A ferrous succinate modulated release formulation and its preparation method

Abstract

This invention discloses a ferrous succinate-based controlled-release formulation, comprising a drug-containing core, an isolation layer, and an enteric coating layer. The drug-containing core contains the active ingredient ferrous succinate tetrahydrate, and the isolation layer contains an antioxidant. This invention avoids the irritation to the stomach caused by iron dissolving in acid, improves patient compliance, and enhances the solubility and absorption of iron at the absorption site. The addition of an antioxidant to the isolation layer of the controlled-release formulation effectively prevents ferrous oxidation caused by high temperature and humidity conditions during the coating and other formulation processes involving the ferrous succinate tetrahydrate drug core. The isolation layer prevents contact between external reactive oxygen species and the drug, while the antioxidant also consumes external reactive oxygen species under storage conditions, ensuring drug stability and reducing impurities during the production process.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations and relates to a ferrous succinate modulated release preparation and its preparation method. Technical Background

[0002] Iron is an essential trace element in the human body, participating in various vital activities such as oxygen metabolism, energy metabolism, electron transfer within mitochondria, muscle function, and hematopoiesis. Iron deficiency or impaired iron utilization leads to weakened oxygen transport and storage capacity, reduced oxygen metabolism levels, and decreased cell vitality. Prolonged iron deficiency depletes the body's reserves, lowers hemoglobin levels and hematocrit, resulting in iron deficiency anemia (IDA). Iron deficiency anemia is prevalent worldwide, affecting 1.62 billion people (approximately 24.8% of the world's population). The incidence rate is as high as 47.4% in preschool children, 41.8% in pregnant women, and 23.9% in the elderly, making it a pressing health issue that requires immediate attention.

[0003] Currently, the main drugs for treating iron deficiency anemia are divided into two categories: erythropoietin (EPO) and iron supplements. EPO is generally used in conjunction with intravenous iron supplementation, so iron supplements remain the most basic and widely available treatment for IDA.

[0004] Iron is mainly in the form of ferrous iron (Fe2+). 2+ In its ferrous form, iron is absorbed by the body in the duodenum, while ferrous iron (Fe2+) is absorbed by the body in its ferrous form. 2+ Compared to trivalent iron (Fe) 3+ It is also less easily absorbed and needs to be reduced to ferrous iron (Fe2+) in the body first. 2+ It is then absorbed. But ferrous iron (Fe) 2+ Dissolving in stomach acid can also irritate the stomach, causing side effects such as nausea and vomiting. This is mainly due to the presence of Fe. 2+ It is related to the generation of reactive oxygen species during the redox cycle.

[0005] Ferrous succinate is a small-molecule organic iron acid and a second-generation oral iron supplement. It has a high iron content and is considered a relatively ideal iron supplement. Currently, marketed formulations include regular tablets, sustained-release tablets, and granules. The raw material used is an amorphous basic salt of ferrous succinate. Its solubility gradually decreases with increasing pH, meaning it dissolves more in gastric juice, which can easily cause side effects, but dissolves less in the intestines, its primary absorption site, thus affecting iron absorption.

[0006] Invention patent CN1732911A discloses a ferrous succinate sustained-release formulation, which overcomes the gastric irritation of ferrous succinate by controlling the slow release of ferrous succinate, but there are no reports of it improving absorption.

[0007] Invention patent application CN115141096A discloses a crystalline form of ferrous succinate tetrahydrate, which has higher solubility and better absorption in intestinal fluid compared to traditional basic salts; however, its stability is poor, and it is prone to discoloration under high humidity conditions. (The last part about ferrous iron (Fe) appears to be unrelated and likely refers to a different patent.) 2+ It is easily oxidized to ferric iron (Fe3+). 3+ It needs to be combined with protective agents, antioxidants, and pore-forming agents to form a raw material composition before it can be used in formulations, which makes the process relatively complex.

[0008] Modified-release formulations refer to a large class of formulations that, compared to ordinary formulations, utilize technological means to adjust the drug's release rate, release site, or release time. Enteric-coated formulations are specially coated or formulated modified-release formulations that resist the acidic environment of the stomach, preventing drug release in the stomach and allowing targeted release after entering the neutral or weakly alkaline environment of the intestine. Currently, enteric-coated formulations are widely used in clinical practice for the formulation development of various drugs, including antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs), and proton pump inhibitors. The enteric materials of conventional enteric-coated formulations are mostly polymers such as acrylic resins and phthalates. Currently, there is no formulation of ferrous succinate into enteric-coated tablets. Summary of the Invention

[0009] The purpose of this invention is to reduce the adverse gastric reactions of current ferrous succinate preparations and improve iron absorption. A release formulation containing ferrous succinate tetrahydrate, which has good solubility in the high pH of the intestine, is prepared and can be specifically released into the intestine. This avoids the irritation to the stomach caused by iron dissolving in acid and improves the solubility and absorption of iron at the absorption site. To further address the instability of ferrous succinate tetrahydrate when used alone and to improve the situation where ferrous succinate is easily oxidized to ferric iron during the coating process and storage, this invention also adds an antioxidant to the isolation layer of the release formulation. This avoids the interaction between ferrous succinate and the enteric material while also preventing the increase of impurities during production and storage. The isolation layer mainly serves the following functions: (1) isolating the acidic groups of the enteric material to protect the stability of the active ingredient; (2) preventing the core component from penetrating and avoiding damage to the enteric membrane. Finally, this invention also provides an industrial method for preparing ferrous succinate release formulations.

[0010] To achieve the above objectives, the technical solution of the present invention is as follows:

[0011] In a first aspect, the present invention provides a ferrous succinate-releasing formulation capable of localized release into the intestine, comprising a drug-containing core, an isolation layer, and an enteric coating layer; wherein the drug-containing core contains the active ingredient ferrous succinate tetrahydrate, and the isolation layer contains an antioxidant.

[0012] The ferrous succinate modulated release formulation is a coated tablet or capsule.

[0013] Preferably, the drug-containing core is ferrous succinate tetrahydrate as the active ingredient, which is mixed evenly with pharmaceutically acceptable excipients and then compressed into tablets to obtain ferrous succinate tablets, or ferrous succinate microcapsules are obtained by coating ferrous succinate tetrahydrate powder onto a blank core using a powder deposition drug delivery method.

[0014] Preferably, the pharmaceutically acceptable excipient is at least one of a diluent, an adhesive, or a lubricant.

[0015] In some specific embodiments of the present invention, when the ferrous succinate-releasing formulation is a coated tablet, the core of the drug is ferrous succinate tetrahydrate as the active ingredient, and the ferrous succinate tablets are prepared by mixing ferrous succinate tetrahydrate with diluent and lubricant in the following weight proportions and then compressing: 45-210 parts ferrous succinate tetrahydrate, 86-254 parts diluent, and 1-4 parts lubricant.

[0016] In some specific embodiments of the present invention, when the ferrous succinate-releasing formulation is a coated tablet, the core of the drug is ferrous succinate tetrahydrate as the active ingredient. Ferrous succinate tetrahydrate is mixed with diluent and lubricant in the following weight proportions and then compressed into tablets to obtain ferrous succinate tablets: 75-150 parts ferrous succinate tetrahydrate, 148-223 parts diluent, and 2 parts lubricant.

[0017] In some specific embodiments of the present invention, when the ferrous succinate-releasing formulation is a coated tablet, the core of the drug is ferrous succinate tetrahydrate as the active ingredient, and the ferrous succinate tablet is prepared by mixing ferrous succinate tetrahydrate with diluent and lubricant in the following weight parts and then compressing: 75 parts ferrous succinate tetrahydrate, 223 parts diluent, 2 parts lubricant or 150 parts ferrous succinate tetrahydrate, 148-198 parts diluent, 2 parts lubricant.

[0018] The diluent is selected from at least one of microcrystalline cellulose and mannitol, preferably a combination of microcrystalline cellulose and mannitol in a weight ratio of 50:50 to 200:50, and more preferably a combination of microcrystalline cellulose and mannitol in a weight ratio of 98:50 to 148:50.

[0019] The lubricant is selected from magnesium stearate.

