Improved iron protein succinate oral solution and preparation method thereof

Abstract

The invention discloses a preparation method of an improved iron proteinsuccinylate oral solution, which comprises the following steps: 1) taking 40-80% of purified water, controlling the solution preparation temperature at 30-40 DEG C, adding poloxamer, sodium methyl hydroxybenzoate, sodium propyl hydroxybenzoate and sorbitol for dissolving, then adding iron proteinsuccinylate, mechanically stirring uniformly, and simultaneously adjusting the pH value to 6.5-7.5; and 2) dissolving the raw material medicines, adding saccharin sodium salt and essence, supplementing purified water to a constant volume, continuing to perform preliminary dispersion by mechanical stirring, performing high-voltage pulse electric field treatment in a high-voltage pulse electric field treatment chamber, and finally performing filtration and subpackaging to obtain the improved iron proteinsuccinylate oral solution. According to the iron proteinsuccinylate oral solution provided by the invention, tests show that the free iron content of the iron proteinsuccinylate oral solution does not exceed 0.1% of the total content of the iron proteinsuccinylate oral solution, sediments and microorganisms are limited to meet specified requirements, and meanwhile, the iron proteinsuccinylate oral solution also has a slow-release effect and excellent stability and safety.

Description

Technical Field

[0001] The invention belongs to the technical field of drug preparation, and particularly relates to an improved protein succinate iron and a preparation method thereof. Background Art

[0002] Iron protein succinylate (ISP) is a polypeptide protein iron supplement drug that has been marketed in more than 20 countries around the world since the 1980s. Iron protein succinylate is a brown or brownish red powder of macromolecular protein complexed iron. It is insoluble in water, 0.1 mol / L hydrochloric acid, methanol, ethanol, and acetone, and slightly soluble in 0.1 mol / L sodium hydroxide solution or phosphate buffer (pH 7.6). The oral iron protein succinylate solution made from iron protein succinylate is indicated for the treatment of absolute and relative iron deficiency anemia, the treatment of invisible or obvious iron deficiency anemia caused by insufficient iron intake or malabsorption, acute or chronic blood loss, and infection in patients of all ages, and the treatment of anemia during pregnancy and lactation. It is well received by consumers and medical professionals. Iron deficiency anemia is mainly caused by blood loss or insufficient iron absorption, including chronic hemorrhagic anemia such as menorrhagia, digestive system ulcers, hemorrhoids, malnutrition, pregnancy, and iron deficiency during childhood. Iron deficiency anemia is one of the common diseases among women and children. Iron deficiency in the body has a great impact on the life safety of pregnant women and fetuses, and the physical and intellectual development of children.

[0003] At present, the main oral solution of protein succinate iron on the market is imported, which is expensive and increases the burden on patients. In the preparation method of the current oral solution of protein succinate iron in China, it is disclosed that the pH of the system can be adjusted, and high temperature and high speed centrifugation can be used to achieve effective dissolution of the oral solution of protein succinate iron, thereby obtaining a technical solution with a free iron content of less than 0.1%, but it still has problems such as poor absorbability, biosafety and stability.

[0004] In view of the above problems, it is urgent to develop a preparation method that can ensure that the protein succinate iron raw material is completely dissolved while effectively ensuring that its protein structure is not destroyed, thereby ensuring that the quality of the product meets the requirements; it can ensure that the protein succinate iron oral solution has excellent stability, and during its preparation and storage process, its microbial level meets the requirements of the Chinese Pharmacopoeia while reducing the amount of antibacterial agents as much as possible. Summary of the invention

[0005] The present invention aims to solve one of the technical problems in the related art at least to a certain extent. To this end, the main purpose of the present invention is to provide an improved oral solution of iron protein succinate and a preparation method thereof.

[0006] The objective of the present invention is achieved through the following technical solutions:

[0007] A method for preparing an improved iron protein succinate oral solution comprises the following steps:

[0008] 1) Take 40% to 80% of the prescription amount of purified water, control the solution temperature at 30°C to 40°C, add poloxamer, sodium methylparaben, sodium propylparaben and sorbitol to dissolve, then add iron protein succinate, stir mechanically to evenly, and add sodium hydroxide solution until the pH of the solution reaches 6.5-7.5;

[0009] 2) After the API is dissolved, saccharin sodium and flavor are added, and purified water is added to make up the volume. After preliminary dispersion by mechanical stirring, high-voltage pulse electric field treatment is performed in a high-voltage pulse electric field treatment chamber, and finally filtration and subpackaging are performed to obtain the improved oral solution of protein succinate iron.

