Levothyroxine sodium pellet and preparation method thereof

Abstract

The levothyroxine sodium pellet sequentially comprises a pellet core, an isolating layer, a drug-containing layer and a sealing layer from inside to outside, and the drug-containing layer comprises levothyroxine sodium or a hydrate thereof. The invention also provides a preparation method of the levothyroxine sodium pellet, which comprises the following steps: in a fluidized bed, spraying the isolating layer coating solution, the drug-containing layer coating solution and the sealing layer coating solution in sequence in a bottom spraying coating manner, so as to form the isolating layer, the drug-containing layer and the sealing layer on the pellet core in sequence.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical preparations, specifically to levothyroxine sodium microspheres and their preparation methods. Background Technology

[0002] Thyroxine, or T4 for short, is an essential endocrine hormone for human growth and development. Its deficiency can lead to hypothyroidism, including bodily disorders such as edema, cretinism, and obesity. Levothyroxine is a synthetic tetraiodothyronine, used clinically in sodium salt form, and is currently recognized by the medical community as the best preparation for thyroid hormone replacement therapy.

[0003] The storage stability of medications containing levothyroxine sodium is critical. Even slight fluctuations in the concentration of thyroid hormones can cause significant adverse reactions in sensitive patients; therefore, thyroid hormones are classified as medications with a narrow therapeutic range. Avoiding dosage changes for thyroid hormones is extremely important. Insufficient levothyroxine sodium can lead to severe symptoms of hypothyroidism such as severe depression, fatigue, weight gain, constipation, cold intolerance, swelling, and difficulty concentrating. Excessive levothyroxine sodium can lead to symptoms of hypothyroidism such as pain, palpitations, or arrhythmias.

[0004] The lowest available strength of levothyroxine sodium tablets (Euthyrox, manufactured by Merck) is 50 μg. For some patients requiring doses of 12.5 μg, 37.5 μg, or 62.5 μg, the tablets need to be split into quarters for combination, which undoubtedly poses a challenge to dosage accuracy. Tablet splitting may result in underdosing or overdosing because the distribution of the active ingredient within the tablet may be uneven, depending on the type of binder chosen and the tablet manufacturing process.

[0005] Based on the pharmacological or toxicological properties of compounds, the Occupational Exposure Band (OEB) establishes a classification standard for selecting appropriate production facilities and operating procedures for each product. Levothyroxine belongs to OEB Category 5, a highly reactive compound. It is crucial to prevent the drug from adhering to the inner walls, ceiling, and pipes of equipment, or from being released into the air during the entire production process. This would not only harm the quality of the drug but also significantly impact the health of the operators.

[0006] The traditional production process of oral solid dosage forms (such as tablets) of levothyroxine sodium involves weighing, pulverizing, premixing, granulation, drying, total mixing, tableting, and coating. All of these processes involve exposure to highly active active pharmaceutical ingredients. In accordance with OEB5 occupational protection requirements, in addition to requiring dedicated production lines, all of the above-mentioned process units must be sealed and controlled by isolators. This process control is complex and requires huge equipment investment. Summary of the Invention

[0007] In a first aspect, this application provides levothyroxine sodium microspheres, which, from the inside out, comprise: a core, an isolation layer, a drug-containing layer, and a sealing layer, wherein the drug-containing layer contains levothyroxine sodium or its hydrate.

[0008] In some embodiments, the content of levothyroxine sodium or its hydrate in the drug-containing layer is 1.5 μg / mg to 40 μg / mg, more specifically 2 μg / mg to 20 μg / mg, and even more specifically 2 μg / mg to 15 μg / mg.

[0009] In some embodiments, the isolation layer, the drug-containing layer, and the sealing layer all contain a film-forming material, and at least the film-forming material of the drug-containing layer contains polyvinyl alcohol. Optionally, the film-forming materials of the isolation layer, the drug-containing layer, and the sealing layer all contain polyvinyl alcohol.

[0010] In some embodiments, the drug-containing layer also includes an anti-adhesive and a stabilizer.

[0011] In some embodiments, the mass ratio of levothyroxine sodium or its hydrate, film-forming material, anti-adhesion agent and stabilizer in the drug-containing layer is 0.01-2:2-10:5-20:0.05-3.

[0012] In some implementations, the isolation layer also includes an anti-adhesive agent and an optional stabilizer.

[0013] In some embodiments, the mass ratio of the film-forming material, anti-adhesion agent, and stabilizer in the isolation layer is 2–10:2–20:0–15.

[0014] In some implementations, the sealing layer also includes an anti-adhesive agent and an optional stabilizer.

[0015] In some embodiments, the mass ratio of the film-forming material, anti-adhesion agent, and stabilizer in the sealing layer is 2–10:5–20:0–15.

[0016] In some embodiments, the film-forming material further comprises one or more of hydroxypropyl methylcellulose, gelatin, hydroxypropyl cellulose, acrylic resin VI, and polyvinylpyrrolidone.

[0017] In some embodiments, the anti-adhesion agent is selected from one or more of talc, magnesium oxide, silicon dioxide, dicalcium phosphate, and magnesium stearate.

[0018] In some embodiments, the stabilizer is selected from one or more of magnesium stearate, amino acids, sodium stearate fumarate, citric acid, sodium citrate, magnesium oxide, and sodium bicarbonate.

[0019] In some embodiments, the core is a sucrose core, a tartaric acid core, a microcrystalline cellulose core, or a silica core.

[0020] In some embodiments, the particle size of the pellet core is 0.1 mm to 2 mm.

[0021] In some embodiments, the weight of the isolation layer is 5% to 15% of the weight of the core, the weight of the drug-containing layer is 2% to 10% of the sum of the weights of the core and the isolation layer, and the weight of the sealing layer is 5% to 15% of the sum of the weights of the core, the isolation layer, and the drug-containing layer.

[0022] In a second aspect, this application provides a method for preparing levothyroxine sodium microspheres according to the first aspect, comprising: in a fluidized bed, using a bottom spray coating method, sequentially spraying in an isolation layer coating liquid, a drug-containing layer coating liquid, and a sealing layer coating liquid, thereby sequentially forming the isolation layer, the drug-containing layer, and the sealing layer on the pellet core.

[0023] In some embodiments, the isolation layer coating liquid contains 2% to 10% film-forming material, 2% to 20% anti-adhesion agent, 0% to 15% stabilizer, and the balance being solvent, based on the total weight of the isolation layer coating liquid.

[0024] In some embodiments, based on the total weight of the drug-coating solution, the drug-coating solution contains 0.01% to 2% levothyroxine sodium or its pentahydrate, 2% to 10% film-forming material, 5% to 20% anti-adhesion agent, 0.05% to 3% stabilizer, and the balance being solvent.

[0025] In some embodiments, the sealing layer coating solution contains 2% to 10% film-forming material, 5% to 20% anti-adhesion agent, 0% to 15% stabilizer, and the balance being solvent, based on the total weight of the sealing layer coating solution.

[0026] In some embodiments, during the formation of the levothyroxine sodium microspheres, the material temperature in the fluidized bed is controlled to be 15°C to 45°C, further to 20°C to 40°C, and even further to 25°C to 35°C.

[0027] In a third aspect, this application provides capsules, granules, dispersible tablets or orally disintegrating tablets comprising levothyroxine sodium microspheres of the first aspect or levothyroxine sodium microspheres prepared according to the method of the second aspect.

[0028] In a fourth aspect, this application provides capsules comprising levothyroxine sodium microspheres of the first aspect or levothyroxine sodium microspheres prepared according to the method of the second aspect, wherein each capsule contains 10-200 μg of levothyroxine sodium or its hydrate.

