Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a compound sodium picosulfate oral solution with high stability and good antibacterial effect and a preparation method thereof.
In order to solve the problems in the prior art, the inventor has unexpectedly found that the sodium picosulfate compound oral liquid adopts the bacteriostatic agents of methylparaben and propylparaben, the pH is adjusted to be within the range of 5.5-7.0 according to a certain weight ratio, and the weight ratio of magnesium oxide, a stabilizing agent and the bacteriostatic agent is controlled, so that the stability of related substances of the product can be provided, the bacteriostatic effect is greatly improved, and the stability of the property is very good.
Specifically, the invention is realized by the following technical scheme:
A compound sodium picosulfate oral solution comprises sodium picosulfate, anhydrous citric acid, magnesium oxide, a stabilizer, a bacteriostat and a pH regulator, wherein the bacteriostat comprises methylparaben and propylparaben, and the mass ratio of the methylparaben to the propylparaben is 15:1-6:1.
Preferably, the pH range of the compound sodium picosulfate oral solution is 5.5-7.0.
Preferably, the weight ratio of the magnesium oxide to the stabilizer to the bacteriostat is 21.875:35:1.3-21.875:72:3.2.
More preferably, each 100mL of oral solution comprises 0.0063g of sodium picosulfate, 2.1875g of anhydrous citric acid, 7.5g of magnesium oxide, 3.5-7.2g of stabilizer, 0.08-0.26g of chelating agent, 0.12-0.28g of bacteriostat and 0.12-0.25g of antioxidant.
Preferably, the stabilizer is at least one of L-malic acid and L-tartaric acid.
Preferably, the pH adjuster is at least one of sodium hydroxide and potassium hydroxide.
The invention also relates to a preparation method of the compound sodium picosulfate oral solution, which comprises the following steps:
(1) Adding magnesium oxide and anhydrous citric acid into purified water, stirring and dissolving completely, sequentially adding a stabilizer and a bacteriostat, and adding a pH regulator to regulate pH after the addition is finished to obtain a preparation liquid 1;
(2) And 2, adding sodium picosulfate into the solution 1, stirring and dissolving uniformly, and then fixing the volume and filtering to obtain the finished product.
Preferably, the purified water in the step (1) has a temperature of 55-65 ℃, the temperature is maintained at 80-90 ℃ after the addition is finished, the maintaining time is 10-45min, and then the purified water is cooled to below 40 ℃ and added with a pH regulator to regulate the pH.
Preferably, the filtration in step (2) is followed by filling with a filling volume of about 160 mL/bottle.
Preferably, the compound sodium picosulfate oral solution further comprises at least one of a chelating agent, an antioxidant, a sweetener, a flavoring agent and a flavoring agent as an inactive ingredient.
The compound sodium picosulfate oral solution is not limited to the types of adding the above inactive ingredients.
More preferably, the compound sodium picosulfate oral solution also comprises a chelating agent and an antioxidant.
More preferably, when the compound sodium picosulfate oral solution further comprises a chelating agent, the chelating agent is contained in an amount of 0.08-0.26g per 100mL of the oral solution.
More preferably, when the compound sodium picosulfate oral solution also comprises an antioxidant, 0.12-0.25g of the antioxidant is contained in each 100mL of the oral solution.
More preferably, the chelating agent is at least one of ethylenediamine tetraacetic acid, disodium edetate calcium.
More preferably, the antioxidant is at least one of sodium metabisulfite, sodium sulfite, sodium bisulfite and sodium thiosulfate.
The invention also relates to a preparation method of the compound sodium picosulfate oral solution, which comprises the following steps:
(1) Adding magnesium oxide and anhydrous citric acid into purified water, stirring and dissolving completely, sequentially adding a stabilizer, a bacteriostat and a chelating agent, and adding a pH regulator to regulate pH after the addition is finished to obtain a preparation liquid 1;
(2) And 2, adding an antioxidant into the solution 1, stirring and dissolving uniformly, adding sodium picosulfate, stirring and dissolving uniformly, and then fixing the volume and filtering to obtain the finished product.
More preferably, the compound sodium picosulfate oral solution further comprises at least one of a sweetener, a flavoring agent and a flavoring agent.
