A method for preparing a calcium acetate oral solution

Abstract

The application discloses a preparation method of calcium acetate oral solution; the monomethyl ammonium glycyrrhizinate is dissolved in a glycerol aqueous solution, a solution is formed through short-time heating, and then the solution is mixed with calcium acetate and other auxiliary materials, so that the problem of insoluble substances can be solved; meanwhile, the calcium acetate oral solution prepared by using the method is transparent and clear in liquid in a 6-month accelerated test, and the uniformity and stability of the product are ensured. Through the creatively improved adding mode of the taste masking agent, the solubility problem of the monomethyl ammonium glycyrrhizinate in the preparation process of the product is solved, and the stability of the product is good. The application further studies the adding mode of the materials and the process parameters, shortens the preparation time, and improves the production efficiency of the medicine.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical composition preparation technology, and in particular relates to a method for preparing calcium acetate oral solution. Background Technology

[0002] Calcium acetate is a phosphate binder used to control hyperphosphatemia in patients with end-stage renal disease. Calcium acetate tablets were approved by the FDA in 1990, and calcium acetate capsules were approved in 2001. To reduce the number of tablets / capsules ingested, improve the convenience of calcium acetate administration, enhance patient adherence, and provide a suitable dosage form for patients with swallowing difficulties, Freshenius Medcl developed an oral solution of calcium acetate, which was launched in the United States on April 18, 2011, under the brand name PHOSLYRA.

[0003] However, the taste of liquid calcium acetate formulations is much worse than that of solid formulations, and they have a strong acetic acid-like odor. Sweeteners and taste masking agents are generally added to improve the taste. Adding glycyrrhizic acid monoammonium salt as a taste masking agent to the formulation during solution development can significantly improve the taste of the formulation. For example, the patent "Liquid Composition of Calcium Acetate" (Publication No.: CN104095838A) provides a composition containing approximately 7-21% calcium acetate (w / v), a sweetener, a polyol, and a taste masking agent, wherein the taste masking agent is glycyrrhizic acid monoammonium salt. However, glycyrrhizic acid monoammonium salt has poor solubility in water, a long dissolution time, and often requires heating for solubilization. Furthermore, it is prone to producing insoluble substances when mixed with calcium acetate. Summary of the Invention

[0004] In view of the shortcomings of the prior art, the present invention provides a method for preparing calcium acetate oral solution. This study provides a material addition method and process parameters to solve the solubility problem of glycyrrhizic acid monoammonium salt in the preparation process of this product, and the product stability meets the requirements.

[0005] To achieve the above-mentioned technical objectives, the technical solution implemented by this invention is as follows:

[0006] A method for preparing a calcium acetate oral solution includes the following steps:

[0007] (1) Weigh the prescribed amount of thickener glycerin and add water (preferably 50%-70% of the volume of the pre-prepared calcium acetate oral solution) to prepare solution 1;

[0008] (2) Add the masking agent glycyrrhizic acid monoammonium salt to solution 1 while heating, heat to 40-80℃ (preferably 60℃-80℃), and stir to dissolve to obtain solution 2;

[0009] (3) Add calcium acetate and other pharmaceutically acceptable excipients to solution 2 as needed, and add water to the volume of the pre-prepared calcium acetate oral solution to obtain the calcium acetate oral solution.

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

[0011] Furthermore, in step (3), the optional antibacterial preservative methylparaben can be dissolved in propylene glycol before being added to the feed.

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

[0013] Furthermore, the masking agent, glycyrrhizic acid monoammonium salt, includes glycyrrhizic acid monoammonium salt A or its hydrate.

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

[0015] The key steps in the preparation method provided by this invention are:

[0016] In steps (1) and (2), glycyrrhizic acid monoammonium salt is dissolved in an aqueous glycerol solution and a solution is formed by brief heating. Then, it is mixed with calcium acetate and other excipients, which can solve the problem of insoluble matter. At the same time, the calcium acetate oral solution prepared by this method is clear and transparent in the accelerated test over 6 months, ensuring the uniformity and stability of the product.

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

[0018] (1) This invention provides a method for preparing calcium acetate oral solution; by creatively improving the way the taste masking agent is added, the solubility problem of glycyrrhizic acid monoammonium salt in the preparation process of this product is solved, and the product has good stability.

