Iron protein succinate orally disintegrating tablet and preparation method thereof

Abstract

The invention provides an iron protein succinate orally disintegrating tablet and a preparation method thereof, and the iron protein succinate orally disintegrating tablet comprises the following components in parts by weight: 35-45 parts of iron protein succinate, 15-25 parts of trehalose, 25-35 parts of mannitol, 5-7 parts of sodium bicarbonate, 0.5-1.5 parts of polysorbate 80, 2-4 parts of strawberry essence, 0.5-1.5 parts of sucralose, and 8-12 parts of glycine. According to the freeze-dried orally disintegrating tablet disclosed by the invention, a skeleton is self-assembled through a main drug, the skeleton is dissolved through alkaline activation protein iron succinate, a three-dimensional net-shaped skeleton is self-assembled through hydrophobic interaction in a freeze-drying process, a gelatin skeleton is not needed for supporting, and the safety is improved; trehalose and mannitol synergistically regulate the porosity, so that the skeleton is light and crisp and can be quickly disintegrated, the ice crystal damage is reduced, and no fragmentation is caused in the transportation process. In addition, the freeze-dried orally disintegrating tablet has good taste and stability, is convenient to carry, improves patient compliance, is free of animal-derived component gelatin, reduces allergy risk, is suitable for children to take, and has good development prospects.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and in particular to an orally disintegrating protein ferric succinate tablet and its preparation method. Background Technology

[0002] Anemia is a pathological condition where the number of red blood cells or hemoglobin in the circulating blood is chronically lower than normal. Anemia is generally classified into three types: iron deficiency anemia (IDA), megaloblastic anemia, and aplastic anemia. Iron deficiency anemia is mainly caused by blood loss or insufficient iron absorption, such as chronic blood loss anemia caused by excessive menstruation in women, digestive system ulcers, hemorrhoids, malnutrition, pregnancy, and iron deficiency anemia during childhood growth. Iron deficiency is particularly pronounced in pregnant women and women of childbearing age. Iron deficiency anemia (IDA) is a type of anemia caused by a deficiency of stored iron in the body, leading to a decrease in hemoglobin synthesis. It is typically characterized by microcytic hypochromic anemia and is the final manifestation of iron deficiency (ID).

[0003] Iron protein succinylate is a polypeptide-based protein iron supplement. As a large-molecule protein-chelated iron, it precipitates at pH values ​​below 4, but reverts to a soluble form under alkaline conditions. Iron protein succinylate is not digested by pepsin in the stomach; upon entering the intestines, it redissolves and is digested by trypsin. After the protein protective membrane is digested, iron begins to be released in the duodenum. The iron in iron protein succinylate is tightly chelated with protein, resulting in no gastrointestinal irritation from iron ions after administration. It also retains the pH sensitivity of casein, giving it intestinal targeting properties.

[0004] Among the marketed products, ferrous protein succinate oral solution has solved the problems of gastrointestinal mucosal irritation and low bioavailability caused by older generation iron supplements. However, ferrous protein succinate oral solution has the following disadvantages: it is inconvenient to carry, it is a solution, its main component contains a large amount of protein, and a large amount of sodium methylparaben (8%) is added to the formula, which limits its widespread use and increases safety risks. In addition, ferrous protein succinate oral solution has poor stability.

[0005] Currently, there are no orally disintegrating tablets made from ferric protein succinate, let alone lyophilized orally disintegrating tablets. Traditional lyophilized orally disintegrating tablets generally use gelatin and mannitol as the backbone source. During the experiment, the inventors found that orally disintegrating tablets prepared using gelatin have a disintegration time of more than 10 seconds. The iron ion stability of ferric protein succinate requires low-temperature processing, which increases costs. Secondly, the taste is not good, with a slight icy and gritty feel, which some young children will refuse to take. In addition, the presence of gelatin may contain allergens, posing an allergic risk to young children and limiting its use.

