A lactulose oral solution and a method for its preparation

Abstract

The application belongs to the technical field of pharmaceutical preparations, and discloses a lactulose oral solution and a preparation method thereof.The lactulose oral solution is composed of lactulose, a stabilizer, a flavoring agent, a pH regulator and purified water, wherein the stabilizer is a complex system of cyclodextrin and threonine, and the lactulose and the stabilizer form a lactulose-stabilizer complex liquid through a specific process.Through the synergistic effect of the complex stabilizer, the application effectively inhibits the hydrolysis of lactulose and significantly improves the stability of the preparation;in combination with the preferred flavoring agent, the taste is optimized, and the inherent sweet and greasy taste and peculiar smell of lactulose are covered up;the application is widely applicable to a wide range of people and can meet the individualized medication needs of the elderly, children and other people, improve the clinical treatment effect and the medication compliance of patients, and has important clinical application value and market prospect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a lactulose oral solution and its preparation method. Background Technology

[0002] Constipation is a common functional digestive disorder worldwide, characterized by reduced bowel movement frequency, hard stools, and difficulty in defecation. It not only reduces patients' quality of life, but long-term recurrent constipation can also induce complications such as intestinal inflammation and intestinal obstruction, posing a significant burden on public health.

[0003] Lactulose, a synthetic disaccharide (composed of galactose and fructose), can reach the colon intact after oral administration because the human intestine lacks the specific enzymes to break it down. Through osmosis, it increases colonic volume, softens stool, and is fermented by colonic flora to produce lactic acid and acetic acid, lowering the intestinal pH and stimulating intestinal peristalsis, thus achieving a laxative effect. In the treatment of hepatic encephalopathy, lactulose can also inhibit the activity of ammonia-producing bacteria by lowering intestinal pH and promote the conversion of ammonia into poorly absorbed ammonium ions, reducing ammonia absorption and thus lowering blood ammonia levels and improving the patient's level of consciousness. Based on these unique mechanisms of action, lactulose has significant advantages such as high safety, few side effects, and wide applicability (including the elderly, children, and pregnant women), and has become a first-line drug for the clinical treatment of functional constipation and the prevention and treatment of hepatic encephalopathy.

[0004] Despite the well-defined pharmacological effects and significant clinical value of lactulose, existing oral lactulose solutions still face several pressing technical challenges: First, poor stability. Lactulose readily undergoes hydrolysis in aqueous solutions, producing galactose and fructose. This hydrolysis rate accelerates significantly under high temperature and humidity conditions, leading to a decrease in the content of active ingredients. Furthermore, the resulting monosaccharides may cause blood sugar fluctuations, limiting its use in diabetic patients with constipation. Second, poor taste. Lactulose itself has a pronounced sweetness, and existing formulations often rely on simple additions of sucrose and flavorings for flavoring. This not only increases the risk of tooth decay but also fails to mask its inherent unpleasant odor, resulting in decreased medication adherence in children and patients with sensitive palates.

[0005] Therefore, developing a lactulose oral solution with high stability and pleasant taste is of great significance for improving clinical treatment effects and patient medication adherence. It can also meet the personalized medication needs of patients in different physiological states (such as diabetic patients, children, and elderly patients), and has broad clinical application prospects and market value. Summary of the Invention

[0006] The present invention aims to overcome the technical defects of existing lactulose oral solutions, such as poor stability and poor taste, and to provide a lactulose oral solution with excellent stability, suitable sweetness, low viscosity and high overall acceptability, as well as its preparation method, so as to meet the personalized medication needs of patients in different physiological states, improve clinical treatment effects and patient medication compliance.

[0007] The present invention relates to a lactulose oral solution, wherein the components, by weight percentage, are as follows: lactulose 30-50%, stabilizer 0.2-0.8%, flavoring agent 0.5-3.0%, pH adjuster as needed, and purified water as the remainder; wherein the stabilizer is a compound system of cyclodextrin and threonine, and the lactulose and stabilizer are processed through a specific process to form a lactulose-stabilizer composite solution to synergistically improve the stability of the formulation; the cyclodextrin is selected from hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and methyl-β-cyclodextrin. One of the following is present: the weight percentage of the oral solution is 0.15-0.6%; the weight percentage of the threonine in the oral solution is 0.05-0.2%; the flavoring agent is selected from one or more of sucralose, steviol glycosides, erythritol, sorbitol, mogroside, and glycyrrhizin; the pH adjuster is selected from one or more of citric acid, sodium hydroxide, lactic acid, sodium bicarbonate, acetic acid, and sodium citrate, used to adjust the pH of the system to 3.5-5.0, preferably pH=4.5.

