A calcium zinc gluconate oral solution composition and its preparation method

Abstract

The present invention relates to the field of pharmaceutical technology, and specifically discloses a calcium gluconate and zinc oral solution composition and a preparation method thereof. The calcium gluconate and zinc oral solution composition includes calcium gluconate, zinc gluconate, lysine hydrochloride, L-lactic acid, a preservative, and purified water; the content of impurity D-lactic acid in the L-lactic acid is less than or equal to 0.35%; the content of the L-lactic acid is 6.3 mg / ml - 7.8 mg / ml. By controlling the content of L-lactic acid and the content of D-lactic acid impurity in the prescription, the present invention can improve the product stability, improve the product quality, does not need to adopt complex equipment and special processes, can reduce the production cost, and is suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of medicine, and particularly relates to a calcium gluconate and zinc oral solution composition and a preparation method thereof. Background Art

[0002] The calcium gluconate and zinc oral solution is a compound preparation composed of calcium gluconate, zinc gluconate and lysine hydrochloride, and is applicable to the treatment of diseases caused by calcium and zinc deficiency. The calcium component contained in this medicine, together with the calcium obtained from food, provides the normal physiological requirements of the human body. Combining lysine to nourish the bones to maintain healthy and tough bones can multiply the absorption of calcium and prevent calcium loss. And the calcium gluconate and zinc oral solution is in the form of an oral solution, without the disintegration and release process of tablets, and can be quickly absorbed and utilized by the human body.

[0003] Chinese Patent CN104800199B discloses a calcium gluconate and zinc oral solution composition and a preparation method thereof, including calcium gluconate, zinc gluconate, L-lysine hydrochloride, lactic acid, and flavoring agents, preservatives, flavoring agents, etc. can also be added. This calcium gluconate and zinc oral solution composition has the advantages of excellent quality, good stability, and simple preparation process. Chinese Patent Application CN 109953980 A discloses a calcium gluconate and zinc oral solution and a preparation method thereof. The key points of the technical solution are that it includes the main drug and auxiliary drugs. The main drug includes calcium gluconate, zinc gluconate and lysine hydrochloride. It is characterized in that the auxiliary drugs contain steviol glycoside, menthol and ethylparaben, mainly to solve the technical problems of high sugar content of existing sucrose and the use of substances such as aspartame, benzoic acid or sodium benzoate.

[0004] Although the existing technologies can solve problems such as taste, high sucrose content, and precipitation, in the preparation process of the calcium gluconate and zinc oral solution, there are still the following problems: (1) This product is in a supersaturated state, with poor stability during long-term storage, easy to precipitate, does not meet the legal standards, and cannot meet the quality requirements. (2) The quality control of drugs covers all aspects of the production process, and the legal standards and control methods are difficult to meet the quality evaluation of this product. The existing technologies have not completely solved the above problems.

[0005] Therefore, there is an urgent need for a calcium gluconate and zinc oral solution composition that maintains stable quality within the validity period, meets the quality requirements, and ensures the safety and effectiveness of the product. Summary of the Invention

[0006] Unless the context clearly indicates otherwise, as used herein, the singular forms "a", "an" and "the" include both singular and plural referents. A numerical range expressed by endpoints includes all the numerical values and fractions within the corresponding range, as well as the expressed endpoints.

[0007] In view of the problems existing in the prior art, the present invention provides a calcium gluconate and zinc gluconate oral solution composition and a preparation method thereof. By adjusting the content of L-lactic acid and controlling the content of impurities in L-lactic acid, the prepared calcium gluconate and zinc gluconate oral solution has stable quality and meets the quality requirements.

[0008] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0009] The present invention provides a calcium gluconate and zinc gluconate oral solution composition, comprising calcium gluconate, zinc gluconate, lysine hydrochloride, L-lactic acid, a preservative and purified water; the content of impurity D-lactic acid in the L-lactic acid is less than or equal to 0.35%; the content of the L-lactic acid is 6.3 mg / ml - 7.8 mg / ml.

[0010] Preferably, the preservative is sodium benzoate.

[0011] Preferably, the calcium gluconate and zinc gluconate oral solution composition further comprises a sweetening agent and a flavoring agent.

