Preparation method of calcium acetate oral solution

Abstract

The invention discloses a preparation method of a calcium acetate oral solution. According to the invention, the mono-ammonium glycyrrhizinate is dissolved in a glycerol aqueous solution, a solution is formed through transient heating, and then the solution is mixed with calcium acetate and other auxiliary materials, so that the problem of generation of insoluble substances can be solved; meanwhile, the calcium acetate oral solution prepared by the method is transparent and clear in a 6-month acceleration test, so that the uniformity and the stability of the product are ensured. By creatively improving the adding mode of the taste masking agent, the problem of solubility of the mono-ammonium glycyrrhizinate in the preparation process of the product is solved, and the stability of the product is good. According to the invention, the material adding mode and process parameters are further researched, the preparation time is shortened, and the production efficiency of medicines is improved.

Description

Technical Field

[0001] The present invention belongs to the technical field of the preparation of pharmaceutical compositions, and particularly relates to a preparation method of calcium acetate oral solution. Background Art

[0002] Calcium acetate is a phosphate binder and can be used to control hyperphosphatemia in patients with end-stage renal disease. Calcium acetate tablets were marketed by the FDA in 1990, and calcium acetate capsules were marketed by the FDA in 2001. To reduce the number of tablets / capsules ingested during medication, improve the convenience of taking calcium acetate, improve the medication compliance of patients, and provide a suitable dosage form for patients with dysphagia, FRESENIUS MEDCL Company in the United States developed a calcium acetate oral solution, which was marketed in the United States on April 18, 2011, under the trade name PHOSLYRA.

[0003] However, the taste of the calcium acetate liquid preparation is much worse than that of the solid preparation, and it also has a strong acetic acid-like smell. Generally, sweeteners and taste masking agents (i.e., flavor masking agents) are added to improve the taste. When ammonium glycyrrhizinate is added as a taste masking agent in the development of the solution preparation, the taste of the preparation can be significantly improved. For example, the patent "Liquid Composition of Calcium Acetate" (Publication No.: CN104095838A) provides a composition containing about 7-21% calcium acetate (w / v), a sweetener, a polyol, and a flavor masking agent, and the flavor masking agent is ammonium glycyrrhizinate. However, ammonium glycyrrhizinate has poor solubility in water and a long dissolution time, and it often needs to be solubilized by heating, and insoluble substances are likely to appear after mixing with calcium acetate. Summary of the Invention

[0004] In view of the deficiencies of the prior art, the present invention provides a preparation method of calcium acetate oral solution. This study provides a way of adding materials and process parameters to solve the solubility problem of ammonium glycyrrhizinate in the preparation process of this product, and the stability of the product meets the requirements.

[0005] In order to achieve the above technical objectives, the technical solutions implemented by the present invention are as follows:

[0006] A preparation method of calcium acetate oral solution, comprising the following steps:

[0007] (1) Weigh the prescription amount of the thickener glycerol, add water accounting for 25%-70% (preferably 50%-70%) of the volume of the pre-prepared calcium acetate oral solution, and prepare Solution 1;

[0008] (2) Add the taste masking agent ammonium glycyrrhizinate to Solution 1 under heating, heat to 40-80°C (preferably 60°C-80°C), and stir to dissolve to obtain Solution 2;

[0009] (3) As needed, calcium acetate and other pharmaceutically acceptable excipients are added to Solution 2, and water is added to make up the volume of the oral calcium acetate solution to be prepared, thus obtaining the oral calcium acetate solution.

[0010] Further, other pharmaceutically acceptable excipients in the oral calcium acetate solution include polyols (including maltitol, propylene glycol, sorbitol, xylitol), sweeteners (including sucralose), flavoring agents (including fruit flavor essence, menthol spice), antibacterial and preservative agents (including methylparaben, potassium sorbate) and povidone.

[0011] Further, the optional antibacterial and preservative agent methylparaben in step (3) can be dissolved in propylene glycol first and then added.

[0012] Further, the temperature of Solution 2 is maintained at 60 °C during the feeding in step (3).

[0013] Further, the taste masking agent ammonium glycyrrhizinate includes ammonium glycyrrhizinate A or its hydrate.

