Pyrinamide oral solution compositions, methods of making and using the same

Abstract

The present application relates to the technical field of pharmaceutical preparation, in particular to a pyrazinamide oral solution composition, a preparation method and application thereof. The pyrazinamide oral solution composition provided by the present application comprises pyrazinamide, nicotinamide and optional cosolvents and crystal inhibitors. Through the unique solubilization and crystal inhibition of nicotinamide and the synergistic effect of other excipients, the pyrazinamide oral solution composition successfully realizes a 30mg / mL pyrazinamide administration concentration in a neutral to weakly acidic system, and the use amount of all excipients is controlled within the safety threshold for children's medication throughout the whole process, thereby solving the problems of the lack of existing pyrazinamide oral preparations for children, the insufficient safety of existing solubilization schemes and the poor stability of pyrazinamide, and better meeting the clinical needs of children's tuberculosis treatment. The oral product of the present application shows bioequivalence with pyrazinamide tablets, and has better compliance, stability and oral absorption effect.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and in particular to pyrazinamide oral solution compositions, their preparation methods, and applications. Background Technology

[0002] Tuberculosis (TB) is a chronic infectious disease caused by the Mycobacterium tuberculosis complex. It can cause pulmonary tuberculosis (PTB) and can also affect other organs such as the liver, kidneys, brain, and lymph nodes, forming extrapulmonary tuberculosis. Pyrazinamide (PZA), also known as carbamoylpiperazine, is an important first-line oral anti-tuberculosis drug in the treatment of TB. Pyrazinamide is widely used clinically and, along with rifampin and isoniazid, is one of the most effective antibacterial drugs in short-course chemotherapy for TB. In addition, pyrazinamide also has good anticancer properties, effectively inhibiting tumor cell division, reducing the number of cancer cells, and causing tumor cells to disappear from ascites. The mechanism of action may be that PZA penetrates into macrophages containing Mycobacterium tuberculosis, where it is converted into pyrazinic acid to exert its antibacterial effect. This drug only has antibacterial activity at a slightly acidic pH. The "Second Batch of Encouraged Research and Development Applications for Pediatric Drugs" and the "20th Edition of the World Health Organization's Standards for Essential Medicines (March 2017)" published in May 2017 explicitly recommend pyrazinamide oral solution (30 mg / ml) as a treatment option for pediatric patients under the indication of anti-tuberculosis. However, as a product in short supply, it has not yet been marketed.

[0003] The 2025 edition of the Pharmacopoeia of the People's Republic of China, Part II, contains the following information: The structural formula of pyrazinamide is shown below:

[0004] Molecular formula: C5H5N3O. This product is pyrazinamide, and calculated on a dried basis, it contains not less than 99.0% C5H5N3O. Relative molecular mass: 123.12; melting point: 188~192℃. This product is a white or off-white crystalline powder, slightly soluble in water and sparingly soluble in methanol or ethanol. Therefore, it is evident that pyrazinamide oral solution (30mg / ml) is a difficult product to develop into an oral solution due to the low solubility of this API in water.

[0005] Currently, no oral solutions of pyrazinamide have been approved for marketing. Patients using solid dosage forms need to drink sufficient water to disperse and absorb the medication in the gastrointestinal tract to exert its anti-tuberculosis effect. However, this increases the risk of non-compliance and dosage adjustment issues for children, the elderly, or other patients with swallowing difficulties. Therefore, developing an oral solution (30 mg / ml) of pyrazinamide to meet this unmet clinical need is a pressing technical challenge.

[0006] Oral solutions typically require the addition of solubilizers to improve the apparent solubility of poorly soluble active ingredients, ensuring a homogeneous and stable drug solution state during storage and use, while also considering taste improvement and pediatric acceptability. However, the safety window for these solubilizers in children is relatively narrow. Excessive single-dose or daily cumulative intake may pose potential risks such as impaired liver and kidney function, increased osmotic loading, central nervous system depression, or metabolic disorders. Therefore, stricter restrictions have been placed on the selection of solubilizer types and dosage control in the development of oral solutions for children.

[0007] Therefore, how to control the dosage of solubilizers and synergistic excipients within a safe and acceptable range for children while ensuring that pyrazinamide reaches the target concentration of 30 mg / mL, maintains stability during the shelf life, and has a suitable taste, and avoids safety hazards caused by excessive excipients, while also considering the feasibility of industrial production, has become an urgent technical problem to be solved in the development of this type of pediatric oral solution. This application focuses on this problem, and through the optimized design of the types and ratios of excipients, it ensures both solubilization effect and formulation quality while keeping the dosage of each excipient within the safe threshold for pediatric use, thereby meeting unmet clinical needs. Summary of the Invention

[0008] In view of this, the technical problem to be solved by the present invention is to provide a pyrazinamide oral solution composition, its preparation method, and its application. However, during the research and development of the present invention, the inventors found that pyrazinamide oral solution is prone to crystallization after solution preparation, especially at low or room temperature. If only solubilizers or co-solvents are added, the required amount is large, which poses a safety problem for children. Adding only anti-crystallization agents is also difficult to solve the crystallization problem. Therefore, a large amount of research was conducted, and the present invention was completed.

[0009] The pyrazinamide oral solution composition provided by the present invention comprises pyrazinamide and nicotinamide.

[0010] In the pyrazinamide oral solution composition of this invention, the mass ratio of pyrazinamide to nicotinamide is 3:(2.5~2.7). For example, the mass ratio of pyrazinamide to nicotinamide is 3:(2.5~2.7), or 3:2.5, or 3:2.6, or 3:2.7. Corresponding to the preferred formulation of this invention with a dosage concentration of 30 mg / mL pyrazinamide and 20~60 mg / mL nicotinamide, experiments show that increasing the amount of nicotinamide at this ratio can significantly improve the solubility and stability of pyrazinamide, but this may lead to a daily intake of nicotinamide exceeding the safety threshold for children. Further research has found that by introducing a specific crystallization inhibitor to synergize with nicotinamide, the stability of the formulation can be maintained or even improved while reducing the dosage of nicotinamide, thus balancing efficacy and safety.

[0011] In order to further improve the dissolution effect of pyrazinamide, the oral solution composition of pyrazinamide also includes a crystal inhibitor and / or a cosolvent.

[0012] Optionally, the crystallization inhibitor is at least one of sodium carboxymethyl cellulose, polyvinylpyrrolidone, highly substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and hydroxyethyl cellulose.

[0013] In this invention, the crystal inhibitor can be a single type used alone, or two or more can be used in combination. The combination system can form a synergistic crystal inhibitory effect with nicotinamide, further blocking the growth of pyrazinamide crystal nuclei and inhibiting drug crystallization during low temperature and long-term storage; and can reduce the dosage of a single component, thereby meeting the standards for safe medication for children.

[0014] For example, if the crystallization inhibitor is one type, it is any one of sodium carboxymethyl cellulose, polyvinylpyrrolidone, highly substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose, highly substituted hydroxypropyl cellulose, and hydroxyethyl cellulose. Hydroxypropyl methyl cellulose is preferred.

