A protein ferric succinyl oral solution and a method of making the same
By optimizing the formulation and preparation process of ferric protein succinate oral solution, the problems of slow dissolution rate and low safety of preservatives have been solved, realizing the production of ferric protein succinate oral solution with rapid dissolution, easy filling and high safety.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- QINGDAO HUANGHAI PHARM CO LTD
- Filing Date
- 2024-12-09
- Publication Date
- 2026-06-09
AI Technical Summary
Existing oral solutions for ferric protein succinate suffer from slow dissolution, high viscosity, and difficulty in filling during preparation. Furthermore, the preservatives used have relatively low safety, affecting product quality and shelf-life stability.
The formulation and process parameters are formulated in specific proportions, including mixing and sieving the ferric protein succinate raw material with sorbitol and then mixing it with solvent, controlling the temperature and pH value, using benzoic acid or sodium benzoate, which are safer, as preservatives, and optimizing the preparation process to improve the dissolution rate and reduce viscosity.
It enables rapid dissolution of protein ferric succinate raw materials, reduces the adverse effects of high temperature on proteins, simplifies the filling process, improves product safety and stability, facilitates commercial production, and ensures that key physicochemical properties meet requirements.
Smart Images
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Abstract
Description
Technical Field
[0001] The present invention belongs to the field of pharmaceutical technology, and specifically relates to an oral solution of iron protein succinate and a preparation method thereof. Technical Background
[0002] The content of iron element in the human body is about 0.004%, which is one of the essential trace elements in the human body and is the trace element with the highest content. Iron element plays an important role in many biochemical reactions in the human body. For example, it participates in the formation of hemoglobin and myoglobin, and participates in the carrying and transportation of oxygen and carbon dioxide; it participates in the synthesis of cytochrome oxidase, thus participating in cell metabolism, etc.; in addition, iron element also has the functions of maintaining normal hematopoietic function, immune function, and preventing epithelial tissue damage. Iron deficiency is a state in which the normal and stable iron metabolism cycle in the human body is disrupted and there is not enough available iron, which is one of the common nutrient deficiencies. The final stage of its development is iron deficiency anemia. The main reasons for iron deficiency include intake disorders, excessive consumption, and the inability of iron intake to meet the needs. Infants, pregnant women, women of childbearing age, and the elderly over 60 years old are the most susceptible groups to iron deficiency.
[0003] Currently, there are mainly two ways to supplement iron: oral iron supplementation and intravenous iron supplementation. Oral iron supplementation is more convenient, economical, safe, and effective. The solubility of divalent iron in oral iron preparations is large and is easily absorbed by the human body. The absorption of trivalent iron in the body is only equivalent to 1 / 3 of divalent iron. Generally, ferrous preparations are preferred. When anemia is severe and needs to be corrected as soon as possible or oral iron supplementation cannot be tolerated, intravenous iron supplementation treatment can be considered.
[0004] The oral solution of iron protein succinate (Ferplex) has the original research drug indication for treating absolute and relative iron deficiency anemia such as latent or overt iron deficiency anemia caused by insufficient iron intake or absorption disorders, acute or chronic blood loss, and infections, anemia during pregnancy and lactation.
[0005] The existing oral solution of iron protein succinate belongs to the second-generation small-molecule oral organic iron agent. It forms a precipitate at a pH value less than 4 and becomes a soluble substance again at a higher pH (pH 7.5 - 8). In addition, this preparation is not digested by pepsin and is hydrolyzed by trypsin at a neutral pH value. The iron contained in this product is protected by a protein film, so it will not cause gastric mucosal damage and starts to be released in the duodenum, and is directly absorbed into the blood through peptide transport. The bioavailability is improved, and generally there will be no gastrointestinal tolerance problems, and it is safer and has a better application prospect.
[0006] Ferric protein succinate is a semi-synthetic macromolecular iron complex with a complex structure, resulting in a complex and time-consuming formulation preparation process. The active pharmaceutical ingredient (API) of ferric protein succinate is highly hygroscopic, easily agglomerating into a colloid upon contact with water, making it difficult to dissolve. Furthermore, the oral solution of ferric protein succinate exists in colloidal form, making the solution viscous, difficult to fill, and impossible to pour out. Current technologies often use heating to promote dissolution, but because the API is already agglomerated in its initial state, even with increased temperature, dissolution still requires a long time. Additionally, since ferric protein succinate is a protein, excessively high temperatures are detrimental to protein stability. Moreover, the existing formulations use sodium methylparaben and sodium propylparaben as preservatives, both of which are readily absorbed after opening, leading to inaccurate weighing. Insufficient dosage results in reduced antibacterial efficiency, failing to guarantee that the product meets microbiological requirements during its shelf life, while excessive dosage raises safety concerns.