[0029] This application has at least one of the following beneficial technical effects:

[0030] The drug microcapsules provided in this application can be prepared into capsules containing 12.5 μg, 25 μg, 50 μg, 75 μg, and 100 μg of active ingredient per capsule, allowing patients to conveniently choose different dosages of the drug formulation and avoiding the problem of dosage instability caused by tablet splitting. Simultaneously, the capsule shell is selected from easy-open capsules, allowing the microcapsules to be removed and dissolved in water, apple juice, or formula milk before consumption, or directly sprinkled onto a semi-solid carrier such as applesauce, yogurt, or pudding, or directly poured into the mouth, moistened with saliva, and swallowed, thereby improving compliance in pediatric patients.

[0031] The active ingredient of levothyroxine sodium is more stable at high concentrations than at low concentrations. At low concentrations, levothyroxine sodium is unstable and easily forms degradation products, and the higher the temperature and humidity of the environment, the more severe the degradation. The drug microcapsules provided in this application consist of, from the inside out, a core, an isolation layer, a drug-containing layer, and a sealing layer. The drug is concentrated in the drug-containing layer, which increases the local concentration of the drug and is beneficial to enhancing the stability of the active ingredient.

[0032] The drug pellets provided in this application contain polyvinyl alcohol (PVA) as a film-forming agent in the drug-containing layer. PVA has excellent water-retention capacity, which can reduce the risk of levothyroxine sodium hydrate losing its water of crystallization. The presence of PVA in at least the drug-containing layer significantly increases the stability of levothyroxine sodium.

[0033] The drug pellets provided in this application contain a stabilizer in the drug-containing layer. Compared with the case without a stabilizer, the presence of a stabilizer in the drug-containing layer can significantly increase the stability of levothyroxine sodium.

[0034] Studies have found that the stability of levothyroxine sodium as a standalone active pharmaceutical ingredient (API) is better than that of API / excipient mixtures, indicating that degradation originates from interactions between the API and excipients. Since the amount of levothyroxine sodium in solid dosage forms (tablets) is much lower than that of the excipients (even 1000 times lower), potential interactions can lead to a sharp decrease in therapeutic activity (i.e., bioavailability). In some embodiments of this application, the API content in the drug-containing layer is 1.5 μg / mg to 40 μg / mg, while commercially available levothyroxine sodium tablets typically weigh 100 mg, with API content usually between 25 μg and 100 μg, and the API content in commercially available tablets is only 0.25 to 1 μg / mg. The smaller the API proportion, the greater the contact probability and area between the active ingredient and the excipients, the more intense the interaction between the API and the excipients, and thus the easier it is for the API to degrade. This invention, through formulation processing, encapsulates levothyroxine sodium only in the drug-containing layer, achieving a high concentration of API locally, greatly enhancing the stability of the API in the formulation.

[0035] In the industrial production process of the microcapsules provided in this application, the only potential exposure of highly active ingredients lies in the active ingredient preparation and fluidized bed deposition drug loading processes. Subsequent process operations such as mixing and capsule filling are not exposed to the environment because the active ingredients are already encapsulated within the microcapsules. Therefore, this greatly simplifies the need for isolator-based airtight control, reducing equipment investment and maintenance costs. Furthermore, the microcapsule preparation process of this application is completed in a fluidized bed, maintaining a closed and negative pressure environment throughout the entire process. This eliminates the need for additional isolator equipment to prevent the spillage of active ingredients, ensuring operator safety and preventing harm to operators from the highly active drugs produced. Attached Figure Description

[0036] The exemplary embodiments covered by this application are further described below with reference to the accompanying drawings, but the drawings are merely for the purpose of enabling those skilled in the art to better understand this application and are not intended to limit the scope of this application.

[0037] Figure 1 A cross-sectional schematic diagram of levothyroxine sodium microspheres provided according to an embodiment of this application is shown. Detailed Implementation

[0038] The inventive concept of this application will be further illustrated below with reference to specific embodiments. However, the specific embodiments listed are for illustrative purposes only and are not intended to limit the scope of this application. Those skilled in the art will recognize that specific features in any of the following embodiments can be used in any other embodiments, as long as they do not depart from the inventive concept described herein.

[0039] Unless otherwise specified, all figures used in this specification and claims to indicate feature dimensions, quantities, and physical properties should be understood to be modified by the term "about" in all cases. Therefore, unless stated to the contrary, the numerical parameters listed in the specification and claims are approximations, and those skilled in the art can utilize the teachings disclosed herein to obtain the desired properties by appropriately modifying these approximations. The use of numerical ranges indicated by endpoints includes all numbers within that range and any range within that range; for example, 1 to 5 includes 1, 1.1, 1.3, 1.5, 2, 2.75, 3, 3.80, 4, and 5, etc.

[0040] Levothyroxine sodium pellets

[0041] like Figure 1 As shown, this application provides levothyroxine sodium microspheres, which, from the inside out, include: a core, an isolation layer, a drug-containing layer, and a sealing layer, wherein the drug-containing layer contains levothyroxine sodium or its hydrate.

[0042] In some implementations, the drug-containing layer comprises levothyroxine sodium pentahydrate.

[0043] According to the inventors' research, under the premise of selecting the same excipients and formulation processes, the stability of the drug-containing layer of active ingredients varies with different concentrations. Levothyroxine sodium is more stable at high concentrations than at low concentrations. At low concentrations, levothyroxine sodium is unstable and easily generates degradation products, and the higher the temperature and humidity of the environment, the more severe the degradation. In the microcapsules provided in this application, the active ingredient of levothyroxine sodium is concentrated in the drug-containing layer, which increases the local concentration of the drug and is beneficial to enhancing the stability of the active ingredient.

[0044] In some embodiments, the levothyroxine sodium microgranules of this application contain levothyroxine sodium or its hydrate in the drug-containing layer at a content of 1.5 μg / mg to 40 μg / mg, more specifically 2 μg / mg to 20 μg / mg, and even more specifically 2 μg / mg to 15 μg / mg. Here, the content of levothyroxine sodium or its hydrate in the drug-containing layer is calculated by dividing the mass of the active ingredient by the total mass of the drug-containing layer (e.g., the total mass of the drug-containing layer is the sum of the masses of levothyroxine sodium pentahydrate, film-forming material, anti-adhesive, and stabilizer).

[0045] Studies have found that the stability of the active pharmaceutical ingredient (API) in levothyroxine sodium pentahydrate alone is better than that in API / excipient mixtures, indicating that degradation originates from interactions between the active ingredient and excipients. The amount of levothyroxine sodium in tablets is much lower than that of the excipients (even 1000 times lower), therefore potential interactions can lead to a sharp decrease in therapeutic activity (i.e., bioavailability). Commercially available levothyroxine sodium tablets typically weigh 100 mg, with API content usually between 25 μg and 100 μg, meaning the API content in commercially available tablets is only 0.25–1 μg / mg. The smaller the API proportion, the greater the probability and area of ​​contact between the active ingredient and the excipients, leading to more intense interactions between the API and excipients, and thus, a greater likelihood of API degradation. This application utilizes a formulation process to contain levothyroxine sodium only in the drug-containing layer, achieving a high concentration of API locally, significantly enhancing the stability of the API in the formulation.

[0046] In some implementations, the isolation layer, the drug-containing layer, and the sealing layer all contain film-forming materials, and at least the film-forming material of the drug-containing layer contains polyvinyl alcohol.