[0012] Preferably, the sweetening agent comprises aspartame and / or acesulfame potassium; the flavoring agent comprises at least one of peach flavor, apple flavor, blueberry flavor, strawberry flavor and sweet orange flavor.

[0013] Preferably, the calcium gluconate and zinc gluconate oral solution composition comprises the following raw materials: 55 g - 60 g of calcium gluconate, 2 g - 4 g of zinc gluconate, 8 g - 12 g of lysine hydrochloride, 6.3 g - 7.8 g of L-lactic acid, 1.0 g - 1.4 g of a preservative, 0.8 g - 2.0 g of a sweetening agent, 0.1 g - 0.3 g of a flavoring agent and 900 ml - 980 ml of purified water.

[0014] The present invention also provides a preparation method of the above calcium gluconate and zinc gluconate oral solution composition, comprising the following steps:

[0015] S1. Heat 70% - 85% of the prescription amount of purified water.

[0016] S2. Add the prescription amounts of calcium gluconate and zinc gluconate to the heated purified water and stir to dissolve.

[0017] S3. After cooling to 25 - 37°C, add the remaining raw materials in the prescription amount, stir to dissolve, add the remaining purified water, filter and then fill to obtain the calcium gluconate and zinc gluconate oral solution composition.

[0018] Preferably, the heating temperature in step S1 is 85 - 95°C.

[0019] Preferably, the purification method of the L-lactic acid is as follows: Take the crude L-lactic acid, evaporate it, then carry out a distillation reaction, and afterwards perform a decolorization treatment using activated carbon to obtain the L-lactic acid.

[0020] Preferably, the temperature of the evaporation is 90 - 100 °C.

[0021] Preferably, the conditions for the distillation are: a heating temperature of 100 - 110 °C and a vacuum degree of 10 mbar - 12 mbar for vacuum distillation.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] (1) By controlling the content of L-lactic acid and the content of D-lactic acid impurities in the prescription, the present invention improves the product stability and product quality.

[0024] (2) The calcium zinc gluconate oral solution of the present invention will not precipitate during long-term storage, and all quality attributes meet the requirements. It has good quality and high stability and complies with the legal standards.

[0025] (3) The present invention does not need to adopt complex equipment and special processes, can reduce production costs, and is suitable for industrial production. Specific Embodiments

[0026] The present invention will be described below through specific examples to make the technical solutions of the present invention easier to understand and master. However, the present invention is not limited thereto. The described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments.

[0027] In the ranges disclosed herein, the endpoints and any values are not limited to the exact ranges or values. These ranges or values should be understood to include values close to these ranges or values. For numerical ranges, between the endpoint values of each range, between the endpoint values of each range and individual point values, and between individual point values, they can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be regarded as specifically disclosed herein.

[0028] Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention. The experimental methods described in the following embodiments are all conventional methods unless otherwise specified; the reagents and materials, unless otherwise specified, can all be obtained from commercial channels.

[0029] It should be noted that

[0030] All L-lactic acid is purchased from Shanghai Enzyme-linked Biochemical Reagent Co., Ltd.

[0031] In the examples and comparative examples of the present invention, the content of D-lactic acid in L-lactic acid was detected according to the method of Example 3 of Patent CN114137126A.

[0032] The purification method of L-lactic acid is as follows: Take 85% crude L-lactic acid, heat it at 100 °C and then perform vacuum concentration with a vacuum degree of 85 mbar. After that, carry out a distillation reaction. The distillation conditions are: temperature 105 °C and the vacuum degree of vacuum distillation is 10 mbar. Then, decolorize it with activated carbon to obtain the product.

[0033] D represents the number of days; M represents the number of months.

[0034] Example 1

[0035] Prepare calcium zinc gluconate oral solution according to the following formula: 60 g of calcium gluconate, 3 g of zinc gluconate, 10 g of lysine hydrochloride, 6.3 g of L-lactic acid (the content of impurity D-lactic acid is 0.35%), 1.4 g of sodium benzoate, and 919.3 ml of purified water.

[0036] Prepare calcium zinc gluconate oral solution according to the following steps: Take 730 ml of purified water and heat it to 90 °C; then add the formula amounts of calcium gluconate and zinc gluconate, keep the temperature at 90 °C, and stir to dissolve; after the temperature drops to 37 °C, add the formula amounts of lysine hydrochloride, L-lactic acid and sodium benzoate, stir to dissolve and then add the remaining purified water. After filtration, fill it to obtain the product.

