Influence of Molecular Structure and Physicochemical Properties of Immunosuppressive Drugs on Micelle Formulation Characteristics and Cutaneous Delivery
Abstract
:1. Introduction
Sirolimus | Pimecrolimus | Tacrolimus | |
---|---|---|---|
Physicochemical properties | |||
Molecular weight (g/mol) * | 914.2 | 810.4 | 804.0 |
logP * | 4.17 | 4.31 | 3.23 |
Aqueous solubility ** | Poor | Poor | Poor |
Ionizable | No | No | No |
Mechanism of action | |||
Inhibitor of mTOR target [13] | Inhibitor of calcineurin target [14] | Inhibitor of calcineurin target [14] | |
Indications | |||
Oral Topical | Graft rejection Facial angiofibromas (off-label) [15,16], Psoriasis (off-label) [17] | - Atopic dermatitis, Psoriasis (off-label) [18] | Graft rejection Atopic dermatitis, Psoriasis (off-label) [19] |
2. Materials and Methods
2.1. Materials
2.2. Analytical Methods
2.2.1. Quantification by UHPLC-UV
2.2.2. Quantification with UHPLC-MS/MS
2.3. Preparation of the Micelle Formulation
2.3.1. Thin-Film Hydration Method
2.3.2. Optimization of Drug and Polymer Content
2.4. Characterization of Micelle Formulations
2.4.1. Drug Solubility in Water and Aqueous Solutions of TPGS
2.4.2. Thermal Properties
2.4.3. Size and Morphology Characterization
2.4.4. Drug Content Determination
2.4.5. Stability
2.4.6. In Vitro Drug Release from the Micelles
2.5. Evaluation of Skin Delivery In Vitro
2.5.1. Porcine Skin Preparation
2.5.2. Drug Delivery under Infinite Dose Conditions
2.5.3. Investigation of Drug Biodistribution Profile
2.5.4. Data Analysis
3. Results
3.1. Development of Micelle Formulations
3.1.1. Drug Solubility in Water and in Aqueous Solutions of TPGS
3.1.2. Optimization and Characterization of Micelle Formulation
3.1.3. DSC Analysis
3.1.4. Drug Release Kinetics from the Micelles
3.2. Skin Delivery from Micelle Formulations 0.2% under Infinite Dose Conditions
4. Discussion
4.1. Development of Micelle Formulations
4.1.1. Aqueous Solubility of the Drugs
4.1.2. Micelle Formulations Characterization
4.1.3. In Vitro Drug Release Profile
4.2. In Vitro Skin Delivery
4.3. Summary of the Comparative Studies
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Parameters | SIR | PIM | TAC |
---|---|---|---|
Column | C8 2.5 μm, 2.1 × 50 mm | C18 2.5 μm, 2.1 × 100 mm | C18 2.5 μm, 2.1 × 100 mm |
Mobile phase | (a) ACN and (b) Milli-Q water + 0.003% TFA (85:15 v/v) | (a) ACN and (b) Milli-Q water + 0.1% FA (95:5 v/v) | (a) ACN and (b) Milli-Q water + 0.1% FA (95:5 v/v) |
Column temperature (°C) | 45 | 45 | 45 |
Flow (mL/min) | 0.5 | 0.5 | 0.5 |
Volume of injection (µL) | 5 | 5 | 5 |
Wavelength (nm) | 278 | 210 | 210 |
Retention time (min) | 0.48 | 0.80 | 0.66 |
Limit of quantification (µg/mL) Limit of detection (µg/mL) | 3.0 1.0 | 5.0 1.6 | 2.0 0.7 |
Parameters | SIR | SIR-D3 | PIM | TAC |
---|---|---|---|---|
Nature of parent ion | [M − H]− | [M − H]− | [M + NH4]+ | [M + NH4]+ |
Parent ion (m/z) | 912.67 | 915.65 | 832.50 | 826.60 |
Daughter ion (m/z) | 590.42 | 321.21 | 593.44 | 616.20 |
Collision energy (V) | 36 | 40 | 30 | 40 |
Cone voltage (V) | 60 | 52 | 60 | 50 |
Capillary voltage (kV) | 3.6 | 3.0 | ||
Source temperature (°C) | 150 | 150 | ||
Desolvation temperature (°C) | 500 | 500 | ||