[0006] Therefore, there is a need to develop a lyophilized orally disintegrating ferric protein succinate tablet that is safe, highly effective, stable, low in cost, easy to carry, convenient to take, and suitable for use by young children. Summary of the Invention

[0007] In view of this, the present invention proposes an orally disintegrating protein ferric succinate tablet and its preparation method.

[0008] The technical solution of this invention is implemented as follows: A type of orally disintegrating ferric protein succinate tablet, by weight, comprises 35-45 parts ferric protein succinate, 15-25 parts trehalose, 25-35 parts mannitol, 5-7 parts sodium bicarbonate, 0.5-1.5 parts polysorbate 80, 2-4 parts strawberry flavoring, 0.5-1.5 parts sucralose, and 8-12 parts glycine.

[0009] Furthermore, by weight, it includes 40 parts ferric protein succinate, 20 parts trehalose, 30 parts mannitol, 6 parts sodium bicarbonate, 1 part polysorbate 80, 3 parts strawberry flavoring, 1 part sucralose, and 10 parts glycine.

[0010] A method for preparing orally disintegrating protein succinate tablets, comprising the following steps: S1. Add sodium bicarbonate to water for injection, add ferric protein succinate under low-speed stirring, then add trehalose, mannitol, glycine and polysorbate 80 in sequence, homogenize, and finally add strawberry flavor and sucralose to form a solution. S2. Pre-freeze the solution of S1 to form fine ice crystals, and then perform gradient drying on the ice crystals to obtain the product. S3. Place the product from S2 into a mold and control its molding to obtain ferric protein succinate tablets.

[0011] Furthermore, in step S1, the sodium bicarbonate is added to water for injection to adjust the pH value to 8.0-9.0.

[0012] Furthermore, in step S1, the rotation speed of the low-speed stirring is 150-250 rpm.

[0013] Furthermore, in step S1, the homogenization is performed at 2000-2200 rpm for 5-8 minutes.

[0014] Furthermore, in step S2, the pre-freezing temperature is -50~-40℃, and the time is 2-3 hours.

[0015] Furthermore, in step S2, the gradient drying specifically involves: first, sublimation drying is performed at a temperature of -25 to -20°C and a vacuum of 10-15 Pa for 10-12 hours, followed by desorption drying at 30-35°C and a vacuum of 5-8 Pa until the moisture content is less than 1.5%.

[0016] Furthermore, in step S3, the mold has a honeycomb structure.

[0017] Compared with the prior art, the beneficial effects of the present invention are: 1. The lyophilized orally disintegrating tablets of the present invention utilize a self-assembled matrix of the active pharmaceutical ingredient. Through alkaline activation of the ferric protein succinate dissolution process, the tablets self-assemble into a three-dimensional network matrix via hydrophobic interactions during lyophilization, eliminating the need for a gelatin matrix support and improving safety. The porosity is synergistically controlled by trehalose and mannitol, ensuring the matrix is ​​both lightweight and brittle, enabling rapid disintegration while minimizing ice crystal damage and preventing breakage during transport. Verification by examples shows that the lyophilized orally disintegrating ferric protein succinate tablets of the present invention completely disintegrate within 5 seconds.

[0018] 2. In the freeze-drying process of the lyophilized orally disintegrating tablets of the present invention, rapid pre-freezing is performed to form a fine and uniform ice crystal structure, followed by sublimation drying and desorption drying to retain the porosity of the active pharmaceutical ingredient's self-assembled framework and completely remove moisture. After freeze-drying, SEM analysis shows that the porosity is greater than 85%.

[0019] 3. The lyophilized orally disintegrating tablets of the present invention have good taste and stability. The lyophilized orally disintegrating tablets rapidly disintegrate into a fine foamy liquid in the oral cavity without any grainy feeling. Glycine can not only chelate metal ions and inhibit the oxidation of the active ingredient, but also reduce lyophilization stress and increase stability. Experimental examples have verified that after accelerated testing at 40°C and 75% RH, the content of the active ingredient hardly decreased and there was no clumping or discoloration.

