Iron protein succinate solid dispersion and preparation method thereof

Abstract

The invention discloses an iron protein succinate solid dispersion and a preparation method thereof, and belongs to the technical field of medicines. The solid dispersion is prepared from iron protein succinate and a solid dispersion matrix, wherein the solid dispersion matrix is polyethylene glycol or hydroxyethyl starch. The solid dispersion provided by the invention only adopts the iron protein succinate and the solid dispersion matrix as raw materials, and by adjusting the ratio of the iron protein succinate to the solid dispersion matrix, the dispersion has the following advantages: no preservative is added; few types of safe auxiliary materials are used in the prescription; the preparation is formed into a soluble solid form and is convenient to take and carry; the requirements on safety and compliance of pregnant women and infants are met; the adverse reaction of constipation caused by an iron supplement is reduced; the preparation method is easy to implement. The solid dispersion provided by the invention also has the characteristics of no obvious rust flavor and no irritation to the mouth and the tongue; the stability of the dispersoid and the stability of particles prepared from the dispersoid are equivalent to those of commercially available iron protein succinate oral solutions.

Description

Technical Field

[0001] The invention relates to the field of medical technology, and in particular to an iron protein succinate solid dispersion and a preparation method thereof. Background Art

[0002] Anemia refers to the pathological phenomenon that the hemoglobin (Hb) concentration, red blood cell (RBC) count and / or hematocrit in a unit volume of peripheral blood are lower than the lower limit of normal values. Among them, the hemoglobin concentration is the most important diagnostic indicator. The standard for diagnosing anemia is Hb <120g / L for adult males, Hb <110g / L for adult females, and Hb <100g / L for pregnant women. Anemia is usually divided into three categories: iron deficiency anemia, megaloblastic anemia, and aplastic anemia. Among them, iron deficiency anemia (IDA) is the main type of anemia. When the body's demand for iron is out of balance with its supply, it leads to the depletion of stored iron in the body (ID), followed by iron deficiency in red blood cells (IDE), and ultimately causes iron deficiency anemia (IDA). IDA is the final stage of iron deficiency (including ID, IDE, and IDA), manifested as microcytic hypochromic anemia and other abnormalities caused by iron deficiency. The annual incidence of iron deficiency is 75.0% to 82.5% in infants aged 6 months to 2 years, 66.7% in women who are pregnant for more than 3 months, 43.3% in women of childbearing age, and 13.2% in adolescents aged 10 to 17 years. The prevalence of IDA in the above groups is 33.8% to 45.7%, 19.3%, 11.4%, and 9.8%, respectively. Iron deficiency is mainly related to the following factors: insufficient complementary food for infants and young children, picky eating in adolescents, excessive menstrual flow / multiple pregnancies / breastfeeding in women, and certain pathological factors (such as subtotal gastrectomy, chronic blood loss, chronic diarrhea, atrophic gastritis, and hookworm infection, etc.).

[0003] Iron-protein succinylate (ISP) is a protein-complexed iron drug. Indications: Treatment of absolute and relative iron deficiency anemia, treatment of latent or overt iron deficiency anemia caused by insufficient iron intake or malabsorption, acute or chronic blood loss, and infection in patients of all ages, and treatment of anemia during pregnancy and lactation. The specification is 15 mL / 800 mg (equivalent to 40 mg of trivalent iron). Iron-protein succinylate oral solution is an organic iron compound that is precipitated at a pH value of less than 4 and becomes a soluble substance again at a higher pH value (pH 7.5-8.0). In addition, the preparation is not digested by pepsin and can be hydrolyzed by trypsin at a neutral pH. Due to these properties, the iron contained in ISP is protected by a protein membrane and does not react with gastric acid and pepsin in gastric juice. Therefore, the preparation is not easy to cause gastric mucosal damage. The iron in ISP begins to be released in the duodenum, especially in the jejunum, because the increase in pH value turns the compound into a soluble substance again and allows the protein membrane to be digested by trypsin. The iron in it is beneficial to the body's physiological absorption, but it will not form a too high absorption peak, showing a constant absorption trend, and gradually reaching the optimal stable state of absorption and storage in various parts of the body. Therefore, ISP generally does not cause gastrointestinal tolerance problems.