[0015] For example, if the crystallization inhibitor is of two types, it may be sodium carboxymethyl cellulose and polyvinylpyrrolidone, or sodium carboxymethyl cellulose and highly substituted hydroxypropyl cellulose, or sodium carboxymethyl cellulose and hydroxyethyl cellulose, or polyvinylpyrrolidone and highly substituted hydroxypropyl cellulose, or polyvinylpyrrolidone and highly substituted hydroxypropyl methyl cellulose, or polyvinylpyrrolidone and hydroxyethyl cellulose, or highly substituted hydroxypropyl methyl cellulose and highly substituted hydroxypropyl cellulose, or hydroxypropyl methyl cellulose and hydroxyethyl cellulose, or hydroxypropyl methyl cellulose and sodium carboxymethyl cellulose, or hydroxypropyl methyl cellulose and polyvinylpyrrolidone.

[0016] For example, if the crystal inhibitor is one of three substances, it may be sodium carboxymethyl cellulose, polyvinylpyrrolidone, and highly substituted hydroxypropyl cellulose; or sodium carboxymethyl cellulose, polyvinylpyrrolidone, and highly substituted hydroxypropyl methyl cellulose; or sodium carboxymethyl cellulose, polyvinylpyrrolidone, and highly substituted hydroxypropyl cellulose; or sodium carboxymethyl cellulose, polyvinylpyrrolidone, and hydroxyethyl cellulose; or sodium carboxymethyl cellulose, highly substituted hydroxypropyl cellulose, and hydroxyethyl cellulose; or sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, and highly substituted hydroxypropyl cellulose; or sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, and hydroxyethyl cellulose; or carboxymethyl cellulose... Sodium cellulose, highly substituted hydroxypropyl cellulose and hydroxyethyl cellulose, or polyvinylpyrrolidone, highly substituted hydroxypropyl cellulose and hydroxypropyl methylcellulose, or polyvinylpyrrolidone, highly substituted hydroxypropyl cellulose and hydroxyethyl cellulose, or polyvinylpyrrolidone, hydroxypropyl methylcellulose and highly substituted hydroxypropyl cellulose, or polyvinylpyrrolidone, highly substituted hydroxypropyl cellulose and hydroxyethyl cellulose, or highly substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose and hydroxyethyl cellulose, or hydroxypropyl methylcellulose, hydroxypropyl cellulose and hydroxyethyl cellulose.

[0017] In a specific implementation, the crystallization inhibitor is hydroxypropyl methylcellulose, or a combination of hydroxypropyl methylcellulose with at least one of polyvinylpyrrolidone, highly substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, and hydroxyethyl cellulose. That is, the crystallization inhibitor is hydroxypropyl methylcellulose, or a combination of hydroxypropyl methylcellulose and hydroxyethyl cellulose, or a combination of hydroxypropyl methylcellulose and highly substituted hydroxypropyl cellulose; or a combination of hydroxypropyl methylcellulose and polyvinylpyrrolidone, or a combination of hydroxypropyl methylcellulose and sodium carboxymethyl cellulose.

[0018] In this invention, the preferred option is to use hydroxypropyl methylcellulose alone, or to use two crystal inhibitors, such as a combination of hydroxypropyl methylcellulose and one of the following crystal inhibitors: hydroxyethyl cellulose, highly substituted hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxyethyl cellulose, and sodium carboxymethyl cellulose. The two crystal inhibitors work together to further enhance the system's ability to inhibit pyrazinamide crystallization, effectively prolong the stable storage period of the formulation, and at the same time reduce the amount of a single component, keeping it within a safe range and avoiding any safety risks to children.

[0019] Optionally, the co-solvent is at least one of α-cyclodextrin, hydroxypropyl β-cyclodextrin, hydroxypropyl γ-cyclodextrin, sulfonyl α-cyclodextrin, sulfonyl β-cyclodextrin, sulfonyl γ-cyclodextrin, hydroxyethyl α-cyclodextrin, hydroxyethyl β-cyclodextrin, hydroxyethyl γ-cyclodextrin, polyoxyethylene 40 hydrogenated castor oil (RH40), poloxamer, polyoxyethylene 32 stearate, vitamin E polyethylene glycol succinate, propylene glycol, and PEG. In some specific embodiments, the co-solvent is at least one of polyoxyethylene 40 hydrogenated castor oil, propylene glycol, poloxamer, hydroxypropyl β-cyclodextrin, sulfonyl β-cyclodextrin, and hydroxypropyl γ-cyclodextrin.

[0020] In this invention, the cosolvent can be a single type used alone, or two or more can be used in combination. The combination system can form a synergistic crystal-inhibiting effect with nicotinamide and the crystal inhibitors mentioned above, further blocking the growth of pyrazinamide crystal nuclei and inhibiting drug crystallization during low temperature and long-term storage; and can reduce the dosage of single components, thereby meeting the standards for safe medication for children.

[0021] For example, if the cosolvent is one, it is any one of polyoxyethylene 40 hydrogenated castor oil, propylene glycol, poloxamer, hydroxypropyl β-cyclodextrin, sulfobutyl β-cyclodextrin, and hydroxypropyl γ-cyclodextrin.

