Calcium acetate oral solution and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and provides a calcium acetate oral solution and a preparation method thereof. The calcium acetate oral solution is prepared by the following method: (1) taking a part of water, heating, sequentially adding mono-ammonium glycyrrhizinate, first polyol and povidone, and uniformly stirring and mixing to obtain a first solution; (2) adding calcium acetate and a preservative into another part of water, uniformly stirring, then adding second polyol and a sweetening agent, and uniformly stirring and mixing to obtain a second solution; and (3) mixing the first solution and the second solution, cooling, adding an aromatic, adjusting the pH value, and fixing the volume, thereby obtaining the product. The first polyhydric alcohol is a C3-C6 small molecule polyhydric alcohol; and the second polyhydric alcohol is C3-C6 micromolecular polyhydric alcohol and sugar alcohol with the carbon number of more than or equal to 7. The calcium acetate oral solution is good in taste, free of pungent smell of an acetic acid sample, high in stability and long in storage life.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology and provides a calcium acetate oral solution and its preparation method. Background Technology

[0002] Hyperphosphatemia is a pathological condition caused by impaired renal function, resulting in impaired phosphorus excretion, abnormal distribution, or excessive intake, leading to serum phosphorus levels exceeding the upper limit of normal. It is one of the main complications in maintenance hemodialysis (MHD) patients.

[0003] To regulate high phosphorus levels in the body, phosphate binders can be used. Calcium acetate can be used as an adjunct to reduce dietary phosphate intake and dialysis, thereby lowering serum phosphorus levels in dialysis patients with renal failure. Its mechanism of action is to bind with phosphates in food to form insoluble calcium phosphate complexes, which are then excreted in feces, leading to a decrease in serum phosphorus concentration. Currently, commercially available calcium acetate is mainly in solid dosage forms. For dialysis patients with end-stage renal disease, the large size of solid dosage forms makes swallowing difficult, which is exacerbated by the need for larger doses. Liquid dosage forms can effectively solve this problem. However, liquid calcium acetate has a much worse taste than solid dosage forms and a strong acetic acid odor, affecting palatability and resulting in poor patient compliance.

[0004] Chinese invention patent CN101522021B discloses a liquid composition of calcium acetate. This liquid pharmaceutical composition contains 7-21% w / v calcium acetate, an artificial sweetener selected from sucralose, potassium butyrate, aspartame, and saccharin, a polyol selected from sorbitol, glycerol, propylene glycol, xylitol, maltitol, and combinations thereof, and a taste masking agent containing monoammonium glycyrrhizate. This calcium acetate liquid composition has fewer side effects and higher patient compliance. However, monoammonium glycyrrhizate has poor solubility in water, a long dissolution time, often requiring heating for solubilization, and is prone to insoluble substances when mixed with calcium acetate.

[0005] To address the aforementioned issues, Chinese invention patent application CN120078716A discloses a method for preparing calcium acetate oral solution. In this method, glycyrrhizic acid monoammonium salt is pre-dissolved in an aqueous glycerol solution, preventing the precipitation of insoluble substances and thus avoiding turbidity. While this method solves the solubility problem of glycyrrhizic acid monoammonium salt and improves the stability of the oral preparation to some extent, the stability of calcium acetate itself in solution is still affected by environmental conditions such as pH changes.

[0006] Currently, there are few liquid calcium acetate preparations available on the market both domestically and internationally, and research on their comprehensive performance is limited. Therefore, developing an oral calcium acetate solution that combines good taste and stability is of great significance. Summary of the Invention

[0007] To address the problems existing in the prior art, this invention provides a calcium acetate oral solution and its preparation method. By adjusting the order of excipient addition, not only is the solubility of glycyrrhizic acid monoammonium salt improved, but the stability of the oral solution is also significantly improved. Simultaneously, the optimization of the sweetener further enhances the palatability, resulting in high patient compliance.

[0008] Terminology Explanation: Unless otherwise defined, all technical terms in this document have the same meanings as commonly understood by one of ordinary skill in the art to which the subject matter of the claims pertains. Unless otherwise stated, all patents, patent inventions, and publications cited in this document are incorporated herein by reference in their entirety. If multiple definitions exist for terms in this document, the definitions in this chapter shall prevail.