The invention also relates to a preparation method of the compound sodium picosulfate oral solution, which comprises the following steps:
(1) Adding magnesium oxide and anhydrous citric acid into purified water, stirring and dissolving completely, sequentially adding a stabilizer, a bacteriostat, a chelating agent, a sweetener and/or a flavoring agent and/or an aromatic agent, and adding a pH regulator to regulate pH after the addition is finished to obtain a liquid preparation 1;
(2) And 2, adding an antioxidant into the solution 1, stirring and dissolving uniformly, adding sodium picosulfate, stirring and dissolving uniformly, and then fixing the volume and filtering to obtain the finished product.
The invention also relates to a preparation method of the compound sodium picosulfate oral solution, which comprises the following steps:
(1) Adding magnesium oxide and anhydrous citric acid into purified water, stirring and dissolving completely, sequentially adding a stabilizer, a bacteriostat and a chelating agent, and adding a pH regulator to regulate pH after the addition is finished to obtain a preparation liquid 1;
(2) Adding antioxidant, sweetener and/or correctant, and/or aromatic into the solution 1, stirring and dissolving uniformly, adding sodium picosulfate, stirring and dissolving uniformly, fixing volume, and filtering.
The sweetener and/or flavoring agent, and/or flavoring agent may be added to the liquid formulation 1 or the liquid formulation 2.
Preferably, the purified water in the step (1) has a temperature of 55-65 ℃, the temperature is maintained at 80-90 ℃ after the addition is finished, the maintaining time is 10-45min, and then the purified water is cooled to below 40 ℃ and added with a pH regulator to regulate the pH.
Preferably, the filtration in step (2) is followed by filling with a filling volume of about 160 mL/bottle.
The beneficial effects of the invention are as follows:
(1) The invention obviously improves the stability of related substances by controlling the pH range of the compound sodium picosulfate oral solution to be 5.5-7.0;
(2) The invention obviously improves the antibacterial effect and stability by controlling the weight ratio of magnesium oxide, a stabilizer and a bacteriostatic agent (methylparaben and propylparaben) and controlling the weight ratio of methylparaben and propylparaben in the bacteriostatic agent;
(3) The compound sodium picosulfate oral solution has higher stability, and the property and related substances are kept stable after being placed at a high temperature of 60 ℃ for 30 days, thus having great significance for improving clinical safety.
Detailed Description
The invention will be further described with reference to specific embodiments, and advantages and features of the invention will become apparent from the description. These examples are merely exemplary and do not limit the scope of the invention in any way. It will be understood by those skilled in the art that various changes and substitutions of details and forms of the technical solution of the present invention may be made without departing from the spirit and scope of the present invention, but these changes and substitutions fall within the scope of the present invention.
The model manufacturers of the raw materials and the auxiliary materials adopted in each embodiment of the invention are shown in table 1.
Table 1 examples use raw and auxiliary material information
| Names of raw and auxiliary materials | Manufacturer' s |
| Magnesium oxide | Hebei Xingtai Metallurgical magnesium Co Ltd |
| Citric acid anhydrous | Lake Nanhua pharmaceutical Co Ltd |
| L-malic acid | Jiangxi alpha Gaokou pharmaceutical Co Ltd |
| L-tartaric acid | Chengdu Hua Yi pharmaceutical excipients manufacturing Limited liability company |
| Sodium hydroxide | Hunan Erkang pharmaceutical Co., ltd |
| Acesulfame potassium | Anhui Weiduo food ingredients Co.Ltd |
| Edetic acid disodium salt | Hunan Erkang pharmaceutical Co., ltd |
| Sodium hydroxide | Nanjing chemical Agents Co Ltd |
| Potassium hydroxide | Nanjing chemical Agents Co Ltd |
| Hydroxy-benzoic acid methyl ester | Hubei kudzuvine shop Yinfu pharmaceutical auxiliary material Limited liability company |
| Propyl hydroxybenzoate | Hubei kudzuvine shop Yinfu pharmaceutical auxiliary material Limited liability company |
| Benzyl alcohol | Chengdu Hua Yi pharmaceutical excipients manufacturing Limited liability company |
| Sodium thiosulfate | Sea wave chemical industry Co Ltd |
| Sodium metabisulfite | Sichuan Jinshan pharmaceutical Co Ltd |
| Sucralose | Jiangxi alpha Gaokou pharmaceutical Co Ltd |
| Sodium picosulfate | Kreative Organics Private Limited |
| Cranberry essence | Tianning fragrance (Jiangsu) Limited |
| Strawberry flavor essence | Tianning fragrance (Jiangsu) Limited |
Example 1
TABLE 2
The preparation method comprises (1) adding magnesium oxide and anhydrous citric acid into purified water at 55-65deg.C, stirring and dissolving completely, sequentially adding stabilizer, antibacterial agent, chelating agent, sweetener and aromatic agent, maintaining at 80-90deg.C for 11min, adjusting pH, cooling to below 40deg.C, adding sodium hydroxide aqueous solution, adjusting pH to 5.8, (2) adding antioxidant, stirring and dissolving uniformly, adding sodium picosulfate, stirring and dissolving uniformly, fixing volume, filtering, and (4) packaging with a bottle of volume of 160 mL/bottle. See table 2 for specific formulations.