[0014] Specifically, based on the content of each component in the oral solution, the oral calcium acetate solution includes: calcium acetate at 66.7 - 200.1 mg / ml, glycerol at 35 - 65 mg / ml, and ammonium glycyrrhizinate at 2 - 3 mg / ml.

[0015] In the preparation method provided by the present invention, the key steps are:

[0016] In steps (1) and (2), ammonium glycyrrhizinate is dissolved in the glycerol aqueous solution, a solution is formed by brief heating, and then it is mixed with calcium acetate and other excipients, which can solve the problem of generating insoluble substances; meanwhile, the oral calcium acetate solution prepared by this method is clear and transparent in the 6 - month accelerated test, ensuring the uniformity and stability of the product.

[0017] Compared with the prior art, the beneficial effects of the present invention are:

[0018] (1) The present invention provides a preparation method of an oral calcium acetate solution; by creatively improving the addition method of the taste masking agent, the solubility problem of ammonium glycyrrhizinate in the preparation process of this product is solved, and the product has good stability.

[0019] (2) The present invention further studies the addition method of materials and process parameters, shortens the preparation time, and improves the production efficiency of the drug. Detailed implementation manners

[0020] It should be noted that the following detailed description is exemplary and is intended to provide further illustration of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the technical field to which the present invention belongs.

[0021] In the embodiment of the present invention, the volume of the pre-prepared calcium acetate oral solution is the volume of the final calcium acetate oral solution to be obtained.

[0022] Comparison of the material addition methods in Example 1

[0023]

[0024] The solubility of ammonium glycyrrhizinate is poor in glycerol at room temperature or under heating conditions; the solubility of ammonium glycyrrhizinate is poor in aqueous solution or glycerol-aqueous solution at room temperature, but is better under heating conditions.

[0025] Material ratio experiment in Example 2

[0026] Based on Example 1, the experiment was continued. Referring to the material addition method in Example 1: ammonium glycyrrhizinate was added to the glycerol-aqueous solution and stirred while heating. When the heating temperature was 80 °C, the dissolution time of ammonium glycyrrhizinate was compared when 10%, 25%, 30%, 50%, and 70% of the volume of the pre-prepared calcium acetate oral solution of purified water was added.

[0027]

[0028]

[0029] When the proportion of purified water added to the solution was 0%, ammonium glycyrrhizinate did not dissolve under stirring at 80 °C; when the proportion of purified water added to the solution was in the range of 25% - 70%, ammonium glycyrrhizinate could be stirred to dissolve at 80 °C, and the dissolution time was within 30 min. Moreover, the greater the proportion of purified water, the shorter the dissolution time. In the range of 25% - 70% of the proportion of purified water, a proportion of purified water of 50 - 70% could be preferably selected, which could significantly shorten the dissolution time and improve the preparation efficiency.

[0030] Dissolution temperature experiment in Example 3

[0031] Based on Example 1, the experiment was continued. Referring to the material addition method in Example 1: ammonium glycyrrhizinate was added to the glycerol-aqueous solution and stirred while heating, and the dissolution time of ammonium glycyrrhizinate at different temperatures (80 °C, 60 °C, 40 °C) was investigated.

[0032]

[0033] The results showed that ammonium glycyrrhizinate could dissolve quickly at 40 °C, 60 °C, and 80 °C, and the dissolution time in a 40 °C water bath was longer than that at 60 °C and 80 °C. Further findings indicated that when the solution obtained by dissolution at 40 °C was left standing at room temperature, the solution gradually became viscous, while the solutions obtained by dissolution at 60 °C and 80 °C remained in good fluidity after standing at room temperature for a long time, which was more conducive to the subsequent preparation process. The preferred dissolution temperature was 60 °C - 80 °C.

[0034] Preparation of Calcium Acetate Oral Solution in Example 4

[0035] Prescription Table

[0036]

[0037]

[0038] To prepare 1000 ml of the calcium acetate oral solution according to Prescription 1, the following steps are included:

[0039] (1) Weigh the thickener glycerol in the prescribed amount, add water (250 - 700 ml) accounting for 25% - 70% of the volume of the calcium acetate oral solution to be prepared in advance, and prepare Solution 1.

