Compound calcium gluconate oral solution and its preparation process

Abstract

The application discloses a compound calcium gluconate oral solution and a preparation process thereof. The compound calcium gluconate oral solution comprises the following raw materials in mass fractions: 40-60 parts of calcium gluconate, 40-60 parts of calcium lactate, 5-5.5 parts of a stabilizer, 140-160 parts of sucrose, 30-40 parts of glucose, 0.1-0.3 parts of essence and the balance of purified water. The pH value of the obtained compound calcium gluconate oral solution is 4.0-5.0, and the stabilizer comprises lactic acid and modified inulin in a mass ratio of 1: (0-0.08). The calcium lactate has a high solubility in water and can also serve as a solubilizer of the calcium gluconate, thereby improving the solubility of the calcium gluconate in water. The lactic acid in the stabilizer can dissociate into lactate ions, further improving the solubility of calcium ions in the system. The modified inulin has a good effect of preventing crystallization, thereby reducing the occurrence of crystallization precipitation.

Description

Technical Field

[0001] This application relates to the field of calcium gluconate oral solutions, and in particular to a compound calcium gluconate oral solution and its preparation process. Background Technology

[0002] Calcium is one of the essential elements for human life. It is not only a major component of bones but also essential for maintaining nerve and muscle function. It supports normal cardiopulmonary and blood clotting functions and plays a crucial role in the permeability of cell membranes and capillaries. Calcium gluconate oral solution is a convenient calcium preparation that can be used to treat various diseases caused by calcium deficiency.

[0003] However, the calcium gluconate oral solution currently sold on the market is in a supersaturated state, and the solubility of calcium gluconate in water is not high. Therefore, calcium ions in calcium gluconate are prone to crystallization at low temperatures, resulting in poor quality stability during storage. This affects the stability, effectiveness, safety, and storability of the calcium gluconate oral solution, thus leading to a decrease in calcium supplementation effect. Summary of the Invention

[0004] To address the issue that calcium gluconate oral solution is prone to crystallization at low temperatures, which affects the safety and stability of the product, this application provides a compound calcium gluconate oral solution and its preparation process.

[0005] In a first aspect, this application provides a compound calcium gluconate oral solution, which comprises the following raw materials in parts by weight:

[0006] Calcium gluconate 40-60 parts;

[0007] 40-60 parts of calcium lactate;

[0008] Stabilizer 5-5.5 parts;

[0009] 140-160 parts sucrose;

[0010] 30-40 parts glucose;

[0011] Fragrance 0.1–0.3 parts;

[0012] Purified water balance;

[0013] The pH value of the compound calcium gluconate oral solution is 4.0 to 5.0.

[0014] Preferably, the flavoring includes one or a combination of peach flavoring, strawberry flavoring, citrus flavoring and blueberry flavoring.

[0015] By adopting the above technical solution, the calcium source in the compound calcium gluconate oral solution of this application is a combination of calcium gluconate and calcium lactate. On the one hand, calcium lactate is also a calcium supplement, and the human body absorbs it more easily. Furthermore, it has a higher solubility in water than calcium gluconate, making it less prone to crystallization. On the other hand, calcium lactate can also act as a solubilizer for calcium gluconate, significantly increasing its solubility in water, allowing it to achieve near-saturation dissolution in the entire system. The combination of calcium lactate and calcium gluconate can significantly inhibit crystallization, and the two calcium sources can mutually promote each other, enhancing the body's absorption capacity.

[0016] Simultaneously, the pH of the obtained compound calcium gluconate oral solution is adjusted to 4.0–5.0. During the storage and long-term transportation of the compound calcium gluconate oral solution, a small portion of the precipitated crystals will settle in the solution. Within this pH range, the compound calcium gluconate oral solution exhibits relatively stable properties and is not prone to precipitation. This reduces the impact of the external environment and temperature on the compound calcium gluconate oral solution and extends its storage time.

[0017] Preferably, the stabilizer comprises lactic acid and modified inulin in a mass ratio of 1:(0 to 0.08).