[0009] It should be understood that the above brief description and the following detailed description are exemplary and for illustrative purposes only, and do not limit the subject matter of the invention in any way. In this invention, the singular is used in conjunction with the plural unless otherwise specifically stated. It should also be noted that, unless otherwise stated, the use of “or” or “or” means “and / or”. Furthermore, the use of the term “comprising” and other forms such as “including,” “containing,” and “contains” are not limiting.

[0010] The definitions of standard chemical terms can be found in "Pharmacopoeia of the People's Republic of China (2020 Edition): China Medical Science and Technology Press: May 2020: 1st Edition".

[0011] Unless otherwise stated, conventional methods within the scope of the art shall be used.

[0012] Unless specifically defined herein, the use of all commercially available products herein employs standard techniques. For example, it may be carried out using the manufacturer's instructions for use with the kit, or in accordance with methods known in the art or the description of this invention. The techniques and methods described herein can generally be implemented according to conventional methods well known in the art, based on the descriptions in the various summary and more specific documents cited and discussed in this specification.

[0013] The terms “optional / arbitrary” or “optionally / arbitrarily” mean that the event or situation described below may or may not occur, including both the occurrence and non-occurrence of the event or situation.

[0014] The term "polyol" as used in this article refers to an organic compound containing two or more hydroxyl groups in its molecule; sugar alcohols are also a type of polyol; C3-C6 refers to polyols with 3-6 carbon atoms; C7 and above refers to polyols with 7 or more carbon atoms.

[0015] The term "%" as used in this article refers to the unit of concentration of a solution (solute dissolved in a liquid)—mass-volume percentage (w / v). Generally, a 1% (w / v) solution means 1 g / 100 mL (1 g of solute per 100 mL of solution).

[0016] The technical solution of the present invention is as follows: This invention provides a method for preparing calcium acetate oral solution, comprising the following steps: (1) Take a portion of water, heat it up and add glycyrrhizic acid monoammonium salt, first polyol and povidone in sequence, stir and mix evenly to obtain the first solution; (2) Take another portion of water, add calcium acetate and preservative, stir well, then add the second polyol and sweetener, stir and mix well to obtain the second solution; (3) Mix the first solution and the second solution, cool down, add the fragrance, adjust the pH value, and make up to volume to obtain the final solution; The first polyol is a small molecule polyol of C3-C6; the second polyol is a small molecule polyol of C3-C6 and a sugar alcohol of C7 and above.

[0017] Further, the calcium acetate oral solution comprises, by weight-volume percentage: 7.0-21.0% (w / v) calcium acetate, 0.2-0.3% (w / v) monoammonium glycyrrhizate, 6.0-8.0% (w / v) first polyol, 20.0-25.0% (w / v) second polyol, 0.1-1.0% (w / v) sweetener, 0.1-1.0% (w / v) flavoring agent, 0.5-1.0% (w / v) povidone, 0.1-0.50% (w / v) antibacterial preservative, and the balance being water.

[0018] In some preferred embodiments of the present invention, the mass ratio of the first polyol to polyvinylpyrrolidone is 9-12:1; the present invention further improves the solubility of glycyrrhizic acid monoammonium salt by optimizing the ratio of the two, and provides suitable solution conditions for the stable existence of calcium acetate in the solution.

[0019] In some preferred embodiments of the present invention, the mass ratio of C3-C6 small molecule polyols and C7 and above sugar alcohols in the second polyol is 1:1-10.

[0020] In some specific embodiments of the present invention, the C3-C6 small molecule polyols are one or more of propylene glycol, glycerol and butylene glycol; and / or the C7 and above sugar alcohols are one or more of maltitol, isomaltitol and lactitol.

[0021] In some preferred embodiments of the present invention, the first polyol is glycerol; and / or the second polyol is propylene glycol and maltitol.

[0022] In some specific embodiments of the present invention, the preservative includes one or more of methylparaben, propylparaben, sorbic acid, potassium sorbate, and sodium sorbate; preferably one or two of methylparaben and propylparaben.

[0023] In some specific embodiments of the present invention, the sweetener includes one or more of sucralose, aspartame, acesulfame potassium, steviol glycoside, mogroside, and ethyl maltol; preferably sucralose and mogroside, sucralose and ethyl maltol, or sucralose, mogroside, and ethyl maltol.

[0024] In some specific embodiments of the present invention, the flavoring agent includes one or more of the following: black cherry flavoring, peppermint flavoring, berry flavoring, cream flavoring, chocolate flavoring, and wintergreen flavoring; preferably black cherry flavoring and peppermint flavoring.