[0020] In some more specific embodiments of the present invention, when the ferrous succinate-releasing formulation is a coated tablet, the core of the drug is ferrous succinate tetrahydrate as the active ingredient, and the ferrous succinate tablets are prepared by mixing the following parts by weight of raw and excipient materials evenly and then compressing them into tablets: 75 parts ferrous succinate tetrahydrate, 148 parts microcrystalline cellulose, 75 parts mannitol, 2 parts magnesium stearate, 150 parts ferrous succinate tetrahydrate, 98 parts microcrystalline cellulose, 50 parts mannitol, 2 parts magnesium stearate, or 150 parts ferrous succinate tetrahydrate, 148 parts microcrystalline cellulose, 50 parts mannitol, 2 parts magnesium stearate.

[0021] In some specific embodiments of the present invention, when the ferrous succinate-releasing formulation is a capsule, the drug-containing core is ferrous succinate tetrahydrate as the active ingredient. Ferrous succinate tetrahydrate, blank pellet core, and binder are taken in the following weight proportions: 10-120 parts ferrous succinate tetrahydrate, 172-289 parts blank pellet core, and 1-8 parts binder. The blank pellet core is placed in a centrifugal granulator, and the powder layering method is used to coat the ferrous succinate tetrahydrate powder onto the blank pellet core while spraying the binder solution.

[0022] In some specific embodiments of the present invention, when the ferrous succinate-releasing formulation is a capsule, the drug-containing core is ferrous succinate tetrahydrate as the active ingredient. Ferrous succinate tetrahydrate, blank pellet core, and binder are taken in the following weight proportions: 75 parts ferrous succinate tetrahydrate, 220 parts blank pellet core, and 5 parts binder. The blank pellet core is placed in a centrifugal granulator, and the powder layering method is used to coat the blank pellet core with ferrous succinate tetrahydrate powder while spraying the binder solution. The ferrous succinate tetrahydrate powder is coated onto the blank pellet core to obtain ferrous succinate microcapsules.

[0023] The adhesive is hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, povidone, copovidone, and sucrose; the mass fraction of the adhesive solution is 1-5%.

[0024] In some specific embodiments of the present invention, the adhesive solution also contains an antioxidant.

[0025] The isolation layer is formed by coating the drug-containing core with an isolation layer coating solution containing an antioxidant; the isolation layer coating solution is a coating solution with a solid content (based on the isolation layer material) of 3-8% prepared by using an ethanol aqueous solution as a solvent to mix the isolation layer material and the antioxidant.

[0026] In some more specific embodiments of the present invention, the solid content of the isolation layer coating liquid is 6%.

[0027] The isolation layer material is selected from one or more combinations of polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, cellulose ether polymers, etc., preferably polyvinyl alcohol or hydroxypropyl methylcellulose.

[0028] The antioxidant is selected from water-soluble antioxidants and / or fat-soluble antioxidants.

[0029] The water-soluble antioxidant is one or more of the following: ascorbic acid (vitamin C), hypophosphite, thioglycerol, sodium bisulfite, sodium metabisulfite, sodium sulfite, and sodium thiosulfate, preferably ascorbic acid, thioglycerol, sodium bisulfite, sodium metabisulfite, sodium sulfite, and sodium thiosulfate; the fat-soluble antioxidant is selected from one or more of the following: ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate (PG), and tocopherol, preferably butylated hydroxyanisole and butylated hydroxytoluene.

[0030] Furthermore, the antioxidant is selected from a combination of water-soluble antioxidants and fat-soluble antioxidants.

[0031] Furthermore, the weight ratio of the water-soluble antioxidant to the fat-soluble antioxidant is 1:4 to 4:1, preferably 2:3 to 3:2.

[0032] In some specific embodiments of the present invention, the antioxidant is selected from at least one of ascorbic acid, thioglycerol, sodium bisulfite, sodium metabisulfite, sodium sulfite, and sodium thiosulfate, and a combination of at least one of butylated hydroxyanisole and butylated hydroxytoluene. The weight ratio of the antioxidant to ferrous succinate tetrahydrate is 1:600 ​​to 1:37.5, preferably 1:300 to 1:37.5, more preferably 1:300 to 1:75, and even more preferably 1:300 to 1:150.

[0033] Specifically, the weight ratio of the antioxidant to ferrous succinate tetrahydrate is 1:600, 1:300, 1:250, 1:200, 1:150, 1:75, and 1:37.5.

[0034] The mass fraction of the ethanol aqueous solution is 76% to 80%.

[0035] Preferably, the isolation layer coating solution is prepared by the following method: dispersing the isolation layer material in 95% ethanol to anhydrous ethanol, then gradually adding water, and adding a fat-soluble antioxidant and / or a water-soluble antioxidant dissolved in water in advance with 95% ethanol to anhydrous ethanol to prepare the coating solution.

[0036] Based on the material of the isolation layer, the weight gain of the isolation layer is 4-8% of that of the drug-containing core.

[0037] In some specific embodiments of the present invention, the weight gain of the isolation layer, based on the isolation layer material, is 4% of the weight of the drug-containing core.

[0038] The enteric coating layer is formed by coating the surface of the isolation layer with an enteric coating solution; the enteric coating solution is a coating solution containing talc, triethyl citrate and enteric material (calculated as a copolymer of enteric material) with a solid content of 15-25%.

[0039] In some specific embodiments of the present invention, the enteric coating solution is a coating solution with a solid content of 20%.

[0040] Preferably, the enteric coating solution is prepared by the following method: talc powder and triethyl citrate are added to an appropriate amount of water, stirred evenly using a high-shear mixer, and slowly poured into the enteric material while stirring continuously to prepare an enteric coating solution with a solid content of 20%.

[0041] The enteric material is one of cellulose derivatives or acrylic resins.

[0042] The cellulose derivatives are selected from one or more of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose succinate.

[0043] The acrylic resin is selected from one or more of the following: methacrylic acid-methyl methacrylate copolymer, methacrylic acid-methyl methacrylate copolymer, and methacrylic acid-ethyl acrylate copolymer.

[0044] The methacrylic acid-methyl methacrylate copolymer is selected from the Eudragit L series, specifically L100, L100-55, and L30D-55.

[0045] The methacrylic acid-methyl methacrylate copolymer is selected from the Eudragit S series, specifically from S100.

[0046] The methacrylate-ethyl acrylate copolymer is selected from Eudragit FS 30D.

[0047] Preferably, the enteric material is selected from L100-55 and L30D-55.

[0048] Based on the copolymer of enteric materials, the weight gain of the enteric layer is 8-30% of the drug-containing core of the protective layer.

[0049] Preferably, when the ferrous succinate modulating formulation is a coated tablet, the weight gain of the enteric layer, calculated based on the copolymer of the enteric material, is 8-15% of the drug-containing core of the encapsulating and isolating layer; when the ferrous succinate modulating formulation is a capsule, the weight gain of the enteric layer, calculated based on the copolymer of the enteric material, is 12-30%, preferably 15-30%, of the drug-containing core of the encapsulating and isolating layer.

[0050] In the ferrous succinate modulated release formulation, the unit dosage of ferrous succinate tetrahydrate is 75-150 mg, preferably 75 mg or 150 mg.

[0051] The ferrous succinate tetrahydrate described in this invention is the ferrous succinate tetrahydrate crystal form of Example 1 in patent application CN119684116A or other ferrous succinate tetrahydrate crystal forms.

[0052] In another aspect, the present invention provides a method for preparing the ferrous succinate-based modulating formulation, wherein when the ferrous succinate-based modulating formulation is a coated tablet, the method includes the following steps:

[0053] Step (1) Preparation of drug-containing core: Using ferrous succinate tetrahydrate as the active ingredient, ferrous succinate tetrahydrate is mixed evenly with pharmaceutically acceptable excipients and compressed into tablets to obtain ferrous succinate tablets.

[0054] Step (2), isolation layer coating: Disperse the isolation layer material in 95% ethanol to anhydrous ethanol, then gradually add water, and add the fat-soluble antioxidant and / or water-soluble antioxidant dissolved in water that have been dissolved in 95% ethanol to anhydrous ethanol in advance to prepare an isolation layer coating solution with a solid content of 6%; place the ferrous succinate tablets in a coating pan, and use the isolation layer coating solution containing antioxidants to coat them to obtain ferrous succinate tablets coated with an isolation layer;

[0055] Step (3), enteric coating: Add talc and triethyl citrate to an appropriate amount of water, stir evenly, slowly pour into the enteric material and stir continuously to prepare an enteric coating solution with a solid content of 15-25%; place the ferrous succinate tablets with the isolation layer in a coating pan for enteric coating to obtain ferrous succinate enteric coated tablets.

