A preparation method of metformin hydrochloride oral solution

Abstract

The invention discloses a method for preparing a metformin hydrochloride oral solution, and belongs to the technical field of pharmaceutical preparations. The method comprises the following steps: after measuring 50% of the total mass of purified water for preparing the metformin hydrochloride oral solution and heating it to 40-50°C, adding a preservative and metformin hydrochloride into the purified water in sequence, mixing and stirring until completely dissolved, and then adding inulin and flavor in sequence and stirring until completely dissolved to obtain a mixed solution; slowly dripping a pH regulator into the mixed solution and stirring continuously until the pH is 4.5-5.8, stopping adding the pH regulator, and then settling the volume to 100% with purified water, filtering and filling to obtain the metformin hydrochloride oral solution. The invention develops a metformin hydrochloride oral solution that can improve the defect of the bitter taste of metformin and avoid the use of sweeteners with potential safety risks, and has practical application value.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a method for preparing a metformin hydrochloride oral solution for treating diabetes. Background Art

[0002] As people's living standards continue to improve, the number of people with three highs increases year by year, and the age of people is getting younger and younger, and the prevalence of diabetes is becoming more and more common. People with diabetes not only need to strictly control their diet on a daily basis, but also prevent various complications. Once diabetes is diagnosed, they need to take medication for life, which makes the patients very painful and seriously affects the happiness index of patients. Therefore, a safe, effective and easy-to-use hypoglycemic drug can bring a lot of comfort to patients.

[0003] Biguanide hypoglycemic drugs are one of the most widely used hypoglycemic drugs on the market. Among them, the most common and widely used is metformin hydrochloride, which can promote anaerobic glycolysis of sugars, increase the uptake of glucose by peripheral tissues such as muscle and fat, and increase insulin-mediated glucose utilization. It is used to treat non-insulin-dependent diabetes mellitus. Metformin hydrochloride was originally developed and produced by foreign pharmaceutical companies. Currently, the relevant dosage forms of metformin hydrochloride on the market in China are mainly solid preparations such as capsules and tablets. Solid preparations have certain limitations for patients with dysphagia or children's medication compliance. The oral solution of metformin hydrochloride is currently produced by a foreign pharmaceutical company, Sun Pharmaceutical Industries Ltd, and the trade name of the oral solution of metformin hydrochloride produced by this company is This product has been launched in countries such as the UK and Germany, but has not yet been introduced to China. Since metformin is bitter in nature, its bitter taste needs to be modified when it is made into an oral preparation. Foreign metformin hydrochloride mainly adopts the addition of pharmaceutical excipient saccharin calcium. As a kind of sweetener, saccharin calcium has a very high sweetness and can well cover up the bitter taste of metformin. However, saccharin calcium has been proven to have potential carcinogenic risks and is not suitable for domestic children.

[0004] To this end, the existing technology has adopted the following improvement measures to address the defects of saccharin calcium, a pharmaceutical excipient in metformin hydrochloride oral solution: (1) Patent CN1695602A discloses "metformin hydrochloride oral solution and preparation method thereof". In this invention, "saccharin calcium" is replaced with other sweetener "stevioside" with safety performance, so as to obtain a metformin hydrochloride oral solution with better taste; (2) Patent CN117281771A discloses "a metformin hydrochloride oral solution and preparation method thereof". In this invention, the sweetener is mainly xylitol with higher safety, and then a very low amount of saccharin calcium is added, and then combined with the use of flavors, the bitter taste of metformin is modified while ensuring that the amount of saccharin calcium is reduced.

[0005] Sweeteners, as a pharmaceutical excipient, have the effect of improving the poor taste of medicines. However, in the preparation process of drugs, reducing the use of unnecessary excipients helps to improve the safety of drugs. Therefore, it is of practical application value to develop a metformin hydrochloride oral solution that can improve the bitter taste of metformin and avoid the use of sweeteners with potential safety risks. Summary of the invention

[0006] In view of the deficiencies of the prior art, the present invention introduces inulin, a water-soluble plant polysaccharide with a blood sugar-lowering effect, into a metformin hydrochloride oral solution to solve the problems raised in the background technology. Specifically, the technical solution of the present invention includes the following contents:

[0007] A metformin hydrochloride oral solution comprises the following raw materials:

[0008] 100 mg / ml of metformin hydrochloride, 2-5 mg / ml of preservatives, 180-200 mg / ml of inulin and 4-5 mg / ml of flavor.