[0018] By adopting the above technical solution, the stabilizer in this application mainly contains lactic acid. Lactic acid can dissociate into lactate ions in the solution, thereby increasing the solubility of calcium ions in the system and maintaining the stability of the system. Simultaneously, modified inulin can also be added to the stabilizer. Inulin is a linear structure of fructosaccharide linked by β-2,1-glycosidic bonds, and glucose residues are linked to the ends of the inulin molecule. Through the numerous hydroxyl coordination groups and glucose residue groups it contains, it can undergo a series of complexation and chelation reactions with calcium gluconate and calcium lactate in the solution. Furthermore, it can significantly improve the stability of the compound calcium gluconate oral solution at low temperatures and reduce the occurrence of crystallization.

[0019] Preferably, the raw materials for the modified inulin include carboxymethyl inulin and ethylene glycol diethyl ether diaminetetraacetic acid in a mass ratio of 1:(0.1-0.2).

[0020] By employing the above technical solution, modified inulin is obtained through a compounding process between carboxymethyl inulin and ethylene glycol diethyl ether diaminetetraacetic acid (EDTA). Compared to ordinary inulin, carboxymethyl inulin exhibits a stronger inhibitory effect on calcium salt crystallization. In addition to its excellent crystallization-inhibiting effect, the molecular chains of carboxymethyl inulin can also adsorb onto the surface of microcrystals, inhibiting the growth process of already formed calcium ion crystals and preventing further deposition, thus effectively improving the stability of compound calcium gluconate oral solution. Simultaneously, carboxymethyl inulin is further compounded with EDTA. EDTA has excellent chelating properties with calcium ions, enabling it to chelate with calcium gluconate and calcium lactate, further inhibiting the precipitation and crystallization of calcium ions.

[0021] Preferably, the modified inulin is prepared according to the following method:

[0022] Preparation of carboxymethyl inulin: Inulin was mixed with sodium hydroxide and ground, then placed in a microwave oven and alkalized at 90-100W for 2-3 minutes; then, ground sodium chloroacetate and reaction solvent were added, and the mixture was placed in a microwave oven again and etherified at 90-100W for 25-40 minutes; after the reaction was completed, the mixture was washed, neutralized and dried to obtain carboxymethyl inulin.

[0023] Preparation of modified inulin: The obtained carboxymethyl inulin was added to deionized water, the pH of the solution was adjusted to 8-8.5, ethylene glycol diethyl ether diaminetetraacetic acid was added, the temperature was raised to 50-60℃, and the reaction was stirred for 3-5 hours. After filtration, washing and drying, modified inulin was obtained.

[0024] Preferably, the reaction solvent is one or both of ethanol and isopropanol; the mass-volume ratio of inulin to the reaction solvent is 1g:(0.85~0.95)ml.

[0025] More preferably, the reaction solvent is isopropanol.

[0026] By adopting the above technical solution, this application uses a microwave method to obtain carboxymethyl inulin. Sodium hydroxide and sodium chloroacetate undergo alkalization and etherification reactions with inulin, respectively, to ultimately obtain carboxymethyl inulin. Compared with other methods, the microwave method allows for more complete contact between reactant molecules and inulin molecules, thereby promoting the reaction. It features rapid heating, sensitive reaction, and uniform heating system. The obtained carboxymethyl inulin further undergoes an etherification reaction with ethylene glycol diethyl ether diaminetetraacetic acid, enhancing the chelation between modified inulin and calcium gluconate and calcium lactate, strengthening the inhibitory effect of the stabilizer on crystallization, and further improving the stability of the obtained compound calcium gluconate oral solution.

[0027] Preferably, the mass ratio of inulin to sodium hydroxide is 1:(0.12-0.16).

[0028] By adopting the above technical solution, during the reaction process, sodium hydroxide can react with the hydroxyl groups contained in inulin. Under the action of sodium hydroxide, the hydroxyl groups become oxygen anions, which can improve the nucleophilicity of inulin itself, which is conducive to the further reaction between inulin and sodium chloroacetate, and improve the reactivity of the active center in the subsequent etherification reaction.

[0029] Preferably, the mass ratio of inulin to sodium chloroacetate is 1:(0.55-0.65).

[0030] By adopting the above technical solution, in the alkaline environment of sodium hydroxide, sodium chloroacetate can undergo an etherification reaction with the hydroxyl groups contained in inulin, i.e., a bimolecular nucleophilic substitution reaction, to obtain carboxymethyl inulin. The modified inulin can significantly enhance the ability to prevent calcium ions from crystallizing, reduce the deposition of calcium salts, and the carboxylic acid ester groups formed by the reaction have the ability to adsorb on the crystal surface, thereby inhibiting the growth of calcium ion crystals and improving the stability of compound calcium gluconate oral solution.

