Compound calcium gluconate oral solution and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a compound calcium gluconate oral solution and a preparation method thereof. The compound calcium gluconate oral solution is prepared from the raw materials in a specific concentration ratio, in a long-term stability experiment, various indexes (microbial load, product character, pH value and component content) of the compound calcium gluconate oral solution are good in performance, traditional bacteriostatic agent components such as nipagin esters, benzoic acids and sorbic acids are not added, and safety is higher; in addition, the compound calcium gluconate oral solution can keep long-term stability after being sterilized at 115 + / -5 DEG C for 30 + / -5 minutes, and does not have a crystallization phenomenon during storage.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a compound calcium gluconate oral solution and a preparation method thereof. Background Art

[0002] Calcium plays a very important role in the physiological activities and metabolism of the human body, especially in the development of bones. It can participate in the formation of bones and the reconstruction of bone tissue after fractures. Calcium also plays a very important role in the body's muscle contraction, nerve transmission, and coagulation function. Calcium can also reduce the permeability of capillaries. Compound calcium gluconate oral solution contains calcium gluconate and calcium lactate, which mainly play the role of calcium supplementation. Among them, calcium gluconate is mainly used as a calcium fortifier and nutrient, with a molecular formula of Ca(C 6 H 11 O 7 ) 2 , easily soluble in boiling water (20g / 100ml), slightly soluble in cold water (3g / 100ml, 20℃). Calcium lactate is used as a calcium supplement, with a molecular formula of C 6 H 10 CaO 6 , easily soluble in hot water, has the effects of promoting the calcification of bones and teeth, maintaining the normal excitability of nerves and muscles, and reducing capillary permeability. Clinically, compound calcium gluconate oral solution is often used to prevent and treat diseases related to calcium deficiency, such as osteoporosis, tetany, rickets, and can also be used for calcium supplementation in children, pregnant women, lactating women, menopausal women, or the elderly. Compound calcium gluconate oral solution has certain problems in terms of stability performance. The calcium gluconate in the prescription of compound calcium gluconate oral solution has a low solubility in cold water, and crystallization is prone to occur during storage. In addition, in order to achieve the purpose of controlling the microbial load in the solution, antibacterial ingredients are often added to existing products, which poses certain safety hazards.

[0003] In view of this, the present invention is proposed. Summary of the invention

[0004] In order to solve the above technical problems, the present invention provides a compound calcium gluconate oral solution and a preparation method thereof.

[0005] Specifically, the technical solution of the present invention is as follows: In a first aspect, the present invention provides a compound calcium gluconate oral solution, comprising the following components: 40-60 g / L calcium gluconate, 40-60 g / L calcium lactate, 8-12 g / L sucralose, and 0.7-0.9 g / L essence; the compound calcium gluconate oral solution uses lactic acid as a pH regulator to adjust the pH to 4.1-4.5; a preparation method of the compound calcium gluconate oral solution comprises: using 90°C±5°C purified water to dissolve calcium gluconate and calcium lactate; cooling to below 40°C, adding sucralose and essence to the solution; cooling again to 30±5°C, and adjusting the pH to 4.3±0.2 with lactic acid.

[0006] Preferably, the compound calcium gluconate oral solution comprises the following components: 60 g / L calcium gluconate, 60 g / L calcium lactate, 10 g / L sucralose, and 0.8 g / L flavor; the compound calcium gluconate oral solution uses lactic acid as a pH regulator, and the pH value is adjusted to 4.1.

[0007] Preferably, the compound calcium gluconate oral solution comprises the following components: 40 g / L calcium gluconate, 40 g / L calcium lactate, 10 g / L sucralose, and 0.8 g / L flavor; the compound calcium gluconate oral solution uses lactic acid as a pH regulator, and the pH value is adjusted to 4.5.

[0008] Preferably, the method for preparing the compound calcium gluconate oral solution further comprises a filtration step, and the pore size of the filter element for filtration is 5±1 μm.

[0009] Preferably, the preparation method of the compound calcium gluconate oral solution further comprises a sterilization step, and the sterilization parameters are: 115±5°C, 30±5min.

[0010] In a second aspect, the present invention provides a method for preparing the compound calcium gluconate oral solution, comprising: using purified water at 90°C±5°C to dissolve calcium gluconate and calcium lactate; cooling to below 40°C, adding sucralose and flavor to the solution; cooling again to 30±5°C, and adjusting the pH value with lactic acid.

[0011] Preferably, the method further comprises a filtering step, wherein the pore size of the filter element used for filtering is 5±1 μm.

