Pharmaceutical composition containing quetiapine fumarate and preparation method thereof

Abstract

The invention discloses a pharmaceutical composition containing quetiapine fumarate and a preparation method of the pharmaceutical composition. The pharmaceutical composition is a 3D printed intragastric floating preparation, and can prolong the retention time of the medicine in the stomach, promote the release and absorption of the medicine, reduce the administration frequency and improve the administration compliance of a patient. The drug release time is controllable, the release is stable, the defect of large fluctuation of the plasma concentration of a quick release preparation is overcome, and compared with the existing sustained release preparation, the stability is more reliable. The 3D printing technology is adopted, the in-vivo release behavior of the medicine can be flexibly adjusted, and personalized administration is achieved; meanwhile, the process is convenient to operate, the preparation uniformity is good, the preparation quality is improved, large-scale continuous production can be better achieved, and medicine production and quality monitoring data can be recorded in real time.

Description

Technical Field

[0001] This invention relates to a pharmaceutical composition containing quetiapine fumarate and its preparation method, and more particularly to a gastric floating pharmaceutical composition containing quetiapine fumarate and its preparation method. Background Technology

[0002] Quetiapine fumarate (C 42 H 50 N6O4S2·C4H4O4, 11-{4-[2-(2-hydroxyethoxy)ethyl-1-piperazinyl]}dibenzo[b,f)(1,4]thiazofumarate (2:1) is an antagonist of various neurotransmitter receptors in the brain and belongs to atypical antipsychotic drugs.

[0003]

[0004] Due to the low solubility of quetiapine fumarate, and the elimination half-lives of quetiapine fumarate and its active metabolite N-dehydroquiniapine being approximately 7 hours and 12 hours respectively, its immediate-release formulation requires twice-daily dosing, but this results in significant fluctuations in blood drug concentrations after administration. Furthermore, while the extended-release formulation of quetiapine fumarate (Seroquel XR) utilizes a three-layer tablet technology to achieve relatively stable drug release, only 25mg, 100mg, and 200mg are available for patients requiring dose titration. For patients requiring 50-75mg or more than 200mg, using different strengths in combination is insufficient to achieve stable release, or results in high dosing frequency and poor patient compliance.

[0005] In addition, CN102525988A discloses a quetiapine fumarate sustained-release tablet, which uses a bilayer tablet technology to achieve a relatively stable drug release. Although this reduces the preparation difficulty compared to a trilayer tablet, it still requires special tableting equipment and the process is cumbersome. CN117547516A also discloses a quetiapine fumarate sustained-release tablet, which uses sodium alginate and hydroxypropyl-β-cyclodextrin as sustained-release agents in the first granulation and hydroxypropyl methylcellulose (K4M or 15M) in the second granulation. Although this prolongs the drug release time, it still requires a complex granulation process. Summary of the Invention

[0006] Purpose of the invention: The present invention aims to provide a pharmaceutical composition containing quetiapine fumarate with controllable and stable release, flexible dosage adjustment, and stable quality, as well as a method for its preparation.

[0007] Technical solution: The pharmaceutical composition containing quetiapine fumarate of the present invention comprises, by weight, 10-40 parts of quetiapine fumarate, 3-5 parts of filler, 10-30 parts of matrix material and 1-2 parts of plasticizer; wherein, the filler is selected from calcium hydrogen phosphate, the matrix material is selected from one or more of hydroxypropyl cellulose, polyoxyethylene, and povidone, and the plasticizer is selected from one or more of triethyl citrate, triethyl glycerol, and polyvinyl alcohol.

[0008] Preferably, in the pharmaceutical composition, the weight ratio of quetiapine fumarate, filler, matrix material, and plasticizer is 10:3:10:2.

[0009] Preferably, the pharmaceutical composition comprises, by weight, 10 parts quetiapine fumarate, 3 parts filler, 10 parts matrix material, and 2 parts plasticizer.