[0010] In certain specific embodiments, the improved oral solution of ferric protein succinate comprises the following components: 800 mg / 15 ml of ferric protein succinate, 10-25 mg / 15 ml of poloxamer, 1400 mg / 15 ml of sorbitol, 15-25 mg / 15 ml of sodium methylparaben, 5-10 mg / 15 ml of sodium propylparaben, 30-50 mg / 15 ml of flavor, 5-15 mg / 15 ml of sodium saccharin, an appropriate amount of sodium hydroxide, and the balance is pure water.

[0011] In certain specific embodiments, the particle size of the ferric protein succinate oral solution is 100-300 mesh.

[0012] In certain specific embodiments, the flavor in step 1) includes, but is not limited to, one or more of black cherry flavor, blackberry flavor, orange flavor, banana flavor, and tangerine flavor.

[0013] In some specific embodiments, the molar concentration of sodium hydroxide in step 1) is 2-3 mol / L.

[0014] In some specific embodiments, the mechanical stirring conditions in step 2) are: a rotation speed of 150-200 r / min and a stirring time of 10-20 min.

[0015] In certain specific embodiments, the condition parameters of the high voltage pulse electric field treatment in step 4) are: electric field intensity of 1.0-2.0 kV / cm, pulse width of 10-30 μm, pulse frequency of 20-40 KHz, and treatment time of 5-10 min.

[0016] In certain specific embodiments, the filtration in step 4) is performed using a 0.22 μm filter.

[0017] Compared with the prior art, the present invention has at least the following advantages:

[0018] 1) The preparation method provided by the present invention adopts poloxamer as a solubilizer, sorbitol as a stabilizer, and combines a high-voltage pulse electric field treatment process under specific parameters (specific electric field strength, pulse width and pulse frequency), so that the protein succinate iron in the present application can be well dissolved in the protein succinate iron oral solution system without destroying the structure. After testing, the free iron content of the protein succinate iron oral solution does not exceed 0.1% of the total content, and the precipitate meets the prescribed requirements.

[0019] 2) The preparation method provided by the present invention adopts poloxamer and high-voltage pulse electric field treatment combined with specific electric field strength, pulse width and pulse frequency, which, on the one hand, increases the residence time of iron protein succinate in the intestine and increases the sustained-release effect; on the other hand, it promotes the absorption of iron protein succinate by the mucosa. The interaction between the two greatly promotes the absorption and utilization of iron protein succinate, reduces the number of dosing times, reduces the toxic and side effects of the drug, and increases patient compliance.

[0020] 3) The preparation method provided by the present invention optimizes the amount of preservative added to the preparation by using sodium methylparaben and sodium propylparaben as preservatives and combining high-voltage pulsed electric field treatment with specific electric field strength, pulse width and pulse frequency with sterilization treatment. While ensuring that the microorganisms of the protein iron succinate oral solution meet the regulations during the stability period, the amount of preservative added is further reduced, and the safety of clinical use is also improved.

[0021] 4) In the preparation method of the present invention, the stability of the protein iron succinate oral solution is greatly improved by controlling the pH value in the process parameters and combining high-voltage pulse electric field treatment with specific electric field strength, pulse width and pulse frequency. This may be because the pH value is at or close to the isoelectric point of the protein iron succinate oral solution, the surface charge of the protein molecules near the isoelectric point is close to zero, and the electrostatic repulsion between molecules is minimal, which is conducive to forming a tighter and more stable molecular structure, thereby improving the stability of the protein iron succinate oral solution. The stability to light and heat is good, and the storage period at room temperature is tentatively set at two years.

[0022] 5) The improved oral solution of iron protein succinate prepared by the present invention meets the import drug registration standard HJ20160143 in all indicators, and other indicators meet the relevant provisions of the general rules of the fourth part of the 2020 edition of the Chinese Pharmacopoeia (0123 oral solution). DETAILED DESCRIPTION

[0023] The present invention will be further described in detail below in conjunction with specific embodiments. The following embodiments are merely illustrative and not restrictive, and the protection scope of the present invention cannot be limited thereto.

