Compound medicine solution and preparation method thereof

Abstract

The invention discloses a compound medicine solution and a preparation method thereof, and belongs to the technical field of pharmacy, the compound medicine solution comprises the following active ingredients: sodium picosulfate, anhydrous citric acid and magnesium oxide; inactive components: a chelating agent, a bacteriostatic agent, an antioxidant, a flavoring agent and a sweetener; the invention also comprises a buffer solution system for keeping the product stable. A series of methods for maintaining the stability of an oral solution system meeting conditions are provided by taking the buffer capacity as an index, the process is finally simplified, and the prepared compound sodium picosulfate oral solution is stable.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceuticals, and in particular relates to a compound drug solution and a preparation method thereof. Background Art

[0002] Compound sodium picosulfate oral solution is a digestive system medication, mainly used for cleaning the colon in adults and children aged 9 years and above for colonoscopy. The main ingredients of this drug include sodium picosulfate, magnesium oxide and anhydrous citric acid. The product dosage forms on the market include granules and oral solutions. Granules are taken orally by dissolving in an appropriate amount of water, which some patients find inconvenient when using.

[0003] The patent with the announcement number CN106456534B discloses a drug liquid composition comprising sodium picosulfate, magnesium oxide, citric acid and malic acid. According to the records therein, the main components citric acid and magnesium oxide can react with each other in the solution to form magnesium citrate, and the unreacted magnesium oxide will accelerate the precipitation of magnesium citrate over time. If the precipitated drug is taken, the desired colonoscopy preparation effect cannot be achieved. The document investigates the effects of citric acid, dl-malic acid, maleic acid, tartrate, fumaric acid, lactic acid, sodium citrate, aspartic acid, succinic acid, glutamic acid, hydrochloric acid, phosphoric acid, sulfuric acid and acetic acid on the quality of the solution. In the selection of organic acids with the same specific weight ratio, the liquid composition using malic acid did not precipitate within 24 months, while the liquid compositions using other organic acids all precipitated within 24 months.

[0004] Patent application with publication number CN117695215A discloses a compound sodium picosulfate oral solution and a preparation method thereof, wherein the effects of malonic acid, sodium gluconate, lactobionic acid, L-configuration lactic acid, and racemic lactic acid on the quality of the solution were investigated, and it was found that no precipitation was found in the oral solution prepared using L-configuration lactic acid, which was better than the control example; the results of racemic lactic acid were poor.

[0005] Sodium picosulfate oral solution generally has the problem of easy precipitation and stability. The above patent documents are all negative about the use of racemic lactic acid, and the use of this acid will cause precipitation problems. Lactic acid is added to the drug as an excipient. In addition to adjusting the pH of the drug to maintain the stability of the drug, the generated lactate can also be used to alleviate and treat metabolic diseases, such as obesity, clearing stool, and various types of constipation (functional constipation, organic constipation, constipation in the elderly, constipation during pregnancy, etc.). Therefore, how to use lactic acid to apply it to sodium picosulfate oral solution, both to solve the precipitation and stability problems of the drug, and to provide lactate that is beneficial to the body, is a difficulty currently existing in the art. Summary of the invention

[0006] The purpose of the present invention is to provide a new compound drug solution and a preparation method thereof.

[0007] To achieve the above purpose, the technical solution adopted by the present invention is: A compound drug solution comprises active ingredients: sodium picosulfate, anhydrous citric acid, and magnesium oxide; inactive ingredients: chelating agents, antibacterial agents, antioxidants, flavoring agents, and sweeteners; and a buffer solution system for maintaining product stability.

[0008] A further improvement of the technical solution of the present invention is that the buffer solution system comprises an organic acid and an alkali metal salt of the organic acid, and the buffer capacity is not less than 0.09.

[0009] The further improvement of the technical solution of the present invention is that the chelating agent includes disodium edetate, the antibacterial agent includes sodium benzoate, the antioxidant includes sodium pyrosulfite, the flavoring agent includes cranberry flavor and sucralose, and the sweetener includes acesulfame potassium.

[0010] A further improvement of the technical solution of the present invention is that the pH of the buffer solution system is 4.7-5.1.

[0011] A further improvement of the technical solution of the present invention is that the organic acid of the buffer solution system is selected from any one of lactic acid, malic acid and citric acid; and the alkali metal salt is selected from any one of the sodium salt and potassium salt of the corresponding organic acid.