[0008] The preparation method of the lactulose oral solution of the present invention includes the following steps: (1) Preparation of lactulose-stabilizer composite solution: Cyclodextrin and threonine were dissolved in purified water at 40-60℃, and then stirred at 5-10℃ for 1-3h. The pH of the system was adjusted to 3.5-5.0 by pH adjuster. A preset amount of lactulose was added and stirring was continued for 20-40min to obtain lactulose-stabilizer composite solution. (2) Post-treatment of total mixing of oral solution: Dissolve the flavoring agent in purified water, adjust the pH of the system to 3.5-5.0 using a pH adjuster, add the above lactulose-stabilizer composite solution, mix evenly, add water to make up to the full volume, and then perform fine filtration, degassing, sterilization, and cooling in sequence, and finally fill to obtain lactulose oral solution.

[0009] Compared with the prior art, the technical advantages of the present invention are as follows: (1) Significantly improved stability: This invention innovatively uses a combination of cyclodextrin and threonine as a stabilizer. The lactulose-stabilizer composite solution formed by their synergistic effect can effectively inhibit the hydrolysis reaction of lactulose in aqueous solution and reduce the formation of galactose and fructose. Accelerated test results show that the lactulose content retention rate of the embodiments of this invention is above 97.5%; long-term test results show that the lactulose content retention rate is still maintained above 98.3%.

[0010] (2) Comprehensive optimization of taste: This invention effectively masks the inherent sweetness and off-flavor of lactulose by using a combination of low-calorie, high-sweetness flavoring agents and a synergistic effect with a stabilizer compound system. Sensory evaluation results show that the formulation of this invention is significantly superior to commercially available formulations in core dimensions such as sweetness suitability, stickiness, smoothness, and aftertaste duration. It has high overall acceptability and can effectively improve medication compliance in children, people with sensitive tastes, etc.

[0011] (3) Wide range of applicable populations: The lactulose oral solution of the present invention has high stability and a suitable taste, and is suitable for various populations such as the elderly and children, meeting the needs of personalized clinical medication, and has important clinical application value and market prospects. Attached Figure Description

[0012] Figure 1 Long-term stability of lactulose oral solution.

[0013] Figure 2 Radar chart evaluating the taste of lactulose oral solution. Detailed Implementation

[0014] To make the objectives and technical solutions of this invention clearer, the following embodiments are provided for further explanation. However, the scope of protection of this invention is not limited to these embodiments; the embodiments are merely for illustrative purposes. Those skilled in the art should understand that any changes or equivalent substitutions that do not depart from the concept of this invention are included within the scope of protection of this invention.

[0015] Example 1: Lactulose Oral Solution formula: Preparation method: (1) Preparation of lactulose-stabilizer composite solution: Cyclodextrin and threonine were dissolved in purified water at 50°C and stirred at 8°C for 2 hours. The pH of the system was adjusted to 4.5 with pH adjuster. Lactulose was added and stirred for 30 minutes to obtain lactulose-stabilizer composite solution.

[0016] (2) Preparation of lactulose oral solution: Dissolve the flavoring agent in purified water, adjust the pH of the system to 4.5 using a pH adjuster, add lactulose-stabilizer composite solution, mix evenly, add water to the total volume, filter finely, degas, sterilize, cool, and fill.

[0017] Example 2 Lactulose Oral Solution formula: Preparation method: (1) Preparation of lactulose-stabilizer composite solution: Cyclodextrin and threonine were dissolved in purified water at 40℃ and stirred at 5℃ for 1h. The pH of the system was adjusted to 3.5 with pH adjuster. Lactulose was added and stirred for 20min to obtain lactulose-stabilizer composite solution.

[0018] (2) Preparation of lactulose oral solution: Dissolve the flavoring agent in purified water, adjust the pH of the system to 3.5 using a pH adjuster, add lactulose-stabilizer composite solution, mix evenly, add water to the total volume, filter finely, degas, sterilize, cool, and fill.

[0019] Example 3 Lactulose Oral Solution formula: Preparation method: (1) Preparation of lactulose-stabilizer composite solution: Cyclodextrin and threonine were dissolved in purified water at 60℃ and stirred at 10℃ for 3h. The pH of the system was adjusted to 5.0 with pH adjuster. Lactulose was added and stirred for 40min to obtain lactulose-stabilizer composite solution.