[0010] Preferably, the skeleton material is polyethylene oxide and the plasticizer is triethyl citrate.

[0011] Preferably, the pharmaceutical composition comprises, by weight, 10 parts quetiapine fumarate, 3 parts calcium hydrogen phosphate, 10 parts polyoxyethylene and 2 parts triethyl citrate.

[0012] More preferably, the pharmaceutical composition contains 50-200 mg of quetiapine fumarate.

[0013] More preferably, the pharmaceutical composition contains 50 mg, 100 mg, or 200 mg of quetiapine fumarate.

[0014] Preferably, the pharmaceutical composition is a gastric flotation preparation, with a flotation time of no more than 15 minutes and a flotation time of no less than 12 hours.

[0015] More preferably, the floating time of the pharmaceutical composition does not exceed 10 minutes.

[0016] Preferably, the dissolution curve similarity factor between the pharmaceutical composition and the reference formulation is not less than 60.

[0017] Further preferably, the method for determining the dissolution curve is as follows: (1) 1-5 hours Dissolution medium: 0.05M citric acid and 0.09N NaOH (pH 4.8), medium volume: 900ml, basket method rotation speed: 200rpm; (2) 5-24 hours Dissolution medium: Add 100 mL of 0.05 M disodium hydrogen phosphate and 0.46 N NaOH (adjust pH to 6.6) to the dissolution medium in (1). Medium volume: 1000 mL, basket rotation speed: 200 rpm.

[0018] The method for preparing the pharmaceutical composition of the present invention includes the following steps: (1) Premixing: Premixing the prescribed amount of active ingredients, fillers, matrix materials and plasticizers; (2) Hot melt extrusion: The premixed material obtained in step (1) is hot melt extruded into filaments; (3) 3D printing: The filament obtained in step (2) is 3D printed to obtain the drug composition.

[0019] This invention achieves an adjustable sustained-release effect of the drug by adjusting the tablet filling rate and exhibits stable buoyancy properties.

[0020] Preferably, the temperature of the hot melt extrusion in step (2) is 145~155℃.

[0021] Further preferred, the temperature of the hot melt extrusion in step (2) is 150°C.

[0022] Preferably, the filling rate of the 3D printed formulation in step (3) is 30%~70%.

[0023] Further preferred, the filling rate of the 3D printed formulation in step (3) is 50%.

[0024] Preferably, in step (3), the printing temperature of 3D printing is 155~165℃, the printing bed temperature is 38~42℃, and the printing speed is 38~42mm / s.

[0025] Further optimization is that the printing temperature of 3D printing in step (3) is 160℃, the printing bed temperature is 40℃, and the printing speed is 40mm / s.

[0026] Preferably, the wire with a diameter of 1.0~2.0 mm is hot-melted extruded in step (2).

[0027] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: The pharmaceutical composition designed in this invention can prolong the drug's residence time in the stomach, promote drug release and absorption, reduce the frequency of administration, and improve patient compliance. The drug release time is controllable and stable, overcoming the drawback of large fluctuations in blood drug concentration in immediate-release formulations, and its stability is more reliable compared to existing sustained-release formulations. Utilizing 3D printing technology allows for flexible adjustment of drug release behavior in vivo, enabling personalized dosing; simultaneously, the process is convenient, resulting in good formulation uniformity and improved formulation quality, which is more conducive to large-scale continuous production, and allows for real-time recording of drug production and quality monitoring data. Detailed Implementation

[0028] The technical solution of the present invention will be further described below with reference to the embodiments.

[0029] Example 1

[0030] 1. Prescription Quetiapine fumarate 100mg Active ingredients Calcium hydrogen phosphate 30mg filler Polyoxyethylene 100mg Skeleton material Triethyl citrate 20mg plasticizer total 250mg 2. Process (1) Premixed Premix the prescribed amounts of quetiapine fumarate, dicalcium phosphate, polyoxyethylene, and triethyl citrate in a mixer.