[0019] (2) The present invention further studied the material addition method and process parameters, which shortened the preparation time and improved the production efficiency of the drug. Detailed Implementation

[0020] It should be noted that the following detailed descriptions are exemplary and intended to provide further illustration of the invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

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

[0022] Example 1: Comparison of Material Addition Methods

[0023]

[0024] Glycyrrhizic acid monoammonium salt has poor solubility in glycerol at room temperature or under heating conditions; glycyrrhizic acid monoammonium salt has poor solubility in aqueous solution or glycerol-aqueous solution at room temperature, but better solubility under heating conditions.

[0025] Example 2 Material Proportion Experiment

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

[0027]

[0028]

[0029] When the proportion of purified water added to the solution is 0%, glycyrrhizic acid monoammonium salt does not dissolve when stirred at 80°C. When the proportion of purified water added to the solution is 25%-70%, glycyrrhizic acid monoammonium salt can be dissolved when stirred at 80°C, and the dissolution time is within 30 minutes. The higher the proportion of purified water, the shorter the dissolution time. Within the range of 25%-70% purified water, a proportion of 50%-70% is preferred, which can significantly shorten the dissolution time and improve the preparation efficiency.

[0030] Example 3: Dissolution Temperature Experiment

[0031] Based on Example 1, the experiment was continued, and the material addition method of Example 1 was followed: glycyrrhizic acid monoammonium salt was added to glycerol-water solution and heated and stirred to investigate the dissolution time of glycyrrhizic acid monoammonium salt at different temperatures (80℃, 60℃, 40℃).

[0032]

[0033] The results showed that glycyrrhizic acid monoammonium salt dissolved relatively quickly at 40℃, 60℃, and 80℃, with the dissolution time in a 40℃ water bath being longer than that in 60℃ and 80℃. Further investigation revealed that solutions dissolved at 40℃ gradually became viscous upon standing at room temperature, while solutions dissolved at 60℃ and 80℃ maintained good fluidity even after prolonged standing at room temperature, which is more beneficial for subsequent preparation processes. Therefore, the optimal dissolution temperature is 60℃-80℃.

[0034] Example 4: Preparation of calcium acetate oral solution

[0035] Prescription

[0036]

[0037]

[0038] Prepare 1000 ml of the calcium acetate oral solution according to prescription 1, including the following steps:

[0039] (1) Weigh the prescribed amount of thickener glycerin and add water (250-700ml) equal to 25%-70% of the volume of the pre-prepared calcium acetate oral solution to prepare solution 1;

[0040] (2) Add the masking agent glycyrrhizic acid monoammonium salt to solution 1 under heating, heat to 40-80℃, stir for about 38 minutes, the material dissolves, and solution 2 is obtained;

[0041] (3) First add povidone to solution 2, then add calcium acetate, sucralose, maltitol and fruit flavoring, and add water to the volume of the pre-prepared calcium acetate oral solution (1000ml) to obtain calcium acetate oral solution.

[0042] Prepare 1000 ml of the calcium acetate oral solution according to prescription 2, including the following steps:

[0043] (1) Weigh the prescribed amount of thickener glycerin and add water (250-700ml) equal to 25%-70% of the volume of the pre-prepared calcium acetate oral solution to prepare solution 1;

[0044] (2) Add the masking agent glycyrrhizic acid monoammonium salt to solution 1 under heating, heat to 60℃-80℃, stir for about 21 minutes, the material dissolves, and solution 2 is obtained;

[0045] (3) Maintain the temperature of solution 2 at 60°C, add calcium acetate, sucralose, maltitol, methylparaben, propylene glycol and fruit flavoring, and add water to the volume of the pre-prepared calcium acetate oral solution (1000ml) to obtain calcium acetate oral solution.

[0046] Prepare 1000 ml of the calcium acetate oral solution according to prescription 3, including the following steps:

[0047] (1) Weigh the prescribed amount of thickener glycerin and add water (250-700ml) equal to 25%-70% of the volume of the pre-prepared calcium acetate oral solution to prepare solution 1;

[0048] (2) Add the masking agent glycyrrhizic acid monoammonium salt to solution 1 under heating, heat to 40-80℃, stir for about 30 minutes to dissolve, and obtain 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 add water to the volume of the pre-prepared calcium acetate oral solution (1000 ml) to obtain calcium acetate oral solution.