[0004] Prescription for iron protein succinate oral solution, per bottle:

[0005]

[0006] The preservatives used in the above prescriptions are mainly 45 mg sodium methylparaben (0.3%) and 15 mg sodium propylparaben (0.1%). The general requirement for the use and dosage of preservatives is to avoid their use as much as possible. The recommended dosage of mixed hydroxybenzoate preservatives is 0.1%~0.2% under necessary conditions. Generally, in the production process of oral liquid preparations, attention is paid to preventing microbial contamination by taking measures such as high temperature, clean environment, and disinfection, but complete sterility cannot be guaranteed. At the same time, iron protein succinate oral solution contains nutrient-rich protein components, which are very easy to breed microorganisms. In order to ensure the preservation requirements within the validity period of the product, an extraordinary amount of preservatives is added. Iron protein succinate oral solution is mainly suitable for infants and pregnant women. The treatment cycle of iron deficiency anemia is generally 3 to 6 months. For infants and young children who are in a critical period of growth and development, long-term use of drugs containing excessive preservatives may inhibit bone growth and affect the development of digestive function to a certain extent, and its harm is more significant than that of normal adults. Some antibacterial agents, such as benzoic acid and its salts, may increase the risk of jaundice in newborns (less than 4 weeks old), and parabens may cause allergic reactions, so the potential risks of antibacterial agents should be paid attention to when they are introduced.

[0007] The above prescription also uses 1.4 g of sorbitol and 1.0 g of propylene glycol. This design is believed to be related to stabilizing the protein structure and improving the taste through prescription analysis. At the same time, since these two substances are small molecule polyols, they are beneficial to antagonize water loss in the body's absorption process of iron and reduce the adverse reaction of constipation. This drug design idea of ​​reducing adverse drug reactions through formulation excipients is common. However, since the above two substances are small molecules and are easily absorbed into the blood, the potential risks that may be brought cannot be ignored, especially for infants and young children. For example, although propylene glycol has only low toxicity, if it is consumed in excess for a long time, it may cause kidney disorders, lactic acidosis, and affect the function of the nervous system. Propylene glycol may also accumulate in children under 4 years old, and possible adverse reactions include central nervous system toxicity, diarrhea caused by high osmotic pressure, etc.

[0008] Patent CN 111000977 A proposes a new solid dosage form of iron protein succinate, which addresses the shortcomings of existing iron protein succinate preparations, such as being inconvenient to carry, unstable solutions in prescriptions, and containing a large amount of preservatives. The new solid dosage form includes iron protein succinate dispersible tablets, iron protein succinate effervescent tablets, iron protein succinate granules, iron protein succinate tablets, iron protein succinate capsules, and iron protein succinate enteric-coated tablets. The components of the iron protein succinate dispersible tablets, by mass percentage, include: 50-80% of the main drug, 10-40% of the filler, 0.5-5% of the pH adjuster, 1-5% of the absorption promoter, 1-8% of the binder, 2-6% of the disintegrant, 0.5-3% of the lubricant, and 0.5-2% of the glidant; the components of the iron protein succinate effervescent tablets, by mass percentage, include: 50-80% of the main drug, 10-40% of the filler, 1-5% of the foaming agent acid source, 1-5% of the foaming agent alkali source, and 0.5 -5%, absorption promoter 1-5%, binder 1-8%, disintegrant 2-6%, lubricant 0.5-3%, glidant 0.5-2%; the components in the iron protein succinate granules, the iron protein succinate tablets, the iron protein succinate capsules and the iron protein succinate enteric-coated tablets include, by mass percentage, 50-80% of the main drug, 10-40% of the filler, 1-5% of the absorption promoter, 0.5-5% of the pH adjuster, 1-8% of the binder, 2-6% of the disintegrant, and 0.5-2% of the glidant.