[0022] For example, if the cosolvent is of two types, it may be polyoxyethylene 40 hydrogenated castor oil and propylene glycol, or polyoxyethylene 40 hydrogenated castor oil and poloxamer, or polyoxyethylene 40 hydrogenated castor oil and hydroxypropyl β-cyclodextrin, or polyoxyethylene 40 hydrogenated castor oil and sulfonyl β-cyclodextrin, or polyoxyethylene 40 hydrogenated castor oil and hydroxypropyl γ-cyclodextrin, or propylene glycol and poloxamer, or propylene glycol and Hydroxypropyl β-cyclodextrin, or propylene glycol and sulfobutyl β-cyclodextrin, or propylene glycol and hydroxypropyl γ-cyclodextrin, or poloxamer and hydroxypropyl β-cyclodextrin, or poloxamer and sulfobutyl β-cyclodextrin, or poloxamer and hydroxypropyl γ-cyclodextrin, or hydroxypropyl β-cyclodextrin and sulfobutyl β-cyclodextrin, or hydroxypropyl β-cyclodextrin and hydroxypropyl γ-cyclodextrin, or sulfobutyl β-cyclodextrin and hydroxypropyl γ-cyclodextrin; For example, if the co-solvent is three types, it may be: 40% hydrogenated castor oil, propylene glycol, and poloxamer; or 40% hydrogenated castor oil, propylene glycol, and hydroxypropyl β-cyclodextrin; or 40% hydrogenated castor oil, propylene glycol, and sulfonyl β-cyclodextrin; or 40% hydrogenated castor oil, propylene glycol, and hydroxypropyl γ-cyclodextrin; or 40% hydrogenated castor oil, poloxamer, and hydroxypropyl β-cyclodextrin; or 40% hydrogenated castor oil, poloxamer, and sulfonyl β-cyclodextrin; or 40% hydrogenated castor oil, hydroxypropyl β-cyclodextrin, and sulfonyl β-cyclodextrin; or 40% hydrogenated castor oil, hydroxypropyl β-cyclodextrin, and hydroxypropyl γ-cyclodextrin; or 40% hydrogenated castor oil, hydroxypropyl β-cyclodextrin, and sulfonyl β-cyclodextrin; or 40% hydrogenated castor oil, hydroxypropyl β-cyclodextrin, and hydroxypropyl β-cyclodextrin. Gamma-cyclodextrin, or polyoxyethylene 40 hydrogenated castor oil, sulfonyl β-cyclodextrin and hydroxypropyl gamma-cyclodextrin, or propylene glycol, poloxamer and hydroxypropyl β-cyclodextrin, or propylene glycol, poloxamer and sulfonyl β-cyclodextrin, or propylene glycol, poloxamer and hydroxypropyl gamma-cyclodextrin, or propylene glycol, hydroxypropyl β-cyclodextrin and sulfonyl β-cyclodextrin, or propylene glycol, hydroxypropyl β-cyclodextrin The compounds are propylene glycol, sulfobutyl β-cyclodextrin and hydroxypropyl γ-cyclodextrin, or poloxamer, hydroxypropyl β-cyclodextrin and sulfobutyl β-cyclodextrin, or poloxamer, hydroxypropyl β-cyclodextrin and hydroxypropyl γ-cyclodextrin, or poloxamer, sulfobutyl β-cyclodextrin and hydroxypropyl γ-cyclodextrin, or hydroxypropyl β-cyclodextrin, sulfobutyl β-cyclodextrin and hydroxypropyl γ-cyclodextrin.

[0023] In a specific implementation, the cosolvent is propylene glycol only, hydroxypropyl β-cyclodextrin only; or it is polyoxyethylene 40 hydrogenated castor oil + hydroxypropyl methylcellulose, or hydroxypropyl β-cyclodextrin + poloxamer + propylene glycol, or sulfobutyl β-cyclodextrin + poloxamer + propylene glycol, or hydroxypropyl γ-cyclodextrin + poloxamer + propylene glycol, or poloxamer + propylene glycol, or hydroxypropyl β-cyclodextrin + propylene glycol, or hydroxypropyl β-cyclodextrin + poloxamer.

[0024] In this invention, the preferred embodiment is to use two or more cosolvents. In these embodiments, the cosolvents work together to further enhance the solubility of pyrazinamide in the system, effectively extend the stable storage period of the formulation, and at the same time, the amount of each component can be controlled within a safe range, without posing a safety risk to children.

[0025] In some embodiments, the present invention provides a pyrazinamide oral solution composition comprising pyrazinamide, nicotinamide, a solubilizer, and a crystallization inhibitor.

[0026] In some embodiments, the pyrazinamide oral solution composition of the present invention comprises at least one of α-cyclodextrin, hydroxypropyl β-cyclodextrin, hydroxypropyl γ-cyclodextrin, sulfobutyl α-cyclodextrin, sulfobutyl β-cyclodextrin, sulfobutyl γ-cyclodextrin, hydroxyethyl α-cyclodextrin, hydroxyethyl β-cyclodextrin, hydroxyethyl γ-cyclodextrin, polyoxyethylene 40 hydrogenated castor oil, poloxamer, polyoxyethylene 32 stearate, vitamin E polyethylene glycol succinate, propylene glycol, and PEG.

[0027] In this invention, the co-solvent serves to further enhance the solubility of pyrazinamide, assisting nicotinamide in achieving the target concentration of 30 mg / mL with low excipient dosage, avoiding the safety risks associated with excessive dosage of a single excipient, further dispersing drug molecules, reducing the probability of crystal nucleus aggregation and growth, and assisting the crystal inhibition system in improving the storage stability of the formulation. Preferably, the co-solvent is selected from at least one of hydroxypropyl β-cyclodextrin, hydroxypropyl γ-cyclodextrin, sulfobutyl β-cyclodextrin, sulfobutyl γ-cyclodextrin, polyoxyethylene 40 hydrogenated castor oil, poloxamer, and propylene glycol PEG.

[0028] In some embodiments, the pyrazinamide oral solution composition of the present invention contains at least one of sodium carboxymethyl cellulose, polyvinylpyrrolidone, highly substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, and hydroxyethyl cellulose.

[0029] In this invention, the crystal inhibitor acts to block the formation and growth of crystal nuclei, and works in conjunction with nicotinamide to inhibit crystallization at the molecular level, preventing pyrazinamide crystallization during low-temperature storage or long-term storage, thus ensuring the homogeneity and quality stability of the formulation. Preferably, in the pyrazinamide oral solution composition of this invention, the crystal inhibitor is at least one of sodium carboxymethyl cellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, and hydroxyethyl cellulose. More preferably, the crystal inhibitor is a combination of hydroxypropyl methylcellulose and hydroxyethyl cellulose. Compared with other crystal inhibitors, the combination of the two can produce the best synergistic crystal-inhibiting effect, effectively blocking the growth of pyrazinamide crystal nuclei at a lower dosage, better maintaining the homogeneity and stability of the formulation, avoiding crystallization during low-temperature storage, and ensuring that the dosage of each component is within the safe range for children.

[0030] In some embodiments, the pyrazinamide oral solution composition of the present invention comprises pyrazinamide 30 mg / mL, nicotinamide 25-60 mg / mL, a solubilizer 190 mg / mL-500 mg / mL and a crystallizer 40 mg / mL-90 mg / mL.

[0031] In some embodiments, the pyrazinamide oral solution composition of the present invention comprises pyrazinamide 30 mg / mL, nicotinamide 25-60 mg / mL, a solubilizer with a total concentration of 190 mg / mL-290 mg / mL, and an inhibitor with a total concentration of 40 mg / mL-90 mg / mL.

[0032] In some embodiments, the pyrazinamide oral solution composition of the present invention has a pyrazinamide concentration of 30 mg / mL, a nicotinamide concentration of 25-27 mg / mL, a solubilizer concentration of 90-400 mg / mL, and an inhibitor concentration of 20-80 mg / mL.

[0033] In some preferred embodiments, the pyrazinamide oral solution composition of the present invention has a pyrazinamide concentration of 30 mg / mL, a nicotinamide concentration of 25-27 mg / mL, a solubilizer concentration of 90-200 mg / mL, and an inhibitor concentration of 20-80 mg / mL.

[0034] In some preferred embodiments, the pyrazinamide oral solution composition of the present invention comprises pyrazinamide 30 mg / mL, nicotinamide 25-27 mg / mL, hydroxypropyl β-cyclodextrin 100-160 mg / mL, propylene glycol 90-200 mg / mL and hydroxypropyl methylcellulose 20-80 mg / mL.