[0012] Preferably, a sterilization step is also included, and the sterilization parameters are: 115±5°C, 30±5min.

[0013] Beneficial effects: The present invention provides a compound calcium gluconate oral solution and a preparation method thereof. The compound calcium gluconate oral solution is prepared from raw materials with a specific concentration ratio. In a long-term stability experiment, various indicators (microbial load, product properties, pH value and component content) perform well, and no traditional antibacterial ingredients such as parabens, benzoic acid, and sorbic acid are added, so the safety is higher. In addition, the compound calcium gluconate oral solution of the present invention can maintain long-term stability without crystallization during storage after being sterilized at 115±5°C for 30±5min. DETAILED DESCRIPTION

[0014] The invention provides a compound calcium gluconate oral solution and a preparation method thereof.

[0015] In the present invention, the ingredients of the compound calcium gluconate oral solution include calcium gluconate, calcium lactate, sweetener, pH regulator, and flavor. Among them, the concentration of the active ingredient calcium gluconate is 4%-6% (w / v), the concentration of calcium lactate is 4%-6% (w / v), the sweetener is sucralose, the pH regulator is lactic acid, and the pH value control range is 4.3±0.2. No traditional antibacterial agents such as parabens, benzoic acid, and sorbic acid are added to the prescription.

[0016] In the present invention, the preparation method comprises the following steps: liquid preparation, filtration, filling, and sterilization; specifically, the following steps are: adding 70% to 80% of the total amount of purified water to the liquid preparation tank and boiling, dissolving calcium gluconate and calcium lactate within a temperature range of 90±5°C, cooling to below 40°C, adding sweeteners and flavors, and finally adjusting the pH value with lactic acid, adding purified water to a sufficient volume, filtering, filling, and sterilizing. Among them, the filtration preferably uses a polypropylene filter element with a pore size of 5μm.

[0017] The tricarboxylic acid cycle (TCA cycle) is a metabolic pathway that is ubiquitous in aerobic organisms. It is distributed in the cytoplasm in prokaryotes and in the mitochondria in eukaryotes. Because several major intermediate metabolites in this cycle are organic acids containing three carboxyl groups, it is called the tricarboxylic acid cycle, such as citric acid, malic acid, succinic acid, etc. It is also called the citric acid cycle (citric acid cycle) or TCA cycle; the tricarboxylic acid cycle is the final metabolic pathway of the three major nutrients (sugars, lipids, and amino acids), and is also the hub of the metabolic connection between sugars, lipids, and amino acids.

[0018] The present invention dissolves calcium gluconate and calcium lactate, which are easy to crystallize in cold water, at high temperature, and adjusts the pH to a specific value with lactic acid after cooling. Lactic acid is used as a pH regulator, which can participate in the tricarboxylic acid cycle in the human body, has low safety risks, and has a good taste. In the prescription, calcium gluconate has a low solubility in cold water, and crystallization is prone to occur during storage. The present invention has found that sterilization at 115°C for 30 minutes can solve the problem of crystallization of calcium gluconate, and crystallization can be avoided for 24 months. In addition, the prescription of the present invention does not contain an antibacterial agent to improve safety, and moist heat sterilization (sterilization at 115°C for 30 minutes) can achieve the purpose of long-term control of microbial load. At the same time, the compound calcium gluconate oral solution can be sterilized at 115±5°C for 30±5 minutes to maintain long-term stability without crystallization during storage.

[0019] In order to make the purpose, technical solution and advantages of the present invention clearer, the technical solution of the present invention will be described clearly and completely below. 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.

[0020] The endpoints and any values ​​of the ranges disclosed in this specification are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

[0021] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "specific implementations", or "some specific implementations" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the embodiment of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0022] In the examples provided in this specification, if no specific techniques or conditions are specified, the techniques or conditions described in the literature in this field or the product instructions are used. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased through regular channels.

[0023] Example 1 This embodiment provides a compound calcium gluconate oral solution, and its formula (calculated per 1000 ml of the compound calcium gluconate oral solution) is shown in Table 1 below: Table 1

[0024] This embodiment provides a method for preparing the above-mentioned compound calcium gluconate oral solution, and its process steps are as follows: (1) Weigh 80% of the prescribed amount of purified water, heat it to 90℃±5℃, add the prescribed amount of calcium gluconate and calcium lactate, and stir to dissolve for 30 minutes.

[0025] (2) Cool down to below 40°C, add the prescribed amount of sucralose and flavor, and stir to dissolve for 10 minutes.

