A fluidized bed process for the preparation of olopatadine hydrochloride granules

Abstract

The application belongs to the technical field of pharmaceutical preparations, and discloses a full-water-phase micro-pellet fluidized bed integrated preparation process of olopatadine hydrochloride granules, which takes a medicinal sucrose-starch compound sucrose pellet core as an inert carrier, and completes the three-layer continuous coating of drug loading layer spray drug loading, isolation layer spray coating and coating layer spray coating through fluidized bed continuous operation, and the whole process is free of wet granulation, dry mixing process and addition of organic volatile solvents such as ethanol. The drug loading layer and the isolation layer are simultaneously compounded with colloidal silicon dioxide and talcum powder to form a double-effect synergistic system of anti-sticking and flow-aiding and dense film forming, and the industry pain points such as micro-pellet wall sticking, granule agglomeration, poor drug content uniformity, large in-vitro dissolution fluctuation, poor product stability and the like in the fluidized bed preparation process are solved from the root. The obtained granules have a drug content uniformity RSD of less than or equal to 1.8%, a 15min drug cumulative dissolution of more than or equal to 88%, a bitter taste of the raw material drug is covered up, and the stability is significantly better than that of the prior art, there is no solvent residue, no need for an explosion-proof production workshop, and the process is suitable for large-scale industrialized continuous production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a fluidized bed process for preparing olopatadine hydrochloride granules via micro-pellet loading. Background Technology

[0002] Olopatadine hydrochloride is an antihistamine with dual effects of antagonizing histamine and stabilizing mast cell membranes. It is widely used in the treatment of allergic rhinitis, allergic conjunctivitis, and other diseases. It has a rapid onset of action, good safety profile, and high patient compliance. However, olopatadine hydrochloride itself has a distinctly bitter taste, and direct oral administration can affect the user experience, especially negatively impacting medication compliance in children and elderly patients.

[0003] Currently, olopatadine hydrochloride is available in oral tablets, granules, nasal preparations, and ophthalmic formulations. Granules are particularly suitable for children and patients with swallowing difficulties due to their convenience and ease of dosage adjustment. Existing olopatadine hydrochloride granules are mostly prepared using a wet granulation process. While this process is mature, it suffers from issues such as poor uniformity of granule content, large fluctuations in in vitro dissolution rates, insufficient masking of the bitter taste of the active pharmaceutical ingredient, and poor long-term storage stability. Furthermore, some preparation processes fail to effectively encapsulate the drug, leading to insufficient product stability and potentially an increase in related substances after long-term storage.

[0004] Fluidized bed microparticle loading is an advanced formulation preparation technology. It involves spraying drug solutions or suspensions onto an inert carrier surface using a fluidized bed device, achieving uniform drug loading. However, many existing processes suffer from drawbacks such as: reversed spraying order of the isolation layer and drug layer; insufficient anti-sticking effect of using only lubricating powder; use of ethanol as an organic solvent system; and slow in vitro drug dissolution rate. This invention achieves a breakthrough in both process and quality through a combination of an all-aqueous phase, three-layer continuous spraying, and a drug / isolation layer, along with a double-layer compounding of colloidal silica and talc, significantly differentiating it from existing technologies.

[0005] Multi-layer coating technology can effectively improve the taste of drugs and enhance the stability of formulations. This invention uses pharmaceutical-grade sucrose-starch composite sucrose pellet cores as an inert carrier. This carrier has advantages such as good flowability, uniform particle size, and excellent drug biocompatibility, making it suitable for fluidized bed continuous spray drug delivery. Colloidal silica and talc are both commonly used pharmaceutical excipients with good flowability and dispersibility, which can improve the processing performance and stability of formulations. Therefore, developing a method for preparing olopatadine hydrochloride granules by adding colloidal silica and homogenized talc to the drug-carrying layer and the isolation layer to further optimize product performance has significant practical application value. Summary of the Invention

