Doxofylline granules and preparation method thereof
By optimizing the fluidized bed granulation process and using hydrophilic polymer auxiliary materials, the formation of doxotheline particles with porous microsphere structures has solved the problems of poor solubility and low dissolution rate of doxotheline, which significantly improves bioavailability and fluidity, simplifies the process and reduces costs.
Patent Information
- Application Number
- CN202510341583.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-03-21
- Publication Date
- 2025-06-06
AI Technical Summary
The solubility of doxotheline in water is extremely low, resulting in slow dissolution after oral administration, low bioavailability, and significant solubility differences in different pH ranges. The existing technology has defects such as stability problems and high cost and safety risks.
By optimizing the fluidized bed granulation process parameters and combining hydrophilic polymer auxiliary materials, doxothepine particles with porous microsphere structures are formed to promote uniform dispersion of drugs and avoid the destruction of drugs by high temperatures.
It significantly improves the dissolution rate and bioavailability of doxotheline, and the particles formed have good fluidity, which is suitable for direct tableting or filling capsules, simplifying the process and reducing costs and energy consumption.
Abstract
Description
Technical Field
[0001] The invention belongs to the field of pharmaceutical preparations, and particularly relates to doxofylline granules and a preparation method thereof. Background Art
[0002] Doxofylline, as a new generation of xanthine derivatives, can effectively relax bronchial smooth muscle by inhibiting phosphodiesterase activity, and is therefore widely used in the treatment of asthma and chronic obstructive pulmonary disease (COPD). However, doxofylline has extremely low solubility in water, resulting in slow dissolution after oral administration, low bioavailability, and significant differences in solubility in different pH ranges. In order to maintain the therapeutic effect, it is usually necessary to increase the dose or administer the drug frequently, but this will undoubtedly increase the risk of side effects such as gastrointestinal irritation.
[0003] At present, some new methods have been developed to improve the solubility of doxofylline. Solid dispersion technology is prepared by co-melting the drug with a carrier material (such as PEG, PVP) or by solvent method, but this method has stability problems such as high-temperature melting leading to drug degradation and easy recrystallization of the drug during long-term storage. Although nanocrystal technology can prepare nanoparticles by high-pressure homogenization or precipitation method to increase the specific surface area of the drug, nanocrystals are easy to agglomerate and require the addition of a large amount of surfactant, which may cause safety risks. In cyclodextrin inclusion technology, β-cyclodextrin can form inclusion complexes with drugs, but the inclusion efficiency is low and the solubility of the inclusion complex is limited. Salt type modification is difficult to prepare salt types such as hydrochloride or sodium salt due to the lack of ionizable groups in the molecular structure of doxofylline. In summary, these existing technologies all have certain defects. The solid dispersion and nanocrystal processes are complex and costly, the solubilization effect of cyclodextrin inclusion technology is insufficient, and the feasibility of salt type modification is low. In addition, the granule structure formed by traditional granulation processes (such as wet granulation) is dense, and the drug release rate is slow, which is difficult to meet the clinical demand for rapid-release preparations. Summary of the invention
[0004] Purpose of the invention: The purpose of the present invention is to provide a doxofylline granule with a high dissolution rate, so as to solve the technical bottleneck of poor solubility and low dissolution rate of doxofylline; another purpose of the present invention is to provide a method for preparing the doxofylline granule.
[0005] Technical solution: The doxofylline granules of the present invention have a porous microsphere structure, and contain doxofylline and a hydrophilic polymer excipient, wherein the hydrophilic polymer excipient is uniformly distributed in the doxofylline granules.
[0006] Preferably, the doxofylline granules contain 3-5% by weight of hydrophilic polymer excipients.
[0007] Preferably, the doxofylline particles have a D90 of 250 μm.
[0008] The preparation method of the doxofylline granules of the present invention comprises fluidized bed granulation of an aqueous solution containing doxofylline solid and at least one hydrophilic polymer auxiliary material.
[0009] Preferably, the hydrophilic polymer excipient includes at least one of hydroxypropyl cellulose, povidone K30 and pregelatinized starch.
[0010] Preferably, the doxofylline solid and the hydrophilic polymer excipient aqueous solution are introduced into the fluidized bed chamber separately.
[0011] Preferably, the concentration of the hydrophilic polymer excipient in the aqueous solution of the hydrophilic polymer excipient is 5-10% (w / v).
[0012] Preferably, the preparation method comprises the following steps: adding doxofylline solid to the feed port of a fluidized bed, adding a hydrophilic polymer auxiliary material aqueous solution to the liquid spray port for spraying, adjusting the fluidized bed spray speed, atomization pressure and air inlet temperature, controlling the drying time, obtaining doxofylline solid particles, and sieving them through a sieving machine to obtain doxofylline particles.
[0013] Preferably, the upper screen of the screening machine has a mesh size of 20-30, and the lower screen has a mesh size of 50-60.
[0014] Preferably, the fluidized bed spray rate is 10-15 mL / min, the atomization pressure is 0.01-0.05 MPa, the air inlet temperature is 50-150° C., and the drying time is 10-30 min.
[0015] Preferably, the inlet air temperature is 80-110°C.
[0016] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: the present invention aims at the technical bottleneck of poor solubility and low dissolution rate of doxofylline, optimizes the fluidized bed granulation process parameters (spray speed, atomization pressure and air inlet temperature, controls drying time), and combines hydrophilic excipients to form a porous structure, promotes the uniform dispersion of the drug in an amorphous state, and avoids the damage of the drug by high temperature, thereby preparing doxofylline granules, and the formed granules have good fluidity, are suitable for direct tableting or capsule filling, and significantly improve the efficiency of formulation development. Compared with the traditional process, the present method has the advantages of simple process, continuous production, low cost, low energy consumption, less pollution, and easy industrial production. DETAILED DESCRIPTION
[0017] The technical solution of the present invention is further described below in conjunction with embodiments.