[0020] (2) Preparation of lactulose oral solution: Dissolve the flavoring agent in purified water, adjust the pH of the system to 5.0 using a pH adjuster, add lactulose-stabilizer composite solution, mix evenly, add water to the total volume, filter finely, degas, sterilize, cool, and fill.

[0021] Comparative Example 1: Lactulose Oral Solution formula: Preparation method: (1) Preparation of lactulose-stabilizer composite solution: Threonine was dissolved in purified water at 50℃ and stirred at 8℃ for 2h. The pH of the system was adjusted to 4.5 with pH adjuster. Lactulose was added and stirred for 30min to obtain lactulose-stabilizer composite solution.

[0022] (2) Preparation of lactulose oral solution: Dissolve the flavoring agent in purified water, adjust the pH of the system to 4.5 using a pH adjuster, add lactulose-stabilizer composite solution, mix evenly, add water to the total volume, filter finely, degas, sterilize, cool, and fill.

[0023] Comparative Example 2: Lactulose Oral Solution formula: Preparation method: (1) Preparation of lactulose-stabilizer composite solution: Cyclodextrin was dissolved in purified water at 50℃ and stirred at 8℃ for 2h. The pH of the system was adjusted to 4.5 with pH adjuster. Lactulose was added and stirred for 30min to obtain lactulose-stabilizer composite solution.

[0024] (2) Preparation of lactulose oral solution: Dissolve the flavoring agent in purified water, adjust the pH of the system to 4.5 using a pH adjuster, add lactulose-stabilizer composite solution, mix evenly, add water to the total volume, filter finely, degas, sterilize, cool, and fill.

[0025] Comparative Example 3: Lactulose Oral Solution formula: Preparation method: (1) Preparation of lactulose-stabilizer composite solution: Polyethylene glycol 400 and threonine were dissolved in purified water at 50°C and stirred at 8°C for 2 hours. The pH of the system was adjusted to 4.5 with pH adjuster. Lactulose was added and stirred for 30 minutes to obtain lactulose-stabilizer composite solution.

[0026] (2) Preparation of lactulose oral solution: Dissolve the flavoring agent in purified water, adjust the pH of the system to 4.5 using a pH adjuster, add lactulose-stabilizer composite solution, mix evenly, add water to the total volume, filter finely, degas, sterilize, cool, and fill.

[0027] Comparative Example 4: Lactulose Oral Solution formula: Preparation method: (1) Preparation of lactulose-stabilizer composite solution: Cyclodextrin and serine were dissolved in purified water at 50°C and stirred at 8°C for 2 hours. The pH of the system was adjusted to 4.5 with pH adjuster. Lactulose was added and stirred for 30 minutes to obtain lactulose-stabilizer composite solution.

[0028] (2) Preparation of lactulose oral solution: Dissolve the flavoring agent in purified water, adjust the pH of the system to 4.5 using a pH adjuster, add lactulose-stabilizer composite solution, mix evenly, add water to the total volume, filter finely, degas, sterilize, cool, and fill.

[0029] Comparative Example 5: Lactulose Oral Solution formula: Preparation method: Dissolve the flavoring agent in purified water, adjust the pH of the system to 4.5 using a pH adjuster, add lactulose, mix well, add water to the total volume, filter, degas, sterilize, cool, and fill.

[0030] Comparative Example 6: Lactulose Oral Solution formula: Preparation method: Dissolve the flavoring agent, cyclodextrin, and threonine in purified water, adjust the pH of the system to 4.5 using a pH adjuster, add lactulose, mix well, add water to the total volume, filter, degas, sterilize, cool, and fill.

[0031] Comparative Example 7: Lactulose Oral Solution formula: Preparation method: (1) Preparation of lactulose-stabilizer composite solution: Cyclodextrin and threonine were dissolved in purified water at 25°C and stirred at 25°C for 2 hours. The pH of the system was adjusted to 4.5 with pH adjuster. Lactulose was added and stirred for 30 minutes to obtain lactulose-stabilizer composite solution.

[0032] (2) Preparation of lactulose oral solution: Dissolve the flavoring agent in purified water, adjust the pH of the system to 4.5 using a pH adjuster, add lactulose-stabilizer composite solution, mix evenly, add water to the total volume, filter finely, degas, sterilize, cool, and fill.