[0026] (3) Cool the temperature to room temperature (30±5℃) and adjust the pH to 4.3 with lactic acid.

[0027] (4) Make up the volume: Add purified water to make up the volume to the prescribed amount and stir for 15 minutes.

[0028] (5) Filtration: The drug solution is filtered through a 5 μm pore size polypropylene filter and then filled into a 10 ml glass bottle.

[0029] (6) Sterilization: Set the parameters to 115°C, 30 minutes of water bath sterilization.

[0030] Example 2 This embodiment provides a compound calcium gluconate oral solution, and its formula (calculated per 1000 ml of the compound calcium gluconate oral solution) is shown in Table 2 below: Table 2

[0031] This embodiment provides a method for preparing the above-mentioned compound calcium gluconate oral solution, and its process steps are as follows: (1) Weigh 80% of the prescribed amount of purified water, heat it to 90℃±5℃, add the prescribed amount of calcium gluconate and calcium lactate, and stir to dissolve for 30 minutes.

[0032] (2) Cool down to below 40°C, add the prescribed amount of sucralose and flavor, and stir to dissolve for 10 minutes.

[0033] (3) Cool the temperature to room temperature (30±5℃) and adjust the pH to 4.1 with lactic acid.

[0034] (4) Make up the volume: Add purified water to make up the volume to the prescribed amount and stir for 15 minutes.

[0035] (5) Filtration: The drug solution is filtered through a 5 μm pore size polypropylene filter and then filled into a 10 ml glass bottle.

[0036] (6) Sterilization: Set the parameters to 115°C, 30 min.

[0037] Example 3 This embodiment provides a compound calcium gluconate oral solution, and its formula (calculated per 1000 ml of the compound calcium gluconate oral solution) is shown in Table 3 below: Table 3

[0038] This embodiment provides a method for preparing the above-mentioned compound calcium gluconate oral solution, and its process steps are as follows: (1) Weigh 80% of the prescribed amount of purified water, heat it to 90℃±5℃, add the prescribed amount of calcium gluconate and calcium lactate, and stir to dissolve for 30 minutes.

[0039] (2) Cool down to below 40°C, add the prescribed amount of sucralose and flavor, and stir to dissolve for 10 minutes.

[0040] (3) Cool the temperature to room temperature (30±5℃) and adjust the pH to 4.5 with lactic acid.

[0041] (4) Make up the volume: Add purified water to make up the volume to the prescribed amount and stir for 15 minutes.

[0042] (5) Filtration: The drug solution is filtered through a 5 μm pore size polypropylene filter and then filled into a 10 ml glass bottle.

[0043] (6) Sterilization: Set the parameters to 115°C, 30 min.

[0044] Example 4 This embodiment provides a compound calcium gluconate oral solution, and its formula (calculated per 1000 ml of the compound calcium gluconate oral solution) is shown in Table 4 below: Table 4

[0045] This embodiment provides a method for preparing the above-mentioned compound calcium gluconate oral solution, and its process steps are as follows: (1) Weigh 80% of the prescribed amount of purified water, heat it to 90℃±5℃, add the prescribed amount of calcium gluconate and calcium lactate, and stir to dissolve for 30 minutes.

[0046] (2) Cool down to below 40°C, add the prescribed amount of sucralose and flavor, and stir to dissolve for 10 minutes.

[0047] (3) Cool the temperature to room temperature (30±5℃) and adjust the pH to 4.5 with lactic acid.

[0048] (4) Make up the volume: Add purified water to make up the volume to the prescribed amount and stir for 15 minutes.

[0049] (5) Filtration: The drug solution is filtered through a 5 μm pore size polypropylene filter and then filled into a 10 ml glass bottle.

[0050] (6) Sterilization: Set the parameters to 115°C, 30 min.

[0051] Comparative Example 1 Referring to the prescription of Example 1, moist heat sterilization treatment was not performed, and other preparation processes were the same as in Example 1.

[0052] Comparative Example 2 Referring to the prescription of Example 1, 0.1% (w / v) sodium benzoate was added as an antibacterial agent, and the other preparation processes were the same as those of Example 1.

[0053] Comparative Example 3 Referring to the prescription of Example 1, cinnamon oil was added, and the prescription amount of cinnamon oil was 0.1% (w / v). Other preparation processes were the same as in Example 1.

[0054] Comparative Example 4 Referring to the recipe of Example 1, the pH value was adjusted to 4.0 with lactic acid, and the other preparation processes were the same as those of Example 1.