[0009] The prescription design of the above patent CN 111000977 A is complex and uses conventional solid preparation excipients. While overcoming the risk factors brought by preservatives, it also introduces a large number of other excipients with certain potential safety risks, such as the absorption promoter selected from sorbitol, sodium lauryl sulfate or Tween 80; the binder selected from povidone K30 or hydroxypropyl methylcellulose, preferably povidone K30; the disintegrant selected from one or more of cross-linked povidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, preferably sodium carboxymethyl starch; the lubricant selected from one or more of magnesium stearate, zinc stearate, sodium stearyl fumarate, hydrogenated castor oil, preferably magnesium stearate; the glidant selected from colloidal silicon dioxide or talc, preferably colloidal silicon dioxide. The "Guidelines for Pharmaceutical Development of Children's Drugs (Chemical Drugs) (Trial)" points out that the minimum types and minimum amounts of excipients should be used as much as possible under the premise of reducing risks and ensuring the efficacy, stability, palatability, microbial control and dosage uniformity of the product. For pregnant women and infants, the prescription design of patent CN 111000977 A is still risky. Summary of the invention

[0010] In view of the above deficiencies in the prior art, the present invention provides a solid dispersion of iron protein succinate, aiming to improve the prior art. The solid dispersion of the present invention has the following improved features: 1. Avoiding the use of preservatives; 2. Using safe excipients in the prescription and with a small number of types; 3. The preparation is formed into a solid form, is easily soluble, and is mixed with liquid before use, which is convenient for taking and carrying; 4. It is suitable for the safety and compliance requirements of pregnant women and infants, such as not containing excipients that can enter the blood circulation and having a suitable taste; 5. Reducing the adverse reaction of constipation caused by iron supplements; 6. The preparation method is easy to implement.

[0011] To achieve the above purpose, the specific technical solutions of the present invention are as follows:

[0012] A solid dispersion of iron protein succinylate, which is prepared from iron protein succinylate (ISP) (main drug) and a solid dispersion matrix (excipient); wherein the solid dispersion matrix is ​​polyethylene glycol (PEG) or hydroxyethyl starch (HES).

[0013] Preferably, the solid dispersion matrix is ​​polyethylene glycol.

[0014] More preferably, the polyethylene glycol is polyethylene glycol 3350 or polyethylene glycol 4000.

[0015] More preferably, the polyethylene glycol is polyethylene glycol 4000.

[0016] Preferably, the mass ratio of the iron protein succinate to the solid dispersion matrix is ​​1:(0.2-3).

[0017] Further preferably, the mass ratio of the iron protein succinate to the solid dispersion matrix is ​​1:(0.5-2).

[0018] Preferably, the iron protein succinate solid dispersion can be made into preparations including: soluble granules, powders, and dispersible tablets.

[0019] Further preferably, the iron protein succinate solid dispersion can be prepared into a powder.

[0020] The present invention also provides a method for preparing the above-mentioned iron protein succinate dispersion, comprising the following steps:

[0021] (1) preparing a mixed powder of iron protein succinate and a solid dispersion matrix into an aqueous solution;

[0022] (2) Adjusting the pH value of the aqueous solution;

[0023] (3) The aqueous solution is filtered and then spray-dried to obtain an iron protein succinate dispersion.

[0024] Preferably, the mass fraction of iron protein succinate in the solution is 5-15%.

[0025] Preferably, the pH value is 6.5-8.0.

[0026] Preferably, the reagent used to adjust the pH value is a dilute hydrochloric acid solution or a dilute sodium hydroxide solution.

[0027] Preferably, the spray drying temperature is 160-190°C.

[0028] Preferably, the iron protein succinate solid dispersion can be made into preparations including: soluble granules, powders, and dispersible tablets.

[0029] Further preferably, the iron protein succinate solid dispersion can be prepared into a powder.

[0030] Preferably, suitable excipients or flavoring agents, such as compressible starch, may be added to the preparation during preparation.

[0031] Compared with the prior art, the present invention is beneficial in that:

[0032] (1) The key auxiliary material polyethylene glycol used in the iron protein succinate solid dispersion provided by the present invention is a macromolecular substance, which has good safety itself, cannot be digested by the gastrointestinal tract, and can be directly excreted. After digestion by the gastrointestinal tract, no small molecules are produced and they do not enter the blood circulation, thereby ensuring the safety of the iron protein succinate solid dispersion;

[0033] (2) The key auxiliary materials polyethylene glycol or hydroxyethyl starch used in the iron protein succinate solid dispersion provided by the present invention are both polyol substances, which can protect the gastrointestinal tract from water loss during iron absorption, thereby reducing the occurrence of constipation;