[0031] Secondly, this application also provides a preparation process for a compound calcium gluconate oral solution, which is prepared according to the following process steps:

[0032] S1. Heat the stabilizer to 70-100°C, add calcium gluconate and calcium lactate, stir to dissolve, and obtain the first mixture.

[0033] S2. Adjust the temperature of the first mixture to 80-85℃, add sucrose and glucose, stir and mix, then lower the temperature to 30-50℃, add flavoring and continue mixing to obtain the second mixture;

[0034] S3. Add purified water to the second mixture, filter and fill the mixture. After filling, keep it at 98-100℃ for 30-40 minutes to obtain compound calcium gluconate oral solution.

[0035] By adopting the above technical solution, in step S3, after the compound calcium gluconate oral solution is filled and sealed, the compound calcium gluconate oral solution is also subjected to heat preservation treatment. Heat preservation treatment can effectively prevent calcium precipitation in the product, reduce crystallization phenomenon in the part of the drug solution in contact with the packaging material, and improve the stability of the compound calcium gluconate oral solution.

[0036] Preferably, in step S3, nitrogen gas is circulated for 8-10 minutes after filtration and before filling.

[0037] By adopting the above technical solution, carbon dioxide in the air will gradually dissolve into the compound calcium gluconate oral solution after long-term storage or transportation, and further form a precipitate with the calcium ions in the solution. Therefore, circulating nitrogen gas for a few minutes before filling can significantly remove carbon dioxide from the tube, preventing the calcium ions in the compound calcium gluconate oral solution from reacting with it to form a precipitate, thereby improving the stability of the compound calcium gluconate oral solution.

[0038] In summary, this application has the following beneficial effects:

[0039] 1. The calcium source in the compound calcium gluconate oral solution of this application is a combination of calcium gluconate and calcium lactate. Calcium lactate is also a calcium supplement for the human body and has high solubility in water. At the same time, calcium lactate can also act as a co-solvent of calcium gluconate, thereby increasing the solubility of calcium gluconate in water and reducing the occurrence of precipitation crystallization.

[0040] 2. The compound calcium gluconate oral solution of this application also contains a stabilizer. The main component of the stabilizer is lactic acid, which can dissociate into lactate ions, thereby increasing the solubility of calcium ions in the system. Simultaneously, the stabilizer may also include modified inulin, which contains a large number of hydroxyl coordination groups and glucose residue groups, capable of undergoing a series of complexation and chelation reactions with calcium gluconate and calcium lactate in the solution. Furthermore, it can significantly improve the stability of the compound calcium gluconate oral solution at low temperatures. Moreover, the modified inulin used is carboxymethyl inulin, which not only has a good effect in preventing crystallization but also inhibits crystal growth, thereby further inhibiting the precipitation and crystallization of calcium ions. Detailed Implementation

[0041] Preparation example of modified inulin

[0042] Preparation Example 1: A modified inulin was prepared according to the following method:

[0043] Weigh 10g of inulin (degree of polymerization 9-10) and mix it with 1.4g of sodium hydroxide and grind it. Place it in a microwave oven and alkalize it at 90W for 2 minutes. Then add 6g of ground sodium chloroacetate and 9ml of isopropanol, and place it in a microwave oven again and etherify it at 90W for 30 minutes. After the reaction is completed, repeatedly wash, neutralize and dry to obtain carboxymethyl inulin.

[0044] 10g of the obtained carboxymethyl inulin was added to 250ml of deionized water, the pH of the solution was adjusted to 8, 1.5g of ethylene glycol diethyl ether diaminetetraacetic acid was added, the temperature was raised to 55℃, and the reaction was stirred for 4h. After filtration, washing and drying, the modified inulin was obtained.

[0045] Preparation Examples 2 to 9 are modified inulin, which differ from Preparation Example 1 only in the proportions of the raw materials used, as shown in Table 1:

[0046] Table 1 Formulation Tables for Preparation Examples 1 to 9

[0047]

[0048] Preparation Example 10, a modified inulin, differs from Preparation Example 1 only in that the amount of sodium chloroacetate added after grinding is 5g.

[0049] Preparation Example 11, a modified inulin, differs from Preparation Example 1 only in that the amount of sodium chloroacetate added after grinding is 7g.