Desolvation gas flow (L/h) | 1000 | 850 | ||
Cone gas flow (L/h) | 0 | 0 | ||
LM resolution 1 | 2.96 | 2.96 | ||
HM resolution 1 | 15.00 | 15.00 | ||
Ion energy 1 (V) | 0.3 | 0.3 | ||
LM resolution 2 | 2.91 | 2.91 | ||
HM resolution 2 | 15.24 | 15.24 | ||
Ion energy 2 (V) | 0.6 | 0.6 | ||
Limit of quantification (ng/mL) | 3.0 | / | 3.0 | 3.0 |
Limit of detection (ng/mL) | 1.0 | / | 1.0 | 1.0 |
Water | At TPGS Concentration (33 mM or 50 mg/mL) | Increase in Solubility | ||
---|---|---|---|---|
Drug solubility (µM) | SIR | 8.24 ± 0.22 | 1214.10 ± 123.50 | 147× |
PIM | 0.17 ± 0.02 | 330.32 ± 31.22 | 1943× | |
TAC | 0.20 ± 0.05 | 636.74 ± 73.45 | 3184× |
Formulation | |||||||||
---|---|---|---|---|---|---|---|---|---|
Target TPGS Content (mg/mL) | Target Drug Content (mg/mL) | Target Drug Loading (mgDRUG/gTPGS) | Drug Loading (mgDRUG/gTPGS) | Incorporation Efficiency (%) | |||||
SIR | PIM | TAC | SIR | PIM | TAC | ||||
Formulation 1 | 50 | 1.00 | 20 | 18.1 ± 0.2 | 17.2 ± 0.0 | 17.0 ± 1.0 | 90.7 ± 0.9 | 85.8 ± 0.0 | 85.1 ± 5.1 |
Formulation 2 | 50 | 1.25 | 25 | 23.3 ± 0.1 | 21.7 ± 0.0 | 23.9 ± 0.1 | 93.3 ± 0.4 | 86.7 ± 0.0 | 95.8 ± 0.5 |
Formulation 3 | 50 | 1.50 | 30 | 27.7 ± 0.8 | 25.8 ± 0.0 | 28.9 ± 1.1 | 92.2 ± 2.6 | 85.9 ± 0.0 | 96.1 ± 3.7 |
Formulation 4 | 50 | 2.00 | 40 | 37.5 ± 0.2 | 36.4 ± 0.0 | 37.6 ± 2.2 | 93.7 ± 0.6 | 91.0 ± 0.0 | 94.0 ± 5.5 |
Formulation 5 | 50 | 2.50 | 50 | 45.8 ± 0.4 | 45.1 ± 0.0 | 48.2 ± 0.0 | 91.7± 0.8 | 90.2 ± 0.0 | 96.4 ± 0.1 |
Formulation 6 | 50 | 5.00 | 100 | 88.4 ± 1.3 | 91.6 ± 0.1 | 101.0 ± 1.4 | 88.4 ± 1.3 | 91.6 ± 0.0 | 101.0 ± 1.4 |
Sirolimus | Pimecrolimus | Tacrolimus | |
---|---|---|---|
MW | *** | ** | ** |
logP | ** | *** | * |
Solubility in water | *** | * | * |
Solubility in aqueous solutions of TPGS | *** | * | ** |
Stability in micelle formulation | ** | *** | *** |
In vitro drug release | *** | * | *** |
Cutaneous drug delivery | * | *** | * |
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Quartier, J.; Lapteva, M.; Boulaguiem, Y.; Guerrier, S.; Kalia, Y.N. Influence of Molecular Structure and Physicochemical Properties of Immunosuppressive Drugs on Micelle Formulation Characteristics and Cutaneous Delivery. Pharmaceutics 2023, 15, 1278. https://doi.org/10.3390/pharmaceutics15041278
Quartier J, Lapteva M, Boulaguiem Y, Guerrier S, Kalia YN. Influence of Molecular Structure and Physicochemical Properties of Immunosuppressive Drugs on Micelle Formulation Characteristics and Cutaneous Delivery. Pharmaceutics. 2023; 15(4):1278. https://doi.org/10.3390/pharmaceutics15041278
Chicago/Turabian StyleQuartier, Julie, Maria Lapteva, Younes Boulaguiem, Stéphane Guerrier, and Yogeshvar N. Kalia. 2023. "Influence of Molecular Structure and Physicochemical Properties of Immunosuppressive Drugs on Micelle Formulation Characteristics and Cutaneous Delivery" Pharmaceutics 15, no. 4: 1278. https://doi.org/10.3390/pharmaceutics15041278
APA StyleQuartier, J., Lapteva, M., Boulaguiem, Y., Guerrier, S., & Kalia, Y. N. (2023). Influence of Molecular Structure and Physicochemical Properties of Immunosuppressive Drugs on Micelle Formulation Characteristics and Cutaneous Delivery. Pharmaceutics, 15(4), 1278. https://doi.org/10.3390/pharmaceutics15041278