Brain Targeting of Quetiapine Fumarate via Intranasal Delivery of Loaded Lipospheres: Fabrication, In-Vitro Evaluation, Optimization, and In-Vivo Assessment
Abstract
:1. Introduction
2. Results and Discussion
2.1. Trial Formulations
2.2. Formulation’s Design
2.2.1. Entrapment Efficiency
2.2.2. Particle Size
2.2.3. Zeta Potential
2.2.4. Drug Release Profiles and Kinetics
2.3. Powder X-ray Diffraction Examination
2.4. Differential Scanning Calorimetry
2.5. Transmission Electron Microscopy
2.6. Stability Study
2.7. In Vivo Study
3. Material and Methods
3.1. Material
3.2. Animals
3.3. Study Design
3.4. Preparation of QT Loaded Lipospheres
3.5. Separation of Unentrapped QTF from the Prepared Lipospheres
3.6. Determination of Entrapment Efficiency.
3.7. Characterization of QTF Lipospheres
3.7.1. Morphological Description
3.7.2. Particle Size Analysis
3.7.3. Differential Scanning Calorimetry (DSC)
3.7.4. In Vitro Release of QTF from Lipospheres
3.7.5. Stability Study
3.8. In-Vivo Study
3.8.1. Separation of Plasma
3.8.2. Dissection and Preparation of Brain Sample
3.8.3. HPLC Conditions
3.8.4. Pharmacokinetic Parameters Analysis
3.9. Statistical Analysis of Results
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Formulations | Drug:Lipid | Core:Coat | %Pluronic | EE% | Vesicles Size (nm) | Zeta Potential | PDI |
---|---|---|---|---|---|---|---|
TB1 | 1:2 | 2:1 | 0.2 | 21.790 ± 2.0482 | 233.75 ± 6.8589 | −24.1 ± 1.0748 | 0.2735 ± 0.0671 |
TB2 | 1:4 | 2:1 | 0.2 | 35.888 ± 1.6683 | 259.7 ± 7.4953 | −19.45 ± 1.7111 | 0.542 ± 0.1555 |
TB3 | 1:6 | 2:1 | 0.2 | 41.670 ± 1.6187 | 275.9 ± 14.2835 | −18.73 ± 0.5515 | 0.3025 ± 0.0615 |
TB4 | 1:8 | 2:1 | 0.2 | 65.331 ± 0.3006 | 294.4 ± 18.2433 | −25.76 ± 0.4737 | 0.333 ± 0.1697 |
TB5 | 1:10 | 2:1 | 0.2 | 50.313 ± 1.5196 | 578.9 ± 34.2239 | −24.05 ± 0.4101 | 0.824 ± 0.0721 |
Formulations | Drug:Lipid | Core:Coat | %Pluronic | EE% | Vesicles Size (nm) | Zeta Potential | PDI | %Drug Released |
---|---|---|---|---|---|---|---|---|
F1 | 1:8 | 2:1 | 0.1 | 40.046 ± 1.800 | 436.35 ± 25.5265 | −21.35 ± 2.8991 | 0.349 ± 0.1605 | 69.1164 |
F2 | 1:8 | 3:1 | 0.1 | 55.186 ± 0.964 | 489.95 ± 17.7483 | −21.85 ± 0.6363 | 0.490 ± 0.0332 | 59.4658 |
F3 | 1:8 | 4:1 | 0.1 | 62.334 ± 0.660 | 528.75 ± 20.4353 | −25.5 ± 1.2727 | 0.516 ± 0.0876 | 52.8374 |
F4 | 1:8 | 2:1 | 0.2 | 65.284 ± 0.366 | 294.4 ± 18.2433 | −25.76 ± 0.4737 | 0.333 ± 0.1697 | 78.6064 |
F5 | 1:8 | 3:1 | 0.2 | 72.675 ± 0.498 | 321.8 ± 16.2634 | −26.35 ± 1.3435 | 0.445 ± 0.1393 | 70.1822 |
F6 | 1:8 | 4:1 | 0.2 | 83.841 ± 1.086 | 338.45 ± 19.7282 | −28.8 ± 1.9798 | 0.491 ± 0.1336 | 63.3056 |
F7 | 1:8 | 2:1 | 0.3 | 51.469 ± 1.437 | 546.4 ± 7.49533 | −20.67 ± 1.3010 | 0.432 ± 0.1187 | 65.5978 |
F8 | 1:8 | 3:1 | 0.3 | 60.444 ± 1.192 | 563.8 ± 82.5900 | −23.57 ± 2.5102 | 0.381 ± 0.0509 | 54.312 |
F9 | 1:8 | 4:1 | 0.3 | 71.409 ± 0.294 | 575.8 ± 46.6690 | −26.09 ± 2.4607 | 0.505 ± 0.1873 | 43.8146 |
Formula Code | Zero Order | First Order | Higuchi Diffusion Model | Kors–Peppas | ||||
---|---|---|---|---|---|---|---|---|
R2 | Eq | R2 | Eq | R2 | Eq | R2 | Eq | |
F1 | 0.8942 | y = 11.392x + 10.299 | 0.9599 | y = −0.0871x + 1.9678 | 0.9677 | y = 30.459x − 2.6565 | 0.9297 | y = 78.795x + 12.312 |
F2 | 0.9242 | y = 9.7096x + 7.2996 | 0.9697 | y = −0.0651x + 1.9779 | 0.97217 | y = 25.592x − 3.1733 | 0.9455 | y = 66.616x + 9.2364 |