[0012] A further improvement of the technical solution of the present invention is that the buffer solution system is a lactic acid-sodium lactate buffer system, and the buffer capacity of the lactic acid-sodium lactate buffer system is between 0.09 and 0.2.

[0013] A further improvement of the technical solution of the present invention is that the compound drug solution comprises the following components in weight ratio: Sodium picosulfate 0.01, anhydrous citric acid 12, magnesium oxide 3.5, chelating agent 0.1-0.5, antibacterial agent 0.05-0.3, antioxidant 0.05-0.5, flavoring agent 0.05-0.5, sweetener 0.05-0.5, lactic acid and sodium lactate 13-16.

[0014] A further improvement of the technical solution of the present invention is that the compound drug solution contains 0.01 g of the active ingredient sodium picosulfate per 160 ml or 175 ml specification.

[0015] A preparation method of a compound drug solution comprises the following steps: according to the product prescription composition, the mass of organic acid and inorganic base in the prescription is calculated according to the buffer capacity, anhydrous citric acid, magnesium oxide and organic acid in the prescription amount are weighed, 80% of the prescription amount of purified water is added according to the mass ratio of the buffer solution to dissolve them, then the prescription amount of inorganic base is added and stirred to form a buffer system with a pH range of 4.7-5.1, finally the prescription amount of sodium picosulfate, chelating agent, antioxidant, flavoring agent and sweetener are added, water is added to the full amount, the solution is stirred to be completely dissolved, a filter membrane is used for filtering, the solution is canned into an oral liquid bottle according to the theoretical filling amount, and the solution is sealed with a cap.

[0016] A use of a compound drug solution, wherein the compound drug solution is used for preparing a drug for treating metabolic diseases, and the compound drug solution is a compound sodium picosulfate oral solution.

[0017] Due to the adoption of the above technical solution, the technical progress achieved by the present invention is: The present invention provides a series of methods for maintaining the stability of an oral solution system that meet the conditions by taking buffer capacity as an index, and finally realizes process simplification. The prepared compound sodium picosulfate oral solution has stable product quality. After a prescribed amount of NaOH is added during the preparation process of the compound sodium picosulfate oral solution of the present application, the pH range is between 4.7 and 5.1, and there is no need to adjust the pH value. The preparation method is simple and easy to operate.

[0018] The invention uses a buffer solution with a certain buffering capacity to obtain a stable compound sodium picosulfate oral solution, and the pH does not need to be adjusted during the production process. The buffer solution system with a certain buffering capacity is preferably a lactic acid-sodium lactate buffer system, thereby realizing a new method for preparing a stable compound sodium picosulfate oral solution. The compound sodium picosulfate oral solution prepared by the method has good quality stability, and no precipitation is found after multiple freeze-thaw cycle inspections.

[0019] The lactic acid-sodium lactate buffer system is used in the preparation of the present invention. In addition to its buffering capacity, the organic acid lactic acid used as an important raw material not only has the advantage of being easily available, but also as a compound produced during human metabolism, in addition to its role as an energy source, lactic acid is also a signal metabolite. The acidic environment of the lactate buffer system is conducive to the growth and reproduction of beneficial bacteria such as bifidobacteria and Lactobacillus acidophilus, and promotes digestive function; the lactate buffer system has the potential to regulate the pH of the gastrointestinal tract, and lactic acid can stimulate intestinal nerves to promote intestinal peristalsis and help defecation. Studies have shown that oral lactate increases the subjective feeling of fullness, reduces the expected future food intake after 60 minutes, increases GLP-1, slows gastric emptying, and suppresses the appetite of young men (Clinical Nutrition 2022;41(2):517-525). The large amount of lactic acid used as an excipient can not only solve the problem of easy precipitation and stability of compound sodium picosulfate oral solution, but also play other potential therapeutic functions, such as clearing stool. DETAILED DESCRIPTION

[0021] The present invention is further described in detail below in conjunction with embodiments: A compound sodium picosulfate oral solution includes active ingredients: sodium picosulfate, anhydrous citric acid, magnesium oxide; inactive ingredients: chelating agent, antibacterial agent, antioxidant, flavoring agent and sweetener; and a buffer solution system for maintaining product stability. The buffer solution system includes an organic acid and an alkali metal salt of the organic acid.

[0022] The chelating agent in the compound sodium picosulfate oral solution includes disodium edetate, the antibacterial agent includes sodium benzoate, the antioxidant includes sodium pyrosulfite, the flavoring agent includes cranberry flavor and sucralose, and the sweetener includes acesulfame potassium.