[0024] When a certain amount, concentration or other value or parameter is expressed in the form of a range, a preferred range, or a preferred upper and lower numerical limit, it should be understood that it is equivalent to specifically revealing any range by combining any pair of upper range limits or preferred numerical values ​​with any lower range limit or preferred numerical value, regardless of whether the range is specifically disclosed. Unless otherwise indicated, the numerical range values ​​listed herein include the endpoints of the range, and all integers and fractions within the range.

[0025] Unless otherwise indicated, all percentages, parts, ratios, etc. herein are by weight.

[0026] The materials, methods, and examples herein are illustrative and are not to be construed as limiting unless specifically stated.

[0027] The present invention provides a general and / or specific description of the materials and test methods used in the experiment. The test methods or test methods involved are all conventional methods unless otherwise specified; the reagents or instruments used are all conventional products available on the market, prepared or used in a conventional manner, unless the manufacturer is specified.

[0028] In the following examples, the particle size of iron protein succinate is 100-300 mesh;

[0029] Example 1

[0030] This embodiment provides a prescription for an improved oral solution of iron protein succinate, comprising:

[0031] Iron protein succinate: 800mg; Poloxamer: 20g; Sorbitol: 1500mg; Sodium methylparaben: 20mg; Sodium propylparaben: 10mg; Black cherry flavor: 45mg; Sodium saccharin: 15mg; Sodium hydroxide: appropriate amount; Purified water: add to 15ml.

[0032] This embodiment also provides a method for preparing the improved iron protein succinate oral solution, which comprises the following steps:

[0033] 1) Take 70% of the prescription amount of purified water, control the solution temperature at 35°C, add poloxamer, sodium methylparaben, sodium propylparaben and sorbitol to dissolve, then add ferric protein succinate, mechanically stir and disperse at a speed of 150r / min for 10min, and at the same time add sodium hydroxide solution (the molar concentration of the sodium hydroxide solution is 3mol / L) until the pH of the solution reaches 7.2;

[0034] 2) After the API is dissolved, saccharin sodium and flavor are added, and purified water is added to make up the volume. The mixture is mechanically stirred and dispersed at a speed of 200 r / min for 5 minutes. At the same time, a high-voltage pulse electric field with an electric field strength of 1.5 kV / cm, a pulse width of 20 μm, and a pulse frequency of 30 kHz is used for treatment for 10 minutes. Finally, the mixture is filtered through 2.2 μm and packaged to obtain the improved oral solution of protein succinate iron.

[0035] In this example, the prepared iron protein succinate oral solution was tested for performance, and the results are shown in Table 1:

[0036] Table 1 Performance parameters of iron protein succinate oral solution in this embodiment

[0037]

[0038] From the data in Table 1, it can be seen that the protein succinate iron oral solution in this application meets the import drug registration standard HJ20160143 for various indicators, and the others meet the relevant provisions under the 2020 edition of the Chinese Pharmacopoeia (Chinese Pharmacopoeia) Part IV General 0123 Oral Solution. The free iron content in the protein succinate iron oral solution does not exceed 0.1%, the sediment content is not more than 0.1ml, and the microbial limits all meet the relevant requirements.

[0039] Example 2

[0040] This example provides a prescription for an improved oral solution of iron protein succinate, which is the same as that of Example 1;

[0041] This embodiment also provides a method for preparing the improved oral solution of iron protein succinate, and its preparation process is basically the same as that of Example 1, except that the proportion of pure water added in step 1) is different, specifically:

[0042] Prescription 1: Take 60% of the prescription amount of purified water, control the preparation temperature at 35°C, add poloxamer, sodium methylparaben, sodium propylparaben and sorbitol to dissolve, then add iron protein succinate, mechanically stir and disperse at a speed of 150r / min for 10min, and add sodium hydroxide solution (the molar concentration of the sodium hydroxide solution is 3mol / L) until the pH of the solution reaches 7.2;

[0043] Prescription 2: Take 80% of the prescription amount of purified water, control the preparation temperature at 35°C, add poloxamer, sodium methylparaben, sodium propylparaben and sorbitol to dissolve, then add iron protein succinate, mechanically stir and disperse at a speed of 150r / min for 10min, and add sodium hydroxide solution (the molar concentration of the sodium hydroxide solution is 3mol / L) until the pH of the solution reaches 7.2;