F3 | 0.8981 | y = 8.7721x + 7.5736 | 0.9397 | y = −0.0557x + 1.9715 | 0.96613 | y = 23.382x − 2.2916 | 0.9331 | y = 60.653x + 9.1322 |
F4 | 0.8666 | y = 12.799x + 13.598 | 0.9585 | y = −0.1142x + 1.9584 | 0.96266 | y = 34.668x − 1.6512 | 0.9083 | y = 88.879x + 15.715 |
F5 | 0.8909 | y = 11.509x + 11.037 | 0.9598 | y = −0.0896x + 1.9647 | 0.9711 | y = 30.881x − 2.2225 | 0.9233 | y = 79.472x + 13.123 |
F6 | 0.9121 | y = 10.658x + 8.0304 | 0.9593 | y = −0.0756x + 1.9766 | 0.9643 | y = 28.165x − 3.5793 | 0.9455 | y = 73.606x + 9.9578 |
F7 | 0.9074 | y = 11.091x + 8.5314 | 0.9578 | y = −0.0811x + 1.9756 | 0.9626 | y = 29.36x − 3.6261 | 0.943 | y = 76.696x + 10.499 |
F8 | 0.9197 | y = 9.2261x + 6.3518 | 0.9568 | y = −0.0593x + 1.9798 | 0.9626 | y = 24.259x − 3.5081 | 0.9525 | y = 63.691x + 8.0321 |
F9 | 0.9010 | y = 7.5196x + 5.2225 | 0.9277 | y = −0.0439x + 1.9804 | 0.9487 | y = 19.831x − 2.9051 | 0.9467 | y = 52.287x + 6.4384 |
Responses | Fresh | After 7 Days | After 30 Days |
---|---|---|---|
Particle size (nm) | 294.4 ± 18.243 | 296.53 ± 10.32 | 301.14 ± 9.27 |
Zeta potential (mV) | −25.76 ± 0.4737 | −25.54 ± 0.98 | −25.27 ± 1.04 |
EE% | 65.284 ± 0.366 | 64.85 ± 1.25 | 63.96 ± 1.87 |
Pharmacokinetic Parameter | QTF Lipospheres IN Suspension | QTF IN Suspension | QTF Oral Suspension | |||
---|---|---|---|---|---|---|
Plasma | Brain | Plasma | Brain | Plasma | Brain | |
Cmax (µg/mL) | 22.08 ± 10.23 | 237.86 ± 34.01 | 6.67 ± 1.37 | 132.37 ± 17.24 | 10.87 ± 0.93 | 190.14 ± 42.30 |
tmax (hr) | 6 ± 0.25 | 4 ± 0.01 | 10 ± 0.05 | 4 ± 2 | 7.33 ± 2.31 | 6 ± 0.01 |
AUC0-24hr (µg hr/g) | 133.65 ± 16.5 | 2361.04 ± 279.46 | 79.09 ± 12.52 | 1733.93 ± 182.37 | 122.65 ± 9.96 | 1098.05 ± 39.72 |
AUC0-∞ (µg hr/g) | 235.85 ± 78.53 | 2478.14 ± 291.32 | 101.64 ± 18.80 | 1778.05 ± 178.50 | 158.82 ± 23.66 | 1147.40 ± 68.09 |
MRT (hr) | 29.61 ± 10.56 | 9.41 ± 0.47 | 16.99 ± 2.64 | 9.14 ± 0.34 | 16.33 ± 5.32 | 7.42 ± 0.50 |
t1/2 (hr) | 22.07 ± 10.22 | 4.87 ± 1.19 | 8.44 ± 1.84 | 3.67 ± 0.54 | 11.32 ± 5.17 | 7.56 ± 2.82 |
DTE % | 228.36 | 169.66 | ||||
DPT % | 51.72 | 48.82 |
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Zaki, R.M.; Aldawsari, M.F.; Alossaimi, M.A.; Alzaid, S.F.; Devanathadesikan Seshadri, V.; Almurshedi, A.S.; Aldosari, B.N.; Yusif, R.M.; Sayed, O.M. Brain Targeting of Quetiapine Fumarate via Intranasal Delivery of Loaded Lipospheres: Fabrication, In-Vitro Evaluation, Optimization, and In-Vivo Assessment. Pharmaceuticals 2022, 15, 1083. https://doi.org/10.3390/ph15091083
Zaki RM, Aldawsari MF, Alossaimi MA, Alzaid SF, Devanathadesikan Seshadri V, Almurshedi AS, Aldosari BN, Yusif RM, Sayed OM. Brain Targeting of Quetiapine Fumarate via Intranasal Delivery of Loaded Lipospheres: Fabrication, In-Vitro Evaluation, Optimization, and In-Vivo Assessment. Pharmaceuticals. 2022; 15(9):1083. https://doi.org/10.3390/ph15091083
Chicago/Turabian StyleZaki, Randa Mohammed, Mohammed F. Aldawsari, Manal A. Alossaimi, Shaikah F. Alzaid, Vidya Devanathadesikan Seshadri, Alanood S. Almurshedi, Basmah Nasser Aldosari, Rehab Mohammad Yusif, and Ossama M. Sayed. 2022. "Brain Targeting of Quetiapine Fumarate via Intranasal Delivery of Loaded Lipospheres: Fabrication, In-Vitro Evaluation, Optimization, and In-Vivo Assessment" Pharmaceuticals 15, no. 9: 1083. https://doi.org/10.3390/ph15091083