[0025] In some specific embodiments of the present invention, in step (1), the temperature for heating is 45-65°C.

[0026] In some specific embodiments of the present invention, in step (1), the amount of water is 5-10% of the total volume of the calcium acetate oral solution.

[0027] In some specific embodiments of the present invention, in step (2), the amount of water is 50-80% of the total volume of the calcium acetate oral solution.

[0028] In some specific embodiments of the present invention, in step (3), glacial acetic acid is used to adjust the pH to 6.0-6.8; the present invention adjusts the pH of the oral solution to below neutral, especially in the range of 6.0-6.8, which can avoid the degradation of calcium acetate in the solution and improve stability.

[0029] The present invention also provides an oral solution of calcium acetate prepared by any of the preparation methods described above.

[0030] Compared with the prior art, the present invention has the following beneficial effects: (1) In this invention, due to the solubilizing effect of povidone, by adjusting the order of raw materials and excipients (adding glycerol and povidone at the same time during the dissolution of glycyrrhizic acid monoammonium salt), not only is the solubility of glycyrrhizic acid monoammonium salt improved, but the stability of the active drug calcium acetate is also further improved. At the same time, by optimizing the ratio of the first polyol to povidone and the second polyol, and adjusting the pH of the solution to a suitable range before filling, the conditions for the stable existence of calcium acetate in the solution are provided, effectively avoiding the degradation of calcium acetate and making the formulation more stable. (2) Mixing the sweetener with calcium acetate first, and then mixing it with a solution of glycyrrhizic acid monoammonium salt, the masking component, has a better masking effect on the sour taste of calcium acetate. At the same time, through further optimization and adjustment of the sweetener, especially the fact that mogroside and ethyl maltol themselves have certain antioxidant properties as sweeteners, not only is the taste further improved, but the stability of the preparation is also further improved. Detailed Implementation

[0031] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0032] The performance of the calcium acetate oral solution of this invention was evaluated using the following methods: I. Taste Evaluation: Ten volunteers were selected to evaluate the taste of the various calcium acetate oral solutions prepared according to this invention. The ten volunteers scored each calcium acetate oral solution according to the following criteria: (1) Sweetness: No sweetness: 0 points; Slight sweetness: 1-3 points; Medium sweetness: 4-6 points; Overly sweet or even salty: 7-10 points. (2) Sour taste: No sour taste: 0 points; Slightly sour taste: 1-3 points; Moderately sour taste: 4-6 points; Very sour taste: 7-10 points.

[0033] The results are expressed as the mean ± standard deviation of the scores given by 10 volunteers.

[0034] II. Stability: (1) High temperature test: Heating at 60℃ for 10 days; (2) Accelerated test: Placed at a temperature of 40±2℃ for 6 months; (3) Long-term test: Placed at a temperature of 25±2℃ for 6 months; The calcium acetate content was determined according to WS-344(X-301)-99. The specific procedure was as follows: Accurately measure an appropriate amount of the product (approximately equivalent to 0.15 g of calcium acetate), dissolve it in 100 mL of water, add 15 mL of sodium hydroxide test solution and approximately 0.1 g of calcium violet indicator, and titrate with 0.05 mol / L disodium ethylenediaminetetraacetate titrant until the solution changes from pink to blue-purple. Each 1 mL of 0.05 mol / L disodium ethylenediaminetetraacetate titrant is equivalent to 7.909 mg of C4H6CaO4.

[0035] Example 1: A calcium acetate oral solution (specifications of 63.1g / 473mL, 33.1g / 473mL and 99.3g / 473mL, respectively) has the following formulation composition as shown in Table 1.

[0036] Table 1 Composition of Prescriptions 1-1 to 1-3 (mass / volume percentage)

[0037] The preparation method is as follows: (1) Take about 6% of the total amount of calcium acetate oral solution in the prescription, heat it to 60°C, and then add the prescribed amount of glycyrrhizic acid monoammonium salt S, glycerin and povidone in sequence. Mix them evenly by sonication to obtain the first solution. (2) Take about 60% of the total amount of calcium acetate oral solution in water, add the prescribed amount of calcium acetate and methylparaben, stir well, then add the prescribed amount of propylene glycol, maltitol and sucralose, stir and mix well to obtain the second solution; (3) Mix the first solution and the second solution, cool down, add the prescribed amount of black cherry food flavoring and mint food flavoring, add glacial acetic acid to adjust the pH value to 6.4±0.2, make up to 473mL, fill and obtain the product.