[0035] In some preferred embodiments, the pyrazinamide oral solution composition of the present invention comprises pyrazinamide 30 mg / mL, nicotinamide 25-27 mg / mL, hydroxypropyl β-cyclodextrin 100-160 mg / mL, propylene glycol 90-200 mg / mL, poloxamer 15-20 mg / mL and hydroxypropyl methylcellulose 20-80 mg / mL.

[0036] In some preferred embodiments, the above-described pyrazinamide oral solution composition of the present invention comprises pyrazinamide 30 mg / mL, nicotinamide 25-27 mg / mL, hydroxypropyl β-cyclodextrin 100-160 mg / mL, propylene glycol 90-200 mg / mL, hydroxypropyl methylcellulose 20-80 mg / mL, highly substituted hydroxypropyl cellulose 0-40 mg / mL, hydroxyethyl cellulose 0-30 mg / mL, sodium carboxymethyl cellulose 0-20 mg / mL, polyvinylpyrrolidone 0-50 mg / mL, and water, with a pH of 4.5-6.5.

[0037] In some preferred embodiments, the pyrazinamide oral solution composition of the present invention comprises pyrazinamide 30 mg / mL, nicotinamide 25-27 mg / mL, hydroxypropyl β-cyclodextrin 100-160 mg / mL, propylene glycol 90-200 mg / mL, poloxamer 15-25 mg / mL, hydroxypropyl methylcellulose 50-70 mg / mL, and sodium carboxymethyl cellulose 15-25 mg / mL.

[0038] In some preferred embodiments, the pyrazinamide oral solution composition of the present invention comprises pyrazinamide 30 mg / mL, nicotinamide 25-27 mg / mL, hydroxypropyl β-cyclodextrin 100-160 mg / mL, propylene glycol 90-200 mg / mL, poloxamer 15-25 mg / mL, hydroxypropyl methylcellulose 30-50 mg / mL, and highly substituted hydroxypropyl cellulose 20-40 mg / mL.

[0039] In some preferred embodiments, the above-described pyrazinamide oral solution composition of the present invention comprises pyrazinamide 30 mg / mL, nicotinamide 25-27 mg / mL, hydroxypropyl β-cyclodextrin 100-160 mg / mL, propylene glycol 300-5200 mg / mL, and hydroxypropyl methylcellulose 60-80 mg / mL, optionally, poloxamer 18-20 mg / mL.

[0040] In some embodiments, the pyrazinamide oral solution composition of the present invention further includes appropriate amounts of antibacterial agents and / or flavoring agents. "Appropriate amounts" here refers to amounts used in the art, such as sweeteners, which can be increased or decreased according to taste preferences within the conventional dosage range. For example, the Chinese Pharmacopoeia stipulates that the dosage of antibacterial agents sorbic acid and benzoic acid or their sodium salts should not exceed 0.3%.

[0041] Exemplarily, the oral solution composition further includes an antibacterial agent at a concentration of 0.01 to 5 mg / mL. For example, the concentration of the antibacterial agent is 0.1 mg / mL, 0.5 mg / mL, 1 mg / mL, 2 mg / mL, 3 mg / mL, or 5 mg / mL. Optional antibacterial agents include at least one selected from sodium benzoate, methylparaben and its salts, ethylparaben and its salts, propylparaben and its salts, sorbitol, and sorbate. In this invention, the antibacterial agent is selectively added. In some cases, a single-dose oral solution can be prepared using an aseptic manufacturing process, in which case the antibacterial agent does not need to be added.

[0042] For example, the oral solution composition further includes a flavoring agent at a concentration of 0.05-4 mg / mL, such as 0.5 mg / mL, 1 mg / mL, 2 mg / mL, 3 mg / mL, or 4 mg / mL. Optional flavoring agents include at least one selected from sodium chloride, sucrose, caramel, sucralose, neotame, sodium saccharin, stevia, vanillin, lemon flavor, strawberry flavor, and cherry flavor. While improving the bitterness of the medication, the sweetness and flavor can be adjusted according to the needs of pediatric patients, thereby improving medication adherence.

[0043] In some embodiments, the above-described pyrazinamide oral solution composition is a true solution, the solvent of which is water, and the pH value is adjusted to 4-7, preferably 4.5-6.5, and more preferably 5-6, using a pH adjuster.

[0044] For example, the pH adjuster is at least one selected from citric acid or its salt, phosphoric acid or its salt, tartaric acid or its salt, lactic acid or its salt, malic acid or its salt, sodium hydroxide, and hydrochloric acid. The pH adjuster adjusts the pH of the oral solution composition of the present invention to 4.0-7, preferably 4.5-6.5, and more preferably 5-6. This pH range meets the activity requirements of pyrazinamide, adapts to the taste requirements of oral administration in children, and further improves the stability of the formulation.

[0045] In some embodiments, the concentrations of each component in the pyrazinamide oral solution composition are as follows: pyrazinamide 30 mg / mL, nicotinamide 25 mg / mL to 60 mg / mL, total solubilizer concentration 50 mg / mL to 250 mg / mL, total crystallizer concentration 20 mg / mL to 80 mg / mL, antibacterial agent 0.5 mg / mL to 2 mg / mL, flavoring agent 0.05 mg / mL to 0.5 mg / mL, with the balance being water, and the pH value being 4.0 to 7.0.

[0046] In one specific embodiment, the pyrazinamide oral solution composition of the present invention comprises the following components at concentrations: pyrazinamide 30 mg / mL, nicotinamide 25-27 mg / mL, hydroxypropyl β-cyclodextrin 100-160 mg / mL, propylene glycol 90-200 mg / mL, hydroxypropyl methylcellulose 20-80 mg / mL, highly substituted hydroxypropyl cellulose 0-40 mg / mL, hydroxyethyl cellulose 0-30 mg / mL, sodium carboxymethyl cellulose 0-20 mg / mL, polyvinylpyrrolidone 0-50 mg / mL, neotame 0.1 mg / mL, sodium benzoate 1 mg / mL, and water, with a pH value of 4.5-6.5.

[0047] In one specific embodiment, the pyrazinamide oral solution composition of the present invention comprises the following concentrations of major components: pyrazinamide 30 mg / mL, nicotinamide 25-27 mg / mL, hydroxypropyl β-cyclodextrin 100-160 mg / mL, propylene glycol 90-200 mg / mL, hydroxypropyl methylcellulose 20-80 mg / mL, neotame 0.1 mg / mL, sodium benzoate 1 mg / mL, with the remainder being water, and a pH value of 4.5-6.5.

[0048] Preferably, the concentrations of each component in the pyrazinamide oral solution composition are as follows: pyrazinamide 30 mg / mL, nicotinamide 25 mg / mL, hydroxypropyl β-cyclodextrin 120 mg / mL, propylene glycol 90 mg / mL, poloxamer 18 mg / mL, hydroxypropyl methylcellulose 60 mg / mL, neotame 0.1 mg / mL, sodium benzoate 1 mg / mL, with the remainder being water, and the pH value being 5.4.