[0044] This example tests the performance of the preparation process of the oral solution of iron protein succinate with different initial amounts of purified water, as shown in Table 3:

[0045] Table 3 Preparation phenomenon of oral solution of iron protein succinate with different initial water addition amounts in this example

[0046] prescription Initial water volume Solution status during preparation Capacity Viscosity Example 1 70％ Easy flowing liquid Normal volume 23.73cp Prescription 1 60％ Sticky jelly Can be fixed 105.54cp Prescription 2 80％ Easy flowing liquid Undetermined volume exceeds the prescribed amount 55.26cp

[0047] From the data in Table 2, it can be seen that the oral solution of iron protein succinate in the present application has good fluidity and viscosity when the initial water addition amount is 70%. Too little water will affect the dissolution state of the product, and too much water will easily exceed the prescribed amount. In order to ensure normal production operation, the initial water addition amount of purified water selected during the preparation process is 70%.

[0048] Example 3

[0049] This example provides a prescription for an improved oral solution of iron protein succinate, which is the same as that of Example 1;

[0050] This embodiment also provides a method for preparing the improved oral solution of iron protein succinate, and its preparation process is basically the same as that of Example 1, except that the preparation temperature in step 1) is different, specifically:

[0051] Prescription 3-1: Take 70% of the prescription amount of purified water, control the preparation temperature at 30°C, add poloxamer, sodium methylparaben, sodium propylparaben and sorbitol to dissolve, then add iron protein succinate, mechanically stir and disperse at a speed of 150r / min for 10min, and at the same time add sodium hydroxide solution (the molar concentration of the sodium hydroxide solution is 3mol / L) until the pH of the solution reaches 7.2;

[0052] Prescription 3-2: Take 70% of the prescription amount of purified water, control the preparation temperature at 40°C, add poloxamer, sodium methylparaben, sodium propylparaben and sorbitol to dissolve, then add iron protein succinate, mechanically stir and disperse at a speed of 150r / min for 10min, and at the same time add sodium hydroxide solution (the molar concentration of the sodium hydroxide solution is 3mol / L) until the pH of the solution reaches 7.2;

[0053] Prescription 3-3: Take 70% of the prescription amount of purified water, control the preparation temperature at 60°C, add poloxamer, sodium methylparaben, sodium propylparaben and sorbitol to dissolve, then add iron protein succinate, mechanically stir and disperse at a speed of 150r / min for 10min, and add sodium hydroxide solution (the molar concentration of the sodium hydroxide solution is 3mol / L) until the pH of the solution reaches 7.2;

[0054] The oral iron protein succinate solutions of this embodiment at different preparation temperatures are all in the state of free-flowing liquids during the preparation process.

[0055] This example tests the product performance of oral protein ferric succinate solutions with different preparation temperatures, and the results are shown in Table 4:

[0056] Table 4 Performance test of oral solution of iron protein succinate with different preparation temperatures in this embodiment

[0057]

[0058] From the data in Table 4, it can be seen that the oral solution of iron protein succinate in the present application uses a lower preparation temperature to increase the viscosity of the product and reduce the product quality, while too high a preparation temperature will cause the destruction of the protein structure and the antibacterial agent structure, directly causing the product to be unqualified. Only by preparing the solution within a certain temperature range can a product preparation with all indicators meeting the requirements be obtained.

[0059] Comparative Example 1

[0060] This comparative example provides a prescription for an improved oral solution of ferric protein succinate, which is the same as that of Example 1;

[0061] This comparative example also provides a method for preparing the improved oral solution of ferric protein succinate, and its preparation process is substantially the same as that of Example 1, except that the solubilizing agent poloxamer is not added to its components.

[0062] Comparative Example 2

[0063] This comparative example provides a prescription for an improved oral solution of ferric protein succinate, which is the same as that of Example 1;

[0064] This comparative example also provides a method for preparing the improved oral solution of iron protein succinate, and its preparation process is basically the same as that of Example 1, except that sorbitol is not added in step 1), specifically:

[0065] Comparative Example 3

[0066] This comparative example provides a prescription for an improved oral solution of ferric protein succinate, which is the same as that of Example 1;

[0067] This comparative example also provides a method for preparing the improved oral solution of iron protein succinate, and its preparation process is basically the same as that of Example 1, except that the stirring speed in step 1) is different, specifically, the speed of mechanical stirring is 250 r / min.