[0056] When the ferrous succinate formulation is a capsule, the following steps are included:

[0057] Step (1) Preparation of drug-containing core: Using ferrous succinate tetrahydrate as the active ingredient, the powder of ferrous succinate tetrahydrate is coated onto the blank pellet core by the powder deposition drug loading method to obtain ferrous succinate micro pellets.

[0058] Step (2), isolation layer coating: Disperse the isolation layer material in 95% ethanol to anhydrous ethanol, then gradually add water, and add the fat-soluble antioxidant and / or water-soluble antioxidant dissolved in water in advance with 95% ethanol to anhydrous ethanol to prepare an isolation layer coating solution with a solid content of 6%; place the ferrous succinate microspheres in a fluidized bed and coat them with the isolation layer coating solution containing antioxidants to obtain ferrous succinate microspheres coated with an isolation layer;

[0059] Step (3), enteric coating: Add talc and triethyl citrate to an appropriate amount of water, stir evenly, slowly pour into the enteric material and stir continuously to prepare an enteric coating solution with a solid content of 15-25%; place the ferrous succinate microspheres coated with the isolation layer in a fluidized bed for enteric coating to obtain ferrous succinate enteric microspheres.

[0060] Step (4), Capsule filling: Ferrous succinate enteric-coated microspheres are filled into capsules.

[0061] In step (1), the blank pellet core is a 40-60 mesh microcrystalline cellulose blank pellet core.

[0062] Preferred preparation of drug-containing core: A blank pellet core is placed in a centrifugal granulator, and ferrous succinate tetrahydrate powder is coated onto the blank pellet core using a powder deposition drug loading method to obtain ferrous succinate micro pellets.

[0063] The beneficial effects of this invention are:

[0064] The ferrous succinate formulation of this invention exhibits low release in pH 1.2 medium, with a dissolution rate of <10% after 2 hours, while it releases rapidly and completely in pH 6.8, with a dissolution rate of >80% after 30 minutes. In vivo, it ensures the release of ferrous (Fe) 2+ It is not released or is released in small amounts in gastric juice to avoid ferrous (Fe) 2+ It reduces gastric irritation caused by dissolution and improves patient compliance; the active ingredient selected is ferrous succinate tetrahydrate, which, compared with basic salts, has a significantly higher dissolution rate in the intestine, the main absorption site, thus improving iron absorption.

[0065] This invention incorporates antioxidants with antioxidant properties into the isolation layer. In particular, the combination of antioxidants with different solubilities can effectively prevent the oxidation of ferrous oxide caused by high temperature and humidity conditions during the formulation process, such as coating, of the drug core containing ferrous succinate tetrahydrate. After the isolation layer is applied, it prevents external reactive oxygen species from contacting the drug. At the same time, the antioxidants can also consume external reactive oxygen species under storage conditions, ensuring the stability of the drug and reducing impurities (high iron) in the production process.

[0066] This invention provides a method for preparing the above-mentioned modulated release formulation. The preparation of the drug-containing core uses an anhydrous (solvent) method, which minimizes the instability of ferrous succinate tetrahydrate. Compared with the method disclosed in CN115141096A, which first prepares a stable composition and then prepares the corresponding formulation, this invention enables the direct application of ferrous succinate tetrahydrate, and the operation is simpler and more suitable for industrial production. Attached Figure Description

[0067] Figure 1 The dissolution curve of ferrous succinate enteric-coated tablets 16-3 in pH 6.8 medium is shown. Detailed Implementation

[0068] The technical solution of the present invention will be described in detail below through specific embodiments.

[0069] The ferrous succinate tetrahydrate used in the examples is the ferrous succinate tetrahydrate crystal form of Example 1 in Chinese Patent Application CN119684116A.

[0070] Example 1

[0071] Table 1. Formula for Ferrous Succinate Enteric-coated Tablets 1

[0072]

[0073] A method for preparing ferrous succinate enteric-coated tablets, comprising the following steps:

[0074] Step (1): Mixing: Add ferrous succinate tetrahydrate, microcrystalline cellulose, mannitol, and magnesium stearate to a container and mix evenly to obtain a mixed powder;

[0075] Step (2): Tableting: The above mixed powder is placed in a tablet press for tableting to obtain unprocessed tablets. Each unprocessed tablet contains 150mg of ferrous succinate tetrahydrate, with a core diameter of 9mm, a hardness of 4-8kg, and a brittleness of <1%.

[0076] Step (3): Preparation of the isolation layer coating solution: First, disperse hydroxypropyl methylcellulose PHARMACOAT 606 in 95% ethanol, then gradually add water and sodium sulfite dissolved in water beforehand to prepare a coating solution with a solid content of 6% (solid content refers to the mass fraction of the isolation layer material) (95% ethanol: water = 80:20 W / W); Isolation layer coating: Place the uncoated tablets in a high-efficiency coating pan (model: SGB-5) and start coating. Control the material temperature at 38-42℃. When the coating weight gain (based on the isolation layer material, the same below) reaches 4% of the drug core, stop coating to obtain ferrous succinate tablets coated with the isolation layer;

[0077] Step (4): Enteric coating: Add talc and triethyl citrate to an appropriate amount of water, stir evenly with a high-shear mixer, slowly pour into the aqueous dispersion (i.e., Eutech L30D-55) and stir continuously to prepare an enteric coating solution with a solid content (solid content refers to the mass fraction of the copolymer in the enteric material Eutech L30D-55) of 20%; place the ferrous succinate tablets coated with the isolation layer in a high-efficiency coating pan (model: SGB-5) and start enteric coating, control the material temperature at 32-37℃, and stop coating when the coating weight gain (based on the copolymer in Eutech L30D-55) reaches 10% of the ferrous succinate tablets coated with the isolation layer, to obtain ferrous succinate enteric tablets (referred to as enteric tablet 1).

[0078] Example 2

[0079] Table 2. Formula 2 for Ferrous Succinate Enteric-coated Tablets

[0080]

[0081] A method for preparing ferrous succinate enteric-coated tablets, comprising the following steps:

[0082] Step (1): Mixing: Add ferrous succinate tetrahydrate, microcrystalline cellulose, mannitol, and magnesium stearate to a container and mix evenly to obtain a mixed powder;

[0083] Step (2): Tableting: The above mixed powder is placed in a tablet press to compress tablets to obtain plain tablets. Each plain tablet contains 150mg of ferrous succinate tetrahydrate, with a core diameter of 9mm, a hardness of 4-8kg, and a brittleness of <1%.

[0084] Step (3): Preparation of the isolation layer coating solution: After dispersing the isolation layer material in 95% ethanol, water is gradually added, and antioxidants that have been dissolved in water are added in advance to prepare a coating solution with a solid content of 6% (95% ethanol: water = 80: 20 W / W); Isolation layer coating: Place the uncoated tablets in a high-efficiency coating pan (model: SGB-5) and start coating. Control the material temperature at 38-42℃. When the coating weight increases to 4%, stop coating to obtain ferrous succinate tablets coated with the isolation layer;

[0085] Step (4): Enteric coating: Add talc and triethyl citrate to an appropriate amount of water, stir evenly with a high-shear mixer, slowly pour into the aqueous dispersion and continue stirring to prepare an enteric coating solution with a solid content of 20%; place the ferrous succinate tablets coated with the isolation layer in a high-efficiency coating pan (model: SGB-5) and start enteric coating, control the material temperature at 32-37℃, and stop coating when the coating weight increases to 10% to obtain ferrous succinate enteric tablet 2 (denoted as enteric tablet 2).

[0086] Example 3

[0087] Table 3. Ferrous Succinate Enteric-coated Tablets Prescription 3

[0088]

[0089] A method for preparing ferrous succinate enteric-coated tablets, comprising the following steps:

[0090] Step (1): Mixing: Add ferrous succinate tetrahydrate, microcrystalline cellulose, mannitol, and magnesium stearate to a container and mix evenly to obtain a mixed powder;

[0091] Step (2): Tableting: The above mixed powder is placed in a tablet press to compress tablets to obtain plain tablets. Each plain tablet contains 150mg of ferrous succinate tetrahydrate, with a core diameter of 9mm, a hardness of 4-8kg, and a brittleness of <1%.