[0047] The inventors' research also found that polyvinyl alcohol (PVA), while acting as a film-forming material, can enhance the stability of microparticles. This may be related to the fact that the hydroxyl groups in PVA help maintain the moisture content of levothyroxine sodium. PVA is a high molecular weight polymer, with 1,3-propanediol as its main molecular structure, a "head-tail" structure, exhibiting hydrophilicity and film-forming properties. The degree of polymerization of PVA is classified into ultra-high degree of polymerization (molecular weight 250,000–300,000), high degree of polymerization (molecular weight 170,000–220,000), medium degree of polymerization (molecular weight 120,000–150,000), and low degree of polymerization (25,000–35,000). Generally, as the degree of polymerization increases, the viscosity of the aqueous solution increases, and the strength and solvent resistance of the film after formation improve, but the solubility in water and the elongation after film formation decrease. Pharmaceutical-grade PVA, unlike chemical-grade PVA, is an extremely safe high molecular weight organic compound, non-toxic to the human body, without side effects, and possesses good biocompatibility.

[0048] In some implementations, the film-forming materials of the isolation layer, the drug-containing layer, and the sealing layer all contain polyvinyl alcohol.

[0049] In some implementations, the drug-containing layer also includes anti-adhesives and stabilizers.

[0050] In some embodiments, the drug-containing layer comprises levothyroxine sodium or its hydrate, polyvinyl alcohol, an anti-adhesive agent, and a stabilizer. In some embodiments, the drug-containing layer may contain only polyvinyl alcohol as a film-forming material. In some embodiments, the drug-containing layer may contain polyvinyl alcohol and other film-forming materials.

[0051] In some embodiments, the raw materials for preparing the drug-containing layer include levothyroxine sodium or its hydrate (e.g., pentahydrate), a film-forming material, an anti-adhesion agent, a stabilizer, and a solvent. During the coating process to form the drug-containing layer, the solvent is lost; therefore, in some embodiments, the drug-containing layer is substantially solvent-free.

[0052] In some embodiments, the mass ratio of levothyroxine sodium or its hydrate, film-forming material, anti-adhesion agent and stabilizer in the drug-containing layer is 0.01-2:2-10:5-20:0.05-3.

[0053] In some embodiments, the mass ratio of levothyroxine sodium or its hydrate, film-forming material, anti-adhesion agent and stabilizer in the drug-containing layer is 0.02-1:3-7:8-12:0.5-1.5.

[0054] In some implementations, the isolation layer also includes an anti-adhesive agent and an optional stabilizer.

[0055] In some embodiments, the raw materials for preparing the isolation layer include a film-forming material, an anti-sticking agent, an optional stabilizer, and a solvent. During the coating process to form the isolation layer, the solvent is lost; therefore, in some embodiments, the isolation layer is essentially solvent-free.

[0056] In some embodiments, the isolation layer may contain only polyvinyl alcohol as a film-forming material. In some embodiments, the film-forming material of the isolation layer does not contain polyvinyl alcohol. In some embodiments, the isolation layer may contain polyvinyl alcohol and other film-forming materials.

[0057] In some implementations, the mass ratio of film-forming material, anti-adhesion agent, and stabilizer in the isolation layer is 2–10:2–20:0–15.

[0058] In some implementations, the mass ratio of film-forming material, anti-adhesion agent, and stabilizer in the isolation layer is 2–5:7–17:0–10.

[0059] In some implementations, the sealing layer also includes an anti-adhesive agent and an optional stabilizer.

[0060] In some embodiments, the raw materials for preparing the sealing layer include a film-forming material, an anti-sticking agent, an optional stabilizer, and a solvent. During the coating process to form the sealing layer, the solvent is lost; therefore, in some embodiments, the sealing layer is essentially solvent-free.

[0061] In some embodiments, the sealing layer may contain only polyvinyl alcohol as a film-forming material. In some embodiments, the film-forming material of the sealing layer does not contain polyvinyl alcohol. In some embodiments, the sealing layer may contain polyvinyl alcohol and other film-forming materials.

[0062] In some implementations, the mass ratio of film-forming material, anti-adhesion agent, and stabilizer in the sealing layer is 2–10:5–20:0–15.

[0063] In some implementations, the mass ratio of film-forming material, anti-adhesion agent, and stabilizer in the sealing layer is 2–5:7–17:0–10.

[0064] In some embodiments, the solvent (e.g., water or ethanol) content in the microspheres provided in this application is less than 5 wt%.

[0065] In some embodiments, the film-forming material of each layer in the microspheres provided in this application is independently selected from one or more of hydroxypropyl methylcellulose, polyvinyl alcohol, gelatin, hydroxypropyl cellulose, acrylic resin VI, and polyvinylpyrrolidone.

[0066] In some embodiments, the anti-adhesion agent used in the levothyroxine sodium microspheres of this application is selected from one or more of talc, magnesium oxide, silicon dioxide, calcium hydrogen phosphate, and magnesium stearate. In some embodiments, the anti-adhesion agent is selected from one or more of talc, calcium bicarbonate, and magnesium stearate.

[0067] In some embodiments, the stabilizer used in the levothyroxine sodium microspheres of this application is selected from one or more of magnesium stearate, amino acids, sodium stearate fumarate, citric acid, sodium citrate, magnesium oxide, and sodium bicarbonate. In some embodiments, the stabilizer is selected from one or more of magnesium stearate, amino acids, citric acid, and magnesium oxide.

[0068] In some implementations, the levothyroxine sodium microcapsules provided in this application have blank cores that do not contain active ingredients.

[0069] In some embodiments, the core is selected from sucrose core, tartaric acid core, microcrystalline cellulose core, and silica core. In some embodiments, the core is sucrose core or tartaric acid core.

[0070] In some implementations, the particle size of the pellet core is 0.1 mm to 2 mm, further 0.2 mm to 1 mm, and even further 0.4 mm to 0.8 mm.

[0071] In some embodiments, in the levothyroxine sodium microcapsules of this application, the weight of the isolation layer is 5% to 15% of the weight of the core, the weight of the drug-containing layer is 2% to 10% of the sum of the weights of the core and the isolation layer, and the weight of the sealing layer is 5% to 15% of the sum of the weights of the core, the isolation layer, and the drug-containing layer.

[0072] Method for preparing levothyroxine sodium microspheres

[0073] This application provides a method for preparing the above-mentioned levothyroxine sodium microspheres, comprising: in a fluidized bed, using a bottom spray coating method, sequentially spraying in an isolation layer coating liquid, a drug-containing layer coating liquid, and a sealing layer coating liquid, thereby sequentially forming an isolation layer, a drug-containing layer, and a sealing layer on the pellet core, wherein the drug-containing layer contains levothyroxine sodium or its hydrate.

[0074] In some embodiments, the pellet core mentioned in the preparation method of this application can be a commercially available pellet core, such as sucrose pellet core, tartaric acid pellet core, microcrystalline cellulose pellet core, or silica pellet core.

[0075] In some implementations, the isolation layer coating liquid contains 2% to 10% film-forming material, 2% to 20% anti-adhesion agent, 0% to 15% stabilizer, and the balance solvent, based on the total weight of the isolation layer coating liquid.

[0076] In some implementations, the release coating liquid contains 2% to 5% film-forming material, 7% to 17% anti-blocking agent, 0% to 10% stabilizer, and the balance solvent, based on the total weight of the release coating liquid.

[0077] In some embodiments, based on the total weight of the drug-coating solution, the drug-coating solution contains 0.01% to 2% levothyroxine sodium or its hydrate, 2% to 10% film-forming material, 5% to 20% anti-adhesion agent, 0.05% to 3% stabilizer, and the balance being solvent.