[0009] Furthermore, the preservative includes sodium benzoate, sodium bicarbonate or potassium bicarbonate.

[0010] Furthermore, the flavor includes cherry flavor.

[0011] Preferably, the metformin hydrochloride oral solution comprises the following raw materials in parts by weight:

[0012] 100mg / ml of metformin hydrochloride, 2mg / ml of preservatives, 180mg / ml of inulin and 5mg / ml of flavor.

[0013] Furthermore, the pH value of the metformin hydrochloride oral solution is 4.5 to 5.8.

[0014] A method for preparing a metformin hydrochloride oral solution, the method comprising the following steps:

[0015] 50% of the total weight of purified water for preparing the oral solution of metformin hydrochloride is measured and heated to 40-50° C., a preservative and metformin hydrochloride are sequentially added to the purified water and mixed and stirred until completely dissolved, and then inulin and flavor are sequentially added and stirred until completely dissolved to obtain a mixed solution;

[0016] The pH regulator is slowly added dropwise to the mixed solution while stirring continuously until the pH value is 4.5 to 5.8, and the addition of the pH regulator is stopped. The volume is then fixed to 100% with purified water, and the metformin hydrochloride oral solution is obtained through filtration and filling.

[0017] Furthermore, the pH adjuster includes hydrochloric acid.

[0018] Furthermore, the stirring speed in the preparation process is 100 to 200 r / min.

[0019] Furthermore, the pH adjuster can be used in the following manner: the total amount of the pH adjuster used for adjusting the pH is added twice, the first time before adding inulin, and the second time when adjusting the pH value, which can make the mixed solution more stable.

[0020] Compared with the prior art, the present invention has the following beneficial effects:

[0021] (1) The present invention prepares a metformin hydrochloride oral solution by mixing inulin, a water-soluble plant polysaccharide having a blood sugar lowering function, with metformin hydrochloride. The bitter taste of metformin hydrochloride is modified by inulin, thereby improving the bitter taste of metformin hydrochloride without using a sweetener. Compared with the prior art that uses extremely low doses of saccharin calcium, a sweetener with a potential safety threat, and other sweeteners, the use of unnecessary pharmaceutical excipient sweeteners is avoided, which helps to improve the safety of the metformin hydrochloride oral solution.

[0022] (2) The present invention combines inulin with metformin hydrochloride, which, on the one hand, improves the bitter taste of metformin hydrochloride. On the other hand, while ensuring that the total dosage of the metformin hydrochloride oral solution of the present invention is consistent with the total dosage of the oral solution containing only metformin hydrochloride, the metformin hydrochloride oral solution of the present invention has a better blood sugar lowering effect.

[0023] (3) The pH of the metformin hydrochloride oral solution of the present invention is between 4.5 and 5.8, and has good stability, which broadens the pH adjustment range of the metformin hydrochloride oral solution and reduces the probability of excessive addition during pH adjustment in a small range, resulting in the final pH value exceeding the range.

[0024] (4) It was unexpectedly found that when inulin was used to modify the bitter taste of metformin hydrochloride, the impurity content of the metformin hydrochloride oral solution prepared by the present invention was lower than that of the conventional metformin hydrochloride oral solution during impurity analysis, especially the content of the impurity dicyandiamide, which was not even detected. This shows that inulin also has the advantages of stabilizing metformin hydrochloride and reducing the decomposition of metformin hydrochloride.

[0025] (5) The covalent cross-linking system of the present invention has a certain promoting effect on improving the bitter taste and stability of metformin hydrochloride. DETAILED DESCRIPTION

[0026] The technical solution of the present invention will be clearly and completely described below through the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work are within the scope of protection of the present invention.

[0027] Unless otherwise specified, the raw materials and reagents used in the present invention are commercially available or can be prepared by known methods.

[0028] Embodiment 1:

[0029] A method for preparing a metformin hydrochloride oral solution, specifically comprising the following steps:

[0030] Take 500 ml of purified water, heat it to 40°C, add 2 g of sodium benzoate and 100 g of metformin hydrochloride in sequence and mix them, then stir and dissolve them at a speed of 100 r / min until the solid is completely dissolved, then add 100 g of inulin and 1 g of cherry essence, keep stirring at a speed of 100 r / min until all are dissolved, slowly add hydrochloric acid dropwise while stirring, stop adding hydrochloric acid when the pH value of the solution is 4.5, add purified water again to make the volume up to 1000 ml, then filter and fill the fixed solution to obtain a metformin hydrochloride oral solution.