[0092] Step (3): Preparation of the isolation layer coating solution: After dispersing the isolation layer material in 95% ethanol, water is gradually added, and antioxidants that have been dissolved in water are added in advance to prepare a coating solution with a solid content of 6% (95% ethanol: water = 80: 20 W / W); Isolation layer coating: Place the uncoated tablets in a high-efficiency coating pan (model: SGB-5) and start coating. Control the material temperature at 38-42℃. When the coating weight increases to 4%, stop coating to obtain ferrous succinate tablets coated with the isolation layer;

[0093] Step (4): Enteric coating: Add talc and triethyl citrate to an appropriate amount of water, stir evenly with a high-shear mixer, slowly pour into the aqueous dispersion and continue stirring to prepare an enteric coating solution with a solid content of 20%; place the ferrous succinate tablets coated with the isolation layer in a high-efficiency coating pan (model: SGB-5) and start enteric coating, control the material temperature at 32-37℃, and stop coating when the coating weight increases to 10% to obtain ferrous succinate enteric tablet 3 (denoted as enteric tablet 3).

[0094] Example 4

[0095] Table 4. Ferrous Succinate Enteric-coated Tablets Prescription 4

[0096]

[0097] A method for preparing ferrous succinate enteric-coated tablets, comprising the following steps:

[0098] Step (1): Mixing: Add ferrous succinate tetrahydrate, microcrystalline cellulose, mannitol, and magnesium stearate to a container and mix evenly to obtain a mixed powder;

[0099] Step (2): Tableting: The above mixed powder is placed in a tablet press to compress tablets to obtain plain tablets. Each plain tablet contains 150mg of ferrous succinate tetrahydrate, with a core diameter of 9mm, a hardness of 4-8kg, and a brittleness of <1%.

[0100] Step (3): Preparation of the isolation layer coating solution: After dispersing the isolation layer material in 95% ethanol, water is gradually added, and antioxidants that have been dissolved in water are added in advance to prepare a coating solution with a solid content of 6% (95% ethanol: water = 80: 20 W / W); Isolation layer coating: Place the uncoated tablets in a high-efficiency coating pan (model: SGB-5) and start coating. Control the material temperature at 38-42℃. When the coating weight increases to 4%, stop coating to obtain ferrous succinate tablets coated with the isolation layer;

[0101] Step (4): Enteric coating: Add talc and triethyl citrate to an appropriate amount of water, stir evenly with a high-shear mixer, slowly pour into the aqueous dispersion and continue stirring to prepare an enteric coating solution with a solid content of 20%; place the ferrous succinate tablets coated with the isolation layer in a high-efficiency coating pan (model: SGB-5) and start enteric coating, control the material temperature at 32-37℃, and stop coating when the coating weight increases to 10% to obtain ferrous succinate enteric tablet 4 (denoted as enteric tablet 4).

[0102] Example 5

[0103] Table 5. Prescription 5 for Ferrous Succinate Enteric-coated Tablets

[0104]

[0105] A method for preparing ferrous succinate enteric-coated tablets, comprising the following steps:

[0106] Step (1): Mixing: Add ferrous succinate tetrahydrate, microcrystalline cellulose, mannitol, and magnesium stearate to a container and mix evenly to obtain a mixed powder;

[0107] Step (2): Tableting: The above mixed powder is placed in a tablet press to compress tablets to obtain plain tablets. Each plain tablet contains 150mg of ferrous succinate tetrahydrate, with a core diameter of 9mm, a hardness of 4-8kg, and a brittleness of <1%.

[0108] Step (3): Preparation of the isolation layer coating solution: After dispersing the isolation layer material in 95% ethanol, water is gradually added, and antioxidants that have been dissolved in water are added in advance to prepare a coating solution with a solid content of 6% (95% ethanol: water = 80: 20 W / W); Isolation layer coating: Place the uncoated tablets in a high-efficiency coating pan (model: SGB-5) and start coating. Control the material temperature at 38-42℃. When the coating weight increases to 4%, stop coating to obtain ferrous succinate tablets coated with the isolation layer;

[0109] Step (4): Enteric coating: Add talc and triethyl citrate to an appropriate amount of water, stir evenly with a high-shear mixer, slowly pour into the aqueous dispersion and continue stirring to prepare an enteric coating solution with a solid content of 20%; place the ferrous succinate tablets coated with the isolation layer in a high-efficiency coating pan (model: SGB-5) and start enteric coating, control the material temperature at 32-37℃, and stop coating when the coating weight increases to 10% to obtain ferrous succinate enteric tablet 5 (denoted as enteric tablet 5).

[0110] Example 6

[0111] Table 6. Ferrous Succinate Enteric-coated Tablets Prescription 6

[0112]

[0113] A method for preparing ferrous succinate enteric-coated tablets, comprising the following steps:

[0114] Step (1): Mixing: Add ferrous succinate tetrahydrate, microcrystalline cellulose, mannitol and magnesium stearate to a container in sequence, mix evenly to obtain a mixed powder;

[0115] Step (2): Tableting: The above mixed powder is placed in a tablet press to compress tablets to obtain plain tablets. Each plain tablet contains 150mg of ferrous succinate tetrahydrate, with a core diameter of 9mm, a hardness of 4-8kg, and a brittleness of <1%.

[0116] Step (3): Preparation of the isolation layer coating solution: After dispersing the isolation layer material in 95% ethanol, water is gradually added, and antioxidants that have been dissolved in 95% ethanol are added to prepare a coating solution with a solid content of 6% (95% ethanol: water = 80: 20 W / W); Isolation layer coating: Place the uncoated tablets in a high-efficiency coating pan (model: SGB-5) and start coating. Control the material temperature at 38-42℃. When the coating weight increases to 4%, stop coating to obtain ferrous succinate tablets coated with the isolation layer;

[0117] Step (4): Enteric coating: Add talc and triethyl citrate to an appropriate amount of water, stir evenly with a high-shear mixer, slowly pour into the aqueous dispersion and continue stirring to prepare an enteric coating solution with a solid content of 20%; place the ferrous succinate tablets coated with the isolation layer in a high-efficiency coating pan (model: SGB-5) and start enteric coating, control the material temperature at 32-37℃, and stop coating when the coating weight increases to 10% to obtain ferrous succinate enteric tablet 6 (denoted as enteric tablet 6).

[0118] Example 7

[0119] Table 7. Formula for Ferrous Succinate Enteric-coated Tablets 7

[0120]

[0121] A method for preparing ferrous succinate enteric-coated tablets, comprising the following steps:

[0122] Step (1): Mixing: Add ferrous succinate tetrahydrate, microcrystalline cellulose, mannitol, and magnesium stearate to a container and mix evenly to obtain a mixed powder;

[0123] Step (2): Tableting: The above mixed powder is placed in a tablet press to compress tablets to obtain plain tablets. Each plain tablet contains 150mg of ferrous succinate tetrahydrate, with a core diameter of 9mm, a hardness of 4-8kg, and a brittleness of <1%.

[0124] Step (3): Preparation of the isolation layer coating solution: After dispersing the isolation layer material in 95% ethanol, water is gradually added, and antioxidants that have been dissolved in 95% ethanol are added to prepare a coating solution with a solid content of 6% (95% ethanol: water = 80: 20 W / W); Isolation layer coating: Place the uncoated tablets in a high-efficiency coating pan (model: SGB-5) and start coating. Control the material temperature at 38-42℃. When the coating weight increases to 4%, stop coating to obtain ferrous succinate tablets coated with the isolation layer;

[0125] Step (4): Enteric coating: Add talc and triethyl citrate to an appropriate amount of water, stir evenly with a high-shear mixer, slowly pour into the aqueous dispersion and continue stirring to prepare an enteric coating solution with a solid content of 20%; place the ferrous succinate tablets coated with the isolation layer in a high-efficiency coating pan (model: SGB-5) and start enteric coating, control the material temperature at 32-37℃, and stop coating when the coating weight increases to 10% to obtain ferrous succinate enteric tablet 7 (referred to as enteric tablet 7).

[0126] Example 8

[0127] Table 8. Prescription for Ferrous Succinate Enteric-coated Tablets

[0128]

[0129] A method for preparing ferrous succinate enteric-coated tablets, comprising the following steps:

[0130] Step (1): Mixing: Add ferrous succinate tetrahydrate, microcrystalline cellulose, mannitol, and magnesium stearate to a container and mix evenly to obtain a mixed powder;

[0131] Step (2): Tableting: The above mixed powder is placed in a tablet press to compress tablets to obtain plain tablets. Each plain tablet contains 150mg of ferrous succinate tetrahydrate, with a core diameter of 9mm, a hardness of 4-8kg, and a brittleness of <1%.

