Colchicine oral solution and preparation process thereof

Abstract

The invention belongs to the field of biological medicine, and discloses a colchicine oral solution and a preparation technology thereof.The colchicine oral solution is prepared from, by mass g / volume ml, 0.005%-0.02% of colchicine, 5%-15% of solvent, 0.85%-1.0% of pH regulator, 0.10%-0.20% of sweetening agent, 0.10%-0.20% of flavoring agent, 0.004%-0.016% of coloring agent and the balance purified water, and the pH of the system is controlled to be 5.7-6.6. According to the invention, by controlling the pH value of the solution system, the stability of the oral solution can be improved under the condition of not using a thickening agent, and a filter membrane can be used for filtering and sterilizing because the thickening agent is not used, so that the use of a bacteriostatic agent is avoided, and the safety of the medicine is improved; in addition, single-dose packaging is adopted, and the problem of microbial contamination of products is thoroughly solved.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and in particular relates to a colchicine oral solution and a preparation process thereof. Background Art

[0002] Colchicine, a tropolone alkaloid extracted from the bulbs and seeds of Colchicum officinale (Liliaceae), has a highly effective anti-gout effect and has been used for over 70 years. Other genera in the Liliaceae family, such as Anguilla, Gloriosa, Euphorbia, and Araceae, also contain colchicine alkaloids. Furthermore, colchicine is also found in Yunnan's Glechoma longituba, Lijiang's Tripterygium wilfordii, and daylily.

[0003] The main mechanisms of action of colchicine include: (1) binding to the subunits of neutrophil microtubules to change the cell membrane function, including inhibiting the chemotaxis, adhesion and phagocytosis of neutrophils; (2) inhibiting phospholipase A2, reducing the release of prostaglandins and leukotrienes by monocytes and neutrophils; (3) inhibiting the production of interleukin-6 (IL-6) by local cells, thereby achieving the effect of controlling local pain, swelling and inflammatory response in the joints.

[0004] Colchicine is primarily used clinically to prevent and treat gout attacks and familial Mediterranean fever. It is also used to reduce the risk of stroke, myocardial infarction, and cardiovascular death in adults with atherosclerotic cardiovascular disease (ASCVD) or multiple risk factors for ASCVD, and to treat cardiovascular disease, reducing the risk of heart attack, stroke, cardiac stenting, coronary artery bypass grafting, and cardiovascular death. Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disease associated with mutations in the MEFV gene. It primarily affects people of Mediterranean descent and often develops in childhood. Recent literature reports have also identified patients with FMF in other ethnic groups.

[0005] However, colchicine is a mitotic toxin with high toxicity. Once overdosed, there is currently no rescue measure, so drug overdose must be avoided. Tablets have defects in dose adjustment and cannot achieve precise dosing for pediatric patients. Compared with oral solid preparations, oral solutions are more convenient for dose adjustment, achieve precise dosing, reduce adverse reactions, and improve medication compliance for adults or children with dysphagia. Therefore, there is an urgent clinical need for colchicine preparations that meet domestic drug quality requirements and can achieve precise dosing for different populations.

[0006] To prevent microbial contamination and growth during normal storage and use, which could lead to drug deterioration and potentially harm to users, multi-dose packaged preparations generally require the addition of an appropriate antimicrobial agent. Commonly used antimicrobial agents include benzalkonium bromide, hydroxyphenyl esters, benzyl alcohol, benzoic acid, and its soluble salts. Benzyl alcohol is a colorless, transparent liquid with an aromatic odor. It has anesthetic properties and is a strong irritant to the eyes, skin, and respiratory system. Ingestion, inhalation, or skin contact can be harmful. Ingestion can cause headaches, nausea, vomiting, gastrointestinal irritation, convulsions, coma, and, in severe cases, death. Upon entering the body, benzyl alcohol is first oxidized to benzoic acid, which then condenses with glycine in the liver and is excreted as hippuric acid. The FDA recommends against the use of medications containing benzyl alcohol in newborns. The European Union also prohibits the use of injectables containing benzyl alcohol in children under three years old. Pregnant or breastfeeding patients, or those with liver or kidney disease, should consult a physician before using preparations containing benzyl alcohol. Parabens are metabolized by the liver into parahydroxybenzoic acid, which is similar in structure to aspirin and may cause allergic reactions. Caution should be exercised when using them in pediatric preparations.

