Preparation method of metformin oral solution

Abstract

The invention provides a preparation method of a metformin oral solution, which comprises the following steps: heating a solvent, sequentially adding a pH regulator, a preservative and a metformin hydrochloride solution, uniformly mixing, adding a flavoring agent, uniformly mixing, adding the pH regulator to regulate the pH value of the solution, and adding pure water to fix the volume to obtain the metformin oral solution. The prepared metformin oral solution is high in stability, high in safety and good in palatability.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a method for preparing a metformin oral solution preparation. 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 the patients 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. The main one is metformin hydrochloride, which can promote anaerobic glycolysis of sugar, 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.

[0004] Currently, this product is only available in capsules and tablets in China. Although oral solutions are available in foreign countries, they are not imported into China. For patients with swallowing difficulties and children, tablets and capsules have obvious disadvantages, such as inconvenience in swallowing and less dosage for children than for adults. However, the design of tablets and capsules is mostly in line with the dosage for adults, which makes it difficult to control the dosage for children when taking the medicine.

[0005] At present, there are more and more children with diabetes in my country. However, according to research, the prescriptions of oral solution on the market abroad are not suitable for children. For example, the saccharin calcium contained in the prescription has been confirmed to have potential carcinogenic risks and is not recommended for children's medicine. In addition, the raw material metformin is bitter in nature and has poor palatability. Summary of the invention

[0006] In order to solve the above problems, the present invention provides a method for preparing a metformin oral solution. The method of the present invention is used to prepare the metformin oral solution, and the prepared metformin oral solution has strong stability, high safety and good palatability.

[0007] The technical solution of the present invention is achieved in this way:

[0008] The invention provides a method for preparing a metformin oral solution. The preparation method comprises the following steps: heating a solvent, sequentially adding a pH regulator, a preservative and a metformin hydrochloride solution, mixing them uniformly and then adding a flavoring agent, mixing them uniformly and then adding a pH regulator to adjust the pH of the solution, and then adding pure water to make up the volume to obtain the metformin oral solution.

[0009] According to the rationality of the dosage, the dosage of metformin hydrochloride is 100 mg mL -1 .

[0010] Furthermore, the preparation method of the metformin hydrochloride solution is as follows: prepare 1% acetic acid solution, add metformin hydrochloride at a concentration of 15 mg / mL -1 The amount of is added into the prepared acetic acid solution, and then mixed with 3% silk fibroin in equal volume to obtain a uniform solution; the uniform solution is dropped into isopropyl myristate and stirred to form an oil-in-water submicron emulsion, and then the submicron emulsion is dropped into water and stirred to form a metformin hydrochloride solution.

[0011] Metformin hydrochloride has a low absorption rate in the body and a fast degradation rate. Silk fibroin is a natural polymer extracted from silk, composed of 18 kinds of amino acids, which effectively ensures the biological safety of the material. Silk fibroin can be degraded by a variety of enzymes such as protease XIV, collagenase IA, etc. in the body, and the degradation products are non-toxic. Silk fibroin can make metformin hydrochloride act at an effective concentration level for a long time, and the water-in-oil-in-water submicroemulsion can further improve the stability and distribution of the metformin hydrochloride solution.

[0012] Furthermore, the solvent is pure water.

[0013] Furthermore, the preservative is sodium benzoate.

[0014] Sodium benzoate can not only serve as a preservative and protect the stability of the preparation, but also act as a co-solvent to help dissolve inulin.

[0015] Furthermore, the amount of sodium benzoate is 20-50 mg·mL -1 .

[0016] Furthermore, the pH adjuster is an acid.

[0017] Furthermore, the first input of pH regulator is 40%-60% of the total amount of pH regulator.

[0018] The amount of hydrochloric acid used in the quantitative preparation is about 0.004 ml / ml.

[0019] It can be seen that acidic substances can help inulin dissolve, and sodium benzoate is more soluble under acidic conditions. Therefore, hydrochloric acid can be added to the solution to help inulin and sodium benzoate dissolve, and the remaining hydrochloric acid is used to maintain the pH of the preparation and maintain the stability of the preparation.

[0020] Furthermore, the flavoring agents are inulin and essence.

[0021] As a flavor corrector, we should abandon saccharin calcium, whose safety is controversial, and choose inulin. Inulin is a safe ingredient that can control blood lipids and blood sugar, and has the effect of enhancing immunity. It is suitable for diabetic patients and can be used with flavors to greatly change the taste of the medicine.

[0022] Furthermore, the dosage of inulin is 100-200 mg·mL -1 .

[0023] Excessive dosage of inulin may induce children to use too much medicine, while too little dosage may not have obvious effect.

[0024] Furthermore, the pH adjuster adjusts the solution pH to 4.2-5.8.

[0025] The present invention also provides a metformin oral solution, which is prepared by the above method.

[0026] Compared with the prior art, the present invention has the following beneficial effects:

[0027] 1. Flavor correctors: Abandon the controversial safety of saccharin calcium and choose inulin. Inulin is a safe ingredient that can control blood lipids and blood sugar, and has the effect of enhancing immunity. It is suitable for diabetic patients. When used with flavors, it can greatly change the taste of the medicine. The preservative sodium benzoate can not only serve as a preservative and protect the stability of the preparation, but also serve as a co-solvent to help dissolve inulin.