[0037] Example 2

[0038] Prepare calcium zinc gluconate oral solution according to the following formula: 55 g of calcium gluconate, 4 g of zinc gluconate, 12 g of lysine hydrochloride, 6.5 g of L-lactic acid (the content of impurity D-lactic acid is 0.15%), 1.3 g of sodium benzoate, 0.8 g of aspartame, and 915.4 ml of purified water.

[0039] Prepare calcium zinc gluconate oral solution according to the following steps: Take 735 ml of purified water and heat it to 95 °C; then add the formula amounts of calcium gluconate and zinc gluconate, keep the temperature at 95 °C, and stir to dissolve; after the temperature drops to 35 °C, add the formula amounts of lysine hydrochloride, L-lactic acid, sodium benzoate and aspartame, stir to dissolve and then add the remaining purified water. After filtration, fill it to obtain the product.

[0040] Example 3

[0041] Prepare calcium zinc gluconate oral solution according to the following formula: 60 g of calcium gluconate, 2 g of zinc gluconate, 8 g of lysine hydrochloride, 7.8 g of L-lactic acid (the content of impurity D-lactic acid is 0.25%), 1.4 g of sodium benzoate, 0.8 g of aspartame, 0.8 g of acesulfame potassium, 0.3 g of peach essence, and 918.9 ml of purified water.

[0042] The calcium zinc gluconate oral solution is prepared according to the following steps: Take 735 ml of purified water and heat it to 85 °C; then add the formula amount of calcium gluconate and zinc gluconate, keep the temperature at 85 °C, and stir to dissolve; after the temperature drops to 25 °C, add the formula amount of lysine hydrochloride, L-lactic acid, sodium benzoate, acesulfame potassium, peach essence and aspartame, stir to dissolve and then add the remaining purified water, filter and fill to obtain the product.

[0043] Example 4

[0044] The calcium zinc gluconate oral solution is prepared according to the following formula: 60 g of calcium gluconate, 3 g of zinc gluconate, 10 g of lysine hydrochloride, 7.0 g of L-lactic acid (the content of impurity D-lactic acid is 0.30%), 1.4 g of sodium benzoate, 0.8 g of aspartame, 0.8 g of acesulfame potassium and 917.8 ml of purified water.

[0045] The calcium zinc gluconate oral solution is prepared according to the following steps: Take 734 ml of purified water and heat it to 90 °C; then add the formula amount of calcium gluconate and zinc gluconate, keep the temperature at 90 °C, and stir to dissolve; after the temperature drops to 35 °C, add the formula amount of lysine hydrochloride, L-lactic acid, sodium benzoate, acesulfame potassium and aspartame, stir to dissolve and then add the remaining purified water, filter and fill to obtain the product.

[0046] Example 5

[0047] The calcium zinc gluconate oral solution is prepared according to the following formula: 60 g of calcium gluconate, 3 g of zinc gluconate, 10 g of lysine hydrochloride, 7.2 g of L-lactic acid (the content of impurity D-lactic acid is 0.35%), 1.4 g of sodium benzoate, 0.8 g of acesulfame potassium, 0.3 g of peach essence and 917.3 ml of purified water.

[0048] The calcium zinc gluconate oral solution is prepared according to the following steps: Take 752 ml of purified water and heat it to 90 °C; then add the formula amount of calcium gluconate and zinc gluconate, keep the temperature at 90 °C, and stir to dissolve; after the temperature drops to 37 °C, add the formula amount of lysine hydrochloride, L-lactic acid, sodium benzoate, acesulfame potassium and peach essence, stir to dissolve and then add the remaining purified water, filter and fill to obtain the product.

[0049] Comparative Example 1

[0050] The calcium zinc gluconate oral solution is prepared according to the following formula: 60 g of calcium gluconate, 2 g of zinc gluconate, 8 g of lysine hydrochloride, 15 g of L-lactic acid (the content of impurity D-lactic acid is 0.35%), 1.4 g of sodium benzoate, 0.8 g of aspartame, 0.8 g of acesulfame potassium, 0.3 g of peach essence and 911.7 ml of purified water.