[0023] The organic acid of the buffer solution system is selected from any one of lactic acid, malic acid and citric acid; the alkali metal salt is selected from any one of the sodium salt and potassium salt of the corresponding organic acid.

[0024] In a preferred embodiment, the buffer solution system is a lactic acid-sodium lactate buffer system.

[0025] A preparation method of a compound sodium picosulfate oral solution comprises the following steps: according to the product prescription composition, the mass of an organic acid and an inorganic base in the prescription is calculated according to the buffer capacity, anhydrous citric acid, magnesium oxide and an organic acid in a buffer system in the prescription amount are weighed, 80% of the prescription amount of purified water is added according to the mass ratio of the buffer solution to dissolve them, a prescription amount of inorganic base is added and stirred to form a buffer system, the pH range of the solution is 4.7-5.1, then the prescription amount of sodium picosulfate, a chelating agent, an antioxidant, a flavoring agent and a sweetener are added, water is added to the full amount, the mixture is stirred to be completely dissolved, a filter membrane is used for filtering, the mixture is canned into an oral liquid bottle according to the theoretical filling amount, and the solution is sealed with a cover.

[0026] The buffer system is one of lactic acid, malic acid and citric acid, and the corresponding base is sodium salt or potassium salt of lactic acid, malic acid and citric acid. The inorganic base is selected from NaOH or KOH. In the present invention, lactic acid is not specifically described, that is, racemic lactic acid, also known as dl-lactic acid.

[0027] According to the above method, compound sodium picosulfate oral solution was prepared and investigated.

[0028] Embodiment 1 Compound drug solution A compound drug solution comprises raw materials of sodium picosulfate in a weight ratio of 0.01, magnesium oxide in a weight ratio of 3.5, anhydrous citric acid in a weight ratio of 12, disodium edetate in a weight ratio of 0.21, sodium benzoate in a weight ratio of 0.09, sodium metabisulfite in a weight ratio of 0.185, acesulfame potassium in a weight ratio of 0.2, sucralose in a weight ratio of 0.2, cranberry flavor in a weight ratio of 0.1, lactic acid in a weight ratio of 10.72, sodium hydroxide in a weight ratio of 2.49 to 4.726, and a proper amount of water.

[0029] Examples 1 to 6 Compound drug solution and preparation method thereof A compound drug solution, the raw materials are 0.01g sodium picosulfate, 3.5g magnesium oxide, 12g anhydrous citric acid, 0.21g disodium edetate, 0.09g sodium benzoate, 0.185g sodium pyrosulfite, 0.2g acesulfame potassium, 0.2g sucralose, 0.1g cranberry flavor, 10.72g lactic acid, and 2.49-4.726g sodium hydroxide, and an appropriate amount of water are finally configured into a 160ml solution. The specific amount of NaOH used in each example is shown in Table 1.

[0030] The preparation method of the compound drug solution is as follows: weigh the prescribed amount of anhydrous citric acid, magnesium oxide, and lactic acid, add 80% of the prescribed amount of purified water according to the mass ratio of the buffer solution to dissolve them, add NaOH and stir to form a buffer system, and finally add the prescribed amount of sodium picosulfate, disodium edetate, sodium benzoate, sodium metabisulfite, cranberry flavor, acesulfame potassium and sucralose, add water to make the solution 160 mL, stir to completely dissolve, filter with a filter membrane, can into an oral liquid bottle according to the theoretical filling amount, and seal with a cover.

[0031] The amounts of lactic acid and sodium hydroxide used in Examples 1 to 6, the buffer capacity and pH of the buffer system are shown in Table 1.

[0032] Table 1

[0033] Embodiment 2 Compound drug solution A compound drug solution comprises raw materials of 0.01 weight ratio of sodium picosulfate, 3.5 weight ratio of magnesium oxide, 12 weight ratio of anhydrous sodium citrate, 0.21 weight ratio of disodium edetate, 0.09 weight ratio of sodium benzoate, 0.185 weight ratio of sodium pyrosulfite, 0.2 weight ratio of acesulfame potassium, 0.2 weight ratio of sucralose, 0.1 weight ratio of cranberry flavor, 3.6 to 12.32 weight ratio of lactic acid, 1.43 to 4.91 weight ratio of sodium hydroxide and an appropriate amount of water.