[0028] 2. After adding inulin, a colloid is produced. First add hydrochloric acid to the solution to help dissolve inulin and sodium benzoate. Hydrochloric acid is used as a pH adjuster in the prescription, and it is also used to adjust the pH of the preparation to maintain the stability of the preparation, so the hydrochloric acid is used in two times. DETAILED DESCRIPTION

[0029] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be clearly and completely described in combination with the embodiments of the present invention. Obviously, the described embodiments are 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 ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0030] Reagent Description:

[0031] Metformin hydrochloride, sodium benzoate, inulin, flavor (Shanghai Gaosha Jianchen cherry liquid flavor), hydrochloric acid

[0032] Preparation Example 1

[0033] Preparation of Metformin Hydrochloride Solution:

[0034] Prepare 1% acetic acid solution and mix metformin hydrochloride at 15 mg / mL -1 The amount of acetic acid solution was added, and then mixed with 3% silk fibroin in equal volume, and magnetically stirred for 60 minutes to obtain the uniform solution; the uniform solution was stirred at 0.5 L·min -1 The uniform solution volume was added dropwise to isopropyl myristic acid at a speed of 2 times the volume of the uniform solution, and the mixture was stirred at 100 r·min at 25°C. -1 Stir to form an oil-in-water submicron emulsion, and then add the oil-in-water submicron emulsion at 0.4 L min -1 The speed was dropped into an equal volume of water at 200 r·min at 25°C. -1 Stir to form a metformin hydrochloride solution.

[0035] Example 1

[0036] 50 ml of pure water was measured and heated to 40° C., and 0.2 ml of hydrochloric acid, 2 g of sodium benzoate, and 10 g of metformin hydrochloride solution were added in sequence, and stirred for 10 min. 18 g of inulin and 5 g of Shanghai Gaosha Jianchen cherry liquid essence with a concentration of 0.5% (v / v) were further added, and stirred for 15 min. Hydrochloric acid was further added to adjust the pH to 4.5, and then pure water was added to make up to 100 ml, and the metformin oral solution was obtained after filtration.

[0037] Example 2

[0038] The difference between this embodiment and embodiment 1 is that the amount of sodium benzoate added is 0.2 g.

[0039] The other parts are exactly the same as those in Example 1.

[0040] Example 3

[0041] The difference between this embodiment and embodiment 1 is that the amount of sodium benzoate added is 1 g. The other parts are exactly the same as those in embodiment 1.

[0042] Example 4

[0043] The difference between this embodiment and embodiment 1 is that the amount of sodium benzoate added is 3 g. The other parts are exactly the same as those in embodiment 1.

[0044] Example 5

[0045] The difference between this embodiment and embodiment 1 is that the amount of sodium benzoate added is 4 g. The other parts are exactly the same as those in embodiment 1.

[0046] Example 6

[0047] The difference between this embodiment and embodiment 1 is that the amount of sodium benzoate added is 5 g. The other parts are exactly the same as those in embodiment 1.

[0048] Example 7

[0049] The difference between this embodiment and embodiment 1 is that the amount of inulin added is 10 g. The other parts are exactly the same as those of embodiment 1.

[0050] Example 8

[0051] The difference between this embodiment and embodiment 1 is that the amount of inulin added is 12 g. The other parts are exactly the same as those of embodiment 1.

[0052] Example 9

[0053] The difference between this embodiment and embodiment 1 is that the amount of inulin added is 14 g. The other parts are exactly the same as those of embodiment 1.

[0054] Example 10

[0055] The difference between this embodiment and embodiment 1 is that the amount of inulin added is 16 g. The other parts are exactly the same as those of embodiment 1.

[0056] Embodiment 11

[0057] The difference between this embodiment and embodiment 1 is that the amount of inulin added is 20 g. The other parts are exactly the same as embodiment 1.

[0058] Example 12

[0059] The difference between this embodiment and embodiment 1 is that the pH is adjusted to 4.2. The other parts are exactly the same as those in embodiment 1.

[0060] Embodiment 13

[0061] The difference between this embodiment and embodiment 1 is that the pH is adjusted to 4.8. The other parts are exactly the same as those in embodiment 1.

[0062] Embodiment 14

[0063] The difference between this embodiment and embodiment 1 is that the pH is adjusted to 5.2. The other parts are exactly the same as those in embodiment 1.

[0064] Embodiment 15

[0065] The difference between this embodiment and embodiment 1 is that the pH is adjusted to 5.5. The other parts are exactly the same as those in embodiment 1.

[0066] Example 16

[0067] The difference between this embodiment and embodiment 1 is that the pH is adjusted to 5.8. The other parts are exactly the same as those in embodiment 1.

[0068] Embodiment 17

[0069] The difference between this embodiment and embodiment 1 is that the amount of hydrochloric acid added is 0.16 ml. The other parts are exactly the same as those of embodiment 1.