[0007] Based on the above problems, it is necessary to develop a formula and preparation method for an oral solution of ferric protein succinate that has a fast dissolution rate, is more stable, and has higher safety. Summary of the Invention
[0008] The purpose of this invention is to provide a formulation of an oral solution containing ferric protein succinate and its preparation method, thereby solving the problem that ferric protein succinate cannot be filled due to its high viscosity during preparation, and selecting a highly safe preservative to ensure that the microbial level of the preparation meets the quality standards, while also ensuring safe use.
[0009] To achieve the above objectives, the present invention adopts the following technical solution:
[0010] A ferric protein succinate oral solution, comprising, by weight percentage of total prescription volume (g for weight, ml for volume), 5.33% ferric protein succinate raw material, 5-20% sweetener, 5-20% solvent, 0.5-2% preservative, 0.1-0.5% sweetener, 0.5-2% flavoring agent, and purified water to a final volume of 15 ml; wherein the preservative is benzoic acid or sodium benzoate.
[0011] Preferably, the oral solution of ferric protein succinate contains, by weight percentage of total prescription volume, 5.33% ferric protein succinate, 5-15% sorbitol, 5-10% propylene glycol, 0.3-1% preservative, 0.05-0.2% sodium saccharin, 0.05-1% jujube flavoring, and purified water to a final volume of 15 ml.
[0012] The sweetener is sorbitol, the solvent is propylene glycol, the sweetener is sodium saccharin, and the flavoring agent is jujube flavoring.
[0013] A method for preparing the aforementioned ferric protein succinate oral solution involves first mixing ferric protein succinate technical material with a sweetener and sieving the mixture, then mixing it with purified water, solvent, preservative, sweetener, and flavoring agent to prepare the ferric protein succinate oral solution.
[0014] Specifically, it includes the following steps:
[0015] 1) Under normal temperature conditions, the ferric protein succinate technical material is mixed with the sweetener and then passed through a 60-80 mesh sieve;
[0016] 2) Dissolve the solvent in 30% purified water at room temperature;
[0017] 3) Add the mixture from step 1) to the solution from step 2) and heat to 65℃~78℃;
[0018] 4) Add alkali solution to the mixture from step 3) to control the pH to 7.0–8.0;
[0019] 5) Add the preservative when the temperature of the solution from step 4) drops to 25–40°C;
[0020] 6) Add sweetener and flavoring agent to the solution from step 5);
[0021] 7) Add the remaining purified water to the solution from step 6) to bring the volume up to 15 ml, stir well, filter, and fill to obtain the ferric protein succinate oral solution.
[0022] Preferably, the temperature in step 3) is 75–78°C.
[0023] Preferably, in step 4), the alkaline solution is a 0.1 mol / L sodium hydroxide solution with a pH of 7.5 to 7.8.
[0024] Compared with the prior art, the advantages of the present invention are:
[0025] 1. This invention, by screening the formulation and process preparation parameters, can increase the dissolution rate of ferric protein succinate raw material, reduce the time ferric protein succinate spends at high temperatures, reduce the adverse effects of high temperatures on ferric protein succinate, and at the same time reduce the viscosity of the solution, making it easier to fill and more suitable for commercial production. The drug preparation process is efficient and simple to operate.
[0026] 2. This invention selects benzoic acid or sodium benzoate, which are more stable and safer preservatives, and have low toxicity and good antibacterial effect.
[0027] 3. In this invention, the active pharmaceutical ingredient (API) of ferric protein succinate is first mixed with sorbitol and sieved to prevent the aggregation of API. After sieving, the API and sorbitol are more easily dispersed evenly in water. Then, sodium hydroxide is slowly added to promote dissolution, which solves the problem of long dissolution time of API. The prepared sample is tested for key physicochemical properties such as content, free iron, dissolution curve, and microbial limit. The results are equivalent to the in vitro dissolution of the reference preparation, and the safety is better. Detailed Implementation
[0028] The following examples provide a more detailed description of the formulation and preparation method of an oral solution containing protein ferric succinate, which is involved in this invention.