[0078] In some embodiments, based on the total weight of the drug-coating solution, the drug-coating solution contains 0.02% to 1.0% of levothyroxine sodium or its hydrate, 3% to 7% of film-forming material, 8% to 12% of anti-adhesion agent, 0.5% to 1.5% of stabilizer, and the balance being solvent.

[0079] In some implementations, the sealing layer coating solution contains 2% to 10% film-forming material, 5% to 20% anti-blocking agent, 0% to 15% stabilizer, and the balance solvent, based on the total weight of the sealing layer coating solution.

[0080] In some implementations, the sealing layer coating solution contains 2% to 5% film-forming material, 7% to 17% anti-blocking agent, 0% to 10% stabilizer, and the balance solvent, based on the total weight of the sealing layer coating solution.

[0081] In some embodiments, the solvent used in the preparation method of this application is water or an aqueous ethanol solution. In some embodiments, the solvent used in the preparation method of this application is an aqueous ethanol solution with a volume concentration of 20%-75%, for example, 20% ethanol, 50% ethanol, or 75% ethanol.

[0082] Studies have shown that levothyroxine sodium is readily degraded under conditions of dehydration and exposure to molecular oxygen, but it is stable when kept in a hydrated state, regardless of whether it is deoxygenated. The raw material for levothyroxine sodium is a pentahydrate, which exhibits antioxidant properties under high temperature and high humidity conditions (60°C, 75% RH). However, when the humidity drops to 0% RH, levothyroxine sodium begins to lose its water of crystallization, and the dehydrated substance subsequently undergoes oxidative decomposition at room temperature. When levothyroxine sodium is used in combination with certain hygroscopic excipients, the excipients can induce the degradation of levothyroxine sodium. The film-forming material used in this application is hygroscopic. To ensure the stability of the active ingredient, water or an aqueous ethanol solution is used as a solvent in this application, which helps to enhance the stability of levothyroxine sodium pentahydrate during the formulation process.

[0083] In some implementations, during the formation of levothyroxine sodium pellets, the material temperature in the fluidized bed is controlled at 15°C to 45°C, further at 20°C to 40°C, and even further at 25°C to 35°C.

[0084] In some embodiments, the method for preparing levothyroxine sodium microspheres according to this application includes the following steps:

[0085] (1) Weigh the film-forming material, solvent, anti-adhesion agent and optional stabilizer, mix and stir evenly to prepare the isolation layer coating solution;

[0086] (2) Pour the blank pellet core into the fluidized bed and spray the isolation layer coating liquid into it using the bottom spray coating method, thereby forming an isolation layer on the blank pellet core to obtain the isolation pellet;

[0087] (3) Weigh the film-forming material, levothyroxine sodium pentahydrate, solvent, stabilizer and anti-adhesion agent, mix and stir evenly to prepare a drug-containing coating solution;

[0088] (4) In a fluidized bed, a drug-containing coating liquid is sprayed in using a bottom spray coating method to form a drug-containing layer on the isolation pellets obtained in step (2) and obtain drug-containing pellets;

[0089] (5) Weigh the film-forming material, solvent, anti-adhesion agent, and optional stabilizer, mix and stir evenly to prepare a sealing layer coating solution; and

[0090] (6) In the fluidized bed, a sealing layer coating liquid is sprayed in by bottom spray coating method, thereby forming a sealing layer on the pills obtained in step (4).

[0091] In some embodiments, in the preparation method of this application, during the process of forming the isolation layer in step (2), the process of forming the drug-containing layer in step (4), and the process of forming the sealing layer in step (6), the solvent is lost (e.g., due to solvent evaporation), so the formed isolation layer, drug-containing layer, and sealing layer are substantially solvent-free.

[0092] In some implementations, during the formation of the isolation layer, the material temperature in the fluidized bed is controlled within the range of 15°C to 45°C, further to 20°C to 40°C, and even further to 25°C to 35°C.

[0093] In some implementations, an isolation layer is formed by coating to increase the weight by 5% to 15% relative to the pellet core.

[0094] In some implementations, during the formation of the drug-containing layer, the material temperature in the fluidized bed is controlled within the range of 15°C to 45°C, further to 20°C to 40°C, and even further to 25°C to 35°C.

[0095] In some implementations, the drug-containing layer is formed by increasing the weight of the coating by 2% to 10% relative to the total weight of the core and the separator.

[0096] In some implementations, during the formation of the closed layer, the material temperature in the fluidized bed is controlled within the range of 15°C to 45°C, further to 20°C to 40°C, and even further to 25°C to 35°C.

[0097] In some implementations, a sealing layer is formed by increasing the weight of the coating by 5% to 15% relative to the total weight of the core, the isolation layer, and the drug-containing layer.

[0098] In the preparation of the levothyroxine sodium microcapsules provided in this application, only the preparation of the drug coating solution and the drug delivery onto the fluidized bed may involve exposure to highly active ingredients. Subsequent processes such as mixing and capsule filling, however, do not expose the active ingredients to the environment because they are encapsulated within the microcapsules. Therefore, this significantly simplifies the need for isolator-based airtight control, reducing equipment investment and maintenance costs. Furthermore, the microcapsule preparation process of this application is completed in a fluidized bed, maintaining a closed and negative pressure environment throughout, eliminating the need for additional isolator equipment to prevent spillage of active ingredients. This ensures operator safety and prevents the highly active drug from causing harm to operators.

[0099] Solid dosage form of levothyroxine sodium microspheres

[0100] On the other hand, this application provides solid dosage forms of levothyroxine sodium microspheres, particularly capsules, granules, dispersible tablets or orally disintegrating tablets, which contain the aforementioned levothyroxine sodium microspheres.

[0101] In some implementations, capsules containing the aforementioned levothyroxine sodium microspheres are provided, particularly easy-open capsules.

[0102] In some embodiments, the capsules provided in this application are in the form of 10-200 μg / capsule, for example, each capsule contains 12.5 μg, 25 μg, 50 μg, 75 μg, 100 μg or 200 μg of levothyroxine sodium or its hydrate.

[0103] The levothyroxine sodium microspheres provided in this application can be formulated into capsules of different specifications, allowing patients to choose different dosages. Meanwhile, the capsule shells are selected from easy-open capsules, such as Sprinkle capsules manufactured by Suzhou Capsule Co., Ltd. The microspheres can be easily removed from the capsules, dissolved in water, apple juice, or formula milk, or sprinkled directly onto semi-solid carriers such as applesauce, yogurt, or pudding, or poured directly into the mouth, moistened with saliva, and swallowed, thereby improving patient compliance in children.

[0104] Example

[0105] Unless otherwise specified, the drugs or reagents used in the following examples and comparative examples are all conventionally available commercial products. Among them:

[0106] Levothyroxine sodium pentahydrate: purchased from Azico Biophore India Private Limited, supplier: Shanghai Huyuan Pharmaceutical Co., Ltd., batch number: 4001 / 3 / 017 / 21;

[0107] Polyvinyl alcohol 03-88: Purchased from Jiangxi Alpha High-Tech Pharmaceutical Co., Ltd., batch number: 20230606.

[0108] Comparative Example 1

[0109] Preparation of levothyroxine sodium microspheres:

[0110]

[0111] Preparation method:

[0112] Weigh polyvinyl alcohol, add water and stir to dissolve, then add talc powder and stir to disperse evenly to obtain the isolation layer coating solution. Weigh sucrose pellet cores and place them in a fluidized bed, controlling the material temperature at 32-37℃, and perform bottom spray coating to obtain isolation pellets. Weigh hydroxypropyl methylcellulose, add water and stir to dissolve, then add levothyroxine sodium pentahydrate, magnesium stearate, and talc powder and stir to disperse evenly to obtain the drug-containing layer coating solution. Place the isolation pellets in a fluidized bed, controlling the material temperature at 28-33℃, and perform bottom spray coating to obtain drug-containing pellets. Weigh polyvinyl alcohol, add water and stir to dissolve, then add talc powder and stir to disperse evenly to obtain the sealing layer coating solution. Place the drug-containing pellets in a fluidized bed, controlling the material temperature at 30-35℃, and perform bottom spray coating to obtain the final product.