[0132] Step (3): Preparation of the isolation layer coating solution: After dispersing the isolation layer material in 95% ethanol, water is gradually added, and antioxidants that have been dissolved in 95% ethanol are added to prepare a coating solution with a solid content of 6% (95% ethanol: water = 80: 20 W / W); Isolation layer coating: Place the uncoated tablets in a high-efficiency coating pan (model: SGB-5) and start coating. Control the material temperature at 38-42℃. When the coating weight increases to 4%, stop coating to obtain ferrous succinate tablets coated with the isolation layer;

[0133] Step (4): Enteric coating: Add talc and triethyl citrate to an appropriate amount of water, stir evenly with a high-shear mixer, slowly pour into the aqueous dispersion and continue stirring to prepare an enteric coating solution with a solid content of 20%; place the ferrous succinate tablets coated with the isolation layer in a high-efficiency coating pan (model: SGB-5) and start enteric coating, control the material temperature at 32-37℃, and stop coating when the coating weight increases to 10% to obtain ferrous succinate enteric tablet 8 (referred to as enteric tablet 8).

[0134] Example 9

[0135] Table 9. Prescription for Ferrous Succinate Enteric-coated Tablets 9

[0136]

[0137] A method for preparing ferrous succinate enteric-coated tablets, comprising the following steps:

[0138] Step (1): Mixing: Add ferrous succinate tetrahydrate, microcrystalline cellulose, mannitol, and magnesium stearate to a container and mix evenly to obtain a mixed powder;

[0139] Step (2): Tableting: The above mixed powder is placed in a tablet press to compress tablets to obtain plain tablets. Each plain tablet contains 150mg of ferrous succinate tetrahydrate, with a core diameter of 9mm, a hardness of 4-8kg, and a brittleness of <1%.

[0140] Step (3): Preparation of the isolation layer coating solution: After dispersing the isolation layer material in 95% ethanol, water is gradually added, and antioxidants that have been dissolved in 95% ethanol are added to prepare a coating solution with a solid content of 6% (95% ethanol: water = 80: 20 W / W); Isolation layer coating: Place the uncoated tablets in a high-efficiency coating pan (model: SGB-5) and start coating. Control the material temperature at 38-42℃. When the coating weight increases to 4%, stop coating to obtain ferrous succinate tablets coated with the isolation layer;

[0141] Step (4): Enteric coating: Add talc and triethyl citrate to an appropriate amount of water, stir evenly with a high-shear mixer, slowly pour into the aqueous dispersion and continue stirring to prepare an enteric coating solution with a solid content of 20%; place the ferrous succinate tablets coated with the isolation layer in a high-efficiency coating pan (model: SGB-5) and start enteric coating, control the material temperature at 32-37℃, and stop coating when the coating weight increases to 10% to obtain ferrous succinate enteric tablets 9 (referred to as enteric tablets 9).

[0142] Example 10

[0143] Table 10. Prescription for Ferrous Succinate Enteric-coated Tablets 10

[0144]

[0145] A method for preparing ferrous succinate enteric-coated tablets, comprising the following steps:

[0146] Step (1): Mixing: Add ferrous succinate tetrahydrate, microcrystalline cellulose, mannitol, and magnesium stearate to a container and mix evenly to obtain a mixed powder;

[0147] Step (2): Tableting: The above mixed powder is placed in a tablet press to compress tablets to obtain plain tablets. Each plain tablet contains 150mg of ferrous succinate tetrahydrate, with a core diameter of 9mm, a hardness of 4-8kg, and a brittleness of <1%.

[0148] Step (3): Preparation of the isolation layer coating solution: After dispersing the isolation layer material in 95% ethanol, water is gradually added, along with butylated hydroxyanisole dissolved in 95% ethanol and sodium sulfite dissolved in water, to prepare a coating solution with a solid content of 6% (95% ethanol: water = 80: 20 W / W); Isolation layer coating: Place the uncoated tablets in a high-efficiency coating pan (model: SGB-5) and begin coating. Control the material temperature at 38-42℃. When the coating weight increases to 4%, stop coating to obtain ferrous succinate tablets coated with the isolation layer;

[0149] Step (4): Enteric coating: Add talc and triethyl citrate to an appropriate amount of water, stir evenly with a high-shear mixer, slowly pour into the aqueous dispersion and continue stirring to prepare an enteric coating solution with a solid content of 20%; place the ferrous succinate tablets coated with the isolation layer in a high-efficiency coating pan (model: SGB-5) and start enteric coating, control the material temperature at 32-37℃, and stop coating when the coating weight increases to 10% to obtain ferrous succinate enteric tablet 10 (denoted as enteric tablet 10).

[0150] Example 11

[0151] Table 11. Prescription for Ferrous Succinate Enteric-coated Tablets

[0152]

[0153] A method for preparing ferrous succinate enteric-coated tablets, comprising the following steps:

[0154] Step (1): Mixing: Add ferrous succinate tetrahydrate, microcrystalline cellulose, mannitol, and magnesium stearate to a container and mix evenly to obtain a mixed powder;

[0155] Step (2): Tableting: The above mixed powder is placed in a tablet press for tableting to obtain unprocessed tablets. Each unprocessed tablet contains 75mg of ferrous succinate tetrahydrate, with a core diameter of 9mm, a hardness of 4-8kg, and a brittleness of <1%.

[0156] Step (3): Preparation of the isolation layer coating solution: After dispersing the isolation layer material in 95% ethanol, water is gradually added, along with butylated hydroxyanisole dissolved in 95% ethanol and sodium sulfite dissolved in water, to prepare a coating solution with a solid content of 6% (95% ethanol: water = 80: 20 W / W); Isolation layer coating: Place the uncoated tablets in a high-efficiency coating pan (model: SGB-5) and begin coating. Control the material temperature at 38-42℃. When the coating weight increases to 4%, stop coating to obtain ferrous succinate tablets coated with the isolation layer;

[0157] Step (4): Enteric coating: Add talc and triethyl citrate to an appropriate amount of water, stir evenly with a high-shear mixer, slowly pour into the aqueous dispersion and continue stirring to prepare an enteric coating solution with a solid content of 20%; place the ferrous succinate tablets coated with the isolation layer in a high-efficiency coating pan (model: SGB-5) and start enteric coating, control the material temperature at 32-37℃, and stop coating when the coating weight increases to 10% to obtain ferrous succinate enteric tablet 11 (referred to as enteric tablet 11).

[0158] Example 12

[0159] Table 12. Prescription for Ferrous Succinate Enteric-coated Tablets 12

[0160]

[0161] A method for preparing ferrous succinate enteric-coated tablets, comprising the following steps:

[0162] Step (1): Mixing: Add ferrous succinate tetrahydrate, microcrystalline cellulose, mannitol, and magnesium stearate to a container and mix evenly to obtain a mixed powder;

[0163] Step (2): Tableting: The above mixed powder is placed in a tablet press for tableting to obtain unprocessed tablets. Each unprocessed tablet contains 75mg of ferrous succinate tetrahydrate, with a core diameter of 9mm, a hardness of 4-8kg, and a brittleness of <1%.

[0164] Step (3): Preparation of the isolation layer coating solution: After dispersing the isolation layer material in 95% ethanol, water is gradually added, along with butylated hydroxyanisole dissolved in 95% ethanol and sodium sulfite dissolved in water, to prepare a coating solution with a solid content of 6% (95% ethanol: water = 80: 20 W / W); Isolation layer coating: Place the uncoated tablets in a high-efficiency coating pan (model: SGB-5) and begin coating. Control the material temperature at 38-42℃. When the coating weight increases to 4%, stop coating to obtain ferrous succinate tablets coated with the isolation layer;

[0165] Step (4): Enteric coating: Add talc and triethyl citrate to an appropriate amount of water, stir evenly with a high-shear mixer, slowly pour into the aqueous dispersion and continue stirring to prepare an enteric coating solution with a solid content of 20%; place the ferrous succinate tablets coated with the isolation layer in a high-efficiency coating pan (model: SGB-5) and start enteric coating, control the material temperature at 32-37℃, and stop coating when the coating weight increases to 10% to obtain ferrous succinate enteric tablet 12 (referred to as enteric tablet 12).

