Lipid-Based Nanocarriers for Ophthalmic Administration: Towards Experimental Design Implementation
Abstract
:1. Introduction
2. Overcoming Ophthalmic Barriers with Lipid-Based Nanocarriers
2.1. Ocular Anatomy and Drug Delivery Approaches
2.2. Improving Drug Access to Ocular Structures with Lipid-Based Nanocarriers
3. Optimising the Outcomes: Statistical Design of Experiments (DoE)
3.1. Quality by Design (QbD)
3.2. Design of Experiments (DoE)
3.3. Two-Level Factorial Designs
3.4. Plackett–Burman Designs
3.5. Optimisation Designs
3.5.1. Three-Level Factorial Designs
3.5.2. Central Composite Designs (CCDs)
3.5.3. Box–Behnken Designs (BBDs)
3.6. Other Experimental Designs
3.7. Data Analysis and Model Application
4. Conclusions and Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Loaded Agent | Pre-Experimental Studies | Independent Variables | Dependent Variables | Improved Formulation (±SD) | Ref. |
---|---|---|---|---|---|
Dexamethasone | Drug-excipient solubility screening Matrix crystallinity studies (DSC, XRD) | Dexamethasone (% w/w) Surfactant (% w/w) Lipid (% w/w) | Size PDI ZP %EE | Size: 92.18 ± 0.49 nm PDI: 0.12 ± 0.02 ZP: −7.62 ± 0.26 mV %EE: 88.31% | [113] |
Dexamethasone | Data obtained in [113] employed | Dexamethasone (% w/w) Surfactant (% w/w) Mucoadhesive polymer (% w/w) | Size PDI ZP %EE d(0.5) Span value | Size: 200.70 ± 7.63 nm PDI: 0.34 ± 0.039 ZP: −7.4 ± 0.1 mV %EE: 86.94% d(0.5): 0.122 Span value: 1.416 | [114] |
Flurbiprofen | Lipid solubility screening Matrix crystallinity studies (DSC) | Flurbiprofen (% w/w) Tween® 80 (% w/w) Stearic acid (% w/w) regarding total lipid Storage temperature (°C) | Size PDI ZP | Size: 288 ± 10.6 nm PDI: 0.245 ± 0.013 ZP: −29.0 ± 0.557 mV Storage temp.: 25 °C %EE: 92.76 ± 2.54% | [107] |
Particle Type | Loaded Agent | Pre-Formulation Studies | Independent Variables | Dependent Variables | Optimal Formulation (±SD) | Ref. |
---|---|---|---|---|---|---|
Cationic SLN | Methazolamide | Drug solubility assay in heterolipid mixtures (data not shown) | Cetostearyl-alcohol-to-glycerol-behenate ratio (% w/w) Tween® 80 (% w/w) | Size PDI ZP %EE | Size: 207.1 ± 6.45 nm PDI: 0.243 ZP: 41.50 ± 0.33 mV EE%: 25.62 ± 0.89% | [120] |
Lipid nano-Particle (w/o/w) | N/a | N/a | Softisan® 100 (% w/w) Lipoid S75 (% w/w) Poloxamer 188 (% w/w) | Size PDI ZP | Size (0.5% CTAB): 194.4 ± 0.43 nm PDI: 0.185 ± 0.02 ZP: +37.20 ± 1.27 mV | [121] |
Nano-emulsion | Brimonidine tartrate | Excipient FT-IR, DSC and XRD studies | Castor oil (% w/w) Lipoid-S75-to-Lipoid-E80 ratio (% w/w) Pluronic® F68 a (% w/w) | Size PDI %EE | Size: 272.7 nm PDI: 0.270 %EE: 79.25 ± 2.85% | [122] |
SLN (in situ gel) | Bimatoprost | Lipid with a melting point about 50–55 °C selection | Glyceryl monostearate (mg) Tween® 80 (% w/w) | Size PDI ZP %EE | Size: 148.4 ± 1.25 nm PDI: 0.156 ± 0.04 ZP: −19.3 ± 1.40 mV EE%: 83.5 ± 0.27% | [123] |
Particle Type | Loaded Agent | Pre-Formulation Studies | Independent Variables | Dependent Variables | Optimal Formulation (±SD) | Remarks | Ref. |