[0034] (3) The key auxiliary materials polyethylene glycol or hydroxyethyl starch used in the iron protein succinate solid dispersion provided by the present invention are both macromolecular substances with good water solubility. Compared with the original drug powder, the prepared solid dispersion directly dissolves, improves dissolution, and has the advantages of rapid re-dissolution and high re-dissolution concentration;

[0035] (4) The protein succinate iron solid dispersion provided by the present invention uses polyethylene glycol or hydroxyethyl starch as the key auxiliary material, both of which are polyhydroxy substances and are good complexing agents for free trivalent iron ions. The prepared solid dispersion has a solution obtained after redissolution, which has the advantages of no obvious rust taste and no irritation to the mouth and tongue compared with the protein succinate iron solution;

[0036] (5) The preparation method of the iron protein succinate dispersion provided by the present invention is simple and easy to implement, and can be implemented without the need for specific dedicated equipment, which is conducive to simplifying the process flow, avoiding the growth of microorganisms, and helping to control production costs;

[0037] (6) The iron protein succinate solid dispersion provided by the present invention solves the shortcomings of the existing iron protein succinate prescriptions, such as instability of the solution, containing a large amount of preservatives, and the entry of small molecule polyols into the blood circulation, while retaining the advantages of the commercially available iron protein succinate oral solution, such as suitable taste, easy dosage, and prevention of constipation. The preparation method provided by the present invention is simple and easy to implement, and meets the ideal effect of the preparation. DETAILED DESCRIPTION

[0038] The technical solution of the present invention will be described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0039] The invention provides an iron protein succinate solid dispersion, which is prepared from iron protein succinate and a solid dispersion matrix; wherein the solid dispersion matrix is ​​polyethylene glycol or hydroxyethyl starch.

[0040] In some examples, the polyethylene glycol is polyethylene glycol 3350 or polyethylene glycol 4000.

[0041] In some examples, the mass ratio of the protein succinate iron to the solid dispersion matrix is ​​1:(0.2~3).

[0042] In some examples, the iron protein succinate solid dispersion can be made into preparations including: soluble granules, powders, and dispersible tablets.

[0043] The present invention also provides a method for preparing the above-mentioned iron protein succinate dispersion, comprising the following steps:

[0044] (1) preparing a mixed powder of iron protein succinate and a solid dispersion matrix into an aqueous solution;

[0045] (2) Adjusting the pH value of the aqueous solution;

[0046] (3) The aqueous solution is filtered and then spray-dried to obtain an iron protein succinate dispersion.

[0047] In some examples, the mass fraction of iron protein succinate in the solution is 5-15%.

[0048] In some examples, the pH value is 6.5-8.0.

[0049] In some examples, the reagent used to adjust the pH value is a dilute hydrochloric acid solution or a dilute sodium hydroxide solution.

[0050] In some examples, the spray drying temperature is 160-190°C.

[0051] In some examples, the iron protein succinate solid dispersion can be made into preparations including: soluble granules, powders, and dispersible tablets.

[0052] In some examples, suitable excipients or flavoring agents, such as compressible starch, may be added during preparation of the formulation.

[0053] Example 1

[0054] A protein succinate iron solid dispersion, the preparation steps of which are as follows:

[0055] (1) Prepare aqueous solutions containing 10% ISP at a mass ratio of ISP raw powder to PEG3350 of 1:3, ISP raw powder to PEG4000 of 1:3, and ISP raw powder to HES of 1:3, and adjust the pH value to 6.5-8.0 with dilute sodium hydroxide solution (1 M).

[0056] (2) The aqueous solution obtained in step 1 was precisely filtered through a 0.8 μm titanium rod filter and then spray-dried at 160-190° C. to obtain PEG3350-ISP dispersion, PEG4000-ISP dispersion, and HES-ISP dispersion.

[0057] The dispersion obtained in Example 1 was subjected to a hygroscopicity test, and the steps were as follows:

[0058] When the temperature is 20℃, saturated salt solutions of ammonium sulfate and calcium chloride are placed at the bottom of the dryer to ensure that the relative humidity (RH) in the dryer is 81% and 32% respectively; according to the standard that each dispersion or ISP original powder contains 800 mg ISP, accurately weigh the sample (vacuum dried to constant weight) into a weighing dish; the weighed samples are placed in two dryers with different RH respectively, and after 1 d, 2 d, 3 d, 4 d, 5 d, and 6 d, the mass of each sample is accurately weighed, and its moisture absorption rate is calculated by the following formula. The experimental results are shown in Table 1.