[0006] This invention provides an integrated fluidized bed preparation process for olopatadine hydrochloride granules, addressing problems in existing fluidized bed preparation techniques such as microparticle adhesion, particle agglomeration, poor drug content uniformity, large in vitro dissolution fluctuations, poor formulation stability, insufficient masking of bitter taste, and high risk of organic solvent residue. To achieve the above objectives, this invention employs the following technical solution: A type of olopatadine hydrochloride granules, using pharmaceutical sucrose-starch composite sucrose pellet core as a carrier, includes, from the inside out, a drug-loading layer, an isolation layer and a coating layer; 1. Drug-loaded layer: Contains olopatadine hydrochloride, sucrose, hydroxypropyl cellulose, colloidal silica, and homogenized talc. Olopatadine hydrochloride serves as the active ingredient; sucrose acts as a filler, improving the stability of the active ingredient and initially improving the taste of the drug; hydroxypropyl cellulose acts as a binder, ensuring a strong bond between the drug-loaded layer and the pharmaceutical sucrose-starch composite sucrose pellet core; colloidal silica enhances the dispersibility of the drug solution and the flowability of the micro-pellets, preventing particle agglomeration; the homogenized talc has a fine particle size, enhancing the lubricity and uniformity of the drug layer. 2. Isolation Layer: Composed of hydroxypropyl cellulose, colloidal silica, and homogenized talc. Hydroxypropyl cellulose forms a dense isolation film, improving the stability of the active ingredient and effectively separating the drug-loaded layer from the coating layer; colloidal silica and homogenized talc work synergistically to further enhance the density and spraying performance of the isolation layer, thereby improving the stability of the formulation; 3. Coating layer: formed by coating powder, which ultimately masks the bitter taste of the drug, improves the appearance of the particles, and enhances the storage stability of the drug.

[0007] The mass percentage of each component is calculated based on the dry basis mass of the pharmaceutical sucrose-starch composite core as 100%. 1. Drug-loaded layer: Olopatadine hydrochloride 0.5%~0.9%, sucrose 5%~10%, hydroxypropyl cellulose 1%~3%, colloidal silica 0.5%~1.0%, homogenized talc 0.3%~1.0%; 2. Isolation layer: 0.8%~2% hydroxypropyl cellulose, 0.4%~1.0% colloidal silica, and 0.4%~1.0% homogenized talc; 3. Coating layer: 12%~18% coating powder.

[0008] Preferably, the particle size D of the pharmaceutical sucrose-starch composite sucrose pellet core is... 90 The particle size is 300~600μm, and the mass ratio of sucrose to starch in the core is 1:0.1~0.5. Pharmaceutical sucrose-starch composite sucrose cores within this particle size range exhibit excellent flowability, making them suitable for continuous fluidized bed spraying. The homogenized talc powder has a particle size D... 90With a particle size of ≤5μm, the ultrafine particle size ensures uniform dispersion in each layer, without hindering drug release or affecting the in vitro dissolution index of the finished product.

[0009] Preferably, the coating powder is the Opadry series gastric coating powder (brand name 39G630001-CN), or a composite pharmaceutical gastric coating powder containing hydroxypropyl methylcellulose, polyethylene glycol and sucralose; wherein polyethylene glycol acts as a plasticizer to improve the flexibility of the coating layer, and sucralose acts as a flavoring agent to further improve the taste of the granules.

[0010] This invention utilizes a fluidized bed process with micro-pellet loading to prepare olopatadine hydrochloride granules. Using pharmaceutical-grade sucrose-starch composite sucrose pellets as a carrier, colloidal silica and homogenized talc are innovatively added to the drug-carrying layer and the isolation layer. Through this multi-layer coating design, the following beneficial effects are achieved: 1. Improved process stability: The fluidized bed micro-pellet loading + three-layer continuous spray coating integrated process replaces the traditional wet granulation, fundamentally solving the problems of uneven drug content and large fluctuations in in vitro dissolution; 2. Synergistic innovation of excipients: Colloidal silica and ultrafine homogeneous talc are added simultaneously to the drug-carrying layer and the isolation layer to form a dispersion-lubrication dual-effect system, which eliminates problems such as micro-pellets sticking to the wall and particles agglomerating during fluidized bed spraying; 3. Excellent stability of finished formulation: Hydroxypropyl cellulose, colloidal silica and homogenized talc in the isolation layer form a dense protective film, which not only avoids the interaction between the drug layer and the coating layer, but also isolates the product from the influence of external environmental factors and extends the shelf life of the product; 4. Rapid drug dissolution and high bioavailability: The active ingredients are uniformly coated on the surface of the pharmaceutical sucrose-starch composite sucrose core. Each layer of excipients does not hinder drug release. The finished product meets the requirement of ≥88% cumulative drug dissolution within 15 minutes, resulting in rapid drug absorption and high bioavailability in the body. 5. Significantly improved taste: The sucrose in the drug-loaded layer and the flavoring agent in the coating layer work synergistically, combined with the multi-layer coating structure, to effectively mask the bitter taste of olopatadine hydrochloride, making it suitable for children and elderly people with difficulty swallowing, and improving patient medication compliance; 6. Production safety and environmental compliance: The entire process adopts an all-aqueous spray system, without the use of ethanol organic solvents, eliminating the risk of solvent residue, and requiring no explosion-proof modifications to the workshop, thus reducing production costs and environmental treatment pressure.

