the solution boiling for more than 15 minutes, cool the solution to about 80℃, add sucrose and dissolve it completely, and continue stirring for about 10 minutes.

[0072] S02: Add methylparaben, propylparaben, and potassium sorbate to the solution and stir for about 30 minutes until completely dissolved.

[0073] S03: Add o-benzoylsulfonylimide to the solution, stir for about 20 minutes to dissolve completely, and then cool to 40°C.

[0074] S04: Add sodium metabisulfite to the solution and stir for 10 minutes to dissolve completely.

[0075] S05: Continue cooling to 25℃, add polysorbate 80 and rifampin to the solution, stir for about 10 minutes to mix evenly, add fragrance and stir for 10 minutes, adjust the pH to 4.0~5.0 using pH adjuster, and continue stirring for about 10 minutes.

[0076] S06: Discharge the material and replenish the remaining water to obtain the final product.

[0077] Example 5

[0078]

[0079] Preparation process:

[0080] Preparation of S01 suspension matrix: Take 70% of the prescribed amount of water, and uniformly disperse agar in the water at room temperature. Turn on the stirring at 50 RPM and place it in an oil bath glass reactor. Set the oil bath heating to 130℃ and keep the solution boiling for more than 15 minutes. Cool the solution to about 80℃, add sucrose and dissolve it completely, and continue stirring for about 10 minutes.

[0081] S02: Add methylparaben, propylparaben, and potassium sorbate to the solution and stir for about 30 minutes until completely dissolved.

[0082] S03: Add o-benzoylsulfonylimide to the solution, stir for about 20 minutes to dissolve completely, and then cool to 40°C.

[0083] S04: Add sodium metabisulfite and polysorbate 80 to the solution and stir for 10 minutes to dissolve completely. Add rifampicin to the solution and stir for about 10 minutes to mix evenly. Then add the fragrance and stir for 10 minutes. Adjust the pH to 4.0-5.0 using a pH adjuster and continue stirring for about 10 minutes.

[0084] S05: Continue cooling to 25℃, discharge the material and replenish the remaining water to obtain the final product.

[0085] Comparative Example 1

[0086]

[0087] Preparation process:

[0088] S01: Preparation of suspension matrix: Take 60% of the prescribed amount of water, evenly disperse agar in the water, turn on the stirring at 100 RPM, place it in a glass reaction vessel, heat to 80℃, add sucrose and dissolve completely, and continue stirring for about 10 minutes.

[0089] S02: Add methylparaben, propylparaben, and potassium sorbate to the solution and stir for about 30 minutes until completely dissolved. Add o-benzoylsulfonylimide to the solution and stir for about 20 minutes until completely dissolved, then cool to 40°C.

[0090] S03: Add sodium metabisulfite to the solution, stir for 10 minutes to dissolve completely, and then cool to 25°C.

[0091] S04: Add rifampicin to a small amount of water containing polysorbate 80 to moisten it, add it to the above suspension matrix, stir for about 10 minutes to mix evenly, add fragrance and stir for 10 minutes, adjust the pH to 4.0~5.0 using a pH adjuster, and continue stirring for about 10 minutes.

[0092] S05: Discharge the material and replenish the remaining water to obtain the final product.

[0093] Test Example 1

[0094] Stability tests were conducted on samples from Examples 1-5 and Comparative Example 1 to observe the recrystallization of the active ingredients in the suspension.

[0095]

[0096] Test Example 2

[0097] Stability samples from Examples 1-5 and Comparative Example 1 were sent for testing to determine the content and related substances.

[0098]

[0099] Finally, it should be noted that the above examples are merely a few specific embodiments of the present invention. Obviously, the present invention is not limited to the above embodiments and many variations are possible. All variations that can be directly derived or conceived by those skilled in the art from the disclosure of the present invention should be considered within the scope of protection of the present invention.

Claims

1. An oral suspension of an anti-tuberculosis drug, the oral suspension comprising: an anti-tuberculosis drug, a suspending agent, a surfactant, an antibacterial agent, an antioxidant, a flavoring agent, and a pH adjuster.

2. The oral suspension of anti-tuberculosis drug according to claim 1, wherein the anti-tuberculosis drug is one or more of rifampin, rifapentine, rifabutin, and rifaximin.

3. The oral suspension of anti-tuberculosis drug according to claim 2, wherein the suspending agent is a mixture of low molecular weight compounds and high molecular weight compounds; the low molecular weight compounds include one or more of glycerol, sucrose, and sorbitol; and the high molecular weight compounds include one or more of astragalus gum, gum arabic, sodium alginate, and agar.

4. The oral suspension of anti-tuberculosis drug according to claim 3, wherein the surfactant is one or more of polysorbate 80, poloxamer 188, and poloxamer 407; The antibacterial agent is one or more of methylparaben, propylparaben, and potassium sorbate. The antioxidant is one or more of butylated hydroxytoluene, sodium metabisulfite, sodium bisulfite, vitamin C, and propyl gallate; the flavoring agent is one or more of o-benzoyl sulfimide and flavoring. The pH adjuster is one or more of diethanolamine and triethanolamine.