[0166] Example 13

[0167] Table 13. Prescription for Ferrous Succinate Enteric-coated Tablets

[0168]

[0169] A method for preparing ferrous succinate enteric-coated tablets, comprising the following steps:

[0170] Step (1): Mixing: Add ferrous succinate tetrahydrate, microcrystalline cellulose, mannitol, and magnesium stearate to a container and mix evenly to obtain a mixed powder;

[0171] Step (2): Tableting: The above mixed powder is placed in a tablet press for tableting to obtain unprocessed tablets. Each unprocessed tablet contains 75mg of ferrous succinate tetrahydrate, with a core diameter of 9mm, a hardness of 4-8kg, and a brittleness of <1%.

[0172] Step (3): Preparation of the isolation layer coating solution: After dispersing the isolation layer material in 95% ethanol, water is gradually added, along with butylated hydroxyanisole dissolved in 95% ethanol and sodium sulfite dissolved in water, to prepare a coating solution with a solid content of 6% (95% ethanol: water = 80: 20 W / W); Isolation layer coating: Place the uncoated tablets in a high-efficiency coating pan (model: SGB-5) and begin coating. Control the material temperature at 38-42℃. When the coating weight increases to 4%, stop coating to obtain ferrous succinate tablets coated with the isolation layer;

[0173] Step (4): Enteric coating: Add talc and triethyl citrate to an appropriate amount of water, stir evenly with a high-shear mixer, slowly pour into the aqueous dispersion and continue stirring to prepare an enteric coating solution with a solid content of 20%; place the ferrous succinate tablets coated with the isolation layer in a high-efficiency coating pan (model: SGB-5) and start enteric coating, control the material temperature at 32-37℃, and stop coating when the coating weight increases to 10% to obtain ferrous succinate enteric tablet 13 (referred to as enteric tablet 13).

[0174] Example 14

[0175] Table 14. Prescription for Ferrous Succinate Enteric-coated Tablets

[0176]

[0177] A method for preparing ferrous succinate enteric-coated tablets, comprising the following steps:

[0178] Step (1): Mixing: Add ferrous succinate tetrahydrate, microcrystalline cellulose, mannitol, and magnesium stearate to a container and mix evenly to obtain a mixed powder;

[0179] Step (2): Tableting: The above mixed powder is placed in a tablet press for tableting to obtain unprocessed tablets. Each unprocessed tablet contains 75mg of ferrous succinate tetrahydrate, with a core diameter of 9mm, a hardness of 4-8kg, and a brittleness of <1%.

[0180] Step (3): Preparation of the isolation layer coating solution: After dispersing the isolation layer material in 95% ethanol, water is gradually added, along with butylated hydroxyanisole dissolved in 95% ethanol and sodium sulfite dissolved in water, to prepare a coating solution with a solid content of 6% (95% ethanol: water = 80: 20 W / W); Isolation layer coating: Place the uncoated tablets in a high-efficiency coating pan (model: SGB-5) and begin coating. Control the material temperature at 38-42℃. When the coating weight increases to 4%, stop coating to obtain ferrous succinate tablets coated with the isolation layer;

[0181] Step (4): Enteric coating: Add talc and triethyl citrate to an appropriate amount of water, stir evenly with a high-shear mixer, slowly pour into the aqueous dispersion and continue stirring to prepare an enteric coating solution with a solid content of 20%; place the ferrous succinate tablets coated with the isolation layer in a high-efficiency coating pan (model: SGB-5) and start enteric coating, control the material temperature at 32-37℃, and stop coating when the coating weight increases to 10% to obtain ferrous succinate enteric tablet 14 (referred to as enteric tablet 14).

[0182] Example 15

[0183] Table 15. Prescription for Ferrous Succinate Enteric-coated Tablets 15

[0184]

[0185] A method for preparing ferrous succinate enteric-coated tablets, comprising the following steps:

[0186] Step (1): Mixing: Add ferrous succinate tetrahydrate, microcrystalline cellulose, mannitol, and magnesium stearate to a container and mix evenly to obtain a mixed powder;

[0187] Step (2): Tableting: The above mixed powder is placed in a tablet press for tableting to obtain unprocessed tablets. Each unprocessed tablet contains 75mg of ferrous succinate tetrahydrate, with a core diameter of 9mm, a hardness of 4-8kg, and a brittleness of <1%.

[0188] Step (3): Preparation of the isolation layer coating solution: After dispersing the isolation layer material in 95% ethanol, water is gradually added, along with butylated hydroxyanisole dissolved in 95% ethanol and sodium sulfite dissolved in water, to prepare a coating solution with a solid content of 6% (95% ethanol: water = 80: 20 W / W); Isolation layer coating: Place the uncoated tablets in a high-efficiency coating pan (model: SGB-5) and begin coating. Control the material temperature at 38-42℃. When the coating weight increases to 4%, stop coating to obtain ferrous succinate tablets coated with the isolation layer;

[0189] Step (4): Enteric coating: Add talc and triethyl citrate to an appropriate amount of water, stir evenly with a high-shear mixer, slowly pour into the aqueous dispersion and continue stirring to prepare an enteric coating solution with a solid content of 20%; place the ferrous succinate tablets coated with the isolation layer in a high-efficiency coating pan (model: SGB-5) and start enteric coating, control the material temperature at 32-37℃, and stop coating when the coating weight increases to 10% to obtain ferrous succinate enteric tablet 15 (referred to as enteric tablet 15).

[0190] Example 16

[0191] Table 16. Prescription for Ferrous Succinate Enteric-coated Tablets

[0192]

[0193] A method for preparing ferrous succinate enteric-coated tablets, comprising the following steps:

[0194] Step (1): Mixing: Add ferrous succinate tetrahydrate, microcrystalline cellulose, mannitol, and magnesium stearate to a container and mix evenly to obtain a mixed powder;

[0195] Step (2): Tableting: The above mixed powder is placed in a tablet press for tableting to obtain unprocessed tablets. Each unprocessed tablet contains 75mg of ferrous succinate tetrahydrate, with a core diameter of 9mm, a hardness of 4-8kg, and a brittleness of <1%.

[0196] Step (3): Preparation of the isolation layer coating solution: After dispersing the isolation layer material in 95% ethanol, water is gradually added, along with butylated hydroxyanisole dissolved in 95% ethanol and sodium sulfite dissolved in water, to prepare a coating solution with a solid content of 6% (95% ethanol: water = 80: 20 W / W); Isolation layer coating: Place the uncoated tablets in a high-efficiency coating pan (model: SGB-5) and begin coating. Control the material temperature at 38-42℃. When the coating weight increases to 4%, stop coating to obtain ferrous succinate tablets coated with the isolation layer;

[0197] Step (4): Enteric coating: Add talc and triethyl citrate to an appropriate amount of water, stir evenly with a high-shear mixer, slowly pour into the aqueous dispersion and continue stirring to prepare an enteric coating solution with a solid content of 20%; place the ferrous succinate tablets coated with the isolation layer in a high-efficiency coating pan (model: SGB-5) to start enteric coating, control the material temperature at 32-37℃, and take samples after the coating weight increases to 6%, 8%, 10%, 12%, and 15% to obtain ferrous succinate enteric tablets, which are respectively named 16-1, 16-2, 16-3, 16-4, and 16-5.

[0198] Example 17

[0199] Table 17. Prescription for Ferrous Succinate Intestinal Capsules 17

[0200]

[0201] A method for preparing ferrous succinate enteric-coated capsules, comprising the following steps:

[0202] Step (1): Preparation of drug-containing core: Add the blank pellet core to the centrifugal granulator (WL type centrifugal pellet mill), use the powder layering drug loading method, control the main machine speed to 100-300 rpm, turn on the spray gun, spray in 3% hydroxypropyl methylcellulose E5 (HPMC-E5) aqueous solution as binder, and gradually add ferrous succinate tetrahydrate (passed through 100 mesh sieve) so that the ferrous succinate tetrahydrate powder is coated on the blank pellet core to obtain ferrous succinate micro pellets;

[0203] Step (2): Preparation of isolation layer coating solution: Disperse the isolation layer material in 95% ethanol, then gradually add water, add butylated hydroxyanisole dissolved in 95% ethanol and sodium sulfite dissolved in water to prepare an isolation layer coating solution with a solid content of 6%; Isolation layer coating: Place ferrous succinate microspheres in a fluidized bed, use an isolation layer coating solution containing antioxidants for coating, control the material temperature at 38-42℃, stop coating when the coating weight increases to 5%, and obtain ferrous succinate microspheres coated with isolation layer;

[0204] Step (3): Enteric coating: Add talc and triethyl citrate to an appropriate amount of water, stir evenly, slowly pour into the enteric material and stir continuously to prepare an enteric coating solution with a solid content of 20%; place the ferrous succinate microspheres with the isolation layer in a fluidized bed for enteric coating, control the material temperature at 32-37℃, and stop coating when the coating weight increases to 15% to obtain ferrous succinate enteric microspheres.