[0049] Preferably, the concentrations of each component in the pyrazinamide oral solution composition are as follows: pyrazinamide 30 mg / mL, nicotinamide 27 mg / mL, hydroxypropyl β-cyclodextrin 120 mg / mL, propylene glycol 100 mg / mL, poloxamer 18 mg / mL, hydroxypropyl methylcellulose 80 mg / mL, neotame 0.1 mg / mL, sodium benzoate 1 mg / mL, with the remainder being water, and the pH value being 5.4.

[0050] Preferably, the concentrations of each component in the pyrazinamide oral solution composition are as follows: pyrazinamide 30 mg / mL, nicotinamide 27 mg / mL, hydroxypropyl β-cyclodextrin 120 mg / mL, propylene glycol 150 mg / mL, poloxamer 20 mg / mL, hydroxypropyl methylcellulose 60 mg / mL, sodium carboxymethyl cellulose 20 mg / mL, neotame 0.1 mg / mL, sodium benzoate 1 mg / mL, with the remainder being water, and the pH value being 4.5.

[0051] Preferably, the concentrations of each component in the pyrazinamide oral solution composition are as follows: pyrazinamide 30 mg / mL, nicotinamide 26 mg / mL, hydroxypropyl β-cyclodextrin 100 mg / mL, propylene glycol 200 mg / mL, poloxamer 18 mg / mL, hydroxypropyl methylcellulose 40 mg / mL, hydroxyethylcellulose 30 mg / mL, neotame 0.1 mg / mL, sodium benzoate 1 mg / mL, with the remainder being water, and the pH value being 6.5.

[0052] Preferably, the concentrations of each component in the pyrazinamide oral solution composition are: pyrazinamide 30 mg / mL, nicotinamide 25 mg / mL, hydroxypropyl β-cyclodextrin 100 mg / mL, propylene glycol 400 mg / mL, hydroxypropyl methylcellulose 60 mg / mL, neotame 0.1 mg / mL, sodium benzoate 1 mg / mL, with the balance being water, and the pH value is 5.9.

[0053] Furthermore, the present invention also provides a method for preparing the pyrazinamide oral solution composition as described above, wherein the nicotinamide, solubilizer and crystal inhibitor are dissolved in water, pyrazinamide is added, the pH value is adjusted after dissolution, and then the volume is adjusted with water to obtain the pyrazinamide oral solution composition.

[0054] Optionally, the method for preparing the pyrazinamide oral solution composition of the present invention further includes the step of adding an antibacterial agent and / or a flavoring agent after adding pyrazinamide.

[0055] Optionally, after adjusting the volume with water, the process may further include filtration and / or filling.

[0056] In some embodiments, the pyrazinamide oral solution composition of the present invention is used in the preparation of a medicament for treating Mycobacterium tuberculosis infection.

[0057] The pyrazinamide oral solution composition provided by this invention can ensure that the pyrazinamide reaches the target concentration while controlling the amount of all excipients within the safe and acceptable range for children. It effectively avoids the safety hazards caused by excessive use of traditional solubilizers. The formulation can remain stable without crystallization during the shelf life, and the taste is suitable for children. At the same time, the preparation process is simple and meets the requirements of large-scale industrial production, which can effectively meet the clinical needs of pediatric tuberculosis treatment.

[0058] Furthermore, the present invention also provides a method for treating Mycobacterium tuberculosis infection, comprising administering the pyrazinamide oral solution composition as described above.

[0059] The pyrazinamide oral solution of the present invention is taken 1 to 3 times daily, but the maximum daily dose shall not exceed 2g.

[0060] The pyrazinamide oral solution composition provided by this invention addresses the challenges of preparing a true oral solution for pyrazinamide, a poorly soluble drug, by adding a solubilizer to solve both the solubility and crystallization issues, while also ensuring child safety. Through research, the inventors have discovered that by adding a solubilizer (nicotinamide), a cosolvent, and a crystallization inhibitor, their synergistic effect solves both the solubility and crystallization problems of pyrazinamide, while simultaneously controlling their dosage within a safe range for children.

[0061] This invention utilizes nicotinamide and optional solubilizers and crystal inhibitors. Through the unique solubilizing and crystal-inhibiting effects of nicotinamide, combined with the synergistic effects of other excipients, a pyrazinamide dosage concentration of 30 mg / mL was successfully achieved in neutral to weakly acidic systems. Simultaneously, the dosage of all excipients was controlled within the safe threshold for pediatric use throughout the process. This invention addresses the issues of the lack of existing oral pyrazinamide formulations for children, the insufficient safety of existing solubilization methods, and the poor stability and tendency for pyrazinamide to crystallize, thus better meeting the clinical needs of treating tuberculosis in children. The oral product of this invention shows bioequivalence to pyrazinamide tablets, while exhibiting better compliance, stability, and oral absorption. Attached Figure Description

[0062] Figure 1 The comparison chart shows the pyrazinamide oral solution of Example 2 versus commercially available pyrazinamide tablets in beagles. Detailed Implementation

[0063] This invention provides a pyrazinamide oral solution composition and its preparation method. Those skilled in the art can refer to this document and appropriately modify the process parameters to achieve the desired result. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included in this invention. The methods and applications of this invention have been described through preferred embodiments. Those skilled in the art can clearly modify or appropriately change and combine the methods and applications described herein without departing from the content, spirit, and scope of this invention to realize and apply the technology of this invention.

[0064] Unless otherwise defined in this invention, the scientific and technical terms associated with this invention shall have the meanings understood by one of ordinary skill in the art.

[0065] The terms “comprising,” “including,” and “having” are used interchangeably to indicate the inclusiveness of a scheme, meaning that the scheme may contain elements other than those listed. It should also be understood that the use of “comprising,” “including,” and “having” herein also provides for schemes “consisting of…”.

[0066] The term "and / or" describes the relationship between related objects, indicating that three relationships can exist. For example, A and / or B can mean: A exists alone, A and B exist simultaneously, or B exists alone. A and B can be singular or plural.

[0067] In this application, "at least one" means one or more, and "more than one" means two or more. "At least one of the following" or similar expressions refer to any combination of these items, including any combination of single or multiple items.

[0068] In this application, "oral solution" refers to a drug prepared into a solution for oral administration by a suitable method. In this application, it specifically refers to an oral solution made by dissolving pyrazinamide in an aqueous medium, which is convenient for patients with difficulty swallowing to take directly by measuring and taking.

[0069] In this application, "oral solution composition" refers to a homogeneous solution composition prepared by adding nicotinamide, an anticrystallizer, a solubilizer, and other pharmaceutically acceptable excipients to pyrazinamide as the active ingredient. It can be taken orally directly or diluted with an appropriate amount of water to meet the needs of different dosages.

