Lactulose oral solution and preparation method thereof

Abstract

The invention provides a lactulose oral solution and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations, the oral solution comprises an active component lactulose, a solvent, a humectant, a stabilizer, a bacteriostatic agent and purified water; the stabilizing agent is prepared from hydroxypropyl chitosan and edetate disodium. The lactulose oral solution can overcome the defect of instability of lactulose through the cooperation of the stabilizer hydroxypropyl chitosan and edetate disodium, so that the lactulose oral solution has good stability.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical preparations, and particularly relates to a lactulose oral solution and a preparation method of the oral solution. BACKGROUND

[0002] Lactulose (chemical name: 4-O-beta-D-galactopyranosyl-D-fructofuranose) is an artificial synthetic disaccharide composed of galactose and fructose. Lactulose is not absorbed in the intestinal tract, and after being decomposed by colonic bacteria, it reduces the intestinal pH value to block the absorption of ammonia. In addition, it can treat constipation by utilizing the high permeability of disaccharides, and it is safe for use because it has no intestinal irritation. Lactulose oral solution was developed by Abbott Company, and was first marketed in Germany in 1982. It is suitable for treating chronic functional constipation, hyperammonemia and diseases caused by elevated blood ammonia. Subsequently, the lactulose oral solution of the original research company was approved for import and marketing in China, and the trade name is Dumy.

[0003] The marketed lactulose preparations mainly include oral solution, powder and oral gel, etc. Lactulose oral solution has the advantages of convenient oral administration and rapid efficacy after administration, and therefore, the patient compliance is strong. Therefore, lactulose oral solution has a wide application in the clinic. However, the existing lactulose oral solution has the problem of poor stability. The trace amount of impurities (such as lactose (impurity C), galactose (impurity B), etc.) in the preparation is prone to Maillard reaction under the influence of light and temperature, resulting in deepening of product color, increase of impurities, and significant reduction of preparation stability. On the other hand, the lactulose oral solution of Japan Zhongwai Pharmaceutical It contains lactulose and citric acid, which can improve the sweet and greasy taste and slow down the degradation of lactulose. However, due to the insufficient buffering capacity, a certain amount of lactulose still degrades during long-term storage. These defects of lactulose oral solution not only increase the difficulty and cost of quality control of the product during transportation and storage, but also may affect the safety and effectiveness of clinical medication. Therefore, how to improve the stability of lactulose oral solution is of great significance for reducing the cost of transportation and storage and improving the safety of medication. SUMMARY

[0004] The technical problem to be solved by the present application is to overcome the instability of lactulose, thereby solving the technical problem of poor stability of lactulose oral solution. At the same time, the lactulose oral solution of the present application also has good taste and odor, which is convenient for patients to accept and increases the patient compliance.

[0005] The present application provides a lactulose oral solution, which comprises an active ingredient lactulose, a solvent, a humectant, a stabilizer, a bacteriostatic agent and purified water; the stabilizer is hydroxypropyl chitosan and edetate disodium.

[0006] The inventors have found through experiments that the problem of poor stability of lactulose can be overcome by adding hydroxypropyl chitosan and disodium edetate as stabilizers in the lactulose oral solution. The inventors have innovatively constructed a double stabilizing system, and used hydroxypropyl chitosan as a stabilizer, which has good biocompatibility and antibacterial properties, and can effectively prevent the degradation of lactulose. It is unexpectedly found that hydroxypropyl chitosan and disodium edetate can produce good synergistic effect to inhibit oxidation reaction. The combination of hydroxypropyl chitosan and disodium edetate in the lactulose oral solution can ensure the stability of the quality of the preparation during storage, effectively solve the problem that lactulose is prone to degradation due to its own properties to generate impurities, and make the obtained lactulose oral solution have long-term storage stability, thereby ensuring the quality and efficacy of the drug preparation.

[0007] In the above lactulose oral solution, the mass ratio of hydroxypropyl chitosan to disodium edetate is 1:0.02-0.07. In order to overcome the problem of stability of lactulose, the inventors have screened the amount ratio of the stabilizers hydroxypropyl chitosan and disodium edetate, and finally found that when the mass ratio of hydroxypropyl chitosan to disodium edetate is 1:0.02-0.07, the stability of the lactulose oral solution can be more significantly improved, and the increase of impurities in the lactulose oral solution can be controlled.

[0008] In the above lactulose oral solution, the solvent is one or more of propylene glycol, polyethylene glycol 300, and polyethylene glycol 400.

[0009] In the above lactulose oral solution, the humectant is one or both of glycerol and sorbitol; the sorbitol is a commercially available sorbitol solution.

[0010] In the above lactulose oral solution, the bacteriostatic agent is one or more of potassium sorbate, hydroxybenzoic acid ester, hydroxybenzoic acid propyl ester, sodium diacetate, and sodium benzoate.