[0031] (2) Hot melt extrusion The premixed material is added to a hot melt extruder, the extrusion temperature is 150℃, and filaments with a diameter of 1.5mm are extruded.

[0032] (3) 3D printing Use an FDM 3D printer and set the following parameters for printing.

[0033] Formulation filling rate 50% Printing temperature 160℃ Printing bed temperature 40℃ Printing speed 40mm / s Example 2

[0034] 1. Prescription Quetiapine fumarate 50mg Active ingredients Calcium hydrogen phosphate 15mg filler Polyoxyethylene 50mg Skeleton material Triethyl citrate 10mg plasticizer total 125mg 2. Process (1) Premix Premix the prescribed amounts of quetiapine fumarate, dicalcium phosphate, polyoxyethylene, and triethyl citrate in a mixer.

[0035] (2) Hot melt extrusion The premixed material is added to a hot melt extruder, the extrusion temperature is 150℃, and filaments with a diameter of 1.5mm are extruded.

[0036] (3) 3D printing Use an FDM 3D printer and set the following parameters for printing.

[0037] Formulation filling rate 50% Printing temperature 160℃ Printing bed temperature 40℃ Printing speed 40mm / s Example 3

[0038] 1. Prescription Quetiapine fumarate 200mg Active ingredients Calcium hydrogen phosphate 60mg filler Polyoxyethylene 200mg Skeleton material Triethyl citrate 40mg plasticizer total 500mg 2. Process (1) Premixed Premix the prescribed amounts of quetiapine fumarate, dicalcium phosphate, polyoxyethylene, and triethyl citrate in a mixer.

[0039] (2) Hot melt extrusion The premixed material is added to a hot melt extruder, the extrusion temperature is 150℃, and filaments with a diameter of 1.5mm are extruded.

[0040] (3) 3D printing Use an FDM 3D printer and set the following parameters for printing.

[0041] Formulation filling rate 50% Printing temperature 160℃ Printing bed temperature 40℃ Printing speed 40mm / s Example 4

[0042] 1. Prescription Quetiapine fumarate 100mg Active ingredients Calcium hydrogen phosphate 30mg filler Polyoxyethylene 100mg Skeleton material Triethyl citrate 20mg plasticizer total 250mg 2. Process (1) Premixed Premix the prescribed amounts of quetiapine fumarate, dicalcium phosphate, polyoxyethylene, and triethyl citrate in a mixer.

[0043] (2) Hot melt extrusion The premixed material is added to a hot melt extruder, the extrusion temperature is 150℃, and filaments with a diameter of 1.5mm are extruded.

[0044] (3) 3D printing Use an FDM 3D printer and set the following parameters for printing.

[0045] Formulation filling rate 70% Printing temperature 160℃ Printing bed temperature 40℃ Printing speed 40mm / s Example 5

[0046] 1. Prescription Quetiapine fumarate 100mg Active ingredients Calcium hydrogen phosphate 30mg filler Polyoxyethylene 100mg Skeleton material Triethyl citrate 20mg plasticizer total 250mg 2. Process (1) Premixed Premix the prescribed amounts of quetiapine fumarate, dicalcium phosphate, polyoxyethylene, and triethyl citrate in a mixer.

[0047] (2) Hot melt extrusion The premixed material is added to a hot melt extruder, the extrusion temperature is 150℃, and filaments with a diameter of 1.5mm are extruded.

[0048] (3) 3D printing Use an FDM 3D printer and set the following parameters for printing.

[0049] Formulation filling rate 30% Printing temperature 160℃ Printing bed temperature 40℃ Printing speed 40mm / s Comparative Example 1 1. Prescription Quetiapine fumarate 100mg Active ingredients microcrystalline cellulose 30mg filler Polyoxyethylene 100mg Skeleton material Triethyl citrate 20mg plasticizer total 250mg 2. Process (1) Premixed Premix the prescribed amounts of quetiapine fumarate, microcrystalline cellulose, polyoxyethylene, and triethyl citrate in a mixer.