[0020] 4. The freeze-dried orally disintegrating tablets of the present invention are convenient to carry, improve patient compliance, contain no animal-derived gelatin, reduce the risk of allergies, are suitable for children, and have good development prospects. Detailed Implementation

[0021] To better understand the technical content of this invention, specific embodiments are provided below to further illustrate the invention.

[0022] Unless otherwise specified, the experimental methods used in the embodiments of this invention are all conventional methods.

[0023] Unless otherwise specified, all materials and reagents used in the embodiments of this invention are commercially available.

[0024] Example 1 The formula is shown in Table 1: Table 1

[0025] Preparation method: A method for preparing orally disintegrating protein succinate tablets, comprising the following steps: S1. Add sodium bicarbonate to water for injection and adjust the pH to 8.5±0.5. Add ferric protein succinate while stirring at 200 rpm, then add trehalose, mannitol, glycine and polysorbate 80 in sequence. Homogenize at 2100 rpm for 7 min. Finally, add strawberry flavor and sucralose to form a solution. S2. The solution of S1 is pre-frozen at -45℃ for 2 hours to form fine ice crystals. The ice crystals are first sublimated and dried at -25℃ and 13Pa vacuum for 11 hours, and then desorbed and dried at 33℃ and 7Pa vacuum until the moisture content is less than 1.5% to obtain the product. S3. The product of S2 is placed in a honeycomb mold to form ferric protein succinate tablets.

[0026] Example 2 The formula is shown in Table 2: Table 2

[0027] Preparation method: S1. Add sodium bicarbonate to water for injection, adjust the pH to 8.5±0.5, add ferric protein succinate while stirring at 150 rpm, then add trehalose, mannitol, glycine and polysorbate 80 in sequence, homogenize at 2000 rpm for 5 min, and finally add strawberry flavor and sucralose to form a solution. S2. The solution of S1 is pre-frozen at -50℃ for 2 hours to form fine ice crystals. The ice crystals are first sublimated and dried at -25℃ and 10 Pa vacuum for 10 hours, and then desorbed and dried at 30℃ and 5 Pa vacuum until the moisture content is less than 1.5% to obtain the product. S3. The product of S2 is placed in a honeycomb mold to form ferric protein succinate tablets.

[0028] Example 3 The formula is shown in Table 3: Table 3

[0029] Preparation method: S1. Add sodium bicarbonate to water for injection, adjust the pH to 8.5±0.5, add ferric protein succinate while stirring at 250 rpm, then add trehalose, mannitol, glycine and polysorbate 80 in sequence, homogenize at 2200 rpm for 8 min, and finally add strawberry flavor and sucralose to form a solution. S2. The solution of S1 is pre-frozen at -40℃ for 3 hours to form fine ice crystals. The ice crystals are first sublimated and dried at -20℃ and 15Pa vacuum for 12 hours, and then desorbed and dried at 35℃ and 8Pa vacuum until the moisture content is less than 1.5% to obtain the product. S3. The product of S2 is placed in a honeycomb mold to form ferric protein succinate tablets.

[0030] Comparative Example 1 The difference from Example 1 is that mannitol is missing, but otherwise it is the same as Example 1.

[0031] The formula is shown in Table 4: Table 4

[0032] Comparative Example 2 The difference from Example 1 is that trehalose is missing, but otherwise it is the same as Example 1.

[0033] The formula is shown in Table 5: Table 5

[0034] Comparative Example 3 Use a gelatin matrix formulation.

[0035] The formula is shown in Table 6: Table 6

[0036] Preparation method: Gelatin and glycine were dissolved in water for injection at 60°C. After cooling to 25°C, ferric protein succinate, mannitol, polysorbate 80, and strawberry flavoring were added. The mixture was homogenized at 2100 rpm for 7 min and dispensed into blister molds pre-cooled to -40°C. The molds were then maintained at -45°C for 2 h to form uniform ice crystals. The mixture was then sublimated and dried at -20°C and 10 Pa, followed by a second drying at 25°C and 5 Pa to remove residual moisture. The blister packs were then sealed in aluminum foil and stored in a moisture-proof and light-proof environment.