---|---|---|---|---|---|---|---|
SLN | Atorvastatin | ·Surfactant- and solvent-pre-screening studies ·Initial formulation trials for factor level and process parameters selection | Set at 3 levels: Poloxamer-188-to-PEG-400 ratio ·Compritol®-888-ATO-to-Phospholipon®-90H ratio | Size %EE | Size: 256.3 ± 10.5 nm PDI: 0.26 ± 0.02 %EE: 73.1 ± 1.52% | ·Improved drug stability Ocular safety Increased ex vivo corneal permeability vs. drug suspension | [125] |
NLC | Flurbiprofen | Lipid-screening tests Selection of critical variables affecting the response | Set at 5 levels: Oil concentration in the total lipid phase (%) Tween® 80 (%) Flurbiprofen (%) | Size PDI %EE 90%LD | Size: 228.3 ± 4.2 nm PDI: 0.156 ± 0.017 %EE: 89.4 ± 0.7% 90%LD: 0.303 ± 0.098 μm | ·Sustained release (Korsmeyer–Peppas model) In vivo ocular safety | [126] |
NLC-based hydrogel | Flurbiprofen | Already performed in [126] | Set at 5 levels: ·Oil concentration in the lipid phase (% w/w) ·Tween® 80 (% w/w) ·Flurbiprofen (% w/w) | Size PDI ZP %EE Destabilisation time | ·Size: ≤199 ± 0.003 nm ·PDI: 0.152 ± 0.017 ·ZP: −23.0± 0.569 mV ·%EE: 88.7± 0.6% | In vivo ocular safety Increased ex vivo corneal permeability vs. flurbiprofen solution | [127] |
NLC | Triamcinolone acetonide | ·Lipid-screening tests ·Process parameter evaluation through preliminary experiments | Set at 5 levels: ·Lipid phase (%) ·Precirol® ATO 5 in the lipid phase (%) ·Lutrol® F68 a (%) ·Triamcinolone acetonide (%) | Size PDI ZP %EE | ·Size < 200 nm ·PDI: ∼0.1 ·ZP: ∼ −45 mV ·%EE: ∼95% | ·Spherical nanoparticle shape ·In vivo ocular safety | [128] |
NLC | Curcumin | ·Lipid screening for drug solubility and stability | Set at 3 levels: ·Poloxamer 188 (%) ·Vitamin E TPGS b (%) ·Olive oil (%) Set at 2 levels (categorical): ·Homogenisation (rpm) ·Sonication time (min) | Size PDI | ·Size: 66.8 ± 2 nm ·PDI: 0.17 ± 0.05 ·%EE: 96 ± 1.6% ·Drug loading: 3.1 ± 0.05% | Improved curcumin stability ·Increased ex vivo corneal permeability vs. curcumin suspension | [106] |
NLC-based hydrogel | Quercetin | ·Preliminary tests for critical factor detection ·Excipient DSC studies | Set at 5 levels: ·Quercetin (% w/v) ·Oil (% w/v) ·Cremophor EL (% w/v) | Size PDI %EE | ·Size: ∼75.54 nm ·PDI: ∼0.180 ·%EE: ∼97.14% | Adequate sol-gel transition (<35 °C; pH 7.4) ·Sustained release of ∼80% quercetin over three days of the NLC-based hydrogel (carboxymethyl chitosan/Poloxamer 407) | [130] |
Particle Type | Loaded Agent | Pre-Formulation Studies | Independent Variables | Dependent Variables | Optimal Formulation (±SD) | Desirability Index | Ref. |
---|---|---|---|---|---|---|---|
NLC | Ibuprofen | ·Lipid- and surfactant-screening studies Plackett–Burman design | ·Surfactant (% w/w) ·Lipid (% w/w) ·Ratio of surfactants | Size PDI ZP EE% | Size: ∼147 nm PDI: ∼0.159 ZP: ∼−25.7 mV EE%: ∼97.89% | Not reported | [116] |