[0070] In this application, "crystallization inhibitor" refers to a pharmaceutical excipient capable of inhibiting or delaying the crystallization of pyrazinamide in solution. By interfering with crystal nucleus formation and crystal growth, it improves the physical stability of the formulation under storage, low-temperature storage, and other conditions, avoiding problems such as decreased content uniformity and inaccurate dosage caused by the crystallization of the active ingredient. The crystallization inhibitor, in combination with nicotinamide and a cosolvent, can further reduce the risk of pyrazinamide crystallization without requiring an additional increase in the amount of cosolvent, thus ensuring the safety of pediatric medication.

[0071] In this application, "cosolvent" refers to a pharmaceutical excipient that can help increase the solubility of the poorly soluble drug pyrazinamide in water. It improves the apparent solubility by forming soluble complexes or inclusion complexes with pyrazinamide. In this invention, the cosolvent is used in combination with nicotinamide to reduce the amount of a single excipient. The target solubility requirement can be achieved with a lower amount of cosolvent, thereby reducing the safety risks of the excipient.

[0072] In this application, "antimicrobial agent" refers to a pharmaceutical excipient capable of inhibiting the growth and reproduction of microorganisms in an oral solution. This prevents microbial contamination of the formulation during production, storage, and repeated use, ensuring the microbiological quality of the product and meeting the microbial limits required during the formulation's shelf life. If the oral solution described in this invention is packaged in a single-dose pack, it may be optional to exclude the antimicrobial agent.

[0073] In this application, "flavoring agent" refers to a pharmaceutical excipient that can mask the unpleasant odor that pyrazinamide itself may have, improve the taste of the formulation, increase the acceptance of the drug by children and patients with swallowing difficulties, reduce drug resistance, and improve medication adherence.

[0074] In this application, "pH adjuster" refers to an agent used to adjust the pH value of the oral solution described in this invention to a slightly acidic range, ensuring sufficient antibacterial activity of pyrazinamide while maintaining the solubility and stability of various pharmaceutical excipients in the formulation, preventing excipient precipitation, and ensuring the physicochemical stability of the product. This invention adjusts the pH value to approximately 4.0-7.0, which meets the acidic requirement for pyrazinamide to exert its antibacterial activity while also taking into account the stability of the excipients and the palatability of the medication.

[0075] In this application, "treatment" refers to reducing the incidence of Mycobacterium tuberculosis infection, alleviating the clinical symptoms of individuals already infected with Mycobacterium tuberculosis, inhibiting the further growth and reproduction of Mycobacterium tuberculosis in the body, reducing the spread of infectious lesions, promoting the absorption and improvement of infectious lesions, reducing the mortality and complication rates of individuals caused by Mycobacterium tuberculosis infection, and ultimately improving the clinical outcomes of individuals infected with Mycobacterium tuberculosis.

[0076] In this application, the subjects of "treatment" include, but are not limited to, humans. Preferred subjects are children and adult tuberculosis patients with swallowing difficulties, especially suitable for young children who cannot swallow pyrazinamide solid dosage forms. It allows for precise dosage adjustment to meet the individualized dosing needs of children of different weights, solving the clinical problems of inaccurate dosage of solid dosage forms and poor medication adherence in the treatment of tuberculosis in children.

[0077] In this application, "medicine" refers to a pharmaceutical composition containing the active ingredient pyrazinamide for the purpose of treating Mycobacterium tuberculosis infection. It exerts its anti-tuberculosis pharmacological activity in the body through oral administration. The medicine of this invention is a solution preparation, which is more suitable for the administration needs of children and patients with swallowing difficulties compared to traditional solid dosage forms. The difference between the medicine of this invention and the pyrazinamide oral solution is that the medicine may contain other active ingredients besides the pyrazinamide oral solution composition of this invention, and can be combined with other anti-tuberculosis drugs to form a compound preparation. For example, the other active ingredients include, but are not limited to, one or more of isoniazid, rifampin, and ethambutol, which can be prepared into a compound oral solution according to the clinical requirements of combined anti-tuberculosis treatment regimens.

[0078] The numerical ranges and parameters involved in this invention have been presented as precisely as possible in the specific embodiments. However, any numerical value inevitably contains standard deviations due to individual test methods. Therefore, unless otherwise expressly stated, it should be understood that all numerical ranges or specific data used in this disclosure may have a reasonable deviation within a certain range, such as ±10%, ±5%, ±1%, or ±0.5%.

[0079] The test materials used in this invention are all common commercial products and can be purchased on the market.

[0080] Unless otherwise specified, in the various compositions prepared below, the total volume of each batch of solution is 1000 ml. The listed formulations contain 1%–30% cosolvent, 0.001%–1% antibacterial agent, 0.01%–60% flavoring agent, and an appropriate amount of pH adjuster, ensuring the solution pH is between 4.0 and 7.0. Preferably, the antibacterial agent content can be 0.01%–0.5%, the flavoring agent content can be 0.05%–15%, and the pH range is 4.5–6.5.

[0081] The process described in this embodiment mainly includes: weighing (weighing various compositions according to the prescription ratio), solution preparation (dissolving the weighed compositions in room temperature water medium, or preparing at a temperature below 60°C, which can reduce the dissolution time by 1 to 2 hours or more, and maintaining the solution pH at 4.0 to 7.0), filtration (filtering the prepared drug solution), filling (dispensing the drug solution into suitable packaging containers, controlling the filling amount within an appropriate range), and packaging (packaging the sealed drug solution into cardboard boxes or aluminum-plastic composite film bags).

[0082] The quality control properties, pH, and related substances described in this invention.

[0083] It should be understood that in the various embodiments of this application, the sequence numbers of the above processes do not imply the order of execution. Some or all steps can be executed in parallel or sequentially. The execution order of each process should be determined by its function and internal logic, and should not constitute any limitation on the implementation process of the embodiments of this application. The present invention is further illustrated below with reference to embodiments: Example 1: Pyrazinamide Oral Solution To screen for a basic formulation that can inhibit precipitation during the storage of pyrazinamide oral solutions while ensuring the safety of excipients, a fixed pyrazinamide concentration of 3 g / 100 mL was established. The types of cyclodextrin, nicotinamide, hydroxypropyl β-cyclodextrin, hydroxypropyl methylcellulose, poloxamer, and propylene glycol were gradually adjusted. Six comparative formulations were established, and stability studies were conducted at 2–8°C for 6 months, at 25°C for 6 months, and at 40°C for 6 months. Simultaneously, a safety assessment was performed based on the FDA's maximum permissible daily dose for oral excipients and the standard excipient dosage for pediatric marketed oral solutions. The formulations are shown in Table 1, where the weights of raw materials and excipients are in grams (g).

[0084] Table 1. Formulation and stability study results of pyrazinamide oral solution in Example 1

[0085] Preparation method: Weigh the raw and auxiliary materials in the prescription ratio, dissolve them in room temperature water medium, adjust the pH to the range specified in the table with acid and alkali, filter and fill (dispense the drug solution into appropriate packaging containers and control the filling amount within the appropriate range).