[0113] Comparative Example 2

[0114] Preparation of levothyroxine sodium microspheres:

[0115]

[0116] Preparation method:

[0117] Weigh polyvinyl alcohol, add water and stir to dissolve, then add talc powder and stir to disperse evenly to obtain the isolation layer coating solution. Weigh sucrose pellet cores and place them in a fluidized bed, controlling the material temperature at 22-37℃, and perform bottom spray coating to obtain isolation pellets. Weigh polyvinyl alcohol and levothyroxine sodium pentahydrate, add 50% ethanol and stir to dissolve, then add magnesium stearate and talc powder and stir to disperse evenly to obtain the drug-containing layer coating solution. Place the isolation pellets in a fluidized bed, controlling the material temperature at 28-33℃, and perform bottom spray coating to obtain drug-containing pellets. Weigh polyvinyl alcohol, add water and stir to dissolve, then add talc powder and stir to disperse evenly to obtain the sealing layer coating solution. Place the drug-containing pellets in a fluidized bed, controlling the material temperature at 30-35℃, and perform bottom spray coating to obtain the final product.

[0118] Comparative Example 3:

[0119] Preparation of levothyroxine sodium microspheres:

[0120]

[0121]

[0122] Preparation method:

[0123] Weigh polyvinyl alcohol, add water and stir to dissolve, then add talc powder and stir to disperse evenly to obtain the isolation layer coating solution. Weigh sucrose pellet cores and place them in a fluidized bed, controlling the material temperature at 32-37℃, and perform bottom spray coating to obtain isolation pellets. Weigh polyvinyl alcohol, add water and stir to dissolve, then add levothyroxine sodium pentahydrate and talc powder and stir to disperse evenly to obtain the drug-containing layer coating solution. Place the isolation pellets in a fluidized bed, controlling the material temperature at 28-33℃, and perform bottom spray coating to obtain drug-containing pellets. Weigh polyvinyl alcohol, add water and stir to dissolve, then add talc powder and stir to disperse evenly to obtain the sealing layer coating solution. Place the drug-containing pellets in a fluidized bed, controlling the material temperature at 30-35℃, and perform bottom spray coating to obtain the final product.

[0124] Example 1

[0125] Preparation of levothyroxine sodium microspheres:

[0126]

[0127] Preparation method:

[0128] Weigh polyvinyl alcohol, add water and stir to dissolve, add talc powder and stir to disperse evenly to obtain the isolation layer coating solution. Weigh tartaric acid pellet cores and place them in a fluidized bed, control the material temperature at 32-38℃, and perform bottom spray coating to obtain isolation pellets. Weigh polyvinyl alcohol and glycine, add water and heat and stir at 50℃ to dissolve, add talc powder and levothyroxine sodium pentahydrate and stir to disperse evenly to obtain the drug-containing layer coating solution. Place the isolation pellets in a fluidized bed, control the material temperature at 30-35℃, and perform bottom spray coating to obtain drug-containing pellets. Weigh polyvinyl alcohol, add water and stir to dissolve, add talc powder and stir to disperse evenly to obtain the sealing layer coating solution. Place the drug-containing pellets in a fluidized bed, control the material temperature at 30-35℃, and perform bottom spray coating to obtain levothyroxine sodium microspheres. The cross-sectional structure is shown in the figure. Figure 1 As shown.

[0129] Example 2

[0130] Preparation of levothyroxine sodium microspheres:

[0131]

[0132] Preparation method:

[0133] Weigh polyvinyl alcohol, add water and stir to dissolve, then add talc powder and stir to disperse evenly to obtain the isolation layer coating solution. Weigh sucrose pellet cores and place them in a fluidized bed, controlling the material temperature at 32-37℃, and perform bottom spray coating to obtain isolation pellets. Weigh polyvinyl alcohol and glycine, add water and stir to dissolve, then add calcium hydrogen phosphate and levothyroxine sodium pentahydrate and stir to disperse evenly to obtain the drug-containing layer coating solution. Place the isolation pellets in a fluidized bed, controlling the material temperature at 30-35℃, and perform bottom spray coating to obtain drug-containing pellets. Weigh polyvinyl alcohol, add water and stir to dissolve, then add talc powder and stir to disperse evenly to obtain the sealing layer coating solution. Place the drug-containing pellets in a fluidized bed, controlling the material temperature at 30-35℃, and perform bottom spray coating to obtain the final product.

[0134] Example 3

[0135] Preparation of levothyroxine sodium microspheres:

[0136]

[0137]

[0138] Preparation method:

[0139] Weigh polyvinyl alcohol, add water and stir to dissolve, then add talc powder and stir to disperse evenly to obtain the isolation layer coating solution. Weigh sucrose pellet cores and place them in a fluidized bed, controlling the material temperature at 30-35℃, and perform bottom spray coating to obtain isolation pellets. Weigh polyvinyl alcohol and citric acid, add water and stir to dissolve, then add talc powder and levothyroxine sodium pentahydrate and stir to disperse evenly to obtain the drug-containing layer coating solution. Control the material temperature at 30-35℃, place the isolation pellets in a fluidized bed, and perform bottom spray coating to obtain drug-containing pellets. Weigh polyvinyl alcohol, add water and stir to dissolve, then add talc powder and stir to disperse evenly to obtain the sealing layer coating solution. Place the drug-containing pellets in a fluidized bed, controlling the material temperature at 30-35℃, and perform bottom spray coating to obtain the final product.

[0140] Example 4

[0141] Preparation of levothyroxine sodium microspheres:

[0142]

[0143] Preparation method:

[0144] Weigh polyvinyl alcohol and citric acid, add water and stir to dissolve, then add talc powder and stir to disperse evenly to obtain the isolation layer coating solution; weigh microcrystalline cellulose pellet cores and place them in a fluidized bed, controlling the material temperature at 30-35℃, and perform bottom spray coating to obtain isolation pellets. Weigh polyvinyl alcohol and citric acid, add water and stir to dissolve, then add talc powder and levothyroxine sodium pentahydrate and stir to disperse evenly to obtain the drug-containing layer coating solution; place the isolation pellets in a fluidized bed, controlling the material temperature at 30-35℃, and perform bottom spray coating to obtain drug-containing pellets. Weigh polyvinyl alcohol, add water and stir to dissolve, then add citric acid and talc powder and stir to disperse evenly to obtain the sealing layer coating solution; place the drug-containing pellets in a fluidized bed, controlling the material temperature at 30-35℃, and perform bottom spray coating to obtain the final product.

[0145] Example 5

[0146] Preparation of levothyroxine sodium microspheres:

[0147]

[0148] Preparation method:

[0149] Weigh polyvinyl alcohol and citric acid, add water and stir to dissolve, then add talc powder and stir to disperse evenly to obtain the isolation layer coating solution. Weigh sucrose pellet cores and place them in a fluidized bed for bottom spray coating, controlling the material temperature at 28-32℃ to obtain isolation pellets. Weigh polyvinyl alcohol and levothyroxine sodium pentahydrate, add water and stir to suspend, then add sodium stearate fumarate and talc powder and stir to disperse evenly to obtain the drug-containing layer coating solution. Place the isolation pellets in a fluidized bed for bottom spray coating, controlling the material temperature at 30℃ to obtain drug-containing pellets. Weigh polyvinyl alcohol and citric acid, add water and stir to dissolve, then add talc powder and stir to disperse evenly to obtain the sealing layer coating solution. Place the drug-containing pellets in a fluidized bed, controlling the material temperature at 30-35℃ for bottom spray coating to obtain the final product.