[0205] Step (4): Capsule filling: Ferrous succinate enteric-coated microspheres are filled into capsules to obtain ferrous succinate enteric-coated capsules 17.

[0206] Example 18

[0207] Table 18. Prescription for Ferrous Succinate Enteric-coated Capsules 18

[0208]

[0209] A method for preparing ferrous succinate enteric-coated tablets, comprising the following steps:

[0210] Step (1): Preparation of drug-containing core: Add the blank pellet core to the centrifugal granulator (WL type centrifugal pellet mill), use the powder layering drug loading method, control the main machine speed to 100-300 rpm, turn on the spray gun, spray in 3% hydroxypropyl methylcellulose (HPMC-E5) as a binder, and gradually add ferrous succinate tetrahydrate (passed through a 100-mesh sieve) so that the ferrous succinate tetrahydrate powder is coated on the blank pellet core to obtain ferrous succinate micro pellets;

[0211] Step (2): Preparation of isolation layer coating solution: Disperse the isolation layer material in 95% ethanol, then gradually add water, add butylated hydroxyanisole dissolved in 95% ethanol and sodium sulfite dissolved in water to prepare an isolation layer coating solution with a solid content of 6%; Isolation layer coating: Place ferrous succinate microspheres in a fluidized bed, use an isolation layer coating solution containing antioxidants for coating, control the material temperature at 38-42℃, stop coating when the coating weight increases to 5%, and obtain ferrous succinate microspheres coated with isolation layer;

[0212] Step (3): Enteric coating: Add talc and triethyl citrate to an appropriate amount of water, stir evenly, slowly pour into the enteric material and stir continuously to prepare an enteric coating solution with a solid content of 20%; place the ferrous succinate microspheres with the isolation layer in a fluidized bed for enteric coating, control the material temperature at 32-37℃, and stop coating when the coating weight increases to 10%, 12%, 15%, 20%, and 25% to obtain ferrous succinate enteric microspheres.

[0213] Step (4): Capsule filling: Ferrous succinate enteric-coated microspheres are filled into capsules. The capsules with different enteric coating weight increases are designated as 18-1, 18-2, 18-3, 18-4, and 18-5, respectively.

[0214] Comparative Example 1

[0215] Table 19. Prescription for Ferrous Succinate Enteric-coated Tablets

[0216]

[0217] A method for preparing ferrous succinate enteric-coated tablets, comprising the following steps:

[0218] Step (1): Mixing: Add ferrous succinate tetrahydrate, microcrystalline cellulose, mannitol, and magnesium stearate to a container and mix evenly to obtain a mixed powder;

[0219] Step (2): Tableting: The above mixed powder is placed in a tablet press for tableting to obtain unprocessed tablets. Each tablet contains 150 mg of ferrous succinate tetrahydrate, with a core diameter of 9 mm, a hardness of 4-8 kg, and a brittleness of <1%.

[0220] Step (3): Coating of the isolation layer: Preparation of the isolation layer coating solution: Disperse hydroxypropyl methylcellulose PHARMACOAT 606 in 95% ethanol, and then gradually add water to prepare a coating solution with a solid content of 6% (95% ethanol: water = 80: 20 W / W); Coating of the isolation layer: Place the uncoated tablets in a high-efficiency coating pan (model: SGB-5), start coating, control the material temperature at 38-42℃, and stop coating when the coating weight increases to 4% to obtain ferrous succinate tablets coated with the isolation layer;

[0221] Step (4): Enteric coating: Add talc and triethyl citrate to an appropriate amount of water, stir evenly with a high-shear mixer, slowly pour into the aqueous dispersion and continue stirring to prepare an enteric coating solution with a solid content of 20%; place the ferrous succinate tablets coated with the isolation layer in a high-efficiency coating pan (model: SGB-5) and start enteric coating, control the material temperature at 32-37℃, and stop coating when the coating weight increases to 10% to obtain ferrous succinate enteric tablets 19.

[0222] Example 19

[0223] Stability comparison of ferrous succinate

[0224] Ferrous succinate tetrahydrate raw material, ferrous succinate enteric-coated tablets prepared in Examples 1-15 and Comparative Example 1, and ferrous succinate enteric-coated capsules prepared in Example 17 were placed under accelerated conditions (40°C, 75%RH) and the changes in ferrous iron content were investigated in the first, third and sixth months.

[0225] The method for determining ferrous iron is as follows: Carefully remove the coating of ferrous succinate enteric-coated tablets or grind ferrous succinate enteric-coated microspheres into a fine powder. Take an appropriate amount, accurately weigh it, and place it in a 250 mL iodine flask. Add 100 mL of freshly boiled and cooled water and 10 mL of hydrochloric acid (36.0-38.0%) to dissolve it. Add 3 g of potassium iodide, immediately seal the flask tightly, and gently shake well. Place it in the dark for 5 minutes, and titrate with sodium thiosulfate titrant (0.1 mol / L). Near the endpoint, add 2 mL of starch indicator solution and continue titrating until the blue color disappears. Correct the titration result with a blank test. Each 1 mL of sodium thiosulfate titrant (0.1 mol / L) is equivalent to 5.585 mg of Fe. 3+ The results are shown in Table 18.

[0226] Table 20. Results of iron content changes under accelerated (40℃, 75%RH) conditions

[0227]

[0228] The results showed that antioxidants had a significant protective effect during the coating process. The initial ferrous content of the raw material was 0.49%, and the ferrous succinate-based formulations in each example had a significantly lower ferrous content than Comparative Example 1 at 0 months. As the amount of antioxidant increased (Examples 1-4, Examples 7-8), the ferrous content decreased significantly. When the weight ratio of antioxidant to active ingredient was above 1:300, a significant antioxidant protective effect was observed, and the ferrous content of the formulations remained below 2% even after 6 months of accelerated processing (Examples 2-4). Furthermore, when water-soluble and fat-soluble antioxidants were used in combination, the antioxidant effect was better, and the protective effect was significantly better than using the same dosage of water-soluble or fat-soluble antioxidants alone.

[0229] Example 20

[0230] Dissolution rate or dissolution profile determination in pH 1.2 and pH 6.8 media

[0231] Ferrous succinate enteric-coated tablets 16-1, 16-2, 16-3, 16-4, 16-5 and ferrous succinate enteric-coated capsules 18-1, 18-2, 18-3, 18-4, 18-5 with different coating weight gain from Example 16 were used to determine their dissolution rate or dissolution curve in hydrochloric acid at pH 1.2 and sodium phosphate buffer at pH 6.8, respectively.

[0232] Dissolution conditions 1: pH 1.2 hydrochloric acid, paddle method (for enteric-coated capsules, a settling basket should be used), 50 rpm, 500 mL, 37.0 ± 0.5 ℃, sample taken 2 hours after dissolution.

[0233] Dissolution conditions 2: pH 6.8 sodium phosphate buffer, paddle method (sedimentation basket should be used for enteric-coated capsules), 50 rpm, 500 mL, 37.0 ± 0.5 ℃, samples were taken at 5, 10, 15, 20 and 30 minutes after dissolution.

[0234] Detection method: Take 5 mL of solution, filter, accurately measure 1 mL of the filtrate and 3 mL of standard iron solution, and place them in 25 mL volumetric flasks. Add 2 mL of hydroxylamine hydrochloride solution (1→10) to each flask, shake well, let stand for 4 minutes, then add 2 mL of o-phenanthroline indicator solution (0.12→100) to each flask, shake well, add 10 mL of 2 mol / L sodium acetate solution to each flask, dilute with water to the mark, shake well, let stand for 15 minutes, and then measure the absorbance at a wavelength of 510 nm using ultraviolet-visible spectrophotometry to calculate the dissolution rate of each tablet.