[0055] Comparative Example 5 Referring to the recipe of Example 1, the pH value was adjusted to 4.6 with lactic acid, and the other preparation processes were the same as those of Example 1.

[0056] Experimental Example 1 Long-term stability (microbial count) investigation: Samples of Examples 1-4, Comparative Examples 1-5 and a commercially available preparation (Name: Compound Calcium Gluconate Oral Solution; Manufacturer: Harbin Pharmaceutical Group Sanjin Pharmaceutical Co., Ltd.; Batch No.: 21072323) were placed at a temperature of 25°C ± 2°C, and samples were taken for analysis after 0 months, 3 months, 6 months, 12 months, 18 months, and 24 months. The microbial limits were detected with reference to the appendix to the 2020 edition of the Chinese Pharmacopoeia (1105 Microbial Limit Test of Non-Sterile Products: Determination of Microorganisms by Microbial Counting Method, 1106 Microbial Limit Test of Non-Sterile Products: Controlled Bacteria Test Method). The plate method was used for aerobic bacteria, and 1 ml of the test sample and 10 ml of the test sample were added with 0.1% sterile peptone buffer to 100 ml, respectively. In the preliminary experiment, 1:10, 1 ml was used as the test solution. After a long period of 24 months, the aerobic bacteria were increased by 1:100 in the test solution. For molds and yeasts, 1 ml of the test sample was used as the test solution. For Escherichia coli, 10 ml of the test sample was added with 0.1% sterile peptone buffer to 100 ml (1:10), and 10 ml was used as the test solution. The results are shown in Table 5.

[0057] Table 5 Long-term stability microbial counts of Examples 1-4, Comparative Examples 1-5 and commercially available preparations Three parallel tests were conducted at the same time, and the results were similar. The long-term stability test results show that the long-term stability of the prescriptions of Examples 1-4 and Comparative Examples 1-5 was investigated for 24 months, and the microorganisms were counted during the stability process. The microbial counts of Examples 1-4 and Comparative Examples 2-5 all met the microbial limit requirements of the Chinese Pharmacopoeia, and there was no significant difference in the microbial counts during the stability investigation of the prescriptions of Examples 1-4 and Comparative Example 2 with the addition of preservatives.

[0058] Experimental Example 2 Long-term stability (properties, pH value and content determination) test: For long-term stability study, samples of Examples 1-4, Comparative Examples 1-5 and a commercially available preparation (name: Compound Calcium Gluconate Oral Solution; manufacturer: Harbin Pharmaceutical Group Sanjin Pharmaceutical Co., Ltd.; batch number: 21072323) were placed at 25°C ± 2°C, 60% ± 5% RH. Samples were taken for testing at 0, 3, 6, 12, 18 and 24 months. The properties, pH value and content of the samples were determined as shown in Table 6.

[0059] Among them, glucuronic acid content determination: Determined in accordance with high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0512). Solvent: Take an appropriate amount of sodium chloride, dissolve it in water and quantitatively dilute it to make a solution containing 0.9μg of sodium chloride per 1ml. Test solution: Take an appropriate amount of this product, accurately measure it, add solvent and quantitatively dilute it to make a solution containing approximately 6mg of calcium gluconate per 1ml, then take 500μl, put it in a centrifuge tube, add sodium hydroxide solution (take an appropriate amount of sodium hydroxide, dissolve it in water and dilute it to make a solution containing 12mg of sodium hydroxide per 1ml) 200μl, 1-phenyl-3-methyl-5-pyrazolone methanol solution (take an appropriate amount of 1-phenyl-3-methyl-5-pyrazolone, dissolve it in methanol and dilute it to make a solution containing 1 ml containing 87mg of 1-phenyl-3-methyl-5-pyrazolone) 300μl, shake well, react in a 70℃ water bath for 30 minutes, take out, cool, add 200μl of hydrochloric acid solution (take 27ml of hydrochloric acid, add appropriate amount of water to 1000ml, shake well), 1ml of water, shake well, add 2ml of chloroform, shake well, centrifuge (speed is 1000 rpm) for 30 seconds, discard the chloroform layer, operate 3 times in the same way, and take the water layer as the test solution. Reference solution: freshly prepared before use; take an appropriate amount of glucuronic acid reference substance, accurately weigh, dissolve and dilute with solvent to make a solution containing 6μg of glucuronic acid per 1ml, accurately measure 500μl, put it in a centrifuge tube, and operate in the same way to make a reference solution. Chromatographic conditions: octadecylsilane bonded silica gel as filler (Agilent Zorbax SB-AQ, 4.6×250mm, 5μm or chromatographic column with equivalent performance); acetonitrile-phosphate buffer (15mmol each of disodium hydrogen phosphate and sodium dihydrogen phosphate per 1000ml, pH adjusted to 7.5 with sodium hydroxide solution) (20:80) as mobile phase; detection wavelength is 254nm; column temperature is 35℃. System suitability requirements: The number of theoretical plates calculated based on the glucuronic acid derivative peak is not less than 5000. Determination method: Accurately measure 50μl of the reference solution and the test solution, respectively, inject them into the liquid chromatograph, and record the chromatogram. Limit: If there is a chromatographic peak in the chromatogram of the test solution with the same retention time as the glucuronic acid derivative peak, calculate the glucuronic acid content by peak area according to the external standard method.