[0007] In addition, the 10-methoxy group in the colchicine structure is easily catalytically hydrolyzed under acidic or alkaline conditions, removing the methyl group and generating impurity F (norcolchicine). Furthermore, the colchicine structure contains tropone, which, upon exposure to light, undergoes a "seven-ring → four-ring → five-ring" cyclization reaction, producing the cis and trans isomers of the CD ring: impurities C (β-lumicolchicine) and G (γ-lumicolchicine).

[0008] Therefore, it is necessary to develop a stable and safer colchicine oral solution preparation.

[0009] In the prior art, Chinese patent application CN110448527 and U.S. Patent US9907751B2 both provide a colchicine oral solution and its prescription composition. The product contains a certain amount of antibacterial agent, but the antibacterial efficacy test results of their embodiments do not meet the requirements of the Chinese Pharmacopoeia. The multi-dose packaging specifications expose the product to the risk of microbial contamination during use. If the antibacterial efficacy of the product is increased by increasing the amount of antibacterial agent, the safety of the product will be reduced. At the same time, both prescriptions contain thickeners, and the liquid medicine is relatively viscous, which is not conducive to the product being sterilized and filtered through 0.45μm and 0.22μm filter cartridges.

[0010] In view of this, the present invention is proposed. Summary of the Invention

[0011] The technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and provide a colchicine oral solution and a preparation process thereof. The present invention can improve the stability of the oral solution without using a thickener by controlling the pH of the oral solution system; since the prescription does not contain a thickener, 0.45 μm and 0.22 μm filter cartridges can be used for sterile filtration in industrial production, avoiding the use of antibacterial agents, and using single-dose packaging to completely solve the problem of microbial contamination of the product. The colchicine oral solution prepared by the present invention does not contain a thickener, but is more stable; and does not contain an antibacterial agent, so it is safer; the single-dose packaging is easy to carry and convenient to use.

[0012] In order to solve the above technical problems, the basic concept of the technical solution adopted by the present invention is:

[0013] The present invention provides a colchicine oral solution, which is composed of the following components in terms of mass g / volume ml ratio:

[0014]

[0015]

[0016] The balance is purified water, wherein the pH of the system is controlled to be 5.7-6.6.

[0017] In a further preferred embodiment, the pH of the system is controlled to be 5.7 to 6.5.

[0018] Preferably, the pH of the system is controlled to be 6.4.

[0019] The colchicine oral solution of the present invention does not contain a thickener or an antibacterial agent, has good stability and high safety, specifically:

[0020] The colchicine oral solution of the present invention controls the pH of the oral solution system to a pH range of 5.7 to 6.6, preferably 6.4, thereby increasing the stability of the colchicine oral solution. Furthermore, since the colchicine oral solution of the present invention does not contain a thickener, micromembrane filtration can be used for sterilization in industrial production, avoiding the use of antibacterial agents and improving product safety.

[0021] The pH of the oral solution system can be controlled by adjusting the amount of the pH regulator in the prescription.

[0022] In a further embodiment, the pH adjuster is selected from one or more of citric acid, sodium citrate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, acetic acid, sodium acetate, and hydrates of the above compounds;

[0023] Preferably, the pH adjuster is citric acid and anhydrous disodium hydrogen phosphate.

[0024] In a further embodiment, the solvent is selected from one or more of glycerol, propylene glycol, and glycerol formal;

[0025] Preferably, the solvent is glycerol and propylene glycol.

[0026] In a further embodiment, the sweetener is selected from one or more of sucralose, saccharin sodium, acesulfame potassium, stevioside, sucrose, fructose, and sorbitol;

[0027] Preferably, the sweetener is sucralose.

[0028] In a further embodiment, the flavoring agent is selected from one or more of cherry flavor, apple flavor, strawberry flavor, sweet orange flavor, mint flavor, and banana flavor;

[0029] Preferably, the flavoring agent is cherry flavor.

[0030] In a further embodiment, the colorant is selected from one or more of allura red, lemon yellow, quinoline yellow, sunset yellow, cochineal and carmine;

[0031] Preferably, the colorant is allura red.

[0032] Further, as a preferred embodiment, the colchicine oral solution is composed of the following components in terms of mass g / volume ml ratio:

[0033]

[0034] The balance is purified water, and the pH of the system is controlled at 6.4.