[0029] Example 1
[0030] Table 1. Composition of the Formula for Ferric Protein Succinate Oral Solution
[0031]
[0032] Prepare 1500ml of the medicine solution according to the above-mentioned standard prescription. The specific preparation process is as follows:
[0033] 1) Raw material pretreatment: Mix 80g of protein succinic acid raw material with 130g of sorbitol and pass through an 80-mesh sieve;
[0034] 2) Propylene glycol dissolution: In a mixing tank, add 110g of propylene glycol to 450ml of purified water and stir until dissolved;
[0035] 3) Add the mixture from step 1) to the solution from step 2) in the mixing tank, and heat to 75°C;
[0036] 4) Slowly add 0.1 mol / L sodium hydroxide to the mixture from step 3) to adjust the pH to 7.6 and dissolve the active pharmaceutical ingredient;
[0037] 5) Dissolving the preservative: Cool the solution from step 4) to 35°C and add 7.5g of sodium benzoate;
[0038] 6) Dissolving sweeteners and flavoring agents: Add 5.5g of jujube flavoring and 1.5g of sodium saccharin to the solution in step 5);
[0039] 7) Volume adjustment: Add the remaining purified water to the solution in step 6) to make up to 1500ml, stir well, filter and fill.
[0040] Example 2
[0041] Table 2. Composition of the Formula for Ferric Protein Succinate Oral Solution
[0042]
[0043]
[0044] Prepare 1500ml of the medicine solution according to the above-mentioned standard prescription. The specific preparation process is as follows:
[0045] 1) Raw material pretreatment: Under normal temperature conditions, mix 80g of protein succinic acid raw material with 225g of sorbitol and pass through an 80-mesh sieve;
[0046] 2) Propylene glycol dissolution: In a mixing tank, add 150g of propylene glycol to 450ml of purified water and stir until dissolved;
[0047] 3) Add the mixture from step 1) to the solution from step 2) in the mixing tank, and heat to 75°C;
[0048] 4) Slowly add 0.1 mol / L sodium hydroxide to the mixture from step 3) and adjust the pH to 7.5 to dissolve the active pharmaceutical ingredient;
[0049] 5) Dissolving the preservative: Cool the solution from step 4) to below 35°C and add 15g of sodium benzoate;
[0050] 6) Dissolving sweeteners and flavoring agents: Add 15g of jujube flavoring and 0.3g of sodium saccharin to the solution in step 5);
[0051] 7) Volume adjustment: Add the remaining purified water to the solution in step 6) to make up to 1500ml, stir well, filter and fill.
[0052] Example 3
[0053] Table 3. Composition of the Formula for Ferric Protein Succinate Oral Solution
[0054]
[0055]
[0056] Prepare 1500ml of the medicine solution according to the above-mentioned standard prescription. The specific preparation process is as follows:
[0057] 1) Raw material pretreatment: Under normal temperature conditions, mix 80g of protein succinic acid raw material with 75g of sorbitol and pass it through an 80-mesh sieve;
[0058] 2) Propylene glycol dissolution: In a mixing tank, add 75g of propylene glycol to purified water and stir until dissolved;
[0059] 3) Add the mixture from step 1) to the solution from step 2) in the mixing tank, and heat to 75°C;
[0060] 4) Slowly add 0.1 mol / L sodium hydroxide to the mixture from step 3) to adjust the pH to 7.5 and dissolve the active pharmaceutical ingredient.
[0061] 5) Dissolving the preservative: Cool the solution from step 4) to below 35°C and add 3g of sodium benzoate;
[0062] 6) Dissolving sweeteners and flavoring agents: Add 7.5g of jujube flavoring and 75g of sodium saccharin to the solution in step 5);
[0063] 7) Volume adjustment: Add the remaining purified water to the solution in step 6) to make up to 1500ml, stir well, filter and fill.
[0064] Comparative Example 1
[0065] Table 4. Composition of the Formula for Ferric Protein Succinate Oral Solution
[0066]
[0067]
[0068] The difference from Example 1 is that the preservatives used in the prescription are sodium methylparaben and sodium propylparaben. 1500ml of the drug solution is prepared according to the above-mentioned standard prescription, and the specific preparation is the same as in Example 1.
[0069] Comparative Example 2
[0070] The difference from Example 1 is that: the protein succinic acid raw material was directly sieved and dissolved in purified water, and then sorbitol and other raw materials were added. Following the standard formulation of Example 1, 1500ml of the solution was prepared. The specific preparation process is as follows:
[0071] 1) Under normal temperature conditions, pass the protein succinic acid raw material through an 80-mesh sieve;
[0072] 2) Propylene glycol dissolution: In a mixing tank, add 110g of propylene glycol to 450ml of purified water and stir until dissolved. Then add 130g of sorbitol and stir until dissolved.