[0033] Comparative Example 8: Lactulose Oral Solution formula: Preparation method: (1) Preparation of lactulose-stabilizer complex: Cyclodextrin and threonine were dissolved in purified water at 50°C and stirred at 8°C for 2 hours. Lactulose was added and stirred for 30 minutes to obtain lactulose-stabilizer complex.

[0034] (2) Preparation of lactulose oral solution: Dissolve the flavoring agent in purified water, adjust the pH of the system to 4.5 using a pH adjuster, add lactulose-stabilizer composite solution, mix evenly, add water to the total volume, filter finely, degas, sterilize, cool, and fill.

[0035] Stability of lactulose oral solution The lactulose content was determined according to the high performance liquid chromatography method (General Chapter 0512) in the Chinese Pharmacopoeia. Reference solution: Accurately weigh approximately 1 g of lactulose reference standard, place it in a 25 ml volumetric flask, dissolve and dilute to the mark with acetonitrile-water (1:1) solution, and shake well. Test solution: Accurately weigh an appropriate amount of this product (approximately equivalent to 1 g of lactulose), place it in a 25 ml volumetric flask, dissolve and dilute to the mark with acetonitrile-water (1:1) solution, and shake well. System suitability solution: Dissolve an appropriate amount of lactulose in acetonitrile-water (1:1) solution to prepare a mixed solution containing 40 mg of each component per ml. Chromatographic conditions: Aminopropylsilane-bonded silica gel was used as the stationary phase; acetonitrile-phosphate buffer (1.15 g of sodium dihydrogen phosphate dissolved in 1000 ml of water) (84:16) was used as the mobile phase; a differential refractive index detector was used; the column temperature and detector cell temperature were both 40℃; the flow rate was 1.5 ml / min; and the injection volume was 20 μl. Assay: Accurately measure the test solution and reference solution, inject them separately into the liquid chromatograph, and record the chromatograms. Calculation was performed using peak area according to the external standard method.

[0036] Accelerated test conditions: temperature 40℃±2℃, relative humidity 75%±5%, 6 months.

[0037] Long-term test conditions: temperature 25℃±2℃, relative humidity 60%±10%, 12 months.

[0038] Table 1. Lactulose content in accelerated testing Accelerated testing simulated a harsh storage environment. The results in Table 1 show that the lactulose oral solutions of Examples 1-3, prepared using the specific formulation of this invention (a composite stabilizer composed of lactulose, cyclodextrin, and threonine) and the preparation process, have a better retention effect of the active ingredient lactulose than those of Comparative Examples 1-8.

[0039] Table 2 Lactulose content in long-term trials The long-term experiments closely simulated real-world storage scenarios. Table 2 shows that the lactulose content in Examples 1-3 remained consistently high and decreased only slightly during long-term storage, demonstrating excellent long-term stability and meeting practical storage requirements. Comparative Examples 1-8, which did not use the stabilizer combination specified in this invention or had incompatible preparation processes, experienced a significant decrease in lactulose content and low retention of active ingredients after long-term storage, further confirming the crucial role of the formulation and preparation method of this invention in improving the long-term stability of lactulose oral solutions.

[0040] Taste evaluation of lactulose oral solution This experiment used a sensory evaluation method, with commercially available lactulose oral solution (National Drug Approval Number HJ20171057) as a control, to quantitatively compare the taste differences between the two groups of lactulose oral solutions from key dimensions such as sweetness and stickiness.

[0041] Evaluator selection and training Selection criteria: Age 18-60 years, gender balance (50% male and 50% female), 20 participants to be recruited. No history of lactulose allergy or taste / olfactory disorders, and no consumption of medications or irritating foods that affect taste within the past week. Ability to accurately distinguish basic sensory differences such as sweetness and stickiness, and pass the reference solution identification test. Sign an informed consent form and voluntarily participate in the entire experiment.

[0042] Training content: Explanation of experimental objectives, procedures, and scale usage, and standardization of evaluation criteria. Reference solutions will be provided for sensory calibration: sucrose solutions (5%, 10%, 15%) for sweetness perception, and sodium carboxymethyl cellulose solutions (0.5%, 1%) for stickiness perception. Pre-experimental drills will be conducted to ensure evaluators are proficient in the standardized "tasting-scoring-rinsing" procedure.