[0150] Example 6

[0151] Preparation of levothyroxine sodium microspheres:

[0152]

[0153]

[0154] Preparation method:

[0155] Weigh polyvinyl alcohol, add water and stir to dissolve, then add talc powder and stir to disperse evenly to obtain the isolation layer coating solution. Weigh sucrose pellet cores and place them in a fluidized bed, controlling the material temperature at 22-37℃, and perform bottom spray coating to obtain isolation pellets. Weigh polyvinyl alcohol and levothyroxine sodium pentahydrate, add 50% ethanol and stir to dissolve, then add magnesium stearate and talc powder and stir to disperse evenly to obtain the drug-containing layer coating solution. Place the isolation pellets in a fluidized bed, controlling the material temperature at 28-33℃, and perform bottom spray coating to obtain drug-containing pellets. Weigh polyvinyl alcohol, add water and stir to dissolve, then add talc powder and stir to disperse evenly to obtain the sealing layer coating solution. Place the drug-containing pellets in a fluidized bed, controlling the material temperature at 30-35℃, and perform bottom spray coating to obtain...

[0156] Example 7

[0157] Preparation of levothyroxine sodium microspheres:

[0158]

[0159] Preparation method:

[0160] Weigh polyvinyl alcohol, add water and stir to dissolve, add talc powder and stir to disperse evenly to obtain the isolation layer coating solution. Weigh sucrose pellet cores and place them in a fluidized bed, controlling the material temperature at 22-37℃, and perform bottom spray coating to obtain isolation pellets. Weigh polyvinyl alcohol and arginine, add water and stir to dissolve, add talc powder and levothyroxine sodium pentahydrate and stir to disperse evenly to obtain the drug-containing layer coating solution. Place the isolation pellets in a fluidized bed, controlling the material temperature at 28-35℃, and perform bottom spray coating to obtain drug-containing pellets. Weigh polyvinyl alcohol, add water and stir to dissolve, add talc powder and stir to disperse evenly to obtain the sealing layer coating solution. Place the drug-containing pellets in a fluidized bed, controlling the material temperature at 30-35℃, and perform bottom spray coating to obtain the final product.

[0161] Example 8

[0162] Preparation of levothyroxine sodium microspheres:

[0163]

[0164] Preparation method:

[0165] Weigh polyvinyl alcohol, add water and stir to dissolve, add talc powder and stir to disperse evenly to obtain the isolation layer coating solution. Weigh sucrose pellet cores and place them in a fluidized bed, control the material temperature at 22-37℃, and perform bottom spray coating to obtain isolation pellets. Weigh polyvinyl alcohol and glycine, add water and stir to dissolve, add talc powder and levothyroxine sodium pentahydrate and stir to disperse evenly to obtain the drug-containing layer coating solution. Place the isolation pellets in a fluidized bed, control the material temperature at 28-33℃, and perform bottom spray coating to obtain drug-containing pellets. Weigh polyvinyl alcohol, add water and stir to dissolve, add talc powder and stir to disperse evenly to obtain the sealing layer coating solution. Place the drug-containing pellets in a fluidized bed, control the material temperature at 32-37℃, and perform bottom spray coating to obtain the final product.

[0166] Example 9

[0167] Preparation of levothyroxine sodium microspheres:

[0168]

[0169]

[0170] Preparation method:

[0171] Weigh polyvinyl alcohol, add water and stir to dissolve, add talc powder and stir to disperse evenly to obtain the isolation layer coating solution. Weigh sucrose pellet cores and place them in a fluidized bed, control the material temperature at 22-37℃, and perform bottom spray coating to obtain isolation pellets. Weigh polyvinyl alcohol, add water and stir to dissolve, add magnesium oxide, talc powder and levothyroxine sodium pentahydrate and stir to disperse evenly to obtain the drug-containing layer coating solution. Place the isolation pellets in a fluidized bed, control the material temperature at 28-33℃, and perform bottom spray coating to obtain drug-containing pellets. Weigh polyvinyl alcohol, add water and stir to dissolve, add talc powder and stir to disperse evenly to obtain the sealing layer coating solution. Place the drug-containing pellets in a fluidized bed, control the material temperature at 30-35℃, and perform bottom spray coating to obtain the final product.

[0172] Example 10

[0173] Preparation of levothyroxine sodium microspheres:

[0174]

[0175] Preparation method:

[0176] Weigh polyvinyl alcohol, add water and stir to dissolve, add talc powder and stir to disperse evenly to obtain the isolation layer coating solution. Weigh sucrose pellet cores and place them in a fluidized bed, control the material temperature at 32-37℃, and perform bottom spray coating to obtain isolation pellets. Weigh polyvinyl alcohol, add water and stir to dissolve, add magnesium stearate, talc powder and levothyroxine sodium pentahydrate and stir to disperse evenly to obtain the drug-containing layer coating solution. Place the isolation pellets in a fluidized bed, control the material temperature at 28-33℃, and perform bottom spray coating to obtain drug-containing pellets. Weigh polyvinyl alcohol, add water and stir to dissolve, add talc powder and stir to disperse evenly to obtain the sealing layer coating solution. Place the drug-containing pellets in a fluidized bed, control the material temperature at 30-35℃, and perform bottom spray coating to obtain the final product.

[0177] Example 11

[0178] Preparation of levothyroxine sodium microspheres:

[0179]

[0180] Preparation method:

[0181] Weigh polyvinyl alcohol, add water and stir to dissolve, then add talc powder and stir to disperse evenly to obtain the isolation layer coating solution. Weigh sucrose pellet cores and place them in a fluidized bed, controlling the material temperature at 22-37℃, and perform bottom spray coating to obtain isolation pellets. Weigh polyvinyl alcohol and levothyroxine sodium pentahydrate, add 50% ethanol and stir to dissolve, then add magnesium stearate and talc powder and stir to disperse evenly to obtain the drug-containing layer coating solution. Place the isolation pellets in a fluidized bed, controlling the material temperature at 28-33℃, and perform bottom spray coating to obtain drug-containing pellets. Weigh polyvinyl alcohol, add water and stir to dissolve, then add talc powder and stir to disperse evenly to obtain the sealing layer coating solution. Place the drug-containing pellets in a fluidized bed, controlling the material temperature at 30-35℃, and perform bottom spray coating to obtain the final product.

[0182] Example 12

[0183] Preparation of levothyroxine sodium microspheres:

[0184]

[0185]

[0186] Preparation method:

[0187] Weigh polyvinyl alcohol, add 50% ethanol and stir to dissolve. Add talc and magnesium stearate and stir to disperse evenly to obtain the isolation layer coating solution. Weigh sucrose pellet cores and place them in a fluidized bed, controlling the material temperature at 30-35℃, and perform bottom spray coating to obtain isolation pellets. Weigh polyvinyl alcohol and levothyroxine sodium pentahydrate, add 50% ethanol and stir to dissolve. Add magnesium stearate and talc and stir to disperse evenly to obtain the drug-containing layer coating solution. Place the isolation pellets in a fluidized bed, controlling the material temperature at 28-33℃, and perform bottom spray coating to obtain drug-containing pellets. Weigh polyvinyl alcohol, add 50% ethanol and stir to dissolve. Add talc and magnesium stearate and stir to disperse evenly to obtain the sealing layer coating solution. Weigh the drug-containing pellets and place them in a fluidized bed, controlling the material temperature at 30-35℃, and perform bottom spray coating to obtain the sealing layer coating solution.