[0050] (2) Hot melt extrusion The premixed material is added to a hot melt extruder, the extrusion temperature is 150℃, and filaments with a diameter of 1.5mm are extruded.

[0051] (3) 3D printing Use an FDM 3D printer and set the following parameters for printing.

[0052] Formulation filling rate 50% Printing temperature 160℃ Printing bed temperature 40℃ Printing speed 40mm / s Comparative Example 2 1. Prescription Quetiapine fumarate 100mg Active ingredients lactose 30mg filler Polyoxyethylene 100mg Skeleton material Triethyl citrate 20mg plasticizer total 250mg 2. Process (1) Premixed Premix the prescribed amounts of quetiapine fumarate, lactose, polyoxyethylene, and triethyl citrate in a mixer.

[0053] (2) Hot melt extrusion The premixed material is added to a hot melt extruder, the extrusion temperature is 150℃, and filaments with a diameter of 1.5mm are extruded.

[0054] (3) 3D printing Use an FDM 3D printer and set the following parameters for printing.

[0055] Formulation filling rate 50% Printing temperature 160℃ Printing bed temperature 40℃ Printing speed 40mm / s Comparative Example 3 1. Prescription Quetiapine fumarate 100mg Active ingredients Mannitol 30mg filler Polyoxyethylene 100mg Skeleton material Triethyl citrate 20mg plasticizer total 250mg 2. Process (1) Premixed Premix the prescribed amounts of quetiapine fumarate, mannitol, polyoxyethylene, and triethyl citrate in a mixer.

[0056] (2) Hot melt extrusion The premixed material is added to a hot melt extruder, the extrusion temperature is 150℃, and filaments with a diameter of 1.5mm are extruded.

[0057] (3) 3D printing Use an FDM 3D printer and set the following parameters for printing.

[0058] Formulation filling rate 50% Printing temperature 160℃ Printing bed temperature 40℃ Printing speed 40mm / s Comparative Example 4 1. Prescription Quetiapine fumarate 100mg Active ingredients Calcium hydrogen phosphate 30mg filler Hydroxypropyl methylcellulose 100mg Skeleton material Triethyl citrate 20mg plasticizer total 250mg 2. Process (1) Premixed Premix the prescribed amounts of quetiapine fumarate, dicalcium phosphate, hydroxypropyl methylcellulose, and triethyl citrate in a mixer.

[0059] (2) Hot melt extrusion The premixed material is added to a hot melt extruder, the extrusion temperature is 150℃, and filaments with a diameter of 1.5mm are extruded.

[0060] (3) 3D printing Use an FDM 3D printer and set the following parameters for printing.

[0061] Formulation filling rate 50% Printing temperature 160℃ Printing bed temperature 40℃ Printing speed 40mm / s Comparative Example 5 1. Prescription Quetiapine fumarate 100mg Active ingredients Calcium hydrogen phosphate 30mg filler Polyoxyethylene 100mg Skeleton material polyethylene glycol 20mg plasticizer total 250mg 2. Process (1) Premixed Premix the prescribed amounts of quetiapine fumarate, dicalcium phosphate, polyoxyethylene, and polyethylene glycol in a mixer.

[0062] (2) Hot melt extrusion The premixed material is added to a hot melt extruder, the extrusion temperature is 150℃, and filaments with a diameter of 1.5mm are extruded.

[0063] (3) 3D printing Use an FDM 3D printer and set the following parameters for printing.

[0064] Formulation filling rate 50% Printing temperature 160℃ Printing bed temperature 40℃ Printing speed 40mm / s Example 6: Formulation Quality Evaluation 1. Method Take the samples prepared in the comparative example and the example, and the reference formulation (Seroquel XR, 100 mg), and determine the dissolution according to the dissolution method of quetiapine fumarate extended-release tablets in the FDA dissolution database (1-5 hours: 0.05 M citric acid and 0.09 N NaOH (pH 4.8), 900 ml, basket method 200 rpm; after 5 hours: add 100 mL of 0.05 M disodium hydrogen phosphate and 0.46 N NaOH, adjust the pH to 6.6, 1000 ml, basket method 200 rpm).