Example 2
TABLE 3 Table 3
The preparation method comprises (1) adding magnesium oxide and anhydrous citric acid into purified water at 55-65deg.C, stirring and dissolving completely, sequentially adding stabilizer, antibacterial agent, chelating agent, sweetener and aromatic agent, maintaining at 80-90deg.C for 45min, adjusting pH, cooling to below 40deg.C, adding sodium hydroxide aqueous solution, adjusting pH to 5.5, (2) adding antioxidant, stirring and dissolving uniformly, adding sodium picosulfate, stirring and dissolving uniformly, fixing volume, filtering, and (4) packaging with a bottle with a packaging volume of 160 mL/bottle. See table 3 for specific formulations.
Example 3
TABLE 4 Table 4
The preparation method comprises (1) adding magnesium oxide and anhydrous citric acid into purified water at 55-65deg.C, stirring and dissolving completely, sequentially adding stabilizer, antibacterial agent, chelating agent, sweetener and aromatic, maintaining at 80-90deg.C for 30min, adjusting pH, cooling to below 40deg.C, adding sodium hydroxide aqueous solution, adjusting pH to 6.5, (2) adding antioxidant, stirring and dissolving uniformly, adding sodium picosulfate, stirring and dissolving uniformly, fixing volume, filtering, and (4) packaging with a bottle with a packaging volume of 160 mL/bottle. See table 4 for specific formulations.
Example 4
TABLE 5
The preparation method comprises (1) adding magnesium oxide and anhydrous citric acid into purified water at 55-65deg.C, stirring and dissolving completely, sequentially adding stabilizer, antibacterial agent, chelating agent, sweetener and aromatic, maintaining at 80-90deg.C for 30min, adjusting pH, cooling to below 40deg.C, adding sodium hydroxide aqueous solution, adjusting pH to 5.5, (2) adding antioxidant, stirring and dissolving uniformly, adding sodium picosulfate, stirring and dissolving uniformly, fixing volume, filtering, and (4) packaging with a bottle with a packaging volume of 160 mL/bottle. See table 5 for specific formulations.
Example 5
TABLE 6
The preparation method comprises (1) adding magnesium oxide and anhydrous citric acid into purified water at 55-65deg.C, stirring and dissolving completely, sequentially adding stabilizer, antibacterial agent, chelating agent, sweetener and aromatic, maintaining at 80-90deg.C for 30min, adjusting pH, cooling to below 40deg.C, adding potassium hydroxide aqueous solution, adjusting pH to 5.9, (2) adding antioxidant, stirring and dissolving uniformly, adding sodium picosulfate, stirring and dissolving uniformly, fixing volume, filtering, and (4) packaging with a bottle with a packaging volume of 160 mL/bottle. See table 6 for specific formulations.