[0070] Embodiment 18

[0071] The difference between this embodiment and embodiment 1 is that the amount of hydrochloric acid added is 0.24 ml.

[0072] The other parts are exactly the same as those in Example 1.

[0073] Embodiment 19

[0074] The difference between this embodiment and embodiment 1 is that the amount of silk fibroin added in the preparation example 1 is 1%.

[0075] The other parts are exactly the same as those in Example 1.

[0076] Embodiment 20

[0077] The difference between this embodiment and embodiment 1 is that the amount of silk fibroin added in the preparation example 1 is 5%.

[0078] The other parts are exactly the same as those in Example 1.

[0079] Comparative Example 1

[0080] The difference between this comparative example and Example 1 is that the amount of hydrochloric acid added is 0 ml.

[0081] The other parts are exactly the same as those in Example 1.

[0082] Comparative Example 2

[0083] The difference between this comparative example and Example 1 is that the amount of hydrochloric acid added is 0.04 ml.

[0084] The other parts are exactly the same as those in Example 1.

[0085] Comparative Example 3

[0086] The difference between this comparative example and Example 1 is that the amount of hydrochloric acid added is 0.08 ml.

[0087] The other parts are exactly the same as those in Example 1.

[0088] Comparative Example 4

[0089] The difference between this comparative example and Example 1 is that the amount of hydrochloric acid added is 0.12 ml.

[0090] The other parts are exactly the same as those in Example 1.

[0091] Comparative Example 5

[0092] The difference between this comparative example and Example 1 is that no silk fibroin is added to the metformin hydrochloride solution.

[0093] Results and Testing

[0094] 1. Determination of antibacterial efficacy.

[0095] It can be seen from Examples 1-6 that sodium benzoate has a good antibacterial effect on microorganisms in the range of 0.2%-0.5%. Considering that the antibacterial agent itself is toxic and may be consumed over time, a concentration of 0.2% is selected as the prescription amount of sodium benzoate.

[0096] 2. Sensory test

[0097] The smell and taste were evaluated by nose sniffing and tasting by different people. The results are shown in Table 1.

[0098] Table 1

[0099] project Experimenter 1 Experimenter 2 Experimenter 3 Experimenter 4 Experimenter 5 Experimenter 6 Example 1 √ √ × √ √ × Example 7 × × × √ × × Example 8 × × × × × × Example 9 √ × √ × × × Example 10 × × √ × × √ Embodiment 11 × √ × √ × √

[0100] As shown in Table 1, the dosage of inulin is 180 g·mL -1 Sensory acceptability is highest.

[0101] 3. Stability test

[0102] The samples were placed at high temperature (60±2℃) for 10 days and their properties, contents and related substances were checked. The results are shown in Table 2.

[0103] Table 2

[0104]

[0105]

[0106] As shown in Table 2, after being placed under high temperature for 10 days, the content of the samples with pH 4.2-5.8 did not change significantly, indicating that the samples with pH 4.2-5.8 were relatively stable under high temperature (60°C) conditions.

[0107] 4. Inulin dissolution test

[0108] The results are shown in Table 3.

[0109] Table 3

[0110] project Inulin dissolution time (min) Dissolution phenomenon Example 1 14 Colorless clear liquid Embodiment 17 15 Colorless clear liquid Embodiment 18 14 Colorless clear liquid Comparative Example 1 15 A lot of colloid Comparative Example 2 15 A lot of colloid Comparative Example 3 15 Some colloids Comparative Example 4 15 A small amount of jelly

[0111] It can be seen from Table 3 that adding a certain amount of hydrochloric acid first can promote the dissolution of inulin.

[0112] 5. Preparation stability test

[0113] The results are shown in Table 4

[0114] Table 4

[0115]

[0116] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A method for preparing a metformin oral solution, characterized in that: The preparation method comprises the following steps: heating the solvent, sequentially adding a pH regulator, a preservative, and a metformin hydrochloride solution, mixing them evenly, adding a flavoring agent, mixing them evenly, adding a pH regulator to adjust the pH of the solution, and then adding pure water to make up the volume to obtain the metformin oral solution.

2. The method for preparing a metformin oral solution according to claim 1, characterized in that: The solvent is pure water.

3. The method for preparing a metformin oral solution according to claim 1, characterized in that: The pH adjuster is an acid.

4. A method for preparing a metformin oral solution according to claim 1 or 3, characterized in that: The first input of pH regulator is 40%-60% of the total amount of pH regulator.

5. The method for preparing a metformin oral solution according to claim 1, characterized in that: The preservative is sodium benzoate.

6. A method for preparing a metformin oral solution according to claim 1 or 5, characterized in that: The sodium benzoate dosage is 20-50 mg·mL -1 .

7. The method for preparing a metformin oral solution according to claim 1, characterized in that: The flavoring agents are inulin and essence.

8. A method for preparing a metformin oral solution according to claim 1 or 7, characterized in that: The inulin dosage is 100-200 mg·mL -1 .

9. The method for preparing a metformin oral solution according to claim 1, characterized in that: The pH regulator adjusts the solution pH to 4.2-5.

8.

10. A metformin oral solution prepared according to the method according to any one of claims 1 to 9.

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