[0011] This invention also provides a method for preparing the above-mentioned olopatadine hydrochloride granules, which adopts an integrated fluidized bed preparation process with micro-particles in an aqueous phase. The specific steps are as follows: 1. Drug-loaded coating: Dissolve olopatadine hydrochloride, sucrose, and hydroxypropyl cellulose in water, add colloidal silica and homogenized talc solution, mix evenly to prepare a drug-containing suspension with a solid content of 8%~15%. Place the pharmaceutical sucrose-starch composite sucrose pellet core in a fluidized bed equipment, turn on the equipment, control the inlet air temperature to 40~50℃, the material temperature to 35~40℃, the spraying speed to 5~8 rpm, and the air volume to 20~50 m³ / h for spraying the drug. After the drug is coated, continue drying for 10~20 minutes until the moisture content of the pellets is ≤3%, to obtain drug-loaded pellets. 2. Isolation layer coating: Hydroxypropyl cellulose is dissolved in water, colloidal silica and homogenized talc solution are added, and stirred evenly to prepare an isolation layer spray with a solid content of 3%~8%; the drug-loaded microspheres obtained in step (1) are placed in a fluidized bed, the inlet air temperature is set to 40~50℃, the material temperature is set to 35~45℃, the spraying speed is set to 5~8rpm, and the air volume is set to 20-50m³ / h for spray coating; after coating, the microspheres are dried for 20-30 minutes until the moisture content of the microspheres is ≤2.5%, and microspheres with isolation layer are obtained; 3. Coating: Add the coating powder to water, stir and disperse evenly to make a coating liquid with a solid content of 12%-20%, and remove impurities by passing it through a 100-mesh sieve; place the micro-particles with isolation layer obtained in step (2) in a fluidized bed for in-situ coating, set the air inlet temperature to 45~60℃, the material temperature to 35~45℃, the spraying speed to 6~12rpm, and the air volume to 30~50m³ / h for spray coating; after coating, dry for 30-50 minutes until the particle moisture content is ≤2.0%, and obtain the finished product of olopatadine hydrochloride granules after sieving. Detailed Implementation

[0012] The present invention will be further described in detail below through specific embodiments, but the present invention is not limited to these embodiments. Example

[0013] Prescription composition:

[0014] Specific preparation process Drug-loaded coating: Olopatadine hydrochloride, sucrose, and hydroxypropyl cellulose were dissolved in water, and colloidal silica and homogenized talc solution were added and stirred until homogeneous; 117g of pharmaceutical-grade sucrose-starch composite sucrose pellet cores were placed in a fluidized bed, with a particle size D of pharmaceutical-grade sucrose-starch composite sucrose pellet cores. 90 The pellets are 500~600μm in size, with a sucrose to starch mass ratio of 1:0.2 inside the pellet core. The fluidized bed inlet air temperature is set to 50℃, the spraying speed to 8rpm, and the air volume to 35m³ / h. The drug is sprayed on, with a total of 75g of drug-loaded spray solution sprayed on. After the drug is applied, the pellets are dried for 20 minutes, with a moisture content of 2.0%, to obtain drug-loaded micro pellets.

[0015] Separation layer coating: Hydroxypropyl cellulose was dissolved in water, and colloidal silica and homogenized talc solution were added to the hydroxypropyl cellulose solution and stirred evenly; the drug-loaded microcapsules were coated by fluidized bed spraying, with the inlet air temperature set at 50℃, spraying speed at 8rpm, air volume at 35m³ / h, and a total spraying volume of 50g; after coating, the microcapsules were dried for 20 minutes, with a moisture content of 1.8%, to obtain microcapsules with a separation layer.