[0011] In the above lactulose oral solution, in order to improve the taste, a flavoring agent can also be added. The flavoring agent is selected from one or more of sodium saccharin, mannitol, stevioside, aspartame, and essence. The essence is an auxiliary material known to those skilled in the art, for example, the essence can be selected from strawberry banana, sweet orange essence, apple essence, banana essence, etc.

[0012] In the above lactulose oral solution, the amount of each component is 63.0-73.0 parts by mass of lactulose, 1.5-3.0 parts by mass of solvent, 1.0-3.0 parts by mass of humectant, 0.51-1.55 parts by mass of stabilizer, 0.01-0.2 parts by mass of bacteriostatic agent, and purified water to make up to 100.0 parts by mass.

[0013] In the above-mentioned lactulose oral solution, the amounts of each component by mass parts are as follows: lactulose 66.7 parts, solvent 2.0 parts, humectant 2.0 parts, stabilizer 1.05 parts, antibacterial agent 0.1 parts, and purified water to make up to 100.0 parts.

[0014] This invention also provides a method for preparing a lactulose oral solution, comprising the following steps:

[0015] 1) Preparation of the matrix: Take the antibacterial agent, stabilizer, solvent and humectant and add them to purified water, stir to dissolve, and obtain the matrix.

[0016] 2) Total mixing: Add raw lactulose to the matrix, stir to dissolve, add purified water to make up the volume, filter through a filter membrane, fill with nitrogen, and obtain lactulose oral solution.

[0017] In the above preparation method, step (2) further includes the step of adding a flavoring agent.

[0018] The lactulose oral solution provided by this invention overcomes the stability problem of lactulose oral solution by combining hydroxypropyl chitosan and disodium edetate, enabling the lactulose oral solution to maintain good stability under long-term storage conditions. This invention can be prepared using conventional formulation preparation processes, making it more suitable for industrial production. Detailed Implementation

[0019] To better understand the technical solution of the present invention, further explanation is provided below with reference to specific implementation examples. However, those skilled in the art should recognize that the present invention is not limited to these embodiments.

[0020] Example 1

[0021]

[0022]

[0023] Preparation method:

[0024] 1) Preparation of matrix: Add propylene glycol, glycerol, hydroxypropyl chitosan, disodium edetate and potassium sorbate to purified water, stir to dissolve, and obtain matrix;

[0025] 2) Total mixture: Add lactulose to the matrix and stir to dissolve; then add strawberry flavoring, stir to dissolve, add purified water to make up to volume, filter through a filter membrane, fill with nitrogen, and obtain lactulose oral solution.

[0026] Example 2

[0027] Ingredients Quantity (kg) Lactulose Polyethylene glycol 400 63.0 Glycerin 2.50 Hydroxypropyl chitosan 2.50 Edetate disodium 1.00 Hydroxybenzoate 0.05 Apple flavor 0.15 Aspartame 0.01 Purified water 0.01 Ingredients Quantity (kg) 30.78

[0028] Preparation method:

[0029] 1) Preparation of matrix: Polyethylene glycol 400, glycerol, hydroxypropyl chitosan, disodium edetate and methylparaben were added to purified water and stirred to dissolve, thus obtaining the matrix;

[0030] 2) Total mixing: Add lactulose to the matrix and stir to dissolve; then add apple flavor and aspartame, stir to dissolve, add purified water to make up to volume, filter through a filter membrane, fill with nitrogen, and obtain lactulose oral solution.

[0031] Example 3

[0032]

[0033]

[0034] Preparation method:

[0035] 1) Preparation of matrix: Propylene glycol, glycerol, hydroxypropyl chitosan, disodium edetate, potassium sorbate, and propylparaben were added to purified water and stirred to dissolve, thus obtaining the matrix;

[0036] 2) Total mixture: Add lactulose to the matrix, stir to dissolve, add purified water to make up to volume, filter through a filter membrane, fill with nitrogen, and obtain lactulose oral solution.

[0037] Example 4

[0038] Lactulose Propylene glycol Polyethylene glycol 300 66.70 Glycerin 2.00 Hydroxypropyl chitosan 1.00 Edetate disodium 1.00 Sodium benzoate 0.50 Banana flavor 0.01 Purified water 0.01 Ingredients Quantity (kg) 0.03 Lactulose 28.75

[0039] Preparation method:

[0040] 1) Preparation of matrix: Add propylene glycol, polyethylene glycol 300, glycerol, hydroxypropyl chitosan, disodium edetate and sodium benzoate to purified water, stir to dissolve, and obtain matrix;

[0041] 2) Total mixture: Add lactulose to the matrix and stir to dissolve; then add banana flavoring, stir to dissolve, add purified water to make up to volume, filter through a filter membrane, fill with nitrogen, and obtain lactulose oral solution.