[0035] Under the formulation of this scheme, in the stability study, after 6 months of accelerated treatment: pH still remained at 6.4, colchicine content still reached 98.5%, impurity F level was low, at 1.42%, and other impurities content was low, at 0.03%. Compared with the oral solution available in the United States ( ), the colchicine oral solution formulated in this regimen has better stability.

[0036] In a further embodiment, the colchicine oral solution is provided in single-dose packaging.

[0037] The colchicine oral solution of the present invention is packaged in a single dose, which completely solves the problem of product microbial limit, makes the product applicable to a wider range of people, has better safety, is easy to carry, and is convenient to use.

[0038] The present invention also provides a process for preparing the colchicine oral solution as described above, comprising the following steps:

[0039] (1) Take an appropriate amount of purified water, add the prescribed amount of pH adjuster and sweetener to the purified water, and stir until completely dissolved; then add the solvent and stir evenly;

[0040] (2) dissolving colchicine with an appropriate amount of purified water and adding the solution obtained in step (1) and stirring evenly;

[0041] (3) dispersing the colorant with a flavoring agent and adding it to the solution obtained in step (2), stirring evenly, and making up the balance with purified water to obtain a medicinal solution;

[0042] (4) After the drug solution is sterilized by filtering through a membrane, it is filled into a single dose.

[0043] In a further solution, in step (4), the drug solution is filtered in two stages, using a 0.45 μm filter membrane and a 0.22 μm filter membrane.

[0044] After adopting the above technical solution, the present invention has the following beneficial effects compared with the prior art:

[0045] 1. The colchicine oral solution of the present invention does not contain a thickener. The pH of the oral solution system is controlled by adjusting the amount of the pH regulator in the prescription to control the pH range of 5.7 to 6.6, preferably at 6.4. This has been found to increase the stability of the colchicine oral solution.

[0046] 2. Since the colchicine oral solution of the present invention does not contain a thickener, the product can be sterilized by micromembrane filtration in industrial production. For example, two-stage sterilization filtration is performed using 0.45 μm and 0.22 μm filter elements, thereby avoiding the use of antibacterial agents and making the product safer.

[0047] 3. The colchicine oral solution of the present invention is packaged in single-dose packaging, which completely solves the problem of product microbial limits, makes the product applicable to a wider range of people, has better safety, is easy to carry, and is convenient to use.

[0048] The specific embodiments of the present invention will be described in further detail below with reference to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] The accompanying drawings are part of the present invention and are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention, but do not constitute an undue limitation of the present invention. Obviously, the drawings described below are only some embodiments. For those of ordinary skill in the art, other drawings can be obtained based on these drawings without inventive effort. In the accompanying drawings:

[0050] Figure 1 This is the content stability test result of the samples with different pH values ​​in Test Example 1 of the present invention after 6 months of acceleration;

[0051] Figure 2 These are the results of investigation on related substances in samples with different pH values ​​in Test Example 1 of the present invention after 6 months of acceleration. DETAILED DESCRIPTION

[0052] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments will be clearly and completely described below in conjunction with the drawings of the embodiments of the present invention. The following embodiments are used to illustrate the present invention but are not used to limit the scope of the present invention.

[0053] Example 1 Preparation of colchicine oral solution

[0054] prescription:

[0055]

[0056]

[0057] Process:

[0058] ① Add an appropriate amount of purified water to a beaker, add the pH adjuster and sweetener in the prescription to the beaker, and stir until completely dissolved;

[0059] ② Add the solvent into the beaker and stir evenly;

[0060] ③ Dissolve colchicine in an appropriate amount of purified water, transfer to a beaker, and stir evenly;

[0061] ④ Disperse the colorant with essence and add it to the beaker, stir evenly, transfer it to a volumetric flask and dilute to volume with purified water;

[0062] ⑤ Filter the drug solution through a 0.45μm filter membrane and a 0.22μm filter membrane respectively, and then fill the solution into a single dose.

[0063] Example 2

[0064] Composition g Colchicine 0.1 Glycerin 50 Propylene glycol 50 Disodium hydrogen phosphate anhydrous 6.36 Citric acid 3.60 Sucralose 1.5 Cherry flavour 1.25 Allure red 0.1 Purified water To 1000 ml

[0065] The preparation process is as in Example 1.