[0016] Coating: Add the coating powder to water, disperse evenly, and pass through a 100-mesh sieve; spray-coat the microspheres with the isolation layer, set the inlet air temperature to 55℃, the spraying speed to 8rpm, and the air volume to 40m³ / h, spraying a total of 105g of coating suspension; after coating, dry for 30 minutes, with a moisture content of 1.5%, and pass through a 20-80 mesh sieve to obtain the finished product of olopatadine hydrochloride granules. Example

[0017] Prescription composition:

[0018] Specific preparation process: Drug coating: Olopatadine hydrochloride, sucrose, and hydroxypropyl cellulose were dissolved in water, and colloidal silica and homogenized talc solution were added and stirred until homogeneous; 117g of pharmaceutical-grade sucrose-starch composite sucrose pellet cores were placed in a fluidized bed, and the particle size D of the pharmaceutical-grade sucrose-starch composite sucrose pellet cores was... 90 The pellets were 400-500 μm in size, with a sucrose to starch mass ratio of 1:0.4. The fluidized bed inlet air temperature was set at 48℃, the spraying speed at 7 rpm, and the air volume at 30 m³ / h. The drug was sprayed onto the pellets, with a total of 70 g of drug-loaded liquid sprayed in. After the drug was applied, the pellets were dried for 25 minutes, with a moisture content of 1.6%, to obtain drug-loaded micro pellets.

[0019] Separation layer coating: Hydroxypropyl cellulose was dissolved in water, and colloidal silica and homogenized talc solution were added to the hydroxypropyl cellulose solution and stirred evenly; the drug-loaded microcapsules were coated by fluidized bed spraying, with the inlet air temperature set at 48℃, spraying speed at 7rpm, air volume at 35m³ / h, and a total spraying volume of 48g; after coating, the microcapsules were dried for 25 minutes, with a moisture content of 1.5%, to obtain microcapsules with a separation layer.

[0020] Coating: Add coating powder to water and disperse to form a coating suspension, which is then passed through a 100-mesh sieve; spray coating is performed on the microspheres with the isolation layer, with the inlet air temperature set at 58℃, the spraying speed at 9rpm, and the air volume at 40m³ / h, for a total spraying of 90g; after coating, dry for 30 minutes, with a moisture content of 1.6%, to obtain the finished product of olopatadine hydrochloride granules. Example

[0021] Prescription composition:

[0022] Specific preparation process: Drug coating: Olopatadine hydrochloride, sucrose, and hydroxypropyl cellulose were dissolved in water, and colloidal silica and homogenized talc solution were added and stirred until homogeneous; 117g of pharmaceutical-grade sucrose-starch composite sucrose pellet cores were placed in a fluidized bed, and the particle size D of the pharmaceutical-grade sucrose-starch composite sucrose pellet cores was... 90 The pellets are 350~550μm in size, with a sucrose to starch mass ratio of 1:0.3 in the pellet core. The fluidized bed inlet air temperature is set at 45℃, the spraying speed at 9rpm, and the air volume at 40m³ / h. The drug is sprayed on, with a total of 80g of drug-loaded spray solution sprayed on. After the drug is applied, the pellets are dried for 25 minutes, with a moisture content of 2.5%, to obtain drug-loaded micro pellets.

[0023] Separation layer coating: Hydroxypropyl cellulose was dissolved in water, and colloidal silica and homogenized talc solution were added to the hydroxypropyl cellulose solution and stirred evenly; the drug-loaded microspheres were coated by fluidized bed spraying, with the inlet air temperature set at 45℃, spraying speed at 9rpm, air volume at 40m³ / h, and a total spraying volume of 40g; after coating, the microspheres were dried for 30 minutes, with a moisture content of 1.8%, to obtain microspheres with a separation layer.

[0024] Coating: Add coating powder to water and disperse to form a coating suspension, which is then passed through a 100-mesh sieve; spray coating is performed on the microspheres with the isolation layer, with the inlet air temperature set at 50℃, the spraying speed at 10rpm, and the air volume at 40m³ / h, for a total spraying of 100g; after coating, dry for 25 minutes, with a moisture content of 1.5%, to obtain the finished product of olopatadine hydrochloride granules.

[0025] Performance testing 1. Stable fluidization state, no organic solvent added throughout the process, no pellet sticking to the wall, no particle agglomeration, and a finished product yield of ≥95%; 2. Content uniformity: Referring to General Chapter 0941 of the 2025 edition of the Chinese Pharmacopoeia, the content uniformity of the granules obtained in Examples 1-3 was tested. The results showed that the content uniformity of each granule met the requirements, with RSD ≤ 1.8%. 3. Dissolution rate: Dissolution rate was tested at 37°C, 900mL water medium, and 50rpm. The results showed that the cumulative drug dissolution rate of the particles obtained in Examples 1-3 reached more than 88% after 15 minutes, and the drug dissolution was rapid and complete. 4. Taste evaluation: Twenty volunteers were invited to evaluate the taste. The results showed that the granules obtained in Examples 1-3 had no obvious bitter taste and had a good taste. 5. Stability test: The granules obtained in Examples 1-3 were placed at 40°C and RH 75% for 3 months, and the changes in related substances and their contents were detected. The results showed that the growth of related substances was slow (increase ≤0.1%), the content of the active pharmaceutical ingredient did not change significantly, and the formulation had excellent stability.