Cationic NLC | Besifloxacin and rhodamine B | ·Initial trials for excipient nature and concentration selection | ·Gelucire® 50/13 (mg/mL) ·Compritol® 888 ATO (mg/mL) ·Labrafac® PG (µL/mL) | Size PDI ZP | Size: ∼173.6 nm PDI: ∼0.188 ZP: ∼16.6 mV EE%: ~80% | 0.278 Maximise ZP Minimise PS Minimise PDI | [134] |
PEGylated NLC | Amphotericin B | ·Lipid- and PEG-screening tests | ·DSPE-PEG−2000 a (% w/v) ·Amphotericin B (% w/v) ·Castor oil (% w/v) ·Cycles of HPH | Size PDI ZP EE% Drug loading | Size: 218 ± 5 nm PDI: 0.3 ± 0.02 EE%: 92.7 ± 2.5% Drug loading: 4.6 ± 0.1 | 0.9 Maximise EE% Maximise drug loading | [135] |
Pegylated NLC | Natamycin | Lipid = screening study | ·Castor oil (% w/v) ·Precirol® ATO 5 (% w/v) ·Span 80 (% w/v) HPH time (min) | Size ZP EE% Drug loading % | Size: ∼241 nm PDI: ∼0.406 %EE: ∼95.35 Drug loading: ∼6.5% | 0.9835 PS < 300 nm Minimise PDI · Maximise %EE · Maximise drug loading | [136] |
SLN | Natamycin | ·Lipid and surfactant solubility screening · Initial trials for factor-level selection | ·Precirol® ATO 5 (% w/w) ·Pluronic® F68 (% w/w) ·Sonication frequency (kHz) | Size ZP %EE | Size: ∼42 nm ZP: ∼26 mV EE%: ~85% | 0.953 ZP = 25–35 mV Minimise PS Maximise %EE | [137] |
SLN | Levofloxacin | ·Solubility screening in solvents and lipids ·Initial trials for factor-level selection | ·Stearic acid (% w/w) ·Tween® 80 (% w/w) ·Sodium deoxycholate (% w/w) | Size %EE | Size: ∼237.82 nm PDI: ∼0.251 EE%: ∼78.71% | Not reported | [138] |
SLN | Gatifloxacin | Not reported | ·Stearic acid and Compritol® 888 ATO mixture (% w/w) ·Poloxamer 188 (% w/w) ·Sodium taurocholate and Transcutol® P mixture (% w/w) | Size EE% % Drug released | Size: 251.4 ± 7.4 nm PDI: 0.338 ± 0.11 ZP: +29.5 ± 2.8 mV EE%: 78.55 ± 3.41 % Drug released: 84.24 ± 2.9 | Not reported | [139] |
·Stearic acid and Gelucire® 50/13 mixture (% w/w) ·Poloxamer 188 (% w/w) ·Sodium taurocholate and ethanol mixture (% w/w) | Size EE% % Drug released | Size: 297.2 ± 8.5 nm PDI: 0.268 ± 0.09 ZP: +30 ± 3.2 mV EE%: 46.58 ± 2.25 % Drug released: 79.23 ± 2.5 |
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González-Fernández, F.M.; Bianchera, A.; Gasco, P.; Nicoli, S.; Pescina, S. Lipid-Based Nanocarriers for Ophthalmic Administration: Towards Experimental Design Implementation. Pharmaceutics 2021, 13, 447. https://doi.org/10.3390/pharmaceutics13040447
González-Fernández FM, Bianchera A, Gasco P, Nicoli S, Pescina S. Lipid-Based Nanocarriers for Ophthalmic Administration: Towards Experimental Design Implementation. Pharmaceutics. 2021; 13(4):447. https://doi.org/10.3390/pharmaceutics13040447
Chicago/Turabian StyleGonzález-Fernández, Felipe M., Annalisa Bianchera, Paolo Gasco, Sara Nicoli, and Silvia Pescina. 2021. "Lipid-Based Nanocarriers for Ophthalmic Administration: Towards Experimental Design Implementation" Pharmaceutics 13, no. 4: 447. https://doi.org/10.3390/pharmaceutics13040447
APA StyleGonzález-Fernández, F. M., Bianchera, A., Gasco, P., Nicoli, S., & Pescina, S. (2021). Lipid-Based Nanocarriers for Ophthalmic Administration: Towards Experimental Design Implementation. Pharmaceutics, 13(4), 447. https://doi.org/10.3390/pharmaceutics13040447