[0018] Example 1
[0019] 2.0 kg of ground doxofylline solid was added to the bottom of the fluidized bed, and 8% hydroxypropyl cellulose aqueous solution was added to the liquid spray port for spraying. The fluidized bed spray speed was adjusted to 10 mL / min, the atomization pressure was 0.01 MPa, and the air inlet temperature was 80°C. After drying for 20 minutes, the doxofylline solid particles were sieved through a sieving machine with 20 mesh on the upper layer and 60 mesh on the lower layer to obtain doxofylline particles with a yield of 96.3%.
[0020] Example 2
[0021] 2.0 kg of ground doxofylline solid was added to the bottom of the fluidized bed, and 8% povidone K30 aqueous solution was added to the spray port for spraying. The fluidized bed spray speed was adjusted to 15 mL / min, the atomization pressure was 0.05 MPa, and the air inlet temperature was 80°C. After drying for 30 minutes, the doxofylline solid particles were sieved through a sieving machine with 20 mesh on the upper layer and 50 mesh on the lower layer to obtain doxofylline particles with a yield of 97.2%.
[0022] Example 3
[0023] 2.0 kg of ground doxofylline solid was added to the bottom of the fluidized bed, 10% pregelatinized starch aqueous solution was added to the liquid spray port for spraying, the fluidized bed spray speed was adjusted to 12 mL / min, the atomization pressure was 0.02 MPa, and the air inlet temperature was 90°C. After drying for 25 minutes, the doxofylline solid particles were sieved through a sieving machine with 20 mesh on the upper layer and 60 mesh on the lower layer to obtain doxofylline particles with a yield of 95.8%.
[0024] Example 4
[0025] 2.0 kg of ground doxofylline solid was added to the bottom of the fluidized bed, 10% pregelatinized starch aqueous solution was added to the liquid spray port for spraying, the fluidized bed spray speed was adjusted to 12 mL / min, the atomization pressure was 0.02 MPa, and the air inlet temperature was 110°C. After drying for 10 minutes, the doxofylline solid particles were sieved through a sieving machine with 20 mesh on the upper layer and 50 mesh on the lower layer to obtain doxofylline particles with a yield of 98.1%.
[0026] Example 5
[0027] 2.0 kg of ground doxofylline solid was added to the bottom of the fluidized bed, 6% povidone K30 aqueous solution was added to the spray port for spraying, the fluidized bed spray speed was adjusted to 10 mL / min, the atomization pressure was 0.01 MPa, and the air inlet temperature was 80°C. After drying for 20 minutes, the doxofylline solid particles were sieved through a sieving machine with 30 mesh on the upper layer and 60 mesh on the lower layer to obtain doxofylline particles with a yield of 96.7%.
[0028] Example 6
[0029] 2.0 kg of ground doxofylline solid was added to the bottom of the fluidized bed, and 5% hydroxypropyl cellulose aqueous solution was added to the liquid spray port for spraying. The fluidized bed spray speed was adjusted to 10 mL / min, the atomization pressure was 0.01 MPa, and the air inlet temperature was 80°C. After drying for 20 minutes, the doxofylline solid particles were sieved through a sieving machine with 30 mesh on the upper layer and 60 mesh on the lower layer to obtain doxofylline particles with a yield of 97.5%.
Claims
1. A doxofylline granule, characterized in that: The doxofylline particles have a porous microsphere structure and contain doxofylline and a hydrophilic polymer auxiliary material, wherein the hydrophilic polymer auxiliary material is uniformly distributed in the doxofylline particles.
2. The doxofylline granules according to claim 1, characterized in that: The doxofylline granules contain 3-5% by weight of hydrophilic polymer auxiliary materials.
3. A method for preparing the doxofylline granules according to claim 1, characterized in that: The invention comprises fluidized bed granulation of an aqueous solution containing doxofylline solid and at least one hydrophilic polymer auxiliary material.
4. The method for preparing doxofylline granules according to claim 3, characterized in that: The hydrophilic polymer auxiliary material includes at least one of hydroxypropyl cellulose, povidone K30 and pregelatinized starch.
5. The method for preparing doxofylline granules according to claim 3, characterized in that: The doxofylline solid and the hydrophilic polymer auxiliary material aqueous solution are introduced into the fluidized bed chamber separately.
6. The method for preparing doxofylline granules according to claim 3, characterized in that: The concentration of the hydrophilic polymer auxiliary material in the hydrophilic polymer auxiliary material aqueous solution is 5-10% (w / v).
7. The method for preparing doxofylline granules according to claim 3, characterized in that: The following steps are involved: The doxofylline solid is added to the fluidized bed feed port, and the hydrophilic polymer auxiliary material aqueous solution is added to the spray port for spraying. The spray speed, atomization pressure and air inlet temperature of the fluidized bed are adjusted, and the drying time is controlled to obtain the doxofylline solid particles, which are sieved by a sieving machine to obtain the doxofylline particles.
8. The method for preparing doxofylline granules according to claim 7, characterized in that: The upper screen of the screening machine has a mesh size of 20-30, and the lower screen has a mesh size of 50-60.
9. The method for preparing doxofylline granules according to claim 7, characterized in that: The fluidized bed spray rate is 10-15mL / min, the atomization pressure is 0.01-0.05Mpa, the inlet air temperature is 50-150℃, and the drying time is 10-30min.
10. The method for preparing doxofylline granules according to claim 9, characterized in that: The inlet air temperature is 80-110℃.