[0050] Preparation Example 12: A modified inulin was prepared according to the following method:

[0051] Weigh 10g of inulin (degree of polymerization 9-10) and add it to 250ml of deionized water. Adjust the pH of the solution to 8, add 1.5g of ethylene glycol diethyl ether diaminetetraacetic acid, raise the temperature to 55℃, stir and react for 4h, and obtain modified inulin after filtration, washing and drying.

[0052] Preparation Example 13, a modified inulin, differs from Preparation Example 1 only in that the amount of ethylene glycol diethyl ether diaminetetraacetic acid added is 0.5 g.

[0053] Preparation Example 14, a modified inulin, differs from Preparation Example 1 only in that the amount of ethylene glycol diethyl ether diaminetetraacetic acid added is 2.5 g.

[0054] Preparation Example 15: A modified inulin was prepared according to the following method:

[0055] Weigh 10g of inulin (degree of polymerization 9-10) and mix it with 1.4g of sodium hydroxide and grind it. Place it in a microwave oven and alkalize it at 90W for 2 minutes. Then add 6g of ground sodium chloroacetate and 9ml of isopropanol, and place it in a microwave oven again and etherify it at 90W for 30 minutes. After the reaction is completed, repeatedly wash, neutralize and dry to obtain carboxymethyl inulin, i.e. modified inulin.

[0056] Example

[0057] Example 1: A compound calcium gluconate oral solution was prepared according to the following process steps:

[0058] S1. Heat 5.2g of stabilizer to 90℃, add 50g of calcium gluconate and 50g of calcium lactate, stir to dissolve and obtain the first mixture;

[0059] S2. Adjust the temperature of the first mixture to 80℃, add 150g of sucrose and 35g of glucose, stir and mix, then lower the temperature to 40℃, add 0.2g of peach flavoring and continue mixing to obtain the second mixture;

[0060] S3. Add purified water to the second mixture to a volume of 1000 ml, filter and fill the mixture. Before filling, circulate nitrogen gas for 8 minutes. After filling, keep the mixture at 100°C for 30 minutes to obtain the compound calcium gluconate oral solution.

[0061] The stabilizer in step S1 is lactic acid.

[0062] The pH value of the obtained compound calcium gluconate oral solution was 4.5.

[0063] Examples 2 to 7 describe a compound calcium gluconate oral solution, which differs from Example 1 only in the proportions of the raw materials used, as shown in Table 2.

[0064] Table 2: Formulation Tables for Examples 1 to 7

[0065]

[0066] In Examples 1 through 7, the stabilizer was lactic acid.

[0067] Example 8, a compound calcium gluconate oral solution, differs from Example 1 only in that the stabilizer is lactic acid in a mass ratio of 1:0.05 and the modified inulin prepared in Example 1.

[0068] Example 9, a compound calcium gluconate oral solution, differs from Example 1 only in that the stabilizer is lactic acid in a mass ratio of 1:0.08 and modified inulin prepared in Example 1.

[0069] Example 10, a compound calcium gluconate oral solution, differs from Example 8 only in that the modified inulin prepared in Example 1 is replaced with an equal amount of the modified inulin prepared in Example 2.

[0070] Example 11, a compound calcium gluconate oral solution, differs from Example 8 only in that an equal amount of modified inulin prepared in Preparation Example 3 is used instead of the modified inulin prepared in Preparation Example 1.

[0071] Example 12, a compound calcium gluconate oral solution, differs from Example 8 only in that the modified inulin prepared in Example 1 is replaced with an equal amount of the modified inulin prepared in Example 4.

[0072] Example 13, a compound calcium gluconate oral solution, differs from Example 8 only in that the modified inulin prepared in Example 1 is replaced with an equal amount of the modified inulin prepared in Example 5.

[0073] Example 14, a compound calcium gluconate oral solution, differs from Example 8 only in that an equal amount of modified inulin prepared in Preparation Example 6 is used to replace the modified inulin prepared in Preparation Example 1.

[0074] Example 15, a compound calcium gluconate oral solution, differs from Example 8 only in that the modified inulin prepared in Example 1 is replaced with an equal amount of the modified inulin prepared in Example 7.