[0073] 3) Add the mixture from step 1) to the solution from step 2) in the mixing tank, and heat to 75°C;
[0074] 4) Slowly add 0.1 mol / L sodium hydroxide to the mixture from step 3) to adjust the pH to 7.6 and dissolve the active pharmaceutical ingredient;
[0075] 5) Dissolving the preservative: Cool the solution from step 4) to 35°C and add 7.5g of sodium benzoate;
[0076] 6) Dissolving sweeteners and flavoring agents: Add 5.5g of jujube flavoring and 1.5g of sodium saccharin to the solution in step 5);
[0077] 7) Volume adjustment: Add the remaining purified water to the solution in step 6) to make up to 1500ml, stir well, filter and fill.
[0078] Comparative Example 3
[0079] The difference from Example 1 is that the preparation temperature is room temperature, and 1500ml of the drug solution is prepared according to the basic formula of Example 1. The specific preparation process is as follows:
[0080] 1) Under normal temperature conditions, mix 80g of protein succinic acid raw material with 130g of sorbitol and pass the mixture through an 80-mesh sieve;
[0081] 2) Propylene glycol dissolution: In a mixing tank, add 110g of propylene glycol to 450ml of purified water and stir until dissolved;
[0082] 3) Under normal temperature conditions, add the mixture from step 1) to the solution from step 2) in the mixing tank;
[0083] 4) Slowly add 0.1 mol / L sodium hydroxide to the mixture from step 3) to adjust the pH to 7.6 and dissolve the active pharmaceutical ingredient;
[0084] 5) Dissolving the preservative: Cool the solution from step 4) to 35°C and add 7.5g of sodium benzoate;
[0085] 6) Dissolving sweeteners and flavoring agents: Add 5.5g of jujube flavoring and 1.5g of sodium saccharin to the solution in step 5);
[0086] 7) Volume adjustment: Add the remaining purified water to the solution in step 6) to make up to 1500ml, stir well, filter and fill.
[0087] Comparative Example 4
[0088] The difference from Example 1 is that the preparation temperature is 80℃, and 1500ml of the drug solution is prepared according to the basic formula of Example 1. The specific preparation process is as follows:
[0089] 1) Raw material pretreatment: Under normal temperature conditions, mix 80g of protein succinic acid raw material with 130g of sorbitol and pass through an 80-mesh sieve;
[0090] 2) Propylene glycol dissolution: In a mixing tank, add 110g of propylene glycol to 450ml of purified water and stir until dissolved;
[0091] 3) Add the mixture from step 1) to the solution from step 2) in the mixing tank, and heat to 80°C;
[0092] 4) Slowly add 0.1 mol / L sodium hydroxide to the mixture from step 3) to adjust the pH to 7.6 and dissolve the active pharmaceutical ingredient;
[0093] 5) Dissolving the preservative: Cool the solution from step 4) to 35°C and add 7.5g of sodium benzoate;
[0094] 6) Dissolving sweeteners and flavoring agents: Add 5.5g of jujube flavoring and 1.5g of sodium saccharin to the solution in step 5);
[0095] 7) Volume adjustment: Add the remaining purified water to the solution in step 6) to make up to 1500ml, stir well, filter and fill.
[0096] Performance testing
[0097] 1. The preservative content of the preparations obtained in Example 1 and Comparative Example 1 was determined. The samples were placed at 40℃±2℃ and RH25%±5% for 3 months, and the preservative content was determined. The results are shown in Table 5.
[0098] Table 5 Results of Preservative Content Determination
[0099]
[0100]
[0101] As shown in Table 5, the sodium benzoate preservative used in Example 1 maintained a stable content during the stability period. However, when sodium methylparaben and sodium propylparaben were used as preservatives, the samples showed a significant decreasing trend after 3 months of stability. The decrease in preservative content would affect the antibacterial effect, and the product would be at risk of failing to meet microbial standards during shelf life. Therefore, the sodium benzoate or benzoic acid used in the embodiments of this invention have better performance and stable content during the stability period, which can ensure that the product meets the microbial requirements during shelf life.