[0086] Table 1 shows that the complete system with only the simultaneous addition of hydroxypropyl β-cyclodextrin, nicotinamide, propylene glycol, RH40, hydroxypropyl methylcellulose, and poloxamer can significantly delay precipitation at low temperatures and during long-term storage. Formulations 2 and 5, which do not contain hydroxypropyl methylcellulose, precipitate at low temperatures within 1-2 days and show precipitation after 2 months of storage at 25°C, exhibiting extremely poor stability. Formulation 6, which simultaneously increases the amounts of nicotinamide and hydroxypropyl methylcellulose, delays precipitation at low temperatures to 7-8 days and maintains a clear solution throughout long-term storage at 25°C and 40°C, with controllable total impurity levels, making it the most stable formulation among the 6 formulations in this batch.

[0087] However, safety assessments showed that the hydroxypropyl methylcellulose concentration in formulation 6 of Table 1 had the best anti-crystallization effect on pyrazinamide, indicating that the higher the hydroxypropyl methylcellulose concentration, the better the anti-crystallization effect. At a concentration of 8 g / 100 mL, since the maximum daily dose of the oral solution of this invention does not exceed 2 g, and the maximum daily dose of hydroxypropyl methylcellulose does not exceed 5.4 g (approximately 5.3 g), it does not exceed the FDA's recommended maximum daily allowable dose of 5.5 g for oral administration. Higher concentrations may pose safety risks to children. Meanwhile, the results in Table 1 also show that the higher the concentration of nicotinamide, the more beneficial it is for the solubilization and anti-crystallization effects of pyrazinamide. For example, the nicotinamide concentration of 6 g / 100 mL in formulation 6 of Table 1 showed the best anti-crystallization effect among all formulations, but this dose is far higher than the FDA's safety limit of 1800 mg based on NOAEL. This invention demonstrates that nicotinamide needs to be maintained in the daily dosage range of 1350–1800 mg; otherwise, when the nicotinamide concentration is below 20 mg / mL, the stability of pyrazinamide significantly decreases at room temperature. When the concentration of hydroxypropyl methylcellulose is 40 mg / mL or higher, pyrazinamide can be stored stably at room temperature (without crystallization). To control the concentration of hydroxypropyl methylcellulose within a safer range, other crystallization inhibitors can be added to reduce the concentration of hydroxypropyl methylcellulose. Formulation 6 confirmed that high nicotinamide levels achieved optimal stability, but this exceeded the safe range for pediatric use. Therefore, it is necessary to reduce the nicotinamide level and find alternative solutions in subsequent experiments.

[0088] Example 2: Pyrazinamide Oral Solution

[0089] Based on the screening results and safety considerations of Example 1, this example focuses on investigating the effects of low-concentration nicotinamide and hydroxypropyl methylcellulose combined with other crystal inhibitors on the solubility and stability of pyrazinamide. Representative crystal inhibitors were selected, such as highly substituted hydroxypropyl cellulose, hydroxyethyl cellulose, PVPK30, sodium carboxymethyl cellulose, and other different cellulose / polymer stabilizing excipients. The dosages of propylene glycol and poloxamer were also adjusted, resulting in a total of 9 optimized formulations. The effects of different polymeric excipients and hydroxypropyl methylcellulose reduction schemes on low-temperature precipitation, long-term storage stability, and solution appearance were investigated. The solution composition formulations are shown in Table 2. The weights of the raw materials and excipients in the table are in grams (g).

[0090] Table 2. Formulation and stability study results of pyrazinamide oral solution in Example 2

[0091] Preparation method: Weigh the raw and auxiliary materials in the prescription ratio, dissolve them in room temperature water medium, adjust the pH to the range specified in the table with acid and alkali, filter and fill (dispense the drug solution into appropriate packaging containers and control the filling amount within the appropriate range).

[0092] The results in Table 2 show that: using formulations 7, 11, and 13, which combine hydroxypropyl methylcellulose with hydroxyethyl cellulose and highly substituted hydroxypropyl cellulose to replace single hydroxypropyl methylcellulose, can significantly reduce the amount of single hydroxypropyl methylcellulose to 2-4 g / 100 mL and 6 g / 100 mL, respectively. The low-temperature precipitation of the system is delayed to 4-6 days, and the solution remains clear throughout 6 months at 25°C with low total impurity content. For other single polymeric stabilizing excipients such as highly substituted hydroxypropyl cellulose and ethyl cellulose, the low-temperature precipitation time of formulations 9-10 is significantly advanced, and precipitation occurs after 3-4 months of long-term storage at 25°C, which cannot meet the shelf life requirements of the formulation. Formula 13 uses a compound system of 4g hydroxypropyl methylcellulose and 3g hydroxyethyl cellulose. Based on a daily dose of 2g pyrazinamide, the daily intake of hydroxypropyl methylcellulose alone is approximately 2700mg, which is lower than the FDA recommended upper limit of 5500mg. It forms a synergistic stabilizing effect with nicotinamide. The low-temperature precipitation inhibition effect is similar to that of the original high hydroxypropyl methylcellulose formula 6. No precipitation occurs after long-term storage at 25℃ and 40℃, and the growth of impurities is slow. No additional poloxamer is added, which avoids the defects of foaming and decreased palatability caused by high poloxamer content. The propylene glycol dosage of 9g / 100mL is far below the FDA daily limit of 29008mg for oral solutions. The dosage of hydroxypropyl methylcellulose and nicotinamide can be adjusted to the FDA safe daily dose range according to the maximum daily dosing volume for children. This formulation validates the core compatibility logic of the invention: under the premise of maintaining the dosage of nicotinamide within the safe range of 1350-1800mg, there is no need for a single high dose of hydroxypropyl methylcellulose. By combining low dose of hydroxypropyl methylcellulose with hydroxyethylcellulose or highly substituted hydroxypropylcellulose, a basically equivalent storage stability effect can be achieved. This not only solves the defect that the solution properties of high-content hydroxypropyl methylcellulose are not suitable for pediatric administration, but also relies on the synergistic effect of nicotinamide and cellulose polymers to avoid precipitation during long-term storage at low temperature or room temperature. The dosage of all excipients can be controlled within the maximum daily dose for oral administration published by the FDA.

[0093] Combining the results of Examples 1 and 2, the oral solutions obtained from each formulation exhibited different stability properties at 2–8°C, and some solutions precipitated. The dosage of nicotinamide and HPMC in the formulation significantly affected the anti-precipitation effect. Furthermore, since the oral solution is primarily used clinically for pediatric tuberculosis patients, the maximum daily dosage of each excipient was considered to ensure that nicotinamide and hydroxypropyl methylcellulose were used within safe limits; excessively high concentrations could have safety implications for children. The results indicate that nicotinamide, hydroxypropyl methylcellulose, ethylcellulose, highly substituted hydroxypropylcellulose, sodium carboxymethylcellulose, nicotinamide, hydroxypropyl β-cyclodextrin, poloxamer, and propylene glycol, in combination, have significant advantages in improving the solubility of pyrazinamide and the stability of the oral solution composition.