[0075] Example 16, a compound calcium gluconate oral solution, differs from Example 8 only in that an equal amount of modified inulin prepared in Example 8 is used instead of the modified inulin prepared in Example 1.

[0076] Example 17, a compound calcium gluconate oral solution, differs from Example 8 only in that the modified inulin prepared in Example 1 is replaced with an equal amount of the modified inulin prepared in Example 9.

[0077] Example 18, a compound calcium gluconate oral solution, differs from Example 1 only in that the stabilizer is lactic acid in a mass ratio of 1:0.1 and the modified inulin prepared in Example 1.

[0078] Example 19, a compound calcium gluconate oral solution, differs from Example 8 only in that an equal amount of modified inulin prepared in Preparation Example 10 is used to replace the modified inulin prepared in Preparation Example 1.

[0079] Example 20, a compound calcium gluconate oral solution, differs from Example 8 only in that the modified inulin prepared in Example 1 is replaced with an equal amount of the modified inulin prepared in Example 11.

[0080] Example 21, a compound calcium gluconate oral solution, differs from Example 8 only in that the modified inulin prepared in Example 1 is replaced with an equal amount of the modified inulin prepared in Example 12.

[0081] Example 22, a compound calcium gluconate oral solution, differs from Example 8 only in that the modified inulin prepared in Example 1 is replaced with an equal amount of the modified inulin prepared in Example 13.

[0082] Example 23, a compound calcium gluconate oral solution, differs from Example 8 only in that the modified inulin prepared in Example 1 is replaced with an equal amount of the modified inulin prepared in Example 14.

[0083] Example 24, a compound calcium gluconate oral solution, differs from Example 8 only in that the modified inulin prepared in Example 1 is replaced with an equal amount of the modified inulin prepared in Example 15.

[0084] Example 25, a compound calcium gluconate oral solution, differs from Example 8 only in that an equal amount of inulin (degree of polymerization 9-10) is used to replace the modified inulin prepared in Preparation Example 1.

[0085] Example 26: A compound calcium gluconate oral solution was prepared according to the following process steps:

[0086] S1. Heat 5.2g of stabilizer to 90℃, add 50g of calcium gluconate and 50g of calcium lactate, stir to dissolve and obtain the first mixture;

[0087] S2. Adjust the temperature of the first mixture to 80℃, add 150g of sucrose and 35g of glucose, stir and mix, then lower the temperature to 40℃, add 0.2g of peach flavoring and continue mixing to obtain the second mixture;

[0088] S3. Add purified water to the second mixture to a volume of 1000 ml, filter and fill the mixture. Do not use nitrogen for flow treatment before filling. After filling, keep the mixture at 100°C for 30 minutes to obtain the compound calcium gluconate oral solution.

[0089] The stabilizer in step S1 is lactic acid.

[0090] Comparative Example

[0091] Comparative Example 1, a compound calcium gluconate oral solution, differs from Example 1 only in that the amount of calcium lactate added is 30g and the amount of calcium gluconate added is 70g.

[0092] Comparative Example 2, a compound calcium gluconate oral solution, differs from Example 1 only in that the amount of calcium lactate added is 70g and the amount of calcium gluconate added is 30g.

[0093] Comparative Example 3, a compound calcium gluconate oral solution, differs from Example 1 only in that it does not contain calcium lactate, and the amount of calcium gluconate added is 100g.

[0094] Comparative Example 4, a compound calcium gluconate oral solution, differs from Example 1 only in that the amount of stabilizer added is 4.5g.

[0095] Comparative Example 5, a compound calcium gluconate oral solution, differs from Example 1 only in that the amount of stabilizer added is 6g.

[0096] Comparative Example 6, a compound calcium gluconate oral solution, was prepared according to the following process steps:

[0097] S1. Mix 50g of calcium gluconate and 50g of calcium lactate, heat to 90℃, and then stir to dissolve to obtain the first mixture;

[0098] S2. Adjust the temperature of the first mixture to 80℃, add 150g of sucrose and 35g of glucose, stir and mix, then lower the temperature to 40℃, add 0.2g of peach flavoring and continue mixing to obtain the second mixture;

[0099] S3. Add purified water to the second mixture to a volume of 1000 ml, filter and fill the mixture. Before filling, circulate nitrogen gas for 8 minutes. After filling, keep the mixture at 100°C for 30 minutes to obtain the compound calcium gluconate oral solution.