[0188] Example 13

[0189] Preparation of levothyroxine sodium microspheres:

[0190]

[0191] Preparation method:

[0192] Weigh polyvinyl alcohol, add water and stir to dissolve, then add talc powder and stir to disperse evenly to obtain the isolation layer coating solution. Weigh sucrose pellet cores and place them in a fluidized bed, controlling the material temperature at 30-35℃, and perform bottom spray coating to obtain isolation pellets. Weigh polyvinyl alcohol and levothyroxine sodium pentahydrate, add 50% ethanol and stir to dissolve, then add magnesium stearate and talc powder and stir to disperse evenly to obtain the drug-containing layer coating solution. Place the isolation pellets in a fluidized bed, controlling the material temperature at 28-33℃, and perform bottom spray coating to obtain drug-containing pellets. Weigh polyvinyl alcohol, add water and stir to dissolve, then add talc powder and stir to disperse evenly to obtain the sealing layer coating solution. Weigh the drug-containing pellets and place them in a fluidized bed, controlling the material temperature at 30-35℃, and perform bottom spray coating to obtain the final product.

[0193] Example 14

[0194] Preparation of levothyroxine sodium microspheres:

[0195]

[0196] Preparation method:

[0197] Weigh polyvinyl alcohol, add water and stir to dissolve, then add talc powder and stir to disperse evenly to obtain the isolation layer coating solution. Weigh sucrose pellet cores and place them in a fluidized bed, controlling the material temperature at 30-35℃, and perform bottom spray coating to obtain isolation pellets. Weigh polyvinyl alcohol and levothyroxine sodium pentahydrate, add 50% ethanol and stir to dissolve, then add magnesium stearate and talc powder and stir to disperse evenly to obtain the drug-containing layer coating solution. Place the isolation pellets in a fluidized bed, controlling the material temperature at 28-33℃, and perform bottom spray coating to obtain drug-containing pellets. Weigh polyvinyl alcohol, add water and stir to dissolve, then add talc powder and stir to disperse evenly to obtain the sealing layer coating solution. Weigh the drug-containing pellets and place them in a fluidized bed, controlling the material temperature at 30-35℃, and perform bottom spray coating to obtain the final product.

[0198] Example 15

[0199] Preparation of levothyroxine sodium microspheres:

[0200]

[0201] Preparation method:

[0202] Weigh polyvinyl alcohol, add water and stir to dissolve, then add talc powder and stir to disperse evenly to obtain the isolation layer coating solution. Weigh sucrose pellet cores and place them in a fluidized bed, controlling the material temperature at 30-35℃, and perform bottom spray coating to obtain isolation pellets. Weigh polyvinyl alcohol and levothyroxine sodium pentahydrate, add 50% ethanol and stir to dissolve, then add magnesium stearate and talc powder and stir to disperse evenly to obtain the drug-containing layer coating solution. Place the isolation pellets in a fluidized bed, controlling the material temperature at 28-33℃, and perform bottom spray coating to obtain drug-containing pellets. Weigh polyvinyl alcohol, add water and stir to dissolve, then add talc powder and stir to disperse evenly to obtain the sealing layer coating solution. Weigh the drug-containing pellets and place them in a fluidized bed, controlling the material temperature at 30-35℃, and perform bottom spray coating to obtain the final product.

[0203] Example 16

[0204] Preparation of levothyroxine sodium microspheres:

[0205]

[0206] Preparation method:

[0207] Weigh polyvinyl alcohol, add water and stir to dissolve, then add talc powder and stir to disperse evenly to obtain the isolation layer coating solution. Weigh sucrose pellet cores and place them in a fluidized bed, controlling the material temperature at 30-35℃, and perform bottom spray coating to obtain isolation pellets. Weigh polyvinyl alcohol and levothyroxine sodium pentahydrate, add 50% ethanol and stir to dissolve, then add magnesium stearate and talc powder and stir to disperse evenly to obtain the drug-containing layer coating solution. Place the isolation pellets in a fluidized bed, controlling the material temperature at 28-33℃, and perform bottom spray coating to obtain drug-containing pellets. Weigh polyvinyl alcohol, add water and stir to dissolve, then add talc powder and stir to disperse evenly to obtain the sealing layer coating solution. Weigh the drug-containing pellets and place them in a fluidized bed, controlling the material temperature at 30-35℃, and perform bottom spray coating to obtain the final product.

[0208] Example 17

[0209] Preparation of levothyroxine sodium microspheres:

[0210]

[0211] Preparation method:

[0212] Weigh hydroxypropyl methylcellulose, add water and stir to dissolve, then add talc and stir to disperse evenly to obtain the isolation layer coating solution. Weigh sucrose pellet cores and place them in a fluidized bed, controlling the material temperature at 30-37℃, and perform bottom spray coating to obtain isolation pellets. Weigh polyvinyl alcohol and levothyroxine sodium pentahydrate, add 50% ethanol and stir to dissolve, then add magnesium stearate and talc and stir to disperse evenly to obtain the drug-containing layer coating solution. Place the isolation pellets in a fluidized bed, controlling the material temperature at 30-35℃, and perform bottom spray coating to obtain drug-containing pellets. Weigh hydroxypropyl methylcellulose, add water and stir to dissolve, then add talc and stir to disperse evenly to obtain the sealing layer coating solution. Place the drug-containing pellets in a fluidized bed, controlling the material temperature at 30-37℃, and perform bottom spray coating to obtain the final product.

[0213] Example Detection

[0214] Related substances testing methods:

[0215] Take 2g of this product (approximately equivalent to 1mg of levothyroxine sodium pentahydrate), add 10ml of diluent (anhydrous ethanol:water:phosphoric acid = 60:40:0.2 (volume ratio)) and vortex for 5min. Transfer the solution to a centrifuge tube and centrifuge (12000rpm, 5min). Collect the supernatant as the test solution. Separately, take an appropriate amount of levothyroxine sodium pentahydrate reference standard, accurately weigh it, dissolve it in diluent, and prepare a solution containing approximately 0.1mg per ml as the reference solution. The determination was performed according to high performance liquid chromatography (General Rule 0512), using octadecylsilane-bonded silica gel as the stationary phase (Ultimate XB-C18, 4.6 nm mate XB, 5 μm or equivalent column); mobile phase A was aminosulfonic acid solution (4.85 g aminosulfonic acid and 0.75 g sodium hydroxide dissolved in 1000 ml of water, and the pH was adjusted to 3.0 with 5 mol / L sodium hydroxide), and mobile phase B was acetonitrile. Linear gradient elution was performed according to the table below. The column temperature was 30 °C; the flow rate was 1.0 ml / min; and the detection wavelength was 225 nm.

[0216] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0.01 71 29 5 71 29 15 62 38 50 62 38 95 32 68 100 32 68 101 71 29 115 80 29

[0217] Accurately measure 50 μl each of the test solution and the reference solution, inject them into the liquid chromatograph, and record the chromatograms. The relative correction factor for impurities is calculated as 1.0. If impurity peaks appear in the chromatogram of the test solution, they are calculated using the area normalization method. Peaks smaller than 0.03% of the peak area ratio in the chromatogram of the test solution are ignored.