[0026] The preparation method of this invention is simple to operate, streamlined in process, and does not require an explosion-proof production workshop, making it suitable for large-scale industrial continuous production; the resulting olopatadine hydrochloride granules have stable quality, meet dissolution standards, have a good taste, and a long storage period, and have broad market application prospects.

Claims

1. A type of olopatadine hydrochloride granules, characterized in that... Using pharmaceutical-grade sucrose-starch composite sucrose pellets as a carrier, the micro-pellets consist of a three-layer composite structure from the inside out: a drug-loading layer, an isolation layer, and a coating layer. The drug-loading layer is composed of olopatadine hydrochloride, sucrose, hydroxypropyl cellulose, colloidal silica, and homogenized talc. The isolation layer is composed of hydroxypropyl cellulose, colloidal silica, and homogenized talc. The coating layer is composed of coating powder. The particles are prepared using a fully aqueous fluidized bed process without the addition of organic solvents.

2. The olopatadine hydrochloride granules according to claim 1, characterized in that... Based on the dry basis weight of the aforementioned pharmaceutical sucrose-starch composite pellet core as 100%: 1) In the drug-loaded layer: olopatadine hydrochloride 0.5%~0.9%, sucrose 5%~10%, hydroxypropyl cellulose 1%~3%, colloidal silica 0.5%~1.0%, talc 0.3%~1.0%; 2) In the isolation layer: hydroxypropyl cellulose 0.8%~2%, colloidal silica 0.4%~1.0%, talc 0.4%~1.0%; 3) In the coating layer: coating powder 12%~18%.

3. The olopatadine hydrochloride granules according to claim 1, characterized in that, The pharmaceutical sucrose-starch composite sucrose pellet core has a particle size D. 90 The particle size is 300~600μm, and the mass ratio of sucrose to starch in the pellet core is 1:0.1~0.5; the talc powder is homogenized, and the particle size D after homogenization is... 90 ≤5μm.

4. The olopatadine hydrochloride granules according to claim 1, characterized in that, The coating powder is a composite pharmaceutical gastric-soluble coating powder, which contains film-forming materials, plasticizers, flavoring agents, and colorants.

5. A method for preparing olopatadine hydrochloride granules as described in claim 1, characterized in that, The integrated process of three-layer continuous spraying in a fully aqueous fluidized bed includes the following steps: 1) Drug-loaded coating: Olopatadine hydrochloride, sucrose, and hydroxypropyl cellulose are dissolved in water, and colloidal silica and homogenized talc powder solution are added and mixed evenly to prepare a spray solution. Using pharmaceutical sucrose-starch composite sucrose pellet core as a carrier, the drug is sprayed in a fluidized bed. The process parameters are controlled as follows: air inlet temperature 40~50℃, material temperature 35~40℃, spraying speed 5~8rpm, air volume 20~50m³ / h. After the drug is coated, the pellets are dried until the moisture content of the pellets is ≤3% to obtain drug-loaded pellets. 2) Isolation layer coating: Hydroxypropyl cellulose is dissolved in water, and colloidal silica and homogenized talc solution are added to make an isolation layer spray solution. The drug-loaded microspheres obtained in step (1) are coated by fluidized bed spray. Process parameters: air inlet temperature 40~50℃, material temperature 35~45℃, spray speed 5~8rpm, air volume 20~50m³ / h. After coating, the microspheres are dried until the moisture content is ≤2.5% to obtain microspheres with isolation layer. 3) Coating layer coating: Disperse the coating powder in water to make a coating suspension, and perform fluidized bed spray coating on the micro pellets with isolation layer obtained in step (2). Process parameters: air inlet temperature 50~60℃, material temperature 45~60℃, spraying speed 6~12rpm, air volume 30~50m³ / h. After coating, dry until the particle moisture content is ≤2.0%, and obtain olopatadine hydrochloride particles after sieving.

6. The preparation method according to claim 5, characterized in that, The drug-loaded layer has a liquid solid content of 8% to 15%, the isolation layer has a liquid solid content of 3% to 8%, and the coating suspension has a solid content of 12% to 20%.

7. Olopatadine hydrochloride granules prepared by any of the methods described in claim 5, characterized in that: the uniformity of drug content in the granules is RSD≤1.8%, the cumulative drug dissolution rate over 15 min is ≥88%, and there is no bitter taste.

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