[0100] The stabilizer in step S1 is lactic acid.

[0101] Comparative Example 7, a compound calcium gluconate oral solution, was prepared according to the following process steps:

[0102] S1. Heat 5.2g of stabilizer to 90℃, add 50g of calcium gluconate and 50g of calcium lactate, stir to dissolve and obtain the first mixture;

[0103] S2. Adjust the temperature of the first mixture to 80℃, add 150g of sucrose and 35g of glucose, stir and mix, then lower the temperature to 40℃, add 0.2g of peach flavoring and continue mixing to obtain the second mixture;

[0104] S3. Add purified water to the second mixture to a volume of 1000 ml, filter and fill the mixture. Before filling, circulate nitrogen gas for 8 minutes. After filling, the compound calcium gluconate oral solution is obtained.

[0105] The stabilizer in step S1 is lactic acid.

[0106] Comparative Example 8, a compound calcium gluconate oral solution, differs from Example 1 only in that the pH value of the obtained compound calcium gluconate oral solution is 6.5.

[0107] Performance testing

[0108] Stability test: Take 10ml*4 bottles of the compound calcium gluconate oral solution obtained in the examples and comparative examples, and place them at 3-5℃ for 30 days. Then, test the calcium gluconate content and calculate the loss rate on day 0, day 10, day 20 and day 30 respectively, and observe the properties of the solution at the same time.

[0109] in:

[0110]

[0111] 0d calcium gluconate content refers to the calcium gluconate content on day 0; Xd calcium gluconate content refers to the calcium gluconate content on day X, where X is 10, 20, or 30.

[0112] The test method for calcium gluconate content is as follows:

[0113] Measure 2 ml of compound calcium gluconate oral solution and place it in an Erlenmeyer flask. Add 80 ml of water, 15 ml of sodium hydroxide solution, and 0.1 g of calcium violet indicator. Then titrate with 0.05 mol / L disodium ethylenediaminetetraacetate solution until the solution changes from purple-red to pure blue. Each 1 ml of disodium ethylenediaminetetraacetate solution is equivalent to 22.42 mg of calcium gluconate, thus determining the calcium gluconate content.

[0114] The specific experimental results are shown in Table 3:

[0115] Table 3. Results of the stability test of compound calcium gluconate oral solution

[0116]

[0117]

[0118]

[0119] According to Table 3, and in conjunction with Examples 1, 2 through 7, it can be seen that no white sediment appeared in Examples 2 through 7 within 30 days, and the loss rate of calcium gluconate was not significantly different from that in Example 1, indicating that the stability of Examples 2 through 7 was not significantly different from that in Example 1. This may be because the difference between Examples 2 through 7 and Example 1 lies only in adjusting the raw material ratio within the required range, indicating that changing the raw material ratio within the required range has no significant impact on the stability and storability of the obtained compound calcium gluconate oral solution.

[0120] Combining Examples 1 and 8, it can be seen that no white deposits appeared in Example 8 within 30 days, and the loss rate of calcium gluconate was lower than that in Example 1, indicating that the stability of Example 8 was increased compared to Example 1. This may be because, compared to Example 1, the stabilizer used in Example 8 also contained modified inulin. Modified inulin can inhibit the formation of calcium ions crystals and can undergo chelation reactions with calcium gluconate and calcium lactate, increasing the solubility of calcium gluconate in solution, thereby improving the stability and storability of the compound calcium gluconate oral solution.

[0121] Combining Examples 8 and 9-17, it can be seen that no white deposits appeared in Examples 9-17 within 30 days, and the loss rate of calcium gluconate was not significantly different from that in Example 8, indicating that the stability of Examples 9-17 was not significantly different from that of Example 8. This may be because the difference between Examples 9-17 and Example 8 lies only in adjusting the raw material ratios and the ratio of modified inulin within the required range. This suggests that changing the raw material ratios and the ratios of modified inulin during the preparation process within the required range has no significant impact on the stability and storability of the resulting compound calcium gluconate oral solution.

[0122] Combining Examples 8 and 18, it can be seen that no white deposits appeared in Example 18 within 30 days, and the loss rate of calcium gluconate was not significantly different from that in Example 8, indicating that the stability of Example 18 was not significantly different from that of Example 8. This may be because the difference between Example 18 and Example 8 lies in the increased amount of modified inulin added to the stabilizer. At this dosage, the effect of modified inulin on the solution has reached saturation; further addition might even reduce the effectiveness of the stabilizer and affect the taste of the oral liquid.