[0066] Example 3

[0067] Composition g Colchicine 0.1 Glycerin 50 Propylene glycol 50 Disodium hydrogen phosphate anhydrous 6.36 Citric acid 2.79 Sucralose 1.5 Cherry flavour 1.25 Allure red 0.1 Purified water To 1000 ml

[0068] The preparation process is as in Example 1.

[0069] Example 4

[0070] Composition g Colchicine 0.1 Glycerin 50 Propylene glycol 50 Disodium hydrogen phosphate anhydrous 6.36 Citric acid 2.19 Sucralose 1.5 Cherry flavour 1.25 Allure red 0.1 Purified water To 1000 ml

[0071] The preparation process is as in Example 1.

[0072] Example 5

[0073] Composition g Colchicine 0.1 Glycerin 50 Propylene glycol 50 Disodium hydrogen phosphate anhydrous 6.36 Citric acid 1.51 Sucralose 1.5 Cherry flavour 1.25 Allure red 0.1 Purified water To 1000 ml

[0074] The preparation process is as in Example 1.

[0075] Example 6

[0076] Composition g Colchicine 0.1 Glycerin 50 Propylene glycol 50 Disodium hydrogen phosphate anhydrous 6.36 Citric acid 0.98 Sucralose 1.5 Cherry flavour 1.25 Allure red 0.1 Purified water To 1000 ml Composition Colchicine Glycerin Propylene glycol Disodium hydrogen phosphate anhydrous Citric acid Sucralose Cherry flavour Allure red Purified water To 1000 ml

[0077] The preparation process is as in Example 1.

[0078] Test Example 1

[0079] The samples prepared by the above-mentioned examples 1-6 and the colchicine oral solution ( ) were placed under accelerated conditions (40°C ± 2°C, 25% RH ± 5%) for 6 months, and the properties, pH, content, and related substances of the samples were investigated for stability. The results are shown in Tables 1 to 4.

[0080] Table 1 Stability test results (properties)

[0081]

[0082] Table 2 Stability test results (pH)

[0083]

[0084] Table 3 Stability test results (content)

[0085]

[0086]

[0087] Table 4 Stability test results (related substances)

[0088]

[0089] Note: Impurity F is not included in the calculation of total impurities; ND means not detected.

[0090] Examples 1 to 6 do not contain thickeners. By adjusting the amount of pH regulator, the pH of the product increased from 5.7 to 7.2. After 6 months of accelerated treatment, the content of hydrolyzed impurity F decreased from 98.1% to 94.3%. The hydrolyzed impurity F increased from 1.27% to 4.32%. At the same time, other related substances (total impurity %) also showed an increasing trend. The pH of Example 4 was 6.6, which was comparable to the oral solution available in the United States ( ) has the same pH value, and the growth trend of impurity F and total impurities is consistent. The pH value of Example 1 is 6.4, and impurity F increases from ND to 1.42%. ) Impurity F increased from 0.33% to 2.58%, and the growth of impurity F was significantly lower than Therefore, the target pH value of this product is determined to be 6.4. Among the solutions of Examples 1-6, the product stability of Example 1 is the best.

[0091] PK results

[0092] In clinical trials, a single dose of a homemade oral solution (Example 1) of 0.5 mg was administered on an empty stomach. max The geometric mean was 2.35 ng / mL, and the AUC 0-t The geometric mean of AUC was 16.96 h*ng / mL, and AUC 0-∞ The geometric mean of the dose was 19.79 h*ng / mL; a single dose of the US commercially available oral solution ( )0.5mg, C max The geometric mean was 2.36 ng / mL, and the AUC 0-t The geometric mean of AUC was 16.96 h*ng / mL, and AUC 0-∞ The geometric mean of the two pharmacokinetic parameters C max , AUC 0-t and AUC 0-∞ After logarithmic transformation, multivariate analysis of variance was performed to calculate the colchicine C in plasma. max , AUC 0-t and AUC 0-∞ The 90% confidence intervals of the geometric mean ratios all fall within the range of 80.00% to 125.00%. Specific data are shown in Table 5.

[0093] Table 5 Results of equivalence analysis of colchicine oral solution

[0094]

[0095]

[0096] The results in Table 5 show that the homemade oral solution is different from the oral solution available in the United States ( ) The differences in absorption rate and degree in the human body are within an acceptable range, that is, the homemade oral solution is bioequivalent to the oral solution sold in the United States, and has the same effectiveness and safety results under the same dosage conditions.