[0059] Moisture absorption rate (%) =

[0060] Where: W0: mass of sample at time 0.

[0061] Wn: The mass of the sample after being placed for nd.

[0062] The dispersion obtained in Example 1 was subjected to an odor comparison experiment, and the steps were as follows:

[0063] The dispersion obtained in the example and the ISP original powder were respectively prepared into aqueous solutions with an ISP content of 800 mg / 15 mL; 2 mL was taken from each aqueous solution, absorbed with cotton wool, and placed in a 50 mL stoppered glass tube; the odor of each sample was compared by nose smell, with "+ +" indicating a slight rust odor; "+" indicating a very slight rust odor; and "-" indicating no rust odor. The experimental results are shown in Table 1.

[0064] The dispersion obtained in Example 1 was subjected to a taste comparison experiment, and the steps were as follows:

[0065] Take 10 mL of each ISP aqueous solution with a content of 800 mg / 15 mL and the commercial product (iron protein succinate oral solution, trade name: Fipry) and pour them into a disposable tasting paper cup; hold the sample in the mouth for 15 seconds, and rinse the mouth slowly during this period to evenly distribute the sample in the mouth; taste the taste of the sample and spit it out, and rinse the mouth at least 5 times to remove the aftertaste in the mouth; keep a blank time of at least 15 minutes between each round of sample testing. The experimental results are shown in Table 1.

[0066] The dispersion obtained in Example 1 was subjected to a solubility test in the following steps:

[0067] According to the standard that each dispersion or ISP raw powder contains 10 g ISP, each dispersion and ISP raw powder of Example 1 were taken and stirred in 200 mL water at 40°C for 5 minutes and observed immediately. The experimental results are shown in Table 1.

[0068] Table 1: Test results of moisture retention, solubility, odor and taste of different formulation dispersions, ISP original powder and commercial products

[0069]

[0070] As can be seen from Table 1, the dispersions with the addition of solid dispersion matrix PEG4000, HES, and PEG3350 are superior to the original ISP powder in terms of moisture retention, solubility, odor, and taste; the odor and taste are comparable to those of the commercially available product.

[0071] Example 2

[0072] A protein succinate iron solid dispersion, the preparation steps of which are as follows:

[0073] (1) Aqueous solutions containing 10% ISP were prepared according to the mass ratio of ISP raw powder to PEG4000 of 1:0.2, 1:0.5, 1:1, 1:2, and 1:3, and the pH value was adjusted to 6.5-8.0 with dilute sodium hydroxide solution (1 M).

[0074] (2) The aqueous solution obtained in step 1 was precisely filtered through a 0.8 μm titanium rod filter and then spray-dried at 160-190° C. to obtain PEG3350-ISP dispersion, PEG4000-ISP dispersion, and HES-ISP dispersion.

[0075] The above dispersion was tested according to the test methods of moisture retention, solubility, odor and taste in Example 1. The experimental results are shown in Table 2.

[0076] Table 2: Moisture retention, solubility, odor and taste test results of dispersions with different ratios of ISP and PEG4000

[0077]

[0078] As can be seen from Table 2, when the mass ratio of ISP to PEG4000 is 1:(0.2~3), the moisture retention, solubility, odor and taste of the dispersion are significantly improved compared with the original ISP powder; the odor and taste are comparable to those of commercial products.

[0079] Example 3

[0080] A protein succinate iron solid dispersion and particles made thereof, the preparation steps are as follows:

[0081] (1) Prepare aqueous solutions containing 10% ISP at a mass ratio of ISP raw powder to PEG4000 of 1:0.5 and 1:2, respectively, and adjust the pH value to 6.5-8.0 with dilute sodium hydroxide solution (1 M).

[0082] (2) The aqueous solution obtained in step 1 was finely filtered through a 0.8 μm titanium rod filter and spray-dried at 160-190° C. to obtain dispersion A (ISP:PEG4000=1:0.5) and dispersion B (ISP:PEG4000=1:2).

[0083] (3) Dispersion A and dispersion B are added to the fluidized bed respectively, with the inlet air temperature at 60℃~80℃. 1% CMC-Na (sodium carboxymethyl cellulose) solution is sprayed on the surface of the dispersion as an adhesive. The moisture content is monitored and the moisture content should be less than 10%. Then, particles A and B are obtained.