[0123] Combining Examples 8 and 19-21, it can be seen that the loss rate of calcium gluconate in Examples 19-21 increased compared to Example 8, with a more significant increase in Example 21, indicating that the stability of Examples 19-21 decreased compared to Example 8. This may be because the difference between Examples 19-21 and Example 8 lies in the adjustment of the amount of sodium chloroacetate used in the modified inulin during preparation. In Example 19, the amount of sodium chloroacetate added was reduced, leading to a decrease in the content of carboxylic acid esters in the modified inulin, thus reducing its ability to inhibit calcium ion crystal growth and resulting in decreased stability. In Example 21, no sodium chloroacetate was added for modification, significantly reducing the ability to prevent calcium ion crystal formation, and consequently decreasing stability. In Example 20, the amount of sodium chloroacetate added was increased, leading to increased side reactions and a decrease in conversion rate during preparation, resulting in a final decrease in stability.

[0124] Combining Examples 8 and 22-24, it can be seen that the loss rate of calcium gluconate in Examples 22-24 increased compared to Example 8, with a more significant increase in Example 24, indicating that the stability of Examples 22-24 decreased compared to Example 8. This may be because the difference between Examples 22-24 and Example 8 lies in the adjustment of the amount of ethylene glycol diethyl ether diaminetetraacetic acid (EDTA) used in the preparation process. In Example 22, the amount of EDTA added was reduced, resulting in a decrease in the chelation effect between EDTA and calcium gluconate and calcium lactate in the compound calcium gluconate oral solution, increasing the possibility of calcium ion precipitation and crystallization, thus leading to a decrease in stability. In Example 24, no EDTA was added for modification, resulting in a more significant decrease in stability. In Example 23, the amount of EDTA was increased, enhancing the chelation effect with calcium gluconate. Excessive reaction led to an increase in the loss rate of calcium gluconate in the system, resulting in decreased stability.

[0125] Combining Examples 8 and 25, it can be seen that the loss rate of calcium gluconate in Example 25 is higher than that in Example 8, indicating that the stability of Example 25 is lower than that of Example 8. This may be because the inulin used as a stabilizer in Example 25 was not modified. Although the glucose residues in inulin can chelate with calcium gluconate, its reactivity is lower than that of modified inulin, resulting in a decrease in its ability to inhibit calcium ion crystallization and further a decrease in stability.

[0126] Combining Examples 1 and 26, it can be seen that the loss rate of calcium gluconate in Example 26 is higher than that in Example 1, and a small amount of white precipitate appears after 30 days, indicating that the stability of Example 26 is lower than that of Example 1. This may be because, in the preparation process of the compound calcium gluconate oral solution in Example 26, nitrogen gas circulation was not performed before filling, causing carbon dioxide in the air to dissolve in the water during long-term storage and form a white precipitate with calcium ions.

[0127] Based on Example 1 and Comparative Examples 1-3, it can be seen that the loss rate of calcium gluconate in Comparative Examples 1-3 is significantly higher than that in Example 1. White precipitates appeared in Comparative Examples 1 and 3 within 30 days, and a large amount of white precipitate appeared in Comparative Example 3 after 30 days, indicating that the stability of Comparative Examples 1-3 is significantly lower than that in Example 1, with Comparative Example 3 showing a more significant decrease. This may be because the only difference between Comparative Examples 1-3 and Example 1 is the adjustment of the calcium lactate addition ratio outside the required range. In Comparative Example 1, the amount of calcium lactate added was reduced, resulting in a decreased solubility of calcium gluconate and a decrease in the solubility of the calcium source in water, thus leading to a decrease in the stability of the resulting oral solution. In Comparative Example 3, no calcium lactate was added, resulting in a significant decrease in the solubility of calcium gluconate in water and a significant decrease in stability.