5. The oral suspension of anti-tuberculosis drug according to claim 4, wherein the oral suspension comprises, by weight, 1-3 parts of anti-tuberculosis drug, 1-3 parts of agar, 30-60 parts of sucrose, 0.05-0.15 parts of methylparaben, 0.01-0.05 parts of propylparaben, 0.05-0.15 parts of potassium sorbate, 0.05-0.2 parts of o-benzoylsulfonylimide, 0.05-0.15 parts of sodium metabisulfite, 0.01-0.02 parts of polysorbate 80, 0.1-0.3 parts of flavoring, 50-60 parts of purified water, and an appropriate amount of triethanolamine, wherein the appropriate amount refers to adjusting the pH of the oral suspension to 4-5.

6. The oral suspension of anti-tuberculosis drug according to claim 5, wherein the oral suspension comprises, by weight, 1.5-2.5 parts rifampin, 1.5-2.8 parts agar, 35-45 parts sucrose, 0.08-0.15 parts methylparaben, 0.02-0.04 parts propylparaben, 0.08-0.12 parts potassium sorbate, 0.08-0.12 parts o-benzoyl sulfimide, 0.08-0.12 parts sodium metabisulfite, 0.012-0.018 parts polysorbate 80, 0.15-0.25 parts flavoring, 52-58 parts purified water, and an appropriate amount of triethanolamine, wherein the appropriate amount refers to adjusting the pH of the oral suspension to 4-5.

7. The oral suspension of anti-tuberculosis drug according to claim 6, wherein the oral suspension comprises, by weight, 2 parts rifampin, 2 parts agar, 40 parts sucrose, 0.12 parts methylparaben, 0.03 parts propylparaben, 0.1 parts potassium sorbate, 0.11 parts o-benzoylsulfonylimide, 0.1 parts sodium metabisulfite, 0.015 parts polysorbate 80, 0.2 parts fragrance, 55.325 parts purified water, and an appropriate amount of triethanolamine, wherein the appropriate amount refers to adjusting the pH of the oral suspension to 4-5.

8. A method for preparing the oral suspension of anti-tuberculosis drug according to any one of claims 1-7, the method comprising the following steps: S01: Preparation of suspension matrix: Take 50%-80% of the prescribed amount of water, uniformly disperse the polymer compound in the water at room temperature, turn on the low speed stirring at 30-70 RPM, place it in an oil bath glass reactor, set the oil bath heating to 110-150℃, keep the solution boiling for more than 10 minutes, cool the solution to 60-90℃, add sucrose and dissolve it completely, and continue stirring for 5-15 minutes; S02: Add methylparaben, propylparaben and potassium sorbate to the solution and stir for 20-40 minutes until completely dissolved; S03: Add o-benzoylsulfonylimide to the solution, stir for 10-30 minutes to dissolve completely, and then cool to 35-45℃; S04: Add antioxidants and surfactants to the solution and stir for 5-15 minutes to dissolve completely; S05: Continue cooling to 20-30℃, add anti-tuberculosis drugs to the solution, stir for 5-15 minutes to mix evenly, add fragrance and stir for 5-15 minutes, adjust the pH to 4.0-5.0 using pH adjuster, and continue stirring for 5-15 minutes; S06: Discharge the material and replenish the remaining water, then fill with nitrogen to obtain the final product.

9. The method for preparing the oral suspension of anti-tuberculosis drug according to claim 8, wherein the preparation method comprises the following steps: S01: Preparation of suspension matrix: Take 70% of the prescribed amount of water, uniformly disperse the polymer compound in the water at room temperature, turn on the low speed of 50 RPM, place it in an oil bath glass reactor, set the oil bath to heat to 130℃, keep the solution boiling for more than 15 minutes, cool the solution to 80℃, add sucrose and dissolve it completely, and continue stirring for 10 minutes. S02: Add methylparaben, propylparaben and potassium sorbate to the solution and stir for 30 minutes to dissolve completely; S03: Add o-benzoylsulfonylimide to the solution, stir for 20 minutes to dissolve completely, and then cool to 40°C; S04: Add antioxidant and surfactant to the solution and stir for 10 minutes to dissolve completely; S05: Continue cooling to 25℃, add anti-tuberculosis drugs to the solution, stir for 10 minutes to mix evenly, add fragrance and stir for 10 minutes, adjust the pH to 4.0~5.0 using pH adjuster, and continue stirring for 10 minutes; S06: Discharge the material and replenish the remaining water, then fill with nitrogen to obtain the final product.

10. The use of the oral suspension of antituberculosis drug according to any one of claims 1-7 or the oral suspension of antituberculosis drug prepared by the preparation method according to claim 8 or 9 in the preparation of a drug for treating tuberculosis.

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