[0068] Comparative Example 4

[0069] This comparative example provides a prescription for an improved oral solution of ferric protein succinate, which is the same as that of Example 1;

[0070] This comparative example also provides a method for preparing the improved oral solution of iron protein succinate, and its preparation process is basically the same as that of Example 1, except that the process parameters of the high-voltage pulse electric field treatment in step 1) are different, specifically:

[0071] After the raw material drug is dissolved, saccharin sodium and flavor are added, and purified water is added to make up the volume. Mechanical stirring and dispersion are continued at a speed of 200r / min for 5 minutes. At the same time, a high-voltage pulse electric field with an electric field strength of 2.5kV / cm, a pulse width of 20μm, and a pulse frequency of 30KHz is used for treatment for 10 minutes. Finally, it is filtered through 2.2μm and packaged to obtain the improved protein succinate iron oral solution.

[0072] Comparative Example 5

[0073] This comparative example provides a prescription for an improved oral solution of ferric protein succinate, which is the same as that of Example 1;

[0074] This comparative example also provides a method for preparing the improved oral solution of iron protein succinate, and its preparation process is basically the same as that of Example 1, except that the process parameters of the high-voltage pulse electric field treatment in step 1) are different, specifically:

[0075] After the raw material drug is dissolved, saccharin sodium and flavor are added, and purified water is added to make up the volume. Mechanical stirring and dispersion are continued at a speed of 200r / min for 5 minutes. At the same time, a high-voltage pulse electric field with an electric field strength of 1.5kV / cm, a pulse width of 35μm, and a pulse frequency of 30KHz is used for treatment for 10 minutes. Finally, it is filtered through 2.2μm and packaged to obtain the improved oral solution of protein succinate iron.

[0076] Comparative Example 6

[0077] This comparative example provides a prescription for an improved oral solution of ferric protein succinate, which is the same as that of Example 1;

[0078] This comparative example also provides a method for preparing the improved oral solution of iron protein succinate, and its preparation process is basically the same as that of Example 1, except that the pH value of the Chinese medicine solution in step 2) is adjusted to 7.8, specifically:

[0079] Take 70% of the prescription amount of purified water, control the preparation temperature at 35°C, add poloxamer, sodium methylparaben, sodium propylparaben and sorbitol to dissolve, then add iron protein succinate, mechanically stir and disperse at a speed of 150r / min for 10min, and at the same time add sodium hydroxide solution (the molar concentration of the sodium hydroxide solution is 3mol / L) until the pH of the solution reaches 7.8;

[0080] Comparative Example 7

[0081] This comparative example provides a prescription for an improved oral solution of ferric protein succinate, which is the same as that of Example 1;

[0082] This comparative example also provides a method for preparing the improved oral solution of protein succinate iron, and its preparation process is basically the same as that of Example 1, except that in step 3), high-voltage pulse electric field treatment is not performed, but high-pressure homogenization treatment is performed with a homogenization pressure of 300 bar and a homogenization number of 2 times.

[0083] Performance Test:

[0084] 1. Sediment, free iron and microbial limit tests

[0085] This application takes Example 1 as an example, and performs performance tests on the oral iron protein succinate solutions obtained in Example 1 and Comparative Examples 1-6 (the test method is the same as that in Example 1), and the results are shown in Table 5:

[0086] Table 5 Performance indicators of iron protein succinate oral solution in Example 1 and each comparative example

[0087] Sediment Free Iron Microbial Limits Example 1 Comply with regulations Not detected Comply with regulations Comparative Example 1 There is sedimentation 0.07％ Comply with regulations Comparative Example 2 There is sedimentation 0.08％ Comply with regulations Comparative Example 3 Failure 1.05％ Comply with regulations Comparative Example 4 Failure 1.26％ Comply with regulations Comparative Example 5 Failure 1.17％ Comply with regulations Comparative Example 6 Comply with regulations 0.06％ Comply with regulations Comparative Example 7 Comply with regulations 0.05％ Not Compliant