[0040] (2) Add the masking agent ammonium glycyrrhizinate to Solution 1 under heating, heat to 40 - 80 °C, and stir for about 38 minutes until the materials are dissolved to obtain Solution 2.

[0041] (3) First add povidone to Solution 2, then add calcium acetate, sucralose, maltitol, and fruit flavor essence, and make up the water to the volume of the calcium acetate oral solution to be prepared in advance (1000 ml) to obtain the calcium acetate oral solution.

[0042] To prepare 1000 ml of the calcium acetate oral solution according to Prescription 2, the following steps are included:

[0043] (1) Weigh the thickener glycerol in the prescribed amount, add water (250 - 700 ml) accounting for 25% - 70% of the volume of the calcium acetate oral solution to be prepared in advance, and prepare Solution 1.

[0044] (2) Add the masking agent ammonium glycyrrhizinate to Solution 1 under heating, heat to 60 °C - 80 °C, and stir for about 21 minutes until the materials are dissolved to obtain Solution 2.

[0045] (3) Maintain the temperature of Solution 2 at 60 °C, add calcium acetate, sucralose, maltitol, methylparaben, propylene glycol, and fruit flavor essence, and make up the water to the volume of the calcium acetate oral solution to be prepared in advance (1000 ml) to obtain the calcium acetate oral solution.

[0046] To prepare 1000 ml of the calcium acetate oral solution according to Prescription 3, the following steps are included:

[0047] (1) Weigh the thickener glycerol in the prescribed amount, add water (250 - 700 ml) which is 25% - 70% of the volume of the pre - prepared calcium acetate oral solution, and prepare Solution 1.

[0048] (2) Add the taste - masking agent ammonium glycyrrhizinate to Solution 1 under heating conditions, heat to 40 - 80 °C, and stir for about 30 min to dissolve, obtaining Solution 2.

[0049] (3) First add povidone to Solution 2, then add Mixture 1 (calcium acetate, sucralose, maltitol) and Mixture 2 (methylparaben and propylene glycol), and make up the water to the volume of the pre - prepared calcium acetate oral solution (1000 ml) to obtain the calcium acetate oral solution.

[0050] In the present invention, methylparaben and propylene glycol are first prepared into a mixture and then fed to improve the solubility and stability of methylparaben. The reasons are as follows: According to the data, the solubility of methylparaben in water at different temperatures is 1:400 (25 °C), 1:50 (50 °C), 1:30 (80 °C); the solubility of methylparaben in propylene glycol is 1:5 (25 °C). It can be seen that the solubility of methylparaben in propylene glycol at room temperature is much greater than that in water. Although increasing the temperature of the aqueous solution can increase the solubility of methylparaben in water, high - temperature conditions may be unfavorable to the stability of methylparaben, and the solubility of methylparaben in water after heating is still less than that in propylene glycol at room temperature.

[0051] Effect comparison of the addition method of methylparaben in Example 5

[0052]

[0053] Methylparaben has good solubility in propylene glycol at room temperature; when methylparaben is added successively to the water - propylene glycol mixed solution, its solubility at room temperature is poor; when methylparaben is added successively to the water - propylene glycol mixed solution, its solubility is good at 80 °C, but methylparaben is easily melted at high temperature. The preferred addition method of methylparaben can be: dissolve methylparaben in propylene glycol, and on the premise of meeting the solubility of methylparaben, minimize the stability risk that may be brought by high temperature as much as possible.

[0054] Comparison of the preparation processes of different calcium acetate oral solutions in the comparative example

[0055] Comparative Example 1: Prepare 1000 ml of the calcium acetate oral solution according to the formulation of Prescription 1, including the following steps: Dissolve ammonium glycyrrhizinate, a taste masking agent, in water (250 ml - 700 ml) accounting for 25% - 70% of the volume of the pre-prepared calcium acetate oral solution, heat it to 40 - 80°C, then add calcium acetate, glycerol, and other pharmaceutically acceptable excipients, and make up the water to the volume of the pre-prepared calcium acetate oral solution (1000 ml) to obtain the calcium acetate oral solution.