[0084] Release test was performed on the dispersion and particles prepared in Example 3:

[0085] According to the single dose standard that each dispersion or granule contains 0.8 g ISP, take dispersion A, dispersion B, granule A and granule B and measure the dissolution and release rate according to the method for determination of dissolution and release rate (method 2 of general rule 0931).

[0086] Release condition 1: 900 mL of artificial gastric juice was used as the release medium, the rotation speed was 50 revolutions per minute, and the operation was carried out according to the law. Samples were taken after 45 minutes.

[0087] Release condition 2: 900 mL of artificial intestinal fluid was used as the release medium, the rotation speed was 50 revolutions per minute, and the operation was carried out according to the law. Samples were taken after 45 minutes.

[0088] Reference solution (release condition 1): accurately pipette 2 mL of the iron standard solution into a 25 mL volumetric flask, add 5.0 mL of artificial gastric juice, and shake well; add 1.0 mL of hydrochloric acid, and shake well; add 5.0 mL of acetate buffer with a pH of 4.0, and shake well; add 1.0 mL of 10% hydroxylamine hydrochloride solution, and shake well; add 1.0 mL of 0.5% o-phenanthroline solution, and shake well, and let stand for 5 min; add 6.0 mL of 2 mol / L sodium hydroxide, and shake well; add water to make up to volume, and let stand for 10 min.

[0089] Test solution (release condition 1): Take 10 mL of the release solution, filter it through a 0.45 μm filter membrane (PES material), take 5.0 mL of the filtrate, place it in a 25 mL volumetric flask, then add 1.0 mL of hydrochloric acid and shake well; add 5.0 mL of acetate buffer with a pH of 4.0 and shake well; add 1.0 mL of 10% hydroxylamine hydrochloride solution and shake well; add 1.0 mL of 0.5% o-phenanthroline solution, shake well, and let stand for 5 min; add 6.0 mL of 2 mol / L sodium hydroxide and shake well; add water to make up to volume and let stand for 10 min.

[0090] Blank solution (release condition 1): Pipette 5.0 mL of artificial gastric juice, add 1.0 mL of hydrochloric acid, and shake well; add 5.0 mL of acetate buffer with a pH of 4.0, and shake well; add 1.0 mL of 10% hydroxylamine hydrochloride solution, and shake well; add 1.0 mL of 0.5% o-phenanthroline solution, shake well, and let stand for 5 min; add 6.0 mL of 2 mol / L sodium hydroxide, and shake well; add water to make up to volume, and let stand for 10 min.

[0091] Reference solution (release condition 2): accurately pipette 2 mL of the iron standard solution into a 25 mL volumetric flask, add 1.0 mL of artificial intestinal fluid, and shake well; add 1.0 mL of hydrochloric acid, and shake well; add 5.0 mL of acetate buffer with a pH of 4.0, and shake well; add 1.0 mL of 10% hydroxylamine hydrochloride solution, and shake well; add 1.0 mL of 0.5% o-phenanthroline solution, and shake well, and let stand for 5 min; add 6.0 mL of 2 mol / L sodium hydroxide, and shake well; add water to make up to volume, and let stand for 10 min.

[0092] Test solution (release condition 2): Take 10 mL of the release solution, filter it through a 0.45 μm filter membrane (PES material), take 1.0 mL of the filtrate, place it in a 25 mL volumetric flask, then add 1.0 mL of hydrochloric acid and shake well; add 5.0 mL of acetate buffer with a pH of 4.0 and shake well; add 1.0 mL of 10% hydroxylamine hydrochloride solution and shake well; add 1.0 mL of 0.5% o-phenanthroline solution, shake well, and let stand for 5 min; add 6.0 mL of 2 mol / L sodium hydroxide and shake well; add water to make up to volume and let stand for 10 min.

[0093] Blank solution (release condition 2): Pipette 1.0 mL of artificial intestinal fluid, add 1.0 mL of hydrochloric acid, and shake well; add 5.0 mL of acetate buffer with a pH of 4.0, and shake well; add 1.0 mL of 10% hydroxylamine hydrochloride solution, and shake well; add 1.0 mL of 0.5% o-phenanthroline solution, shake well, and let stand for 5 min; add 6.0 mL of 2 mol / L sodium hydroxide, and shake well; add water to make up to volume, and let stand for 10 min.