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

[0051] Example 5: Comparison of the effects of different methods of adding methylparaben

[0052]

[0053] Methylparaben has good solubility in propylene glycol at room temperature; when added sequentially to a mixture of water and propylene glycol, its solubility at room temperature is poor; when added sequentially to a mixture of water and propylene glycol, its solubility is good at 80°C, but methylparaben is prone to melting at high temperatures; the preferred method of adding methylparaben is to dissolve it in propylene glycol, thereby minimizing the stability risks that high temperatures may pose while ensuring the solubility of methylparaben.

[0054] Comparison of preparation processes for calcium acetate oral solutions with different proportions

[0055] Comparative Example 1: Prepare 1000 ml of the calcium acetate oral solution according to the formulation of Formula 1, including the following steps: dissolve the masking agent glycyrrhizic acid monoammonium salt in water (250 ml - 700 ml) at 25% - 70% of the volume of the pre-prepared calcium acetate oral solution, heat to 40 - 80°C, then add calcium acetate, glycerin and other pharmaceutically acceptable excipients, and add 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 Formula 1, but without adding glycyrrhizic acid monoammonium salt, including the following steps: dissolve calcium acetate, glycerin and other pharmaceutically acceptable excipients in water (700 ml) at 70% of the volume of the pre-prepared calcium acetate oral solution, and add 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 Formula 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 a portion of glycerol (38 g glycerol), then add a 10% glycyrrhizic acid monoammonium salt glycerol mixture (3 g glycyrrhizic acid monoammonium salt and 27 g glycerol) while stirring, then add povidone, and stir for 60 min without dissolving, resulting in an aqueous mixture with white solid precipitated; dissolve methylparaben in propylene glycol and add it to the above aqueous mixture while stirring, then add water to the volume of the pre-prepared calcium acetate oral solution (1000 ml), and continue stirring for 30 min without dissolving the white solid.

[0058] Example 5: Taste and Stability Test

[0059] The samples obtained from formulations 1-3 of Example 4 and Comparative Examples 1-2 of the present invention were stored at 40℃±2℃ and 75%±5%RH for 6 months. The taste, appearance and pH value of the retained samples were measured at 0 months, 1 month and 6 months, respectively. The specific data are shown in the table below.

[0060]

[0061]

[0062] The results showed that the oral solutions of calcium acetate in prescriptions 1-3 had good taste and texture, and their appearance and pH value remained largely unchanged. As shown in Comparative Example 1, if the monoammonium glycyrrhizate was not pre-dissolved in an aqueous glycerol solution, insoluble matter would precipitate out, resulting in a cloudy solution. Therefore, dissolving the monoammonium glycyrrhizate in an aqueous glycerol solution is necessary.

[0063] The results of Comparative Example 2 show that the insoluble matter is caused by glycyrrhizic acid monoammonium salt and API and other components.

[0064] Example 6: Determination of Calcium Acetate Content

[0065] Content determination: Accurately weigh an appropriate amount of calcium acetate oral solution (approximately equivalent to 0.3g of calcium acetate), add 300ml of water, 6ml of 42% sodium hydroxide solution and approximately 200mg of calcium carboxylic acid indicator, and titrate with disodium ethylenediaminetetraacetate titrant (0.1mol / L) until the solution changes from purple-red to blue and remains so for 30s. Each 1ml of disodium ethylenediaminetetraacetate titrant (0.1mol / L) is equivalent to 15.82mg of calcium acetate (C4H6CaO4). Calculate the calcium acetate content in the sample.

[0066] The results showed that the calcium acetate oral solutions prepared in Examples 1-3 of the present invention all met the requirements, with a content of 90.0-110.0% of the corresponding theoretical value, while the calcium acetate oral solution prepared in Comparative Example 3 had a lower calcium acetate content, at 85.2%.