[0043] Sample preparation and processing Control group: Commercially available lactulose oral solution (National Drug Approval Number HJ20171057), stored according to the instructions, and equilibrated to 37°C before the experiment.

[0044] Example 1 group: Prepared according to the provided preparation method, ensuring batch uniformity, and also equilibrated to 37°C.

[0045] Sample coding: A random three-digit blind coding method is used. The appearance (color, clarity) of the two groups of samples must be consistent to avoid visual interference.

[0046] Sample dosage: Each sample is dispensed into 10mL / cup for single use to avoid cross-contamination.

[0047] Evaluation indicators and quantitative scales Five core indicators were set, and an equidistant scale of 1-7 points was used (1 point = best, 7 points = worst), as shown in Table 3.

[0048] Table 3 Evaluation Indicators and Quantitative Scales Evaluation operation steps Evaluators received coded samples in random order and first drank 50mL of purified water to clean their mouths. They then held 15mL of the sample in their mouths, allowing it to fully contact the oral mucosa for 15 seconds, chewed and tasted it, and then spat it out. Immediately, they scored the five indicators according to the scale and recorded the scores on the evaluation form. They rinsed their mouths three times with purified water, and after a 5-minute interval, evaluated the next group of samples. After all evaluators had completed their evaluations, the evaluation forms were collected and the results were tallied.

[0049] Statistical analysis methods Data processing and difference analysis: Paired t-tests (SPSS 22.0 software) were used to compare the scores of each indicator between the two groups of samples. P < 0.05 was considered statistically significant.

[0050] Results presentation: Calculate the mean ± standard deviation of each indicator and draw a radar chart of taste characteristics.

[0051] Table 4 Taste Evaluation Results Compared with commercially available formulations, P < 0.05.

[0052] Table 4 Figure 2 Overall taste evaluation showed that the lactulose oral solution of Example 1 exhibited superior characteristics compared to commercially available formulations in all core taste dimensions, especially in terms of aftertaste, which was better and did not leave a long-lasting residue, reducing the burden on the taste buds. Overall, it was more acceptable and easier for users to accept, which helped improve medication adherence among different groups of people.

Claims

1. A lactulose oral solution, characterized in that, The components of the lactulose oral solution are as follows by weight percentage: lactulose 30-50%, stabilizer 0.2-0.8%, flavoring agent 0.5-3.0%, pH adjuster appropriate amount, and purified water balance; the stabilizer is cyclodextrin and threonine; the lactulose and stabilizer form a lactulose-stabilizer complex solution.

2. The lactulose oral solution according to claim 1, characterized in that, The cyclodextrin is selected from one of hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and methyl-β-cyclodextrin.

3. The lactulose oral solution according to claim 1, characterized in that, The lactulose oral solution contains 0.15-0.6% cyclodextrin by weight.

4. The lactulose oral solution according to claim 1, characterized in that, The lactulose oral solution contains 0.05-0.2% threonine by weight.

5. The lactulose oral solution according to claim 1, characterized in that, The cyclodextrin is hydroxypropyl-β-cyclodextrin.

6. The lactulose oral solution according to claim 1, characterized in that, The flavoring agent is selected from one or more of sucralose, steviol glycosides, erythritol, sorbitol, mogrosides, and glycyrrhizin.

7. The lactulose oral solution according to claim 1, characterized in that, The pH adjuster is selected from one or more of citric acid, sodium hydroxide, lactic acid, sodium bicarbonate, acetic acid, and sodium citrate.

8. The lactulose oral solution according to claim 1, characterized in that, The lactulose-stabilizer composite solution is prepared as follows: cyclodextrin and threonine are dissolved in purified water at 40-60℃, stirred at 5-10℃ for 1-3 hours, the pH of the system is adjusted to 3.5-5.0 with a pH adjuster, lactulose is added, and the mixture is stirred for 20-40 minutes to obtain the lactulose-stabilizer composite solution.

9. A method for preparing the lactulose oral solution according to any one of claims 1-8, characterized in that, The preparation method of the lactulose oral solution is as follows: the flavoring agent is dissolved in purified water, the pH of the system is adjusted to 3.5-5.0 using a pH adjuster, a lactulose-stabilizer composite solution is added, mixed evenly, water is added to the total volume, finely filtered, degassed, sterilized, cooled, and filled.

10. The lactulose oral solution according to claim 1, characterized in that, The pH adjuster adjusts the pH of the system to 4.5.

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