[0031] Embodiment 2:

[0032] A method for preparing a metformin hydrochloride oral solution, specifically comprising the following steps:

[0033] 500 ml of purified water was measured and heated to 42°C, and then 3 g of sodium bicarbonate and 100 g of metformin hydrochloride were added in sequence and mixed, and then stirred and dissolved at a speed of 120 r / min until the solid was completely dissolved, and then 120 g of inulin and 2 g of cherry essence were added, and stirring was continued at a speed of 120 r / min until all dissolved, and hydrochloric acid was slowly added dropwise while stirring. When the pH value of the solution reached 4.5, the addition of hydrochloric acid was stopped, and purified water was added again to make the volume to 1000 ml, and then the fixed solution was filtered and encapsulated to obtain a metformin hydrochloride oral solution.

[0034] Embodiment 3:

[0035] A method for preparing a metformin hydrochloride oral solution, specifically comprising the following steps:

[0036] 500 ml of purified water was measured and heated to 44°C, and then 2 g of sodium bicarbonate and 100 g of metformin hydrochloride were added in sequence and mixed, and then stirred and dissolved at a speed of 140 r / min until the solid was completely dissolved, and then 140 g of inulin and 3 g of cherry essence were added, and stirring was continued at a speed of 140 r / min until all dissolved, and hydrochloric acid was slowly added dropwise while stirring. When the pH value of the solution was 4.5, the addition of hydrochloric acid was stopped, and purified water was added again to make the volume to 1000 ml, and then the fixed solution was filtered and encapsulated to obtain a metformin hydrochloride oral solution.

[0037] Embodiment 4:

[0038] A method for preparing a metformin hydrochloride oral solution, specifically comprising the following steps:

[0039] 500 ml of purified water was measured and heated to 46° C., and then 4 g of potassium bicarbonate and 100 g of metformin hydrochloride were added in sequence and mixed, and then stirred and dissolved at a speed of 160 r / min until the solid was completely dissolved, and then 160 g of inulin and 4 g of cherry essence were added, and stirring was continued at a speed of 160 r / min until all dissolved, and hydrochloric acid was slowly added dropwise while stirring. When the pH value of the solution reached 4.5, the addition of hydrochloric acid was stopped, and purified water was added again to make the volume to 1000 ml, and then the fixed solution was filtered and encapsulated to obtain a metformin hydrochloride oral solution.

[0040] Embodiment 5:

[0041] A method for preparing a metformin hydrochloride oral solution, specifically comprising the following steps:

[0042] Measure 500 ml of purified water, heat it to 48°C, add 2 g of sodium benzoate and 100 g of metformin hydrochloride in sequence and mix them, then stir and dissolve them at a speed of 180 r / min until the solid is completely dissolved, then add 180 g of inulin and 5 g of cherry flavor, keep stirring at a speed of 180 r / min until all are dissolved, slowly add hydrochloric acid dropwise while stirring, stop adding hydrochloric acid when the pH value of the solution is 4.5, add purified water again to make the volume up to 1000 ml, then filter and fill the fixed solution to obtain a metformin hydrochloride oral solution.

[0043] Embodiment 6:

[0044] A method for preparing a metformin hydrochloride oral solution, specifically comprising the following steps:

[0045] Measure 500 ml of purified water, heat it to 50°C, add 5 g of sodium benzoate and 100 g of metformin hydrochloride in sequence and mix them, then stir and dissolve them at a speed of 200 r / min until the solid is completely dissolved, then add 200 g of inulin and 4 g of cherry flavor, keep stirring at a speed of 200 r / min until all are dissolved, slowly add hydrochloric acid dropwise while stirring, stop adding hydrochloric acid when the pH value of the solution is 4.5, add purified water again to make the volume up to 1000 ml, then filter and fill the fixed solution to obtain a metformin hydrochloride oral solution.