[0065] The drift time and floating time of the samples prepared in the comparative examples and embodiments were measured.

[0066] The content uniformity of the samples prepared in the comparative examples and embodiments was determined.

[0067] The samples prepared in the comparative and examples were placed to accelerate long-term stability.

[0068] 2. Results Table 1. Results of in vitro dissolution evaluation

[0069] Table 2 Floatability Evaluation Results

[0070] Table 3 Uniformity Evaluation Results

[0071] Table 4. Stability evaluation results (related substances: total impurities)

[0072] As shown in Tables 1-4, the quetiapine fumarate gastric floating formulation prepared by the 3D printing gastric floating technology of this invention exhibits significant sustained-release effects and good stability, and formulations with different dosages and sustained-release effects can be customized according to patient needs. Table 2 shows that the quetiapine fumarate gastric floating formulation prepared by this invention has a floating time of no more than 15 minutes and a floating time of no less than 12 hours, especially the formulations prepared in Examples 1-3 and 5, whose floating time is no more than 10 minutes. In Examples 4 and 5, the floating time can be effectively controlled by adjusting the filling rate of the formulation to achieve different sustained-release effects. Table 3 shows that the formulation prepared by the process of this invention has good uniformity. Furthermore, Table 4 shows that the floating formulation prepared by 3D printing has better stability than the reference formulation.

Claims

1. A pharmaceutical composition comprising quetiapine fumarate, characterized in that, The pharmaceutical composition comprises quetiapine fumarate 10-40 parts, a filler 3-5 parts, a matrix material 10-30 parts and a plasticizer 1-2 parts by weight; wherein the filler is selected from calcium hydrogen phosphate, the matrix material is selected from one or more of hydroxypropyl cellulose, polyoxyethylene and povidone, and the plasticizer is selected from one or more of triethyl citrate, glyceryl triethyl and polyvinyl alcohol.

2. The pharmaceutical composition of claim 1, wherein, The weight ratio of quetiapine fumarate, the filler, the matrix material and the plasticizer is 10:3:10:

2.

3. The pharmaceutical composition of claim 1, wherein, The pharmaceutical composition comprises quetiapine fumarate 10 parts, a filler 3 parts, a matrix material 10 parts and a plasticizer 2 parts by weight.

4. The pharmaceutical composition of claim 1, wherein, The matrix material is polyoxyethylene, and the plasticizer is triethyl citrate.

5. The pharmaceutical composition of claim 1, wherein, The pharmaceutical composition comprises quetiapine fumarate 10 parts, calcium hydrogen phosphate 3 parts, polyoxyethylene 10 parts and triethyl citrate 2 parts by weight.

6. The pharmaceutical composition of claim 5, wherein, The pharmaceutical composition contains quetiapine fumarate 50-200 mg.

7. The pharmaceutical composition of claim 1, wherein, The pharmaceutical composition is a gastric floating preparation, the floating time is not less than 12 hours.

8. A method of preparing the pharmaceutical composition of claim 1, wherein, The method comprises the following steps: (1) premixing: premixing the active ingredient, the filler, the matrix material and the plasticizer in the prescription amount; (2) hot melt extrusion: hot melt extruding the premixed material obtained in step (1) to form a filament; (3) 3D printing: 3D printing the filament obtained in step (2) to obtain the pharmaceutical composition.

9. The production method according to claim 8, characterized by, The temperature of the hot melt extrusion in step (2) is 145-155 ℃.

10. The preparation method according to claim 8, characterized in that, The filling rate of the preparation in 3D printing in step (3) is 30%-70%.

Images