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

[0068] Comparative Example 4: Following the preparation methods provided in Examples 1 and 2 of the patent "Liquid Composition of Calcium Acetate" (Publication No.: CN104095838A), calcium acetate and a sweetener were dissolved in water. The flavoring agent and glycerol USP were mixed together to obtain a homogeneous solution. A flavor masking agent was added and mixed with the calcium acetate solution. A paraben preservative was dissolved in propylene glycol. Optional additional flavor masking agents or sweeteners were mixed with the calcium acetate solution. All solutions, including any other polyols, were stirred together and a suitable amount of pure water was added to obtain a homogeneous solution. Magnasweet monoammonium glycyrrhizate was added in the form of a 10% solution.

[0069] Repeating this method resulted in a turbid solution, failing to resolve the solubility issue of glycyrrhizic acid monoammonium salt.

[0070] Comparative Example 5: To investigate the cause of insoluble matter formation, the following experiment was conducted:

[0071] ① Weigh out 25%-70% of the volume of water used to prepare the calcium acetate oral solution, and add the prescribed amount of raw material and some excipients (except propylene glycol and antibacterial agent) in sequence. Stir until all are dissolved to obtain solution 1. Add glycyrrhizic acid monoammonium salt to solution 1 while heating at 40-80℃. Insoluble matter will appear.

[0072] ② Weigh out 25%-70% of the volume of water used to prepare the calcium acetate oral solution. First, add some of the excipients (except propylene glycol and antibacterial agent) in sequence and stir until dissolved. Then, add glycyrrhizic acid monoammonium salt while heating at 40-80℃ and stir until dissolved. Next, add povidone and stir until dissolved. Finally, add the active pharmaceutical ingredient (API) and insoluble matter will appear.

[0073] Therefore, it is inferred that the mixing of the active pharmaceutical ingredient powder and the glycyrrhizic acid monoammonium salt powder resulted in the formation of insoluble substances.

[0074] The reason is that calcium acetate is a strong base-weak acid salt, which hydrolyzes to produce an alkaline solution, while glycyrrhizic acid monoammonium salt is acidic. The pH is between 3 and 4. When the two phases come into direct contact, the local environment may become acidic, resulting in the formation of acetate ions and hydrogen ions (i.e., acetic acid). Glycyrrhizic acid monoammonium salt is insoluble in acetic acid, thus producing an insoluble substance.

[0075] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing a calcium acetate oral solution, characterized in that, Based on the content of each component in the oral solution, the calcium acetate oral solution comprises: calcium acetate at 66.7-200.1 mg / ml, glycerol at 35-65 mg / ml, glycyrrhizic acid monoammonium salt at 2-3 mg / ml, other pharmaceutically acceptable excipients, and the balance being water as a solvent; comprising the following steps: (1) Weigh out the prescribed amount of thickener glycerin, add water to 25%-70% of the volume of the pre-prepared calcium acetate oral solution, and prepare solution 1; (2) Add the masking agent glycyrrhizic acid monoammonium salt to solution 1 while heating it. The heating temperature is 60-80℃, and the solution is stirred to dissolve it to obtain solution 2. (3) Add calcium acetate and other pharmaceutically acceptable excipients to solution 2 as needed, and add water 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, characterized in that, The volume of water added in step (1) is 50%-70% of the volume of the pre-prepared calcium acetate oral solution.

3. The method for preparing calcium acetate oral solution according to claim 1, characterized in that, Other pharmaceutically acceptable excipients in the calcium acetate oral solution include one or more of polyols, sweeteners, flavorings, antibacterial preservatives, and povidone; the sweetener is sucralose.

4. The method for preparing calcium acetate oral solution according to claim 3, characterized in that, The polyols include maltitol, propylene glycol, sorbitol, and xylitol.

5. The method for preparing calcium acetate oral solution according to claim 3, characterized in that, Fragrances include fruit flavorings and menthol flavorings.

6. The method for preparing calcium acetate oral solution according to claim 3, characterized in that, Antibacterial and preservative agents include methylparaben and potassium sorbate.

7. The method for preparing calcium acetate oral solution according to claim 4, characterized in that, The antibacterial preservative is methylparaben. In step (3), the antibacterial preservative methylparaben is first dissolved in propylene glycol to obtain a mixture, and then fed into the feed.

8. The method for preparing calcium acetate oral solution according to claim 1, characterized in that, The masking agent, glycyrrhizic acid monoammonium salt, is glycyrrhizic acid monoammonium salt A.

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