[0046] Embodiment 7:

[0047] A method for preparing a metformin hydrochloride oral solution, specifically comprising the following steps:

[0048] 500 ml of purified water was measured and heated to 50°C, and then 5 g of sodium benzoate and 100 g of metformin hydrochloride were added in sequence and mixed, and then stirred and dissolved at a speed of 200 r / min until the solid was completely dissolved, and then 200 g of inulin and 4 g of cherry flavor were added, and the stirring was continued at a speed of 200 r / min until all dissolved; 5 g of anionic polymer sodium carboxymethyl cellulose was weighed and dissolved with 20 g of deionized water, and then 5 g of 5g of water-soluble polyhydroxyglycerol and 5g of water-soluble polyhydroxy gum arabic are mixed with sodium carboxymethyl cellulose, heated to 35°C, and stirred for reaction for 4 hours to obtain a covalently cross-linked cosolvent. 10g of the cosolvent is mixed with the system consisting of the above-mentioned metformin hydrochloride and inulin, and then hydrochloric acid is slowly added dropwise while stirring. When the pH value of the solution is 4.5, the addition of hydrochloric acid is stopped, and purified water is added again to make the volume to 1000ml, and then the fixed solution is filtered and encapsulated to obtain a metformin hydrochloride oral solution.

[0049] The metformin hydrochloride oral solutions of Examples 1 to 7 were subjected to nasal sniffing and taste testing, and the statistical data are as follows:

[0050]

[0051]

[0052] In the table, “×” indicates that both the odor and taste are not good, and “√” indicates that the odor is good and the taste is not bitter.

[0053] From the above results, it can be seen that when the addition amount of inulin is 180-200 mg / ml, the flavor is 4-5 mg / ml and the preservative is 2-5 mg / ml, the metformin hydrochloride oral solution of the present invention has a good taste, and when the addition amount of inulin is 180 mg / ml, the flavor is 5 mg / ml and the preservative is 2 mg / ml, the effect is the best;

[0054] When the inulin content is further increased, the bitter taste modification effect of the metformin hydrochloride oral solution is slightly insufficient. However, by adding a certain amount of co-solvent modified by cross-linking, the metformin hydrochloride oral solution also has a good taste.

[0055] The metformin hydrochloride oral solution of Example 5 was adjusted to pH 4.2, 4.5, 4.8, 5.2, 5.5 and 5.8 respectively with hydrochloric acid and sodium bicarbonate, and then placed together at 60°C ± 2°C for 10 days, and the properties, content and related substances were checked. The results are shown in the following table:

[0056]

[0057]

[0058] It can be seen from the table that after being treated at a high temperature of 60±2°C for 10 days, the impurities of the metformin hydrochloride oral solution with a pH in the range of 4.5 to 5.8 did not change significantly, and the solution was relatively stable.

[0059] Study the effect of formula addition order on the stability of metformin hydrochloride oral solution:

[0060] Example 5 is taken as the research object:

[0061] Test Example 1:

[0062] The order of adding materials: purified water → sodium benzoate + metformin hydrochloride → inulin + essence → hydrochloric acid to adjust pH → purified water to make up to volume.

[0063] Test Example 2:

[0064] The order of adding materials: purified water → inulin + essence → sodium benzoate + metformin hydrochloride → hydrochloric acid to adjust pH → purified water to make up to volume.

[0065] Test Example 3:

[0066] The order of adding materials: purified water → sodium benzoate + metformin hydrochloride + 10% of the total amount of hydrochloric acid → inulin + essence → 90% of the total amount of hydrochloric acid to adjust pH → purified water to make up to volume.

[0067] Test example 4:

[0068] The order of adding materials: purified water → sodium benzoate + metformin hydrochloride + 30% of the total amount of hydrochloric acid → inulin + essence → 70% of the total amount of hydrochloric acid to adjust pH → purified water to make up to volume.

[0069] Test Example 5:

[0070] The order of adding materials: purified water → sodium benzoate + metformin hydrochloride + 50% of the total amount of hydrochloric acid → inulin + essence → 50% of the total amount of hydrochloric acid to adjust pH → purified water to make up to volume.

[0071] Study the effect of formula addition order on the stability of metformin hydrochloride oral solution:

[0072] Example 7 is taken as the research object:

[0073] Test Example 6:

[0074] The order of adding materials: purified water → sodium benzoate + metformin hydrochloride + 70% of the total amount of hydrochloric acid + 10g of cosolvent → inulin + essence → 30% of the total amount of hydrochloric acid to adjust pH → purified water to make up to volume.