[0038] The taste and stability of calcium acetate oral solutions of prescriptions 1-3 to 1-3 were evaluated, and the results are shown in Table 2.

[0039] Table 2 Performance Evaluation Results of Formulas 1-1 to 1-3

[0040] As can be seen from the table above, prescriptions 1-1 to 1-3 correspond to different specifications of oral solutions, and their sourness scores are all between 1 and 3, with only a slight sour taste. The irritating sour taste of calcium acetate is significantly improved, and the sweetness is obvious, resulting in a better taste and high patient compliance. At the same time, after 10 days of accelerated storage, high temperature, and long-term storage at room temperature (6 months), the content of calcium acetate hardly changes, indicating high stability.

[0041] Example 2 A calcium acetate oral solution (63.1g / 473mL) has the following formulation as shown in Table 3.

[0042] Table 3 Composition of Prescriptions 2-1 to 2-5 (mass / volume percentage)

[0043] The preparation method is the same as in Example 1.

[0044] The taste and stability of calcium acetate oral solutions of prescriptions 2-1 to 2-5 were evaluated, and the results are shown in Table 4.

[0045] Table 4 Performance evaluation results of prescriptions 2-1 to 2-5

[0046] As can be seen from the table above, the calcium acetate oral solutions of prescriptions 2-1 to 2-5 also have suitable sweetness and sourness, and a moderate taste. Regarding stability, the calcium acetate content of prescription 2-2 showed a significant decreasing trend after being placed under different conditions. Compared with prescription 2-1, only the type of the second polyol was different. Although the sweetness increased and the sourness decreased further, the stability decreased significantly. It can be seen that the type of sugar alcohol in the second polyol has a significant impact on stability while adjusting the taste of the solution. Selecting sugar alcohols with C7 or higher can significantly improve the stability of calcium acetate while ensuring the taste of the solution.

[0047] Example 3 A calcium acetate oral solution (63.1g / 473mL) has the following formulation: (see Table 5)

[0048] Table 5 Composition of Prescriptions 3-1 to 3-4 (mass / volume percentage)

[0049] The preparation method is the same as in Example 1.

[0050] The taste and stability of calcium acetate oral solutions of prescriptions 3-1 to 3-4 were evaluated, and the results are shown in Table 6.

[0051] Table 6 Performance Evaluation Results of Formulas 3-1 to 3-4

[0052] As shown in the table above, the sweeteners in prescriptions 3-1 to 3-4 are different, but all exhibit high stability and a pleasant taste. Compared to prescription 1-1, prescriptions 3-1 to 3-3 (especially prescription 3-3) show improved sweetness and further reduced acidity (average score below 1 point), indicating that mogrosides and / or ethyl maltol, combined with sucralose, can further improve the taste of calcium acetate oral solution. Regarding stability, prescriptions 3-1 and 3-2 show no significant improvement compared to prescription 1-1, while prescriptions 3-3 and 3-4 show further improvement. This suggests that mogrosides and ethyl maltol, in addition to acting as sweeteners to improve taste in combination with sucralose, also synergistically enhance the stability of calcium acetate, which may be related to their antioxidant properties.

[0053] Comparative Example 1 A calcium acetate oral solution, with the same formulation as formulation 1-1, is prepared according to the method of patent CN202510236025.X, as detailed below: (1) Take the prescribed amount of glycerin and add water equal to about 60% of the total amount of calcium acetate oral solution to obtain solution 1; (2) Add the prescribed amount of glycyrrhizic acid monoammonium salt S to solution 1 while heating, heat to 60°C, and stir until fully dissolved to obtain solution 2; (3) Maintain the temperature of solution 2 at 60°C, add the prescribed amounts of calcium acetate, sucralose, maltitol, methylparaben, propylene glycol, black cherry food flavoring and mint food flavoring, and make up to 473 mL. Fill the container to obtain the product.

[0054] Comparative Example 2 A calcium acetate oral solution, with the same formulation as formulation 1-1, is prepared as follows: (1) Take about 6% of the total amount of calcium acetate oral solution in the prescription, heat it to 60°C, and then add the prescribed amount of glycyrrhizic acid monoammonium salt S and glycerin in sequence. Mix evenly by ultrasonication to obtain the first solution. (2) Take about 60% of the total amount of calcium acetate oral solution in water, add the prescribed amount of calcium acetate and methylparaben, stir well, then add the prescribed amount of propylene glycol, maltitol, povidone and sucralose, stir and mix well to obtain the second solution; (3) Mix the first solution and the second solution, cool down, add the prescribed amount of black cherry food flavoring and mint food flavoring, add glacial acetic acid to adjust the pH value to 6.4±0.2, make up to 473mL, fill and obtain the product.