[0088] It can be seen from the data in Table 5 that the oral solution of iron protein succinate prepared in the present application has microorganisms that meet the requirements, and the sediment and free iron content are low during the production and storage process, which meets the relevant technical requirements; by comparing Example 1 with Comparative Examples 1, 2 and 7, it can be seen that when poloxamer is not added, or sorbitol is not added, or high-voltage pulse electric field strength treatment is not performed, the sediment and free iron content are both high, and even do not meet the relevant technical requirements; by comparing Example 1 with Comparative Examples 3, 4 and 5, it can be seen that the process parameters in the present application have a great influence on the quality of the product, among which the stirring speed, or the intensity / pulse width of the high-voltage electric field, when it exceeds the parameter range in the present application, will cause the sediment and free iron content of the oral solution of iron protein succinate prepared by the production to greatly exceed the standard, which may be because when the parameters are too large, the structure of the raw material iron protein succinate is destroyed, which leads to an increase in the sediment and free iron content, and even does not meet the relevant technical requirements. The present application also tests the samples for the stirring speed in the preparation method, or the intensity / pulse width of the high-voltage electric field. When they are lower than the parameter range in the present application, it can be seen that the precipitation of the prepared oral solution of protein succinate iron will exceed the standard and fail to meet the relevant requirements. This may be because the low process parameters cannot meet the good dissolution and dispersion requirements, which leads to excessive precipitation.

[0089] In summary, by comparing the comparative example with Example 1, it is found that the high-voltage pulse electric field treatment in the high-voltage pulse electric field treatment chamber can obtain an oral solution of iron protein succinate with good quality attributes, which meets the relevant technical requirements.

[0090] 2. Stability test:

[0091] According to the requirements of the 9001 Stability Test Guidelines of the Fourth General Rules of the 2020 Edition of the Chinese Pharmacopoeia, the stability of the oral solution of iron protein succinate prepared in Example 1, Comparative Example 6 and Comparative Example 7 was investigated. Ten bottles of each sample were placed in a 75% constant humidity dryer, and then the dryer was placed in a 40°C constant temperature oven. Samples were taken for testing at 1, 2, 3, and 6 months, and various indicators were investigated and compared with the initial test indicators. The results are shown in Table 6.

[0092] The free iron content is measured by the following method: 5 ml of the samples prepared in Example 1 and Comparative Examples 4-6 are accurately measured respectively, placed in a centrifuge tube, 0.1 mol / L hydrochloric acid solution is added dropwise to adjust the pH to 2.0-3.0 to completely precipitate, 10 ml of water is added, shaken, and centrifuged at 2000 revolutions per minute for 15 minutes. The supernatant is placed in a 50 ml measuring bottle, and the precipitate is washed with 15 ml of water. Centrifuge as before, combine the supernatants, dilute to the mark with water, shaken, filter, take 10 ml of the filtrate, place in a 50 ml measuring bottle, add acetic acid-sodium acetate buffer (pH 4.6) 5 ml, 1% hydroxylamine hydrochloride solution 2.5 ml, 0.1% o-phenanthroline solution 5 ml, dilute to the mark with water, shaken, and used as the test solution. Take 5 ml of standard iron solution (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0807), place in a 50 ml volumetric flask, add 5 ml of acetic acid-sodium acetate buffer (pH 4.6), 2.5 ml of 1% hydroxylamine hydrochloride solution, 5 ml of 0.1% o-phenanthroline solution, dilute to the scale with water, shake well, as the control solution. The test solution and the control solution are placed for 10 minutes each, and the absorbance is measured at a wavelength of 510 nm according to the UV-visible spectrophotometry (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0401), and the free iron content is calculated.

[0093] The preparation method of 1% hydroxylamine hydrochloride solution is as follows: take 1.0g of hydroxylamine hydrochloride, weigh accurately, put it in a 100ml volumetric flask, dissolve it with water and dilute it to the scale, shake well; note that it needs to be prepared just before use.

[0094] Preparation method of 0.1% o-phenanthroline solution: Take 100 mg of o-phenanthroline, weigh accurately, put it in a 100 ml volumetric flask, dissolve it with a little ethanol, dilute it to the scale with water, and shake well; prepare it before use.