[0034] Examples 7 to 13 Compound drug solutions and preparation methods thereof A compound drug solution, wherein the raw materials are 0.01 g of sodium picosulfate, 3.5 g of magnesium oxide, 12 g of anhydrous sodium citrate, 0.21 g of disodium edetate, 0.09 g of sodium benzoate, 0.185 g of sodium metabisulfite, 0.2 g of acesulfame potassium, 0.2 g of sucralose, 0.1 g of cranberry flavor, 3.6-12.32 g of lactic acid, and 1.43-4.91 g of sodium hydroxide, and an appropriate amount of water is finally configured into a 160 ml solution.

[0035] The preparation method of the compound drug solution is as follows: weigh anhydrous citric acid, magnesium oxide, and lactic acid, add 128 mL of purified water according to the mass ratio of the buffer solution to dissolve them, add NaOH and stir to form a buffer system with a pH value of 4.8, finally add the prescribed amount of sodium picosulfate, disodium edetate, sodium benzoate, sodium metabisulfite, cranberry flavor, acesulfame potassium and sucralose, add water to make the solution 160 mL, stir to completely dissolve, filter with a filter membrane, can it into an oral liquid bottle according to the theoretical filling amount, and seal it with a cover.

[0036] The amounts of lactic acid and sodium hydroxide used in Examples 7 to 13 and the buffer capacity of the buffer system are shown in Table 2.

[0037] Table 2

[0038] Comparative Example 1 Compound drug solution and preparation method thereof Weigh 12 g of anhydrous citric acid, 3.5 g of magnesium oxide, and 8.38 g of dl-malic acid and add them to 128 mL of purified water. Then add the prescribed amount of 0.01 g of sodium picosulfate, 0.21 g of disodium edetate, 0.09 g of sodium benzoate, 0.185 g of sodium metabisulfite, 0.2 g of acesulfame potassium, 0.2 g of sucralose, and 0.1 g of cranberry flavor. Add water to make the solution 160 mL, stir to completely dissolve, and adjust the pH to 4.7 with NaOH.

[0039] Comparative Example 2 Compound drug solution and preparation method thereof The compound drug solution contains the following components: sodium picosulfate 0.01 g / bottle, magnesium oxide 3.5 g / bottle, anhydrous citric acid 12 g / bottle, L-lactic acid 7.4 g / bottle, disodium edetate 0.3 g / bottle, sodium benzoate 0.3 g / bottle, sodium metabisulfite 0.5 g / bottle, appropriate amount of sodium hydroxide, and appropriate amount of purified water.

[0040] Preparation method: Weigh the prescribed amount of sodium picosulfate, magnesium oxide, anhydrous citric acid, L-configuration lactic acid, sodium hydroxide, disodium edetate, sodium benzoate and sodium metabisulfite, mix evenly, then add 80% of the prescribed amount of purified water and stir evenly, use sodium hydroxide solution to adjust the pH to 5, add water to the full amount and stir evenly, filter with a filter membrane, can into an oral liquid bottle according to the theoretical filling amount, and seal with a cap. Each bottle is 175ml.

[0041] Experimental Example 1 Investigating the Effect of Different pH on the Acid Stability of Compound Sodium Picosulfate Oral Solution The samples of Examples 1 to 6 and Comparative Example 1 were tested for quality stability. The freeze-thaw cycle experiment was: freezing at -20°C for more than 12 hours and placing at 20°C for 8 hours as one cycle. The influencing factor experiment was placed at 40°C for 30 days and placed at 4500Lux±500Lux for 30 days. The results are shown in Table 3.

[0042] Table 3 Stability test results

[0043] Note: △△△ means the total impurity content is greater than 3%, △△ means the total impurity content is greater than 2%, △ means the total impurity content is equivalent to or lower than the reference preparation. * means precipitation is observed in the properties, the number of * represents the degree of precipitation, and the more * the more serious the precipitation.

[0044] Unless otherwise specified in the present invention, the reference preparations are all the original marketed product compound sodium picosulfate oral solution with the trade name of Clenpiq, the manufacturer of which is Ferring Pharmaceuticals Inc., and the batch number of which is T04099AA.

[0045] Experimental Example 2 Investigating the effects of different lactic acid concentrations and buffering capacity on the acid stability of compound sodium picosulfate oral solution at the same pH (pH = 4.8) The samples of Examples 7 to 13 and Comparative Example 2 were subjected to stability tests. The freeze-thaw cycle test method was: freezing at -20°C for more than 12 hours and placing at 20°C for 8 hours, which was one cycle. The results are shown in Table 4.