[0055] The taste and stability of the calcium acetate oral solutions prepared in Comparative Examples 1 and 2 were evaluated, and the results are shown in Table 7.

[0056] Table 7 Performance evaluation results of calcium acetate oral solutions prepared in Comparative Examples 1 and 2

[0057] As can be seen from the table above, compared with formulation 1-1 of the present invention, the oral solution of Comparative Example 1 has a lower sweetness, a slightly higher acidity, and a slightly worse taste; in addition, the stability of calcium acetate in the oral solutions of Comparative Example 1 and Comparative Example 2 is significantly reduced. Specifically, the oral solution prepared using the method of existing technology CN202510236025.X still has certain stability problems with calcium acetate. The present invention, through process improvement, not only solves the solubility problem of glycyrrhizic acid monoammonium salt, but also further improves the stability of calcium acetate; in addition, the order of addition of povidone in the present invention also plays a key role in stability.

[0058] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing a calcium acetate oral solution, characterized in that, Includes the following steps: (1) Take a portion of water, heat it up and add glycyrrhizic acid monoammonium salt, first polyol and povidone in sequence, stir and mix evenly to obtain the first solution; (2) Take another portion of water, add calcium acetate and preservative, stir well, then add the second polyol and sweetener, stir and mix well to obtain the second solution; (3) Mix the first solution and the second solution, cool down, add the fragrance, adjust the pH value, and make up to volume to obtain the final solution; The first polyol is a small molecule polyol of C3-C6; the second polyol is a small molecule polyol of C3-C6 and a sugar alcohol of C7 and above.

2. The preparation method according to claim 1, characterized in that, The calcium acetate oral solution comprises, by weight-volume percentage: 7.0-21.0% (w / v) calcium acetate, 0.2-0.3% (w / v) monoammonium glycyrrhizate, 6.0-8.0% (w / v) first polyol, 20.0-25.0% (w / v) second polyol, 0.1-1.0% (w / v) sweetener, 0.1-1.0% (w / v) flavoring agent, 0.5-1.0% (w / v) povidone, 0.1-0.50% (w / v) antibacterial preservative, and the balance being water.

3. The preparation method according to claim 1, characterized in that, The mass ratio of the first polyol to povidone is 9-12:1; and / or the mass ratio of C3-C6 small molecule polyols and C7 and above sugar alcohols in the second polyol is 1:1-10.

4. The preparation method according to claim 1, characterized in that, The C3-C6 small molecule polyols are one or more of propylene glycol, glycerol, and butylene glycol; and / or the C7 and above sugar alcohols are one or more of maltitol, isomaltitol, and lactitol.

5. The preparation method according to claim 1, characterized in that, The first polyol is glycerol; and / or the second polyol is propylene glycol and maltitol.

6. The preparation method according to claim 1, characterized in that, The preservative includes one or more of methylparaben, propylparaben, sorbic acid, potassium sorbate, and sodium sorbate; preferably one or two of methylparaben and propylparaben. And / or the sweeteners include one or more of sucralose, aspartame, acesulfame potassium, steviol glycosides, mogrosides, and ethyl maltol; preferably sucralose and mogrosides, sucralose and ethyl maltol, or sucralose, mogrosides, and ethyl maltol. And / or the flavoring agents include one or more of the following: black cherry flavoring, peppermint flavoring, berry flavoring, cream flavoring, chocolate flavoring, and wintergreen flavoring; preferably black cherry flavoring and peppermint flavoring.

7. The preparation method according to any one of claims 1-6, characterized in that, In step (1), the temperature for heating is 45-65℃.

8. The preparation method according to any one of claims 1-6, characterized in that, In step (1), the amount of water is 5-10% of the total volume of the calcium acetate oral solution; and / or in step (2), the amount of water is 50-80% of the total volume of the calcium acetate oral solution.

9. The preparation method according to claim 1, characterized in that, In step (3), glacial acetic acid is used to adjust the pH to 6.0-6.

8.

10. The calcium acetate oral solution prepared by any one of the preparation methods described in claims 1-9.

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