Example 6
TABLE 7
The preparation method comprises (1) adding magnesium oxide and anhydrous citric acid into purified water at 55-65deg.C, stirring and dissolving completely, sequentially adding stabilizer, antibacterial agent, chelating agent, sweetener and aromatic, maintaining at 80-90deg.C for 20min, adjusting pH, cooling to below 40deg.C, adding potassium hydroxide aqueous solution, adjusting pH to 5.8, (2) adding antioxidant, stirring and dissolving uniformly, adding sodium picosulfate, stirring and dissolving uniformly, fixing volume, filtering, and (4) packaging with a bottle with a packaging volume of 160 mL/bottle. See table 7 for specific formulations.
Example 7
TABLE 8
The preparation method comprises (1) adding magnesium oxide and anhydrous citric acid into purified water at 55-65deg.C, stirring and dissolving completely, sequentially adding stabilizer, antibacterial agent, chelating agent, sweetener and aromatic, maintaining at 80-90deg.C for 30min, adjusting pH, cooling to below 40deg.C, adding potassium hydroxide aqueous solution, adjusting pH to 6.2, (2) adding antioxidant, stirring and dissolving uniformly, adding sodium picosulfate, stirring and dissolving uniformly, fixing volume, filtering, and (4) packaging with a bottle with a packaging volume of 160 mL/bottle. See table 8 for specific formulations.
Example 8
TABLE 9
The preparation method comprises (1) adding magnesium oxide and anhydrous citric acid into purified water at 55-65deg.C, stirring and dissolving completely, sequentially adding stabilizer, antibacterial agent, chelating agent, sweetener and aromatic, maintaining at 80-90deg.C for 30min, adjusting pH, cooling to below 40deg.C, adding sodium hydroxide aqueous solution, adjusting pH to 6.9, (2) adding antioxidant, stirring and dissolving uniformly, adding sodium picosulfate, stirring and dissolving uniformly, fixing volume, filtering, and (4) packaging with a bottle with a packaging volume of 160 mL/bottle. See table 9 for specific formulations.
Comparative example 1
The difference from example 1 is only that methylparaben and propylparaben are replaced with 1.4g sodium benzoate.
Comparative example 2
The difference from example 1 is only that the pH is 5.4.
Comparative example 3
The difference from example 1 is only that the pH is 7.1.
Comparative example 4
The difference from example 1 is that the dosages of methyl hydroxybenzoate and propyl hydroxybenzoate are respectively 1.6g and 0.1g, and the weight ratio is 16:1.
Comparative example 5
The difference from example 1 is that the dosages of methyl hydroxybenzoate and propyl hydroxybenzoate are respectively 1.18g and 0.22g, and the weight ratio is 5.5:1.
Comparative example 6
The difference from example 4 is that the amount of magnesium oxide is 21.875g, the amount of stabilizer is 35g, the amount of bacteriostat is 1.28 (methylparaben 1.2g, propylparaben 0.08 g), and the weight ratio of magnesium oxide, stabilizer and bacteriostat is 21.875:35:1.28.
Comparative example 7
The difference from example 4 is that the amount of magnesium oxide is 21.875g, the amount of stabilizer is 35g, the amount of bacteriostat is 1.28g (methylparaben 1.22g, propylparaben 0.1 g), and the weight ratio of magnesium oxide, stabilizer and bacteriostat is 21.875:35:1.32.
Comparative example 8
The difference from example 4 was that the amount of magnesium oxide was 21.875g, the amount of L-tartaric acid was 34g, the amount of bacteriostatic agent was 1.3g (methylparaben 1.22g, propylparaben 0.08 g), and the weight ratio of magnesium oxide, stabilizer and bacteriostatic agent was 21.875:34:1.3.
Comparative example 9
The difference from example 4 is that the amount of magnesium oxide is 21.875g, the amount of stabilizer is L-malic acid, the amount of stabilizer is 34g, the amount of bacteriostat is 1.3g (methylparaben 1.22g, propylparaben 0.08 g), and the weight ratio of magnesium oxide, stabilizer and bacteriostat is 21.875:34:1.3.
Comparative example 10
The difference from example 7 is that the stabilizer is L-malic acid with the dosage of 73g, and the weight ratio of magnesium oxide, stabilizer and bacteriostat is 21.875:73:3.2.
Comparative example 11
The difference from example 7 is that the amount of the bacteriostatic agent used was 3.25g (3 g of methylparaben, 0.25g of propylparaben), and the weight ratio of magnesium oxide, stabilizer and bacteriostatic agent was 21.875:72:3.25.