[0060] Calcium gluconate content determination: Calcium (Ca): Accurately measure 2 ml of this product, place it in a conical flask, add 80 ml of water, 15 ml of sodium hydroxide test solution and 0.1 g of calcipurpurogen indicator, and titrate with disodium ethylenediaminetetraacetic acid titrant (0.05 mol / L) until the solution changes from purple-red to pure blue. Each 1 ml of disodium ethylenediaminetetraacetic acid titrant (0.05 mol / L) is equivalent to 2.004 mg of Ca.

[0061] Table 6 Long-term stability test results Note: Glucuronate is the degradation product of calcium gluconate.

[0062] The long-term stability of the prescriptions of Examples 1-4 and Comparative Examples 1-5 was investigated for 24 months, and the stability process properties, pH value, glucuronate, and calcium gluconate content were investigated. The results showed that: Examples 1-4 did not show crystallization in the long-term 24 months; both Comparative Examples 1 and 5 showed crystallization; the glucuronate in Comparative Example 4 increased; the amount of cinnamon oil in Comparative Example 3 was large, and the solution became turbid; the stability of Examples 1-4 was consistent with that of commercially available preparations, which was better than Comparative Examples 1 and Comparative Examples 3-5. In the embodiments of the present invention, the microbial limit and stability of Comparative Example 2 (adding an antibacterial agent) can be achieved without adding an antibacterial agent, and the safety of the preparation can be improved without adding an antibacterial agent.

[0063] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. Compound calcium gluconate oral solution, characterized in that, The compound calcium gluconate oral solution comprises the following components: 40-60 g / L calcium gluconate, 40-60 g / L calcium lactate, 8-12 g / L sucralose, and 0.7-0.9 g / L essence. The compound calcium gluconate oral solution uses lactic acid as a pH regulator to adjust the pH value to 4.1-4.

5. The preparation method of the compound calcium gluconate oral solution comprises: using purified water at 90°C±5°C to dissolve calcium gluconate and calcium lactate; cooling the solution to below 40°C, adding sucralose and essence to the solution; cooling the solution to 30±5°C, and adjusting the pH value to 4.3±0.2 with lactic acid.

2. The compound calcium gluconate oral solution according to claim 1, characterized in that: The compound calcium gluconate oral solution comprises the following components: 60 g / L calcium gluconate, 60 g / L calcium lactate, 10 g / L sucralose, and 0.8 g / L essence. The compound calcium gluconate oral solution uses lactic acid as a pH regulator, and the pH value is adjusted to 4.

1.

3. The compound calcium gluconate oral solution according to claim 1, characterized in that: The compound calcium gluconate oral solution comprises the following components: 40 g / L calcium gluconate, 40 g / L calcium lactate, 10 g / L sucralose, and 0.8 g / L essence. The compound calcium gluconate oral solution uses lactic acid as a pH regulator, and the pH value is adjusted to 4.

5.

4. The compound calcium gluconate oral solution according to claim 1, characterized in that: The preparation method of the compound calcium gluconate oral solution also includes a filtration step, and the pore size of the filter element used for filtration is: 5±1 μm.

5. The compound calcium gluconate oral solution according to claim 4, characterized in that: The preparation method of the compound calcium gluconate oral solution also includes a sterilization step, and the sterilization parameters are: 115±5° C., 30±5 min.

6. The method for preparing the compound calcium gluconate oral solution according to any one of claims 1 to 5, characterized in that: include: Use purified water at 90℃±5℃ to dissolve calcium gluconate and calcium lactate; cool down to below 40℃, add sucralose and flavor to the solution; cool down to 30±5℃, and adjust the pH value with lactic acid; The filtration step is also included, and the pore size of the filter element used for filtration is: 5±1μm; It also includes a sterilization step, and the sterilization parameters are: 115±5℃, 30±5min.

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