[0235] Table 21. Dissolution test results in pH 1.2 and pH 6.8 media

[0236]

[0237] The results are shown in Table 21 and Figure 1 The results showed that for ferrous succinate enteric-coated tablets, when the weight gain of the enteric coating reached 8% or more, the enteric-coated tablets had good acid resistance, with less than 10% dissolution in 2 hours, and rapid dissolution in pH 6.8 medium, with complete dissolution in 30 minutes; while for ferrous succinate enteric-coated capsules, when the weight gain of the enteric coating reached 15% or more, the enteric coating had good acid resistance.

Claims

1. A ferrous succinate modulated-release formulation, comprising a drug-containing core, an isolation layer, and an enteric coating layer, characterized in that: The drug-containing core contains the active ingredient ferrous succinate tetrahydrate, and the isolation layer contains an antioxidant, wherein the weight ratio of the antioxidant to ferrous succinate tetrahydrate is 1:600 ​​to 1:37.

5.

2. The ferrous succinate modulated release formulation according to claim 1, characterized in that: The drug-containing core is ferrous succinate tetrahydrate as the active ingredient, which is mixed evenly with pharmaceutically acceptable excipients and then compressed into tablets to obtain ferrous succinate tablets, or ferrous succinate microcapsules are obtained by coating ferrous succinate tetrahydrate powder onto a blank core using a powder deposition drug loading method.

3. The ferrous succinate modulated release formulation according to claim 2, characterized in that: The core of the drug is ferrous succinate tetrahydrate as the active ingredient. Ferrous succinate tablets are prepared by mixing ferrous succinate tetrahydrate with diluent and lubricant in the following weight proportions and then compressing the mixture: 45-210 parts ferrous succinate tetrahydrate, 86-254 parts diluent, and 1-4 parts lubricant, preferably 75-150 parts ferrous succinate tetrahydrate, 148-223 parts diluent, and 2 parts lubricant; wherein the diluent is selected from at least one of microcrystalline cellulose and mannitol, and the lubricant is selected from magnesium stearate. Alternatively, the drug-containing core may use ferrous succinate tetrahydrate as the active ingredient. Ferrous succinate tetrahydrate, blank pellet core, and binder are prepared according to the following weight proportions: 10-120 parts ferrous succinate tetrahydrate, 172-289 parts blank pellet core, and 1-8 parts binder. The blank pellet core is placed in a centrifugal granulator, and a powder deposition method is used, simultaneously spraying the binder solution and supplying ferrous succinate tetrahydrate powder to coat the blank pellet core, thus obtaining ferrous succinate microgranules. The binder may be hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, povidone, copovidone, or sucrose; the mass fraction of the binder solution is 1-5%.

4. The ferrous succinate modulating formulation according to claim 3, characterized in that: The core of the drug is ferrous succinate tetrahydrate as the active ingredient. Ferrous succinate tetrahydrate is mixed with diluent and lubricant in the following weight proportions and then compressed into tablets to obtain ferrous succinate tablets: 75 parts ferrous succinate tetrahydrate, 223 parts diluent, 2 parts lubricant or 150 parts ferrous succinate tetrahydrate, 148-198 parts diluent, 2 parts lubricant.

5. The ferrous succinate modulated release formulation according to claim 3, characterized in that: The diluent is a combination of microcrystalline cellulose and mannitol in a weight ratio of 50:50 to 200:50, preferably a combination of microcrystalline cellulose and mannitol in a weight ratio of 98:50 to 148:

50.

6. The ferrous succinate modulated release formulation according to claim 1, characterized in that: The isolation layer is formed by coating the drug-containing core with an isolation layer coating solution containing an antioxidant. The isolation layer coating solution is a coating solution with a solid content of 3-8%, prepared by using an aqueous ethanol solution as a solvent to mix the isolation layer material and the antioxidant. The isolation layer material is selected from one or more combinations of polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, and cellulose ether polymers, preferably polyvinyl alcohol or hydroxypropyl methylcellulose. The antioxidant is selected from water-soluble antioxidants and / or fat-soluble antioxidants. The antioxidant is selected from one or more combinations of ascorbic acid, hypophosphite, thioglycerol, sodium bisulfite, sodium metabisulfite, sodium sulfite, and sodium thiosulfate, preferably ascorbic acid, thioglycerol, sodium bisulfite, sodium metabisulfite, sodium sulfite, and sodium thiosulfate; the fat-soluble antioxidant is selected from one or more combinations of ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, and tocopherol, preferably butylated hydroxyanisole and butylated hydroxytoluene. The enteric coating layer is formed by coating the surface of the isolation layer with an enteric coating solution, and the weight gain of the enteric coating layer is 8-30% of the drug-containing core of the isolation layer. The enteric coating solution is a coating solution containing talc, triethyl citrate, and enteric material with a solid content of 15-25%. The enteric material is one of cellulose derivatives and acrylic resins. The cellulose derivative is selected from one or more of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose succinate. The acrylic resin is selected from one or more of methacrylic acid-methyl methacrylate copolymer, methacrylic acid-methyl methacrylate copolymer, and methacrylic acid-ethyl acrylate copolymer.

7. The ferrous succinate modulated release formulation according to claim 6, characterized in that: The antioxidant is selected from a combination of water-soluble and fat-soluble antioxidants; the weight ratio of the water-soluble and fat-soluble antioxidants is 1:4 to 4:1, preferably 2:3 to 3:

2.

8. The ferrous succinate modulated release formulation according to claim 1, characterized in that: The weight ratio of the antioxidant to ferrous succinate tetrahydrate is 1:300 to 1:37.5, preferably 1:300 to 1:75, and more preferably 1:300 to 1:

150.

9. The ferrous succinate modulated release formulation according to claim 6, characterized in that: The methacrylic acid-methyl methacrylate copolymer is selected from the Eudragit L series; the methacrylic acid-methyl methacrylate copolymer is selected from the Eudragit S series; and the methacrylic acid-ethyl acrylate copolymer is selected from Eudragit FS 30D.

10. A method for preparing the ferrous succinate modulated release formulation described above, characterized in that: When the ferrous succinate modulated-release formulation is a coated tablet, the following steps are included: Step (1) Preparation of drug-containing core: Using ferrous succinate tetrahydrate as the active ingredient, ferrous succinate tetrahydrate is mixed evenly with pharmaceutically acceptable excipients and compressed into tablets to obtain ferrous succinate tablets. Step (2), isolation layer coating: Disperse the isolation layer material in 95% ethanol to anhydrous ethanol, then add water, and add the fat-soluble antioxidant and / or water-soluble antioxidant dissolved in water that have been dissolved in 95% ethanol to anhydrous ethanol to prepare an isolation layer coating solution with a solid content of 6%; place the ferrous succinate tablets in a coating pan, and use the isolation layer coating solution containing antioxidants to coat them to obtain ferrous succinate tablets coated with an isolation layer; Step (3), enteric coating: Add talc and triethyl citrate to an appropriate amount of water, stir evenly, slowly pour into the enteric material and stir continuously to prepare an enteric coating solution with a solid content of 15-25%; place the ferrous succinate tablets with the isolation layer in a coating pan for enteric coating to obtain ferrous succinate enteric coated tablets. When the ferrous succinate formulation is a capsule, the following steps are included: Step (1) Preparation of drug-containing core: Using ferrous succinate tetrahydrate as the active ingredient, the powder of ferrous succinate tetrahydrate is coated onto the blank pellet core by the powder deposition drug loading method to obtain ferrous succinate micro pellets. Step (2), isolation layer coating: Disperse the isolation layer material in 95% ethanol to anhydrous ethanol, then add water, and add the fat-soluble antioxidant and / or water-soluble antioxidant dissolved in 95% ethanol to anhydrous ethanol to prepare an isolation layer coating solution with a solid content of 6%; place the ferrous succinate microspheres in a fluidized bed and coat them with the isolation layer coating solution containing antioxidants to obtain ferrous succinate microspheres coated with an isolation layer; Step (3), enteric coating: Add talc and triethyl citrate to an appropriate amount of water, stir evenly, slowly pour into the enteric material and stir continuously to prepare an enteric coating solution with a solid content of 15-25%; place the ferrous succinate microspheres coated with the isolation layer in a fluidized bed for enteric coating to obtain ferrous succinate enteric microspheres. Step (4), Capsule filling: Ferrous succinate enteric-coated microspheres are filled into capsules.

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