[0051] The calcium zinc gluconate oral solution is prepared according to the following steps: Take 730 ml of purified water and heat it to 85 °C; then add the formula amounts of calcium gluconate and zinc gluconate, keep the temperature at 85 °C, and stir to dissolve; after the temperature drops to 25 °C, add the formula amounts of lysine hydrochloride, L-lactic acid, sodium benzoate, acesulfame potassium, peach essence and aspartame, stir to dissolve and then add the remaining purified water, filter and fill to obtain.

[0052] Comparative Example 2

[0053] The calcium zinc gluconate oral solution is prepared according to the following formula: 60 g of calcium gluconate, 2 g of zinc gluconate, 8 g of lysine hydrochloride, 5 g of L-lactic acid (the content of impurity D-lactic acid is 0.25%), 1.4 g of sodium benzoate, 0.8 g of aspartame, 0.8 g of acesulfame potassium, 0.3 g of peach essence and 921.7 ml of purified water.

[0054] The calcium zinc gluconate oral solution is prepared according to the following steps: Take 738 ml of purified water and heat it to 85 °C; then add the formula amounts of calcium gluconate and zinc gluconate, keep the temperature at 85 °C, and stir to dissolve; after the temperature drops to 25 °C, add the formula amounts of lysine hydrochloride, L-lactic acid, sodium benzoate, acesulfame potassium, peach essence and aspartame, stir to dissolve and then add the remaining purified water, filter and fill to obtain.

[0055] Comparative Example 3

[0056] The calcium zinc gluconate oral solution is prepared according to the following formula: 60 g of calcium gluconate, 2 g of zinc gluconate, 8 g of lysine hydrochloride, 10 g of L-lactic acid (the content of impurity D-lactic acid is 0.50%), 1.4 g of sodium benzoate, 0.8 g of aspartame, 0.8 g of acesulfame potassium, 0.3 g of peach essence and 916.7 ml of purified water.

[0057] The calcium zinc gluconate oral solution is prepared according to the following steps: Take 733 ml of purified water and heat it to 85 °C; then add the formula amounts of calcium gluconate and zinc gluconate, keep the temperature at 85 °C, and stir to dissolve; after the temperature drops to 25 °C, add the formula amounts of lysine hydrochloride, L-lactic acid, sodium benzoate, acesulfame potassium, peach essence and aspartame, stir to dissolve and then add the remaining purified water, filter and fill to obtain.

[0058] Comparative Example 4

[0059] Prepare calcium zinc gluconate oral solution according to the following formula: 60 g of calcium gluconate, 2 g of zinc gluconate, 8 g of lysine hydrochloride, 7.8 g of L-lactic acid (the content of impurity D-lactic acid is 0.40%, and the content of impurity DL-lactic acid is 0.10%), 1.4 g of sodium benzoate, 0.8 g of aspartame, 0.8 g of acesulfame potassium, 0.3 g of peach essence, and 918.9 ml of purified water.

[0060] Prepare calcium zinc gluconate oral solution according to the following steps: Take 735 ml of purified water and heat it to 85 °C; then add the formula amounts of calcium gluconate and zinc gluconate, keep the temperature at 85 °C, and stir to dissolve; after the temperature drops to 25 °C, add the formula amounts of lysine hydrochloride, L-lactic acid, sodium benzoate, acesulfame potassium, peach essence and aspartame, stir to dissolve and then add the remaining purified water, filter and fill to obtain.

[0061] Effect example: Detection of related substances

[0062] Detection method:

[0063] Equipment: High performance liquid chromatograph, the detector is an ultraviolet absorption detector or a DAD detector;

[0064] Chromatographic column: Kromasil 100-5-C18 (4.6 mm × 250 cm, 5 μm);

[0065] Mobile phase: Mobile phase A is 50 mmol / L sodium acetate buffer solution containing 1% N,N-dimethylformamide, and the pH is adjusted to 5.0; Mobile phase B is acetonitrile-methanol-aqueous solution; Mobile phase C is acetonitrile-aqueous solution;

[0066] Detection wavelength: 360 nm; Column temperature: 27 °C; Flow rate: 1.2 ml / min; The running program is shown in Table 1:

[0067] Table 1 Running program

[0068]

[0069] Measure 5.0 ml of the test sample of the calcium zinc gluconate oral solution to be tested, place it in a 20 ml volumetric flask, dilute it to the mark with water, and shake well. Measure 1.0 ml, place it in a 10 ml volumetric flask, and add 5% sodium carbonate solution

[0070] 1.0 ml and 1.0 ml of 2,4-dinitrofluorobenzene acetonitrile solution with a concentration of 1%, shake well, place it in the dark at 60 °C

[0071] After heating in a water bath at 60 °C for 60 min, take it out, let it cool, dilute it to the mark with phosphate buffer solution, shake well, and use it as the test sample solution to detect related substances.