[0056] Comparative Example 2: Prepare 1000 ml of the calcium acetate oral solution according to the formulation of Prescription 1, but without adding ammonium glycyrrhizinate, including the following steps: Dissolve calcium acetate, glycerol, and other pharmaceutically acceptable excipients in water (700 ml) accounting for 70% of the volume of the pre-prepared calcium acetate oral solution, make up the water to the volume of the pre-prepared calcium acetate oral solution (1000 ml) to obtain the calcium acetate oral solution.

[0057] Comparative Example 3: Prepare 1000 ml of the calcium acetate oral solution according to the formulation of Prescription 3, including the following steps: Dissolve calcium acetate in 500 ml of water, then add sucralose and maltitol in sequence and stir to dissolve, then add part of glycerol (38 g of glycerol), then add a 10% ammonium glycyrrhizinate glycerol mixture (3 g of ammonium glycyrrhizinate and 27 g of glycerol) under stirring, then add povidone, and stir for 60 min but it does not dissolve, obtaining a water-containing mixture with white solid matter precipitated; Dissolve methylparaben in propylene glycol, and add it to the above water-containing mixture under stirring, make up the water to the volume of the pre-prepared calcium acetate oral solution (1000 ml), and continue stirring for 30 min but the white solid matter still does not dissolve.

[0058] Taste and Stability Test of Example 5

[0059] Store the samples obtained from Examples 4 (Prescriptions 1 - 3) of the present invention and Comparative Examples 1 - 2 at 40°C ± 2°C and 75% ± 5% RH for 6 months, and measure the taste, appearance properties, and pH value of the remaining samples at 0 month, 1 month, and 6 months respectively. The specific data are shown in the following table.

[0060]

[0061]

[0062] The results show that the taste of the calcium acetate oral solutions of Prescriptions 1 - 3 is good, and the appearance properties and pH value basically do not change. From the result of Comparative Example 1, it can be seen that if ammonium glycyrrhizinate is not pre-dissolved in the glycerol aqueous solution, it will lead to the precipitation of insoluble substances and the turbidity of the solution. Therefore, the operation of dissolving ammonium glycyrrhizinate in the glycerol aqueous solution is necessary.

[0063] As can be seen from the results of Comparative Example 2, the insoluble matter is caused by components such as ammonium glycyrrhizinate and API.

[0064] Determination test of calcium acetate content in Example 6

[0065] Content determination: Weigh accurately an appropriate amount of calcium acetate oral solution (equivalent to about 0.3 g of calcium acetate), add 300 ml of water, 6 ml of 42% sodium hydroxide solution and about 200 mg of calcon carboxylic acid indicator, and titrate with disodium edetate titrant (0.1 mol / L) until the solution changes from purplish red to blue and remains unchanged for 30 s. Each 1 ml of disodium edetate titrant (0.1 mol / L) is equivalent to 15.82 mg of calcium acetate (C 4 H 6 CaO 4 ), and calculate the content of calcium acetate in the test sample.

[0066] The results show that the calcium acetate oral solutions prepared in Examples 1-3 of the present invention all meet the requirements, and the content is 90.0-110.0% of the corresponding theoretical value, while the calcium acetate content in the calcium acetate oral solution prepared in Comparative Example 3 is on the low side, and the content is 85.2%.

[0067] The preparation method provided by the present invention can not only shorten the process time and improve the drug production efficiency, but also ensure that the production results meet the expectations when preparing a high-content calcium acetate oral solution with stable process and controllable operation process, and ensure the uniformity and stability of drug quality.

[0068] Comparative Example 4: Referring to the preparation methods provided in Examples 1 and 2 of the patent "Liquid Composition of Calcium Acetate" (Publication No.: CN104095838A), calcium acetate and a sweetening agent were dissolved in water. The flavoring agent and glycerol USP were mixed with each other to finally obtain a uniform solution. A taste masking agent was added and mixed with the calcium acetate solution. The paraben preservative was dissolved in propylene glycol. An optional additional taste masking agent or sweetening agent was mixed with the calcium acetate solution. All solutions including any other polyols were stirred together and an appropriate amount of pure water was added to obtain a uniform solution. Among them, ammonium glycyrrhizinate (magnasweet) was added in the form of a 10% solution.