[0046] Table 4

[0047] Note: * indicates precipitation was observed in the properties, the number of * indicates the degree of precipitation, and the more * the more serious the precipitation is.

[0048] Experimental Example 3 Three batches of compound drug solutions in Example 11 of the present application and the purchased reference preparation were subjected to long-term tests at 25°C ± 2°C and 60% ± 5% RH. The long-term test data are shown in Table 5. The homemade samples of the present invention have good stability. The data of each related substance (impurity A, D, other single impurities, and other total impurities) on the 0th day and the 18th month of the long-term stability period are significantly better than the reference preparation (i.e., the original marketed product). Impurity A: 4-[RS]-[(4-hydroxyphenyl)(pyridin-2-yl)methyl]benzenesulfonate sodium, impurity D: (hydroxy(pyridin-2-yl)methylene)bis(4,1-phenyl)disulfonate sodium.

[0049] Table 5 Long-term test data of Example 11 and reference preparation

[0050] In addition, in addition to its laxative therapeutic effect, compound sodium picosulfate oral solution can be used to relieve and treat metabolic diseases such as obesity, clear stool, and for various types of constipation (functional constipation, organic constipation, elderly constipation, pregnancy constipation, etc.) due to the presence of a large amount of lactate in the prescription.

Claims

1. A compound drug solution, characterized in that: It includes active ingredients: sodium picosulfate, anhydrous citric acid, magnesium oxide; inactive ingredients: chelating agents, antibacterial agents, antioxidants, flavoring agents and sweeteners; and also includes a buffer solution system for maintaining product stability.

2. A compound pharmaceutical solution according to claim 1, characterized in that: The buffer solution system comprises an organic acid and an alkali metal salt of the organic acid, and the buffer capacity is not less than 0.

09.

3. A compound pharmaceutical solution according to claim 1, characterized in that: Chelating agents include disodium edetate, antibacterial agents include sodium benzoate, antioxidants include sodium metabisulfite, flavoring agents include cranberry flavor and sucralose, and sweeteners include acesulfame potassium.

4. A compound pharmaceutical solution according to claim 1, characterized in that: The solution pH of the buffer solution system is 4.7-5.

1.

5. A compound pharmaceutical solution according to claim 2, characterized in that: The organic acid of the buffer solution system is selected from any one of lactic acid, malic acid and citric acid; the alkali metal salt is selected from any one of the sodium salt and potassium salt of the corresponding organic acid.

6. A compound pharmaceutical solution according to claim 5, characterized in that: The buffer solution system is a lactic acid-sodium lactate buffer system, and the buffer capacity of the lactic acid-sodium lactate buffer system is between 0.09 and 0.

2.

7. A compound pharmaceutical solution according to claim 2, characterized in that: The invention comprises the following components in weight ratio: 0.01 sodium picosulfate, 12 anhydrous citric acid, 3.5 magnesium oxide, 0.1-0.5 chelating agent, 0.05-0.3 antibacterial agent, 0.05-0.5 antioxidant, 0.05-0.5 flavoring agent, 0.05-0.5 sweetener, and 13-16 lactic acid and sodium lactate.

8. A compound pharmaceutical solution according to claim 7, characterized in that: The compound drug solution contains 0.01 g of active ingredient sodium picosulfate per 160 ml or 175 ml specification.

9. A method for preparing a compound drug solution, characterized in that: According to the prescription composition of the compound drug solution of claim 8, the mass of the organic acid and the inorganic base in the prescription is calculated according to the buffer capacity, the anhydrous citric acid, magnesium oxide and organic acid in the prescription amount are weighed, and 80% of the prescribed amount of purified water is added according to the mass ratio of the buffer solution to dissolve them, and then the prescribed amount of inorganic base is added and stirred to form a buffer system with a pH range of 4.7-5.1, and finally the prescribed amount of sodium picosulfate, chelating agent, antioxidant, flavoring agent and sweetener are added, water is added to the full amount, stirred to completely dissolve, filtered with a filter membrane, canned into an oral liquid bottle according to the theoretical filling amount, and sealed with a cover.

10. A use of a compound drug solution, characterized in that: The compound drug solution is used for preparing drugs for treating metabolic diseases, and the compound drug solution is a compound sodium picosulfate oral solution.

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