[0072] The calcium zinc gluconate oral solutions prepared in Examples 1-5 and Comparative Examples 1-4 were respectively placed at 60°C, 40°C, 25°C, and 2-8°C, and the quality during the stability period of this product was comprehensively evaluated using the indicators of appearance, pH value, clarity and color, and related substances, in combination with the standard limit requirements. The appearance, pH value, clarity and color were detected with reference to the general rules of the Chinese Pharmacopoeia.

[0073] The test results are shown in Tables 2-4.

[0074] Table 2 Results of the stability test at 60°C

[0075]

[0076]

[0077]

[0078] Table 3 Results of the stability test at 40°C

[0079]

[0080] Table 4 Results of the stability tests at 25°C and 2-8°C

[0081]

[0082]

[0083] The above results show that when the L-lactic acid content in Examples 1-5 is within a specific range and the D-lactic acid content in L-lactic acid is less than or equal to 0.35%, the appearance, pH value, clarity and color, and related substances of the prepared calcium zinc gluconate oral solution meet the limit requirements after being placed at 60°C for 30 days, 40°C for 6 months, 25°C for 6 months, and 2-8°C for 30 days, with good quality and high stability; while the calcium zinc gluconate oral solutions in the groups of Comparative Examples 1-4 will show phenomena such as deepening of color, precipitation, and exceeding the limit of related substances under the above conditions, with poor stability, not meeting the quality standards, and not being suitable for industrial production.

[0084] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than a limitation on the protection scope of the present invention. Any simple modification or equivalent replacement of the technical solution of the present invention by those of ordinary skill in the art does not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A calcium zinc gluconate oral solution composition, characterized in that: It comprises the following raw materials: L-lactic acid, 55 g - 60 g of calcium gluconate, 2 g - 4 g of zinc gluconate, 8 g - 12 g of L-lysine hydrochloride, 1.0 g - 1.4 g of preservative, 0.8 g - 2.0 g of sweetener, 0.1 g - 0.3 g of essence, and 900 ml - 980 ml of purified water; the content of impurity D-lactic acid in the L-lactic acid is less than or equal to 0.35%; the content of the L-lactic acid is 6.3 mg / ml - 7.8 mg / ml; the purification method of the L-lactic acid is: taking crude L-lactic acid, evaporating it and then carrying out a distillation reaction, and then using activated carbon for decolorization treatment to obtain the L-lactic acid.

2. The calcium zinc gluconate oral solution composition according to claim 1, wherein: The preservative is sodium benzoate.

3. The calcium zinc gluconate oral solution composition according to claim 1, wherein: The sweetener includes aspartame and / or acesulfame potassium; the essence includes at least one of peach essence, apple essence, blueberry essence, strawberry essence, and orange essence.

4. The calcium zinc gluconate oral solution composition according to claim 1, characterized in that: The temperature of the evaporation is 90 - 100 °C.

5. The calcium zinc gluconate oral solution composition according to claim 1, characterized in that: The conditions for the distillation are: heating temperature 100 - 110 °C, and the vacuum degree of vacuum distillation is 10 mbar - 12 mbar.

6. A method for preparing the calcium zinc gluconate oral solution composition according to any one of claims 1-5, characterized in that: It includes the following steps: S1. Heating 70% - 85% of the prescription amount of purified water; S2. Adding the prescription amounts of calcium gluconate and zinc gluconate to the heated purified water and stirring to dissolve; S3. After cooling to 25 - 37 °C, adding the remaining raw materials in the prescription amount, stirring to dissolve, adding the remaining purified water, filtering, and then filling to obtain the calcium gluconate and zinc oral solution composition.

7. The preparation method according to claim 6, characterized in that: The heating temperature in step S1 is 85 - 95 °C.

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