[0069] Repeating this method, the resulting solution was turbid and the solubility problem of ammonium glycyrrhizinate could not be solved.

[0070] Comparative Example 5: In order to study the cause of the formation of insoluble matter, the following experiment was carried out:

[0071] ① Weigh the water in an amount of 25% - 70% of the volume of the pre-prepared calcium acetate oral solution, and successively add the prescription amount of the active pharmaceutical ingredient and part of the excipients (except propylene glycol and bacteriostat), and stir until all are dissolved to obtain Solution 1; add ammonium glycyrrhizinate to Solution 1 under heating at 40 - 80 °C, and insoluble substances appear.

[0072] ② Weigh the water in an amount of 25% - 70% of the volume of the pre-prepared calcium acetate oral solution, first successively add part of the excipients (except propylene glycol and bacteriostat), and stir until dissolved; add ammonium glycyrrhizinate under heating at 40 - 80 °C and stir until dissolved; then add povidone and stir until dissolved; add the active pharmaceutical ingredient, and insoluble substances appear.

[0073] Therefore, it is inferred that the mixing of the active pharmaceutical ingredient powder and ammonium glycyrrhizinate powder results in the appearance of insoluble substances.

[0074] Analyze the reason: Calcium acetate is a salt of a strong base and a weak acid, and its hydrolysis is alkaline. Ammonium glycyrrhizinate is acidic with a pH of 3 - 4. When the two phases come into direct contact, the local area may be acidic, and acetate ions and hydrogen ions (i.e., acetic acid) appear. Ammonium glycyrrhizinate is insoluble in acetic acid, thus generating insoluble substances.

[0075] The above are only the preferred embodiments of the present invention and are not used to limit the present invention. For those skilled in the art, the present invention can have various changes and modifications. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A method for preparing calcium acetate oral solution, characterized in that: According to the content of each component in the oral solution, the calcium acetate oral solution comprises: 66.7-200.1 mg / ml of calcium acetate, 35-65 mg / ml of glycerol, 2-3 mg / ml of glycyrrhizic acid monoammonium salt, and the balance is water as a solvent; comprising the following steps: (1) Weigh the prescribed amount of thickener glycerin and add 25% to 70% of the volume of the pre-prepared calcium acetate oral solution in water to prepare solution 1; (2) adding a taste masking agent, monoammonium glycyrrhizinate, to solution 1 under heating at a temperature of 40-80° C., and stirring to dissolve to obtain solution 2; (3) As needed, calcium acetate and other pharmaceutically acceptable excipients are added to Solution 2, and water is added to the volume of the pre-prepared calcium acetate oral solution to obtain the calcium acetate oral solution.

2. The method for preparing calcium acetate oral solution according to claim 1, wherein The volume of water added in step (1) is 50%-70% of the volume of the pre-prepared calcium acetate oral solution.

3. The preparation method of calcium acetate oral solution according to claim 1, characterized in that, The heating temperature in step (2) is 60°C-80°C.

4. The method for preparing calcium acetate oral solution according to claim 1, characterized in that: In the calcium acetate oral solution, other pharmaceutically acceptable excipients include one or more of polyols, sweeteners, aromatics, antibacterial preservatives and povidone.

5. The method for preparing calcium acetate oral solution according to claim 4, characterized in that: The polyols include maltitol, propylene glycol, sorbitol and xylitol.

6. The method for preparing calcium acetate oral solution according to claim 4, characterized in that: The sweetener is sucralose.

7. The method for preparing calcium acetate oral solution according to claim 4, characterized in that: Fragrances include fruit flavors and menthol flavors.

8. The method for preparing calcium acetate oral solution according to claim 4, characterized in that: Antibacterial preservatives include methylparaben and potassium sorbate.

9. The method for preparing calcium acetate oral solution according to claim 4, characterized in that: In step (3), the antibacterial preservative methylparaben is first dissolved in propylene glycol to obtain a mixture, and then the raw materials are added.

10. The method for preparing calcium acetate oral solution according to claim 1, characterized in that: The taste masking agent monoammonium glycyrrhizinate includes monoammonium glycyrrhizinate A or its hydrate.

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