[0094] Example 3 Bioequivalence testing of commercially available pyrazinamide tablets and oral products

[0095] Bioequivalence studies were conducted using commercially available tablets (250 mg) and the oral pyrazinamide product (10 ml: 300 mg) prepared in Example 1 (Formula 1) in fasting beagles (n=6, 3 each of the self-prepared oral product and the control group of commercially available tablets). The dosage was calculated based on the dogs' body weight. Blood samples were collected before administration and at 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 24 h after administration. The samples were centrifuged, and the drug concentration in the blood solution was analyzed. The trend of concentration changes in the blood solution (CT mean curve) is shown in the attached figure. Figure 1 The pharmacokinetic parameter ratios are shown in the table below (S represents commercially available tablets, Z represents self-made oral products).

[0096] Table 3 Pharmacokinetic Detection Results

[0097] Biological sample results showed that the commercially available S tablet was bioequivalent to the self-made oral product Z in vivo (confidence interval 95.5%~107.6%).

[0098] Example 4: Oral Solution Packaging Specifications

[0099] According to the instructions for use of the oral solution product, the product is designed for single use and multiple use.

[0100] The packaging volume of pyrazinamide oral solution can be 5~100ml, preferably 10ml, 20ml, 50ml, or 100ml.

[0101] Packaging materials can be in bags or bottles.

[0102] The above experimental results show that the oral pyrazinamide product prepared by this invention has good stability, and the oral pyrazinamide solution product of this invention is bioequivalent to existing commercially available tablets in vivo.

[0103] The above are merely preferred embodiments of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A pyrazinamide oral solution composition, characterized in that: The composition comprises pyrazinamide, nicotinamide, a cosolvent, and a crystal inhibitor.

2. The pyrazinamide oral solution composition according to claim 1, characterized in that, The co-solvent is at least one of hydroxypropyl β-cyclodextrin, hydroxypropyl γ-cyclodextrin, sulfobutyl β-cyclodextrin, polyoxyethylene 40 hydrogenated castor oil, poloxamer, and propylene glycol. The crystallization inhibitor comprises hydroxypropyl methylcellulose, or a combination of hydroxypropyl methylcellulose with at least one of polyvinylpyrrolidone, highly substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, and hydroxyethyl cellulose.

3. The pyrazinamide oral solution composition according to claim 2, characterized in that, The co-solvent is one or more of hydroxypropyl β-cyclodextrin, hydroxypropyl γ-cyclodextrin, sulfobutyl β-cyclodextrin, polyoxyethylene 40 hydrogenated castor oil, poloxamer, and propylene glycol; The crystallization inhibitor is hydroxypropyl methylcellulose, or a combination of one or more of hydroxypropyl methylcellulose and sodium carboxymethyl cellulose, polyvinylpyrrolidone, highly substituted hydroxypropyl cellulose and hydroxyethyl cellulose.

4. The pyrazinamide oral solution composition according to claim 1, characterized in that, It contains pyrazinamide 30 mg / mL, nicotinamide 25 mg / mL ~ 60 mg / mL, cosolvent 190 mg / mL ~ 500 mg / mL and crystal inhibitor 40 mg / mL ~ 90 mg / mL.

5. The pyrazinamide oral solution composition according to claim 1, characterized in that, It contains pyrazinamide 30 mg / mL, nicotinamide 25 mg / mL ~ 27 mg / mL, cosolvent 190 mg / mL ~ 290 mg / mL and crystal inhibitor 40 mg / mL ~ 90 mg / mL.

6. The pyrazinamide oral solution composition according to claim 1, characterized in that, The concentrations of pyrazinamide, nicotinamide, cosolvent, and inhibitor were 30 mg / mL, 25-27 mg / mL, 90-400 mg / mL, and 20-80 mg / mL, respectively.

7. The pyrazinamide oral solution composition according to claim 1, characterized in that: The composition comprises pyrazinamide 30 mg / mL, nicotinamide 25-27 mg / mL, hydroxypropyl β-cyclodextrin 80-150 mg / mL, propylene glycol 90-200 mg / mL and hydroxypropyl methylcellulose 20-80 mg / mL.

8. The pyrazinamide oral solution composition according to claim 1, characterized in that: The composition comprises pyrazinamide 30 mg / mL, nicotinamide 25-27 mg / mL, hydroxypropyl β-cyclodextrin 80-150 mg / mL, propylene glycol 90-200 mg / mL, hydroxypropyl methylcellulose 20-80 mg / mL, highly substituted hydroxypropyl cellulose 0-40 mg / mL, hydroxyethyl cellulose 0-30 mg / mL, sodium carboxymethyl cellulose 0-20 mg / mL, and polyvinylpyrrolidone 0-50 mg / mL.

9. The pyrazinamide oral solution composition according to claim 1, characterized in that, It also includes antibacterial agents and / or flavoring agents.

10. The pyrazinamide oral solution composition according to claim 8, characterized in that: The antibacterial agent is at least one of sodium benzoate, methylparaben and its salts, ethylparaben and its salts, propylparaben and its salts, sorbitol, and sorbate. The flavoring agent is at least one of sodium chloride, sucrose, caramel, sucralose, neotame, sodium saccharin, stevioside, vanillin, lemon flavoring, strawberry flavoring, and cherry flavoring.

11. The pyrazinamide oral solution composition according to claim 1, characterized in that, The composition is a true solution, the solvent of which is water, and the pH value of the solution is 4 to 7.

12. The pyrazinamide oral solution composition according to claim 11, characterized in that, The pH value of the solution is 4.5~6.

5.

13. The pyrazinamide oral solution composition according to any one of claims 1 to 12, characterized in that, The concentrations of the main components are as follows: pyrazinamide 30 mg / mL, nicotinamide 25-27 mg / mL, hydroxypropyl β-cyclodextrin 80-150 mg / mL, propylene glycol 90-200 mg / mL, hydroxypropyl methylcellulose 20-80 mg / mL, highly substituted hydroxypropyl cellulose 0-40 mg / mL, hydroxyethyl cellulose 0-30 mg / mL, sodium carboxymethyl cellulose 0-20 mg / mL, polyvinylpyrrolidone 0-50 mg / mL, neotame 0.1 mg / mL, sodium benzoate 1 mg / mL, and water, with a pH of 4.5-6.

5.

14. The pyrazinamide oral solution composition according to claim 13, characterized in that, It also contains a crystal inhibitor selected from at least one of sodium carboxymethyl cellulose, polyvinylpyrrolidone, highly substituted hydroxypropyl cellulose and hydroxyethyl cellulose.

15. A method for preparing the pyrazinamide oral solution composition according to any one of claims 1 to 13, characterized in that, The nicotinamide, solubilizer, and crystallizer are dissolved in water, pyrazinamide is added, along with an antibacterial agent and / or flavoring agent. After dissolution, the pH is adjusted, and then the solution is diluted with water to obtain the pyrazinamide oral solution composition.

16. Application of nicotinamide in promoting the dissolution of pyrazinamide and / or inhibiting the crystallization of pyrazinamide.

Images