[0042] Example 5

[0043] Propylene glycol Sorbitol Hydroxypropyl chitosan 66.70 Edetate disodium 2.00 Sodium diacetate 2.00 Strawberry flavor 1.45 Purified water 0.10 ​ 0.10 ​ 0.03 ​ 27.62

[0044] Preparation method:

[0045] 1) Preparation of matrix: Add propylene glycol, sorbitol, hydroxypropyl chitosan, disodium edetate and sodium diacetate to purified water, stir to dissolve, and obtain matrix;

[0046] 2) Total mixture: Add lactulose to the matrix and stir to dissolve; then add strawberry flavoring, stir to dissolve, add purified water to make up to volume, filter through a filter membrane, fill with nitrogen, and obtain lactulose oral solution.

[0047] Comparative Example

[0048]

[0049] The preparation method is the same as in Example 1.

[0050] Stability test

[0051] The lactulose oral solution samples prepared in Examples 1-5 and Comparative Examples 1-6 were placed in a stability test chamber under accelerated conditions (40±2℃, RH75±5%) for 6 months. The contents (%) of impurity B (galactose), impurity C (lactose), and other total impurities (excluding impurities B and C) were detected by high performance liquid chromatography at 0 months and 6 months. The sample properties were also observed. The results are shown in Table 1.

[0052] Table 1

[0053]

[0054] Accelerated testing of the lactulose oral solutions obtained in the above examples and comparative examples reveals that the lactulose oral solutions obtained in Examples 1-6 of this invention, through the combination of hydroxypropyl chitosan and disodium edetate, exhibit good stability. The accelerated testing effectively controlled the increase of impurities B, C, and other total impurities, ensuring patient safety. In Comparative Examples 1, 2, 5, and 6, where hydroxypropyl chitosan and disodium edetate were not added simultaneously, the impurities in the resulting lactulose oral solutions significantly increased after 6 months of accelerated testing. In Comparative Examples 3 and 4, where the ratio of hydroxypropyl chitosan to disodium edetate was not within the range of 1:0.02-0.07, the impurity content increased slightly, but the formulation quality remained relatively stable.

[0055] It should be understood that the specific embodiments described above are merely illustrative or explanatory of the principles of the invention and do not constitute a limitation thereof. Therefore, any modifications, equivalent substitutions, improvements, etc., made without departing from the spirit and scope of the invention should be included within the protection scope of the invention. Furthermore, the appended claims are intended to cover all variations and modifications falling within the scope and boundaries of the appended claims, or equivalent forms of such scope and boundaries.

Claims

1. A lactulose oral solution characterized in that, The oral solution comprises active ingredient lactulose, solvent, humectant, stabilizer, bacteriostatic agent and purified water; the stabilizer is hydroxypropyl chitosan and disodium edetate.

2. The lactulose oral solution according to claim 1, characterized in that, The mass ratio of hydroxypropyl chitosan to disodium edetate is 1:0.02-0.

07.

3. The lactulose oral solution of claim 1, wherein, The solvent is one or more of propylene glycol, polyethylene glycol 300 and polyethylene glycol 400.

4. The lactulose oral solution of claim 1, wherein, The humectant is one or both of glycerol and sorbitol.

5. The lactulose oral solution of claim 1, wherein, The bacteriostatic agent is one or more of potassium sorbate, hydroxybenzoic acid methyl ester, hydroxybenzoic acid propyl ester, sodium diacetate and sodium benzoate.

6. The lactulose oral solution of claim 1, wherein, The oral solution further comprises a flavoring agent; the flavoring agent is selected from one or more of sodium saccharin, mannitol, stevioside, aspartame and essence.

7. The lactulose oral solution of claim 1, wherein, The amount of each component is 63.0-73.0 parts by mass of lactulose, 1.5-3.0 parts by mass of solvent, 1.0-3.0 parts by mass of humectant, 0.51-1.55 parts by mass of stabilizer, 0.01-0.2 parts by mass of bacteriostatic agent and purified water to make up to 100.0 parts by mass.

8. The lactulose oral solution according to claim 7, characterized in that, The amount of each component is 66.7 parts by mass of lactulose, 2.0 parts by mass of solvent, 2.0 parts by mass of humectant, 1.05 parts by mass of stabilizer, 0.1 parts by mass of bacteriostatic agent and purified water to make up to 100.0 parts by mass.

9. A process for the preparation of the lactulose oral solution according to claim 1, characterized in that, The method comprises the following steps: 1) Preparation of the matrix: add the bacteriostatic agent, stabilizer, solvent and humectant to purified water, stir and dissolve to obtain the matrix. 2) Total mixing: add the raw material lactulose to the matrix, stir and dissolve, add purified water to constant volume, filter through a filter membrane, fill with nitrogen and fill to obtain the lactulose oral solution.

10. The method of claim 9, wherein, The step (2) further comprises the step of adding a flavoring agent. The method comprises the following steps: 1) Preparation of the matrix: add the bacteriostatic agent, stabilizer, solvent and humectant to purified water, stir and dissolve to obtain the matrix. 2) Total mixing: add the raw material lactulose to the matrix, stir and dissolve, add purified water to constant volume, filter through a filter membrane, fill with nitrogen and fill to obtain the lactulose oral solution. The step (2) further comprises the step of adding a flavoring agent.

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