[0102] 2. The preparation process of Example 1 was compared with the preparation methods of Comparative Examples 2, 3, and 4. The results are as follows:
[0103] Table 6 Comparison of Detection Results
[0104]
[0105] As shown in Table 6, in this embodiment of the invention, the protein ferric succinate raw material was mixed with sorbitol, sieved, and then the solution was prepared. The dissolution time was significantly shorter than that of Comparative Example 2, where the protein ferric succinate raw material was hygroscopic and prone to aggregation, so sieving the raw material alone did not achieve the desired dispersion effect. Furthermore, in this embodiment of the invention, the mixing time under heating conditions was significantly shorter than that under room temperature conditions. This reduced the mixing time while ensuring the activity of the protein ferric succinate remained unaffected. In Comparative Example 3, the room temperature mixing time was longer, increasing the overall mixing time. Increasing the temperature can shorten the dissolution time of the raw material, but excessively high temperatures can cause protein denaturation, producing insoluble flocculent matter, which is an irreversible reaction. Therefore, in the preparation process of Comparative Example 4, brown flocculent matter appeared in the solution after about 10 minutes of dissolution of the raw material; this matter did not dissolve after cooling. Therefore, the specific reaction temperature and time in this embodiment of the invention shortened the dissolution time while ensuring the activity of the protein ferric succinate remained unaffected.
[0106] 3. The preparation method of this invention is more efficient and simple to operate. The preparation time is significantly shorter than that of Comparative Example 1 and Comparative Example 2 while ensuring that the activity of the oral solution of ferric protein succinate is not affected. It is easier to commercialize and produce. Moreover, the content of various key physicochemical properties, such as free iron, all meet the requirements. The dissolution curve is consistent with the dissolution curve of the original preparation.
[0107] Table 7 Results of Key Physicochemical Properties Testing
[0108]
[0109] In summary, the method of this invention involves mixing the active pharmaceutical ingredient (API) with sorbitol, sieving the mixture, and then dispersing it evenly in purified water at room temperature to prevent the API from agglomerating into viscous clumps. Temperature control further enhances the dissolution rate of the API, shortens the preparation time, and prevents protein degradation from prolonged exposure to high temperatures. The formulation also incorporates safer preservatives to improve product safety. This invention simplifies the production process through optimization and control of the preparation process, making filtration and filling easier to operate, and resulting in a safer solution.
Claims
1. A protein ferric succinate oral solution, characterized in that, The oral solution of ferric protein succinate, by weight percentage of the total prescription volume, consists of 5.33% ferric protein succinate, 5-20% sweetener, 5-20% solvent, 0.5-2% preservative, 0.1-0.5% sweetener, 0.5-2% flavoring agent, and purified water to a final volume of 15 ml; the preservative is benzoic acid or sodium benzoate.
2. The ferric protein succinate oral solution according to claim 1, characterized in that, The oral solution of ferric protein succinate contains, by weight percentage of total prescription volume, 5.33% ferric protein succinate, 5-15% sorbitol, 5-10% propylene glycol, 0.3-1% preservatives, 0.05-0.2% sodium saccharin, 0.05-1% jujube flavoring, and purified water to a final volume of 15 ml.
3. The ferric protein succinate oral solution according to claim 1 or 2, characterized in that, The sweetener is sorbitol, the solvent is propylene glycol, the sweetener is sodium saccharin, and the flavoring agent is jujube flavoring.
4. A method for preparing the ferric protein succinate oral solution according to claim 1, characterized in that: First, the ferric protein succinate technical material is mixed with sweetener and sieved. Then, it is mixed with purified water, solvent, preservative, sweetener and flavoring agent to prepare ferric protein succinate oral solution.
5. The method for preparing the ferric protein succinate oral solution according to claim 4, characterized in that: Includes the following steps: 1) Under normal temperature conditions, the ferric protein succinate technical material is mixed with the sweetener and then passed through a 60-80 mesh sieve; 2) Dissolve the solvent in 30% purified water at room temperature; 3) Add the mixture from step 1) to the solution from step 2) and heat to 65℃~78℃; 4) Add alkali solution to the mixture from step 3) to control the pH to 7.0–8.0; 5) Add the preservative when the temperature of the solution from step 4) drops to 25–40°C; 6) Add sweetener and flavoring agent to the solution from step 5); 7) Add the remaining purified water to the solution from step 6) to bring the volume up to 15 ml, stir well, filter, and fill to obtain the ferric protein succinate oral solution.
6. The method for preparing the ferric protein succinate oral solution according to claim 5, characterized in that, Step 3) Temperature 75~78℃. Step 4) The alkaline solution is a 0.1 mol / L sodium hydroxide solution with a pH of 7.5 to 7.8.