[0097] Comparative Example Antibacterial Efficacy Test of Colchicine Oral Solution Available in the United States

[0098] For oral solution available in the United States ( ) were carried out, and the results are shown in Table 6. According to the Chinese Pharmacopoeia, the evaluation standard of the bacteriostatic efficacy of the test sample is shown in Table 7. The "lg reduction value" in the table refers to the difference between the lg value of the number of bacteria measured at each interval and the lg value of the number of bacteria inoculated in 1 ml (g) of the test sample.

[0099] Table 6 Results of the bacteriostatic efficacy test

[0100]

[0101] Table 7 Evaluation standard of the bacteriostatic efficacy

[0102]

[0103] Note: NI indicates no increase, which means that the number of the test bacteria increased by no more than 0.5 lg compared with the number of the test bacteria measured at the previous time

[0104] According to the results in the above table, the U.S. commercially available oral solution (Coluracol®) does not meet the requirements of the Chinese Pharmacopoeia for the bacteriostatic efficacy.

[0105] The colchicine oral solution of the present application does not contain a bacteriostatic agent, and thus the bacteriostatic efficacy test cannot be carried out.

[0106] The above description is only preferred embodiments of the present application and is not intended to limit the present application in any form. Although the present application has been disclosed with the preferred embodiments as above, it is not intended to limit the present application, and any person skilled in the art can make some changes or modifications to the above-mentioned technical content without departing from the technical solution of the present application, and any simple modification, equivalent change and modification made according to the technical essence of the present application to the above embodiments are still within the scope of the present application.​

Claims

1. A colchicine oral solution, characterized in that Calculated by mass g / volume ml ratio, it is composed of the following components: The balance is purified water, wherein the pH of the system is controlled to be 5.7-6.

6.

2. The colchicine oral solution according to claim 1, wherein The pH of the system is controlled to be 6.2-6.5, preferably 6.

4.

3. The colchicine oral solution according to claim 1 or 2, wherein The pH regulator is selected from one or more of citric acid, sodium citrate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, acetic acid, sodium acetate and hydrates of the above compounds; Preferably, the pH adjuster is citric acid and anhydrous disodium hydrogen phosphate.

4. The colchicine oral solution according to any one of claims 1 to 3, characterized in that The solvent is selected from one or more of glycerol, propylene glycol, and glycerol formal; Preferably, the solvent is glycerol and propylene glycol.

5. The colchicine oral solution according to any one of claims 1 to 4, characterized in that The sweetener is selected from one or more of sucralose, saccharin sodium, acesulfame potassium, stevia, sucrose, fructose, and sorbitol; Preferably, the sweetener is sucralose.

6. The colchicine oral solution according to any one of claims 1 to 5, characterized in that The flavoring agent is selected from one or more of cherry flavor, apple flavor, strawberry flavor, sweet orange flavor, mint flavor, and banana flavor; Preferably, the flavoring agent is cherry flavor.

7. The colchicine oral solution according to any one of claims 1 to 6, characterized in that The colorant is selected from one or more of allura red, lemon yellow, quinoline yellow, sunset yellow, cochineal red and carmine; Preferably, the colorant is allura red.

8. The colchicine oral solution according to any one of claims 1 to 6, characterized in that Calculated by mass g / volume ml ratio, it is composed of the following components: The balance is purified water, and the pH of the system is controlled to be 6.

4.

9. A process for preparing the colchicine oral solution according to any one of claims 1 to 8, characterized in that: The following steps are involved: (1) Take an appropriate amount of purified water, add the prescribed amount of pH adjuster and sweetener to the purified water, and stir until completely dissolved; then add the solvent and stir evenly; (2) dissolving colchicine with an appropriate amount of purified water and adding the solution obtained in step (1) and stirring evenly; (3) dispersing the colorant with a flavoring agent and adding it to the solution obtained in step (2), stirring evenly, and making up the balance with purified water to obtain a medicinal solution; (4) After the drug solution is sterilized by filtering through a membrane, it is filled into a single dose.

10. The preparation process according to claim 9, characterized in that: In step (4), the drug solution is filtered through a 0.45 μm filter membrane and a 0.22 μm filter membrane in two stages.

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