[0075] Test Example 7:

[0076] The order of adding materials: purified water → sodium benzoate + metformin hydrochloride + 90% of the total amount of hydrochloric acid + 10g of cosolvent → inulin + flavor → 10% of the total amount of hydrochloric acid to adjust pH → purified water to make up to volume.

[0077] The dissolution of the metformin hydrochloride oral solutions of Test Examples 1 to 7 was observed, and the results are shown in the following table:

[0078]

[0079] It can be seen from the data in the table that the total amount of hydrochloric acid for adjusting pH is divided into batches, and the hydrochloric acid is added once before adding inulin, which helps to stabilize and uniformly dissolve the mixed solution and the final dissolution state of the metformin hydrochloride oral solution;

[0080] By adding a covalently cross-linked cosolvent, the cross-linking system helps to prevent the aggregation of inulin, thereby achieving uniform and stable dispersion of the prepared metformin hydrochloride oral solution.

[0081] Mouse experiments:

[0082] Ten normal mice were taken and raised normally as the normal group. Forty diabetic mice (criterion for diabetic mice: fasting blood glucose ≥ 11.1 mmoL / L) were divided into experimental groups 1, 2, 3 and 4, with 10 mice in each group. The mice were given an oral dose of 0.3 g / kg once a day by gavage. Experimental group 1 was fed with the oral solution of metformin hydrochloride prepared in Example 5, experimental group 2 was fed with the oral solution of metformin hydrochloride prepared in Example 7, and experimental group 3 was fed with the oral solution of metformin hydrochloride produced by Sun Pharmaceuticals Ltd. Experimental group 4 was used as a positive control and fed with an equal amount of purified water. Fasting blood glucose, body weight and serum insulin were measured 14 days later. The results are as follows:

[0083]

[0084] The results showed that compared with experimental group 4 (positive control), fasting blood glucose of diabetic mice in experimental groups 1, 2 and 3 was significantly reduced, and serum insulin and body weight were significantly increased, indicating that both groups of drugs can effectively control blood glucose. Compared with experimental group 3, fasting blood glucose of experimental groups 1 and 2 was lower, body weight was better controlled, and serum insulin content was higher. It can be seen that under the same dosage, the oral solution of metformin hydrochloride of the present invention has a better hypoglycemic effect.

[0085] The metformin hydrochloride oral solutions in Examples 5 and 7 were mixed with the metformin hydrochloride solution produced by Sun Pharmaceuticals Ltd. The samples were tested and analyzed, and the results are shown in the following table:

[0086]

[0087]

[0088] It can be seen from the data in the table that the inulin in the metformin hydrochloride oral solution of the present invention can improve the stability of metformin hydrochloride and reduce the degradation of impurities;

[0089] The oral solution prepared by adding a covalently cross-linked modified solvent to metformin hydrochloride can prevent the aggregation or sedimentation of drug particles. The formed stable covalently cross-linked network structure can hinder the adverse reactions of drug molecules with oxygen, etc., further improving the stability of metformin hydrochloride.

[0090] The above-described embodiments are compared with the technical solutions and beneficial effects of the present invention, and it should be understood that the above description is only a specific embodiment of the present invention and is not intended to limit the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, which fall within the scope of the present invention to be protected.

Claims

1. A method for preparing a metformin hydrochloride oral solution, characterized in that: The specific process includes the following: Measure 500 ml of purified water, heat it to 50°C, add 5 g of sodium benzoate and 100 g of metformin hydrochloride in sequence, mix them, and then stir and dissolve them at a speed of 200 r / min until the solid is completely dissolved, then add 200 g of inulin and 4 g of cherry flavor, keep stirring at a speed of 200 r / min until all are dissolved; Weigh 5 g of anionic polymer sodium carboxymethyl cellulose and stir and dissolve it with 20 g of deionized water, then add 5 g of water-soluble polyhydroxy glycerol and 5 g of water-soluble polyhydroxy gum arabic and mix with sodium carboxymethyl cellulose, heat to 35 ° C, stir and react for 4 hours to obtain a covalently cross-linked cosolvent, take 10 g of the cosolvent and mix it with the system consisting of metformin hydrochloride and inulin, then slowly add hydrochloric acid while stirring, stop adding hydrochloric acid when the pH value of the solution is 4.5, add purified water again to make the volume to 1000 ml, then filter and fill the fixed solution to obtain a metformin hydrochloride oral solution.

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