Comparative example 12
The difference from example 7 is that the amount of the bacteriostatic agent used was 3.45g (3.25 g of methylparaben, 0.2g of propylparaben), and the weight ratio of magnesium oxide, stabilizer and bacteriostatic agent was 21.875:72:3.45.
Comparative example 13
The difference from example 1 was only that the chelating agent was used in an amount of 0.7g, accounting for 0.07%.
Comparative example 14
The difference from example 1 was only that the chelating agent was used in an amount of 2.7g, accounting for 0.27%.
Comparative example 15
The difference from example 1 is that the amount of antioxidant is 2.6g, and the proportion is 0.26%.
Comparative example 16
The difference from example 1 is that the amount of antioxidant is 1.1g, and the ratio is 0.11%.
Comparative example 17
The difference from example 1 is only that the bacteriostatic agent is 1.4g methylparaben.
Comparative example 18
The difference from example 1 is only that the bacteriostatic agent is 1.4g of propyl paraben.
Evaluation of results of examples and comparative examples
The oral liquids obtained in examples 1 to 8 and comparative examples 1 to 18 were compared with the commercial control preparation (lot number: U04004AA, manufacturer: ferring Pharmaceuticals Inc) for the substances, stability of the properties, bacteriostatic efficacy, and the specific criteria are shown in Table 10, and the results are shown in tables 11 to 14.
The method for examining the stability of the compound Pike oral liquid comprises the steps of placing a reference preparation, each example and preparation samples obtained by each comparative example at a high temperature of 60 ℃ for 10 days, 20 days and 30 days to detect the changes of characters and related substances.
The antibacterial efficacy detection method of the compound pitke oral liquid provided by the invention comprises the steps of culturing and detecting bacteria of a reference preparation, each example and each preparation sample obtained by each comparative example for 0 day, 14 days and 28 days, and referring to the 2020 edition of Chinese pharmacopoeia, judging the standard as follows:
table 10 antibacterial effectiveness judgment criteria for oral liquid
Table 11 examples 1-8 high temperature 60 ℃ stability results
Table 12 reference formulations and comparative examples 1-18 high temperature 60 ℃ stability results
TABLE 13 results of bacteriostatic efficacy for example 1-example 8
* The results of the injection meet the requirements.
Table 14 results of antibacterial efficacy of reference formulations and comparative examples 1-18
* Note that, for cost saving, no antibacterial efficacy check was made for the comparative examples 14, 15, 16, which clearly do not meet the requirements.
Example 1 is the most preferred example among examples 1 to 8.
The stability of the reference preparation meets the requirement, and the antibacterial efficacy of the reference preparation also meets the requirement, but is at the lower limit;
Comparative example 1 the bacteriostat is an example of other commonly used bacteriostat types, the bacteriostasis efficacy of the obtained preparation sample does not meet the requirement, and the properties are also flawed;
Comparative examples 2 to 3 are examples having a pH outside the range of 5.5 to 7.0, and at least one of the bacteriostatic efficacy of the obtained preparation sample or the stability of the related substance is unsatisfactory to a different extent;
comparative examples 4-5 are examples of bacteriostat methylparaben to propylparaben weight ratio outside the range, and the obtained preparation samples have at least one of bacteriostasis efficacy and character stability which are not satisfactory.
Comparative examples 6 to 12 are examples in which the weight ratio of magnesium oxide to stabilizer to bacteriostat is outside the range, and the obtained preparation sample has at least one poor bacteriostasis effect and stability.
Examples 13-14 are examples outside the range of chelating agent levels, and comparative examples 15-16 are examples outside the range of oxidizing agent levels, resulting in formulations with samples having at least one of poorer bacteriostatic efficacy and stability;
the bacteriostat of comparative examples 17-18 is methylparaben and propylparaben which are used independently, and the bacteriostasis effect can not meet the requirement.
The foregoing detailed description is directed to one of the possible embodiments of the present invention, which is not intended to limit the scope of the invention, but is to be accorded the full scope of all such equivalents and modifications so as not to depart from the scope of the invention.