[0095] Table 6 Stability of iron protein succinate oral solution in Example 1 and each comparative example

[0096]

[0097] From the data in Table 6, it can be seen that the properties and pH value of the improved oral solution of iron protein succinate in the present application are very stable, and no free iron is detected; by comparing Example 1 with Comparative Example 6, it can be seen that changing the pH value will affect the stability of the oral solution of iron protein succinate; by comparing Example 1 with Comparative Example 7, it can be seen that although the solubility of iron protein succinate can be effectively improved by adopting high-pressure homogenization, the effect on its stability is limited. The present application adopts a specific pH value in the preparation method, combined with a specific high-voltage pulse electric field treatment, so that not only the iron protein succinate can be well dissolved in the oral solution system of iron protein succinate, but also the prepared oral solution of iron protein succinate has excellent stability. It can be seen from the accelerated test that the storage time of the oral solution of iron protein succinate in the present application at room temperature is tentatively set at two years.

[0098] 2. In vitro release experiment

[0099] The determination was carried out according to the second method of General Rules 0931 of the 2020 edition of the Chinese Pharmacopoeia. The results are shown in Table 7:

[0100] Table 7 Oral solubility and release of iron protein succinate in Example 1 and each comparative example

[0101] Release rate (%) 1h 4h 8h 12h Example 1 18.6％ 36.2％ 52.4％ 76.5％ Comparative Example 1 26.3％ 58.6％ 80.6％ 96.3％ Comparative Example 7 28.1％ 60.2％ 84.6％ 97.5％

[0102] As shown in Table 7, the 12h release of the iron protein succinate oral solution provided by the present invention is 76.5%, which is significantly lower than that of Comparative Example 1 and Comparative Example 7, indicating that the iron protein succinate oral solution provided by the present invention has a good sustained release effect. By comparing the technical solutions of Example 1, Comparative Example 1 and Comparative Example 7, it can be seen that adding a solubilizing agent and using a high-voltage pulse electric field treatment can coordinate the sustained release effect of the iron protein succinate oral solution.

[0103] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein by equivalents. These modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present invention, and they should all be included in the scope of the claims and specification of the present invention.

Claims

1. A method for preparing an improved iron protein succinate oral solution, characterized in that: The steps include: 1) Take 40% to 80% of the prescription amount of purified water, control the solution temperature at 30°C to 40°C, add poloxamer, sodium methylparaben, sodium propylparaben and sorbitol to dissolve, then add iron protein succinate, stir mechanically to evenly, and adjust the pH of the solution to 6.5-7.5; 2) After the API is dissolved, saccharin sodium and flavor are added, and purified water is added to make up the volume. After preliminary dispersion by mechanical stirring, high-voltage pulse electric field treatment is performed in a high-voltage pulse electric field treatment chamber, and finally filtration and subpackaging are performed to obtain the improved oral solution of protein succinate iron.

2. The method for preparing the improved ferric protein succinate oral solution according to claim 1, characterized in that: The improved oral solution of ferric protein succinate comprises the following components: 800 mg / 15 ml of ferric protein succinate, 10-25 mg / 15 ml of poloxamer, 1400 mg / 15 ml of sorbitol, 15-25 mg / 15 ml of sodium methylparaben, 5-10 mg / 15 ml of sodium propylparaben, 30-50 mg / 15 ml of flavor, 5-15 mg / 15 ml of sodium saccharin, an appropriate amount of sodium hydroxide, and the balance is pure water.

3. The method for preparing the improved ferric protein succinate oral solution according to claim 1, characterized in that: The particle size of the iron protein succinate oral solution is 100-300 meshes.

4. The method for preparing the improved ferric protein succinate oral solution according to claim 1, characterized in that: The flavors in step 1) include, but are not limited to, one or more of black cherry flavor, blackberry flavor, orange flavor, banana flavor, and tangerine flavor.

5. The method for preparing the improved ferric protein succinate oral solution according to claim 4, characterized in that: The molar concentration of sodium hydroxide in step 1) is 2-3 mol / L.

6. The method for preparing the improved ferric protein succinate oral solution according to claim 1, characterized in that: The mechanical stirring conditions in step 2) are: a rotation speed of 150-200 r / min and a stirring time of 10-20 min.

7. The method for preparing the improved oral solution of ferric protein succinate according to claim 9, characterized in that: The condition parameters of the high-voltage pulse electric field treatment in step 4) are: electric field intensity of 1.0-2.0 kV / cm, pulse width of 10-30 μm, pulse frequency of 20-40 KHz, and treatment time of 5-10 min.

8. The method for preparing the improved oral solution of ferric protein succinate according to claim 4, characterized in that: In step 4), the filtration is performed using a 0.22 μm filter.

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