[0128] Based on Examples 1 and Comparative Examples 4-6, it can be seen that the loss rate of calcium gluconate in Comparative Examples 4-6 is significantly higher than that in Example 1. White deposits appeared in Comparative Examples 4 and 6 within 30 days, with Comparative Example 6 showing more white deposits after 30 days. This indicates that the stability of Comparative Examples 4-6 is significantly lower than that of Example 1, with Comparative Example 6 showing a more pronounced decrease. This may be because the only difference between Comparative Examples 4-6 and Example 1 is the adjustment of the stabilizer addition ratio outside the required range. In Comparative Example 4, the amount of stabilizer added was reduced, resulting in a decreased ability to improve the solubility of calcium ions in the system, thus leading to decreased stability. In Comparative Example 6, no stabilizer was added, resulting in a more significant performance degradation.

[0129] Combining Example 1 and Comparative Example 7, it can be seen that the loss rate of calcium gluconate in Comparative Example 7 is significantly higher than that in Example 1, and a small amount of white precipitate appears after 30 days, indicating that the stability of Comparative Example 7 is lower than that of Example 1. This may be because the compound calcium gluconate oral solution obtained in Comparative Example 7 was not kept warm after filling and sealing, which made it easy for crystals to precipitate at the interface between the drug solution and the packaging material, thus leading to decreased stability.

[0130] Combining Example 1 and Comparative Example 8, it can be seen that the loss rate of calcium gluconate in Comparative Example 8 is significantly higher than that in Example 1, and white precipitate appears within 30 days, indicating that the stability of Comparative Example 8 is lower than that of Example 1. This may be because the pH value of the compound calcium gluconate oral solution obtained in Comparative Example 8 is 6.5, and the near-neutral environment reduces the solubility of calcium gluconate in water, making it easier for crystals to precipitate.

[0131] This specific embodiment is merely an explanation of this application and is not intended to limit it. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.

Claims

1. A compound calcium gluconate oral solution, characterized in that, The compound calcium gluconate oral solution comprises the following raw materials in parts by weight: Calcium gluconate 40-60 parts; 40-60 parts of calcium lactate; Stabilizer 5-5.5 parts; 140-160 parts sucrose; 30-40 parts glucose; Fragrance 0.1–0.3 parts; Purified water balance; The pH value of the compound calcium gluconate oral solution is 4.0–5.0; The stabilizer comprises lactic acid and modified inulin in a mass ratio of 1:(0-0.08); The modified inulin raw materials include carboxymethyl inulin and ethylene glycol diethyl ether diaminetetraacetic acid in a mass ratio of 1:(0.1-0.2); The modified inulin was prepared according to the following method: Preparation of carboxymethyl inulin: Inulin was mixed with sodium hydroxide and ground, then placed in a microwave oven and alkalized at 90-100W for 2-3 minutes; then, ground sodium chloroacetate and reaction solvent were added, and the mixture was placed in a microwave oven again and etherified at 90-100W for 25-40 minutes; after the reaction was completed, the mixture was washed, neutralized and dried to obtain carboxymethyl inulin. Preparation of modified inulin: The obtained carboxymethyl inulin was added to deionized water, the pH of the solution was adjusted to 8-8.5, ethylene glycol diethyl ether diaminetetraacetic acid was added, the temperature was raised to 50-60℃, and the reaction was stirred for 3-5 hours. After filtration, washing and drying, modified inulin was obtained. The mass ratio of inulin to sodium chloroacetate is 1:(0.55-0.65); The compound calcium gluconate oral solution was prepared according to the following process steps: S1. Heat the stabilizer to 70-100°C, add calcium gluconate and calcium lactate, stir to dissolve, and obtain the first mixture. S2. Adjust the temperature of the first mixture to 80-85℃, add sucrose and glucose, stir and mix, then lower the temperature to 30-50℃, add flavoring and continue mixing to obtain the second mixture; S3. Add purified water to the second mixture, filter and fill the mixture. After filling, keep it at 98-100℃ for 30-40 minutes to obtain compound calcium gluconate oral solution. In step S3, nitrogen gas is circulated for 8-10 minutes after filtration and before filling.

2. The compound calcium gluconate oral solution according to claim 1, characterized in that, The reaction solvent is one or both of ethanol and isopropanol; the mass-volume ratio of inulin to the reaction solvent is 1g:(0.85~0.95)ml.

3. The compound calcium gluconate oral solution according to claim 1, characterized in that, The mass ratio of inulin to sodium hydroxide is 1:(0.12-0.16).

4. The compound calcium gluconate oral solution according to claim 1, characterized in that, The flavorings include one or a combination of peach flavoring, strawberry flavoring, sour orange flavoring, and blueberry flavoring.

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