[0218] Dissolution test method: Take this product and perform the dissolution and release test according to the method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II). Use 500 ml of 0.2% SDS in 0.01 mol / L hydrochloric acid solution as the dissolution medium, rotate at 50 rpm, and maintain a medium temperature of 37℃. After 5 min, 10 min, 15 min, 20 min, 30 min, and 45 min, take an appropriate amount of the solution and centrifuge (12000 rpm, 5 min). Take the supernatant as the test solution. Separately, take an appropriate amount of levothyroxine sodium pentahydrate reference standard, dissolve and dilute it in methanol to prepare a solution containing approximately 0.1 mg per ml as a stock solution. Accurately measure 1 ml of the stock solution and place it in a 500 ml volumetric flask. Add dissolution medium and dilute to the mark to obtain the reference solution. Determine the reference solution according to the high performance liquid chromatography method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512). The column was packed with octadecylsilane-bonded silica gel. The mobile phase was a 50:50 mixture of sodium dodecyl sulfate-phosphate aqueous solution (2g sodium dodecyl sulfate, 0.5ml phosphoric acid, and 1000ml water were mixed and stirred until dissolved) and acetonitrile (0.5ml phosphoric acid was mixed with 1000ml acetonitrile). The column temperature was 35℃, the detection wavelength was 226nm, and the theoretical plate number, calculated based on levothyroxine sodium pentahydrate, should be no less than 2000. The amount of levothyroxine dissolved in each cup at different times was calculated using the external standard method.

[0219] Test results

[0220] Table 1. Comparison of the stability of the marketed formulation (Euthyrox) under different storage conditions in Comparative Examples 1-3, Examples 6-10, Examples 16-17.

[0221]

[0222]

[0223] Based on the stability-related substances results of Comparative Example 2 (active ingredient content in the drug layer was 0.51 μg / mg) and Example 6 (39.5 μg / mg), it can be seen that, under the premise of selecting the same excipients and formulation process, microspheres with a higher content of active ingredient in the drug layer have better stability than microspheres with a lower content of active ingredient in the drug layer. This indicates that levothyroxine sodium pentahydrate is more stable at high concentrations than at low concentrations; at low concentrations, levothyroxine sodium pentahydrate is unstable and easily forms degradation products.

[0224] Based on the stability-related results of Comparative Example 3 (containing no stabilizer in the drug layer) and Example 10, it is evident that the presence of a stabilizer in the drug layer significantly increases the stability of levothyroxine sodium. Stability data from Examples 7-10 demonstrate that amino acids, magnesium oxide, and magnesium stearate can significantly increase the stability of the formulation.

[0225] Based on the stability-related results of Comparative Example 1 (containing no polyvinyl alcohol in the drug layer) and Example 10, it can be seen that the presence of polyvinyl alcohol in the drug layer can significantly increase the stability of levothyroxine sodium.

[0226] Table 2 Dissolution rates of different formulation specifications

[0227]

[0228] The dissolution test results in Table 2 show that the micro-pellet formulations of different specifications in this application can all be rapidly released in vitro, and the release behavior is consistent.

[0229] The above description is merely a specific embodiment of the invention covered by this application, but the scope of protection of this application is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in this application should be included within the scope of protection of this application. Therefore, the scope of protection of this application should be determined by the scope of the claims.

Claims

1. Levothyroxine sodium microspheres, which, from the inside out, consist of: The product comprises a core, an isolation layer, a drug-containing layer, and a sealing layer, wherein the drug-containing layer contains levothyroxine sodium or its hydrate.

2. The levothyroxine sodium microspheres according to claim 1, wherein the content of levothyroxine sodium or its hydrate in the drug-containing layer is 1.5 μg / mg to 40 μg / mg, more preferably 2 μg / mg to 20 μg / mg, and even more preferably 2 μg / mg to 15 μg / mg.

3. The levothyroxine sodium microspheres according to claim 1 or 2, wherein the isolation layer, the drug-containing layer and the sealing layer all contain a film-forming material, and at least the film-forming material of the drug-containing layer contains polyvinyl alcohol; optionally, the film-forming materials of the isolation layer, the drug-containing layer and the sealing layer all contain polyvinyl alcohol.

4. The levothyroxine sodium microspheres according to claim 3, wherein... The drug-containing layer also includes anti-adhesives and stabilizers. Optionally, the mass ratio of levothyroxine sodium or its hydrate, film-forming material, anti-adhesion agent, and stabilizer in the drug-containing layer is 0.01–2:2–10:5–20:0.05–3; or The isolation layer also includes an anti-adhesive agent and an optional stabilizer. Optionally, the mass ratio of the film-forming material, anti-adhesion agent, and stabilizer in the isolation layer is 2–10:2–20:0–15; or The sealing layer also includes an anti-adhesive agent and an optional stabilizer. Optionally, the mass ratio of the film-forming material, anti-adhesion agent, and stabilizer in the sealing layer is 2-10:5-20:0-15.

5. The levothyroxine sodium microspheres according to claim 4, wherein... The film-forming material further comprises one or more of hydroxypropyl methylcellulose, gelatin, hydroxypropyl cellulose, acrylic resin VI, and polyvinylpyrrolidone; and / or The anti-adhesion agent is selected from one or more of talc, magnesium oxide, silicon dioxide, dicalcium phosphate, and magnesium stearate; and / or The stabilizer is selected from one or more of magnesium stearate, amino acids, sodium stearate fumarate, citric acid, sodium citrate, magnesium oxide, and sodium bicarbonate.

6. The levothyroxine sodium microcapsules according to any one of claims 1 to 5, wherein the core is a sucrose core, a tartaric acid core, a microcrystalline cellulose core, or a silica core. Optionally, the particle size of the pellet core is 0.1 mm to 2 mm.

7. The levothyroxine sodium microcapsules according to any one of claims 1 to 6, wherein the weight of the isolation layer is 5% to 15% of the weight of the core, the weight of the drug-containing layer is 2% to 10% of the sum of the weights of the core and the isolation layer, and the weight of the sealing layer is 5% to 15% of the sum of the weights of the core, the isolation layer, and the drug-containing layer.

8. A method for preparing levothyroxine sodium microspheres according to any one of claims 1 to 7, comprising: Within a fluidized bed, a bottom-spray coating method is used to sequentially spray in an isolation layer coating solution, a drug-containing layer coating solution, and a sealing layer coating solution, thereby forming the isolation layer, drug-containing layer, and sealing layer sequentially on the pellet core. Preferably, based on the total weight of the isolation layer coating liquid, the isolation layer coating liquid contains 2% to 10% film-forming material, 2% to 20% anti-adhesion agent, 0% to 15% stabilizer, and the balance being solvent; Preferably, based on the total weight of the drug-containing coating solution, the drug-containing coating solution contains 0.01% to 2% levothyroxine sodium or its pentahydrate, 2% to 10% film-forming material, 5% to 20% anti-adhesion agent, 0.05% to 3% stabilizer, and the balance being solvent; Preferably, based on the total weight of the sealing layer coating solution, the sealing layer coating solution contains 2% to 10% film-forming material, 5% to 20% anti-adhesion agent, 0% to 15% stabilizer, and the balance being solvent; Preferably, during the formation of the levothyroxine sodium microspheres, the material temperature in the fluidized bed is controlled to be 15°C to 45°C, further to 20°C to 40°C, and even further to 25°C to 35°C.

9. Capsules, granules, dispersible tablets or orally disintegrating tablets comprising levothyroxine sodium microspheres according to any one of claims 1 to 7 or levothyroxine sodium microspheres prepared according to the method of claim 8.

10. A capsule comprising levothyroxine sodium microspheres according to any one of claims 1 to 7 or levothyroxine sodium microspheres prepared according to the method of claim 8, wherein, Each capsule contains 10-200 μg of levothyroxine sodium or its hydrate.

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