[0094] Determination method: Take the test sample and reference solution, and measure the absorbance at a wavelength of 510 nm according to the UV-visible spectrophotometry (General Rules 0401 of Part IV of the Chinese Pharmacopoeia 2020 Edition) (zero adjustment using blank solution), and calculate the iron release amount according to the external standard method. The test results are shown in Table 3.

[0095] Table 3: Release test results of different preparations

[0096]

[0097] As can be seen from Table 3, the iron release results of dispersion A, dispersion B, particles A and particles B are basically consistent with the commercially available products.

[0098] The sample prepared in Example 3 was subjected to a stability test to examine the free iron content, iron content, and microbial level. The test was conducted under accelerated conditions for 6 months. The experimental results are shown in Table 4.

[0099] Table 4: Stability test results of dispersion A, dispersion B, granules A, granules B, and commercial products

[0100]

[0101] Table 4: Microbial Limits 1 *: The total number of aerobic bacteria per 1 g should not exceed 1000 cfu; the total number of molds and yeasts should not exceed 100 cfu; Escherichia coli should not be detected;

[0102] Microbial Limits 2 *: The total number of aerobic bacteria in each mL should not exceed 100 cfu; the total number of molds and yeasts should not exceed 10 cfu; Escherichia coli should not be detected;

[0103] Fipli*: “Month 0” means 2 months after the production date;

[0104] The free iron content and iron content in the table are calculated based on ISP.

[0105] As can be seen from Table 4, the free iron content, iron content and microbial level of dispersion A, dispersion B, granules A and granules B did not change, and the stability was comparable to that of the commercial product.

[0106] In summary, the solid dispersion provided by the present invention only uses protein succinate iron and solid dispersion matrix as raw materials, and by adjusting the ratio between the two, the dispersion has the following advantages: no preservatives are added; safe excipients and few types are used in the prescription; the preparation is formed into a soluble solid form, which is easy to take and carry; it is suitable for the safety and compliance requirements of pregnant women and infants; it reduces the adverse reaction of constipation caused by iron supplements; and the preparation method is easy to implement. The solid dispersion provided by the present invention also has the characteristics of no obvious rust taste and no irritation to the mouth and tongue; the stability of the dispersion and the particles made thereof are comparable to the commercially available protein succinate iron oral solution.

[0107] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A solid dispersion of iron protein succinate, characterized in that: The solid dispersion is prepared from iron protein succinate and a solid dispersion matrix; wherein the solid dispersion matrix is ​​polyethylene glycol or hydroxyethyl starch.

2. A solid dispersion of iron protein succinate according to claim 1, characterized in that: The solid dispersion matrix is ​​polyethylene glycol.

3. A solid dispersion of iron protein succinate according to claim 2, characterized in that: The polyethylene glycol is polyethylene glycol 3350 or polyethylene glycol 4000.

4. A solid dispersion of iron protein succinate according to claim 1, characterized in that: The mass ratio of the protein succinate iron to the solid dispersion matrix is ​​1:(0.2-3).

5. A solid dispersion of iron protein succinate according to claim 4, characterized in that: The mass ratio of the protein succinate iron to the solid dispersion matrix is ​​1:(0.5-2).

6. The iron protein succinate solid dispersion according to claim 1, characterized in that: The iron protein succinate solid dispersion can be made into preparations including: soluble granules, powders, and dispersible tablets.

7. The iron protein succinate solid dispersion according to claim 6, characterized in that: The preparation that can be made of the iron protein succinate solid dispersion is a powder.

8. The method for preparing a solid dispersion of iron protein succinate according to any one of claims 1 to 7, characterized in that: The following steps are involved: (1) preparing a solution of a mixed powder of iron protein succinate and a solid dispersion matrix; (2) Adjusting the pH value of the solution; (3) The solution is filtered and then spray-dried to obtain an iron protein succinate dispersion.

9. The method for preparing a solid dispersion of iron protein succinate according to claim 8, characterized in that: The mass fraction of iron protein succinate in the solution is 5-10%.

10. The method for preparing a solid dispersion of iron protein succinate according to claim 8, characterized in that: The pH value is 6.5~8.0.

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