[0037] Comparative Example 4 A novel solid dosage form of protein ferric succinate prepared using method CN111000977A.

[0038] Test Example 1 The samples prepared in Examples 1-3 and Comparative Examples 1-4 were subjected to performance testing, and the disintegration time was recorded.

[0039] Disintegration time: Take 6 tablets of the test sample and start the disintegration instrument to check. It should disintegrate completely within 60 seconds.

[0040] The results are recorded in Table 7.

[0041] Table 7

[0042] As can be seen from Table 7, the orally disintegrating iron protein succinate tablets prepared in Examples 1-3 of the present invention can rapidly disintegrate in the oral cavity, which can improve patient medication compliance and is suitable for young children. All of them have been observed to be formed.

[0043] Test Example 2 The stability of the samples prepared in Examples 1-3 and Comparative Examples 1-4 was tested.

[0044] Test method: The samples prepared in Examples 1-3 and Comparative Examples 1-4 were placed in an environment of 40℃±2℃ and 75%±5% relative humidity for 6 months for accelerated testing, and the effective ingredient content was detected by sampling.

[0045] The results are shown in Table 8.

[0046] Table 8

[0047] As shown in Table 8, the orally disintegrating protein succinate tablets prepared in Examples 1-3 have good stability and can maintain efficacy and safety for a long time. In the accelerated test, the content of the active ingredient remained basically unchanged, and there was no clumping or discoloration.

[0048] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A protein ferric succinate orally disintegrating tablet, characterized in that, By weight, it includes 35-45 parts ferric protein succinate, 15-25 parts trehalose, 25-35 parts mannitol, 5-7 parts sodium bicarbonate, 0.5-1.5 parts polysorbate 80, 2-4 parts strawberry flavoring, 0.5-1.5 parts sucralose, and 8-12 parts glycine.

2. The orally disintegrating protein ferric succinate tablet as described in claim 1, characterized in that, By weight, it includes 40 parts ferric protein succinate, 20 parts trehalose, 30 parts mannitol, 6 parts sodium bicarbonate, 1 part polysorbate 80, 3 parts strawberry flavoring, 1 part sucralose, and 10 parts glycine.

3. The method for preparing ferric protein succinate orally disintegrating tablets as described in claim 1, characterized in that, The specific steps include: S1. Add sodium bicarbonate to water for injection, add ferric protein succinate under low-speed stirring, then add trehalose, mannitol, glycine and polysorbate 80 in sequence, homogenize, and finally add strawberry flavor and sucralose to form a solution. S2. Pre-freeze the solution of S1 to form fine ice crystals, and then perform gradient drying on the ice crystals to obtain the product. S3. Place the product from S2 into a mold and control its molding to obtain ferric protein succinate tablets.

4. The method for preparing ferric protein succinate orally disintegrating tablets as described in claim 3, characterized in that, In step S1, the sodium bicarbonate is added to water for injection to adjust the pH value to 8.0-9.

0.

5. The method for preparing ferric protein succinate orally disintegrating tablets as described in claim 3, characterized in that, In step S1, the speed of the low-speed stirring is 150-250 rpm.

6. The method for preparing an orally disintegrating protein succinate tablet as described in claim 3, characterized in that, In step S1, the homogenization is performed at 2000-2200 rpm for 5-8 minutes.

7. The method for preparing ferric protein succinate orally disintegrating tablets as described in claim 3, characterized in that, In step S2, the pre-freezing temperature is -50~-40℃, and the time is 2-3 hours.

8. The method for preparing ferric protein succinate orally disintegrating tablets as described in claim 3, characterized in that, In step S2, the gradient drying specifically involves: first, sublimation drying is performed at a temperature of -25 to -20°C and a vacuum of 10-15 Pa for 10-12 hours, followed by desorption drying at 30-35°C and a vacuum of 5-8 Pa until the moisture content is less than 1.5%.

9. The method for preparing an orally disintegrating protein succinate tablet as described in claim 3, characterized in that, In step S3, the mold has a honeycomb structure.

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