Current Status of Amino Acid-Based Permeation Enhancers in Transdermal Drug Delivery
Abstract
:1. Introduction
2. Skin Structure and Skin Permeation Routes
- ♦
- Low molecular mass (<500 Da);
- ♦
- Adequate solubility in oil and water (Cv is large);
- ♦
- Moderate lipophilicity (K = 1–5, a too-large value may inhibit clearance by viable tissues);
- ♦
- Low melting point (<250 °C); melting points reflect the non-covalent interactions between drug molecules and relate to drug solubility in the SC.
3. Permeation Enhancement Strategies and Mechanisms
4. Chemical Penetration Enhancers (CPEs)
- ♦
- It should be non-toxic, non-irritating, and non-allergenic;
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- It should be specific to drug permeation without any other bioactivity;
- ♦
- It should present a rapid onset of effect, foreseeable and reproducible;
- ♦
- Its effect should be reversible when removed from the application site;
- ♦
- It should present unidirectional activity, enabling drug permeation without water loss from inner tissues;
- ♦
- It should be biocompatible with drug and excipients;
- ♦
- It should have cosmetic acceptance from consumers.
4.1. Classification of CPE
4.2. Structure-Activity Relationships
4.3. Safety of CPE
5. Amino Acid-Based Enhancers
5.1. Free Amino Acids
5.2. Non-Ionic Amphiphiles
5.3. Surfactants
5.4. Gelling Agents
5.5. Ionic Liquids
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
References
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Solvents | |
Fatty acids and alcohols | |
Lactams | |
Terpenes | |
Sugar and vitamin derivatives | |
Esters | |
Amino acid derivatives | |
Polar Head Amino Acid | Enhancer Structure | ER | Flux Rate /µg·cm−2·h−1 | Drug | Donor Conditions | Cytotoxicity | Ref | |
---|---|---|---|---|---|---|---|---|
6-(Dimethylamino)hexanoic acid | DDAK | 17.8 | 42.2 ± 14.3 | Theophylline | 5% drug in 60% PG | 75.6 ± 12.7 µM IC50—HaCaT | 175.2 ± 27.6 µM IC50—3T3 | [61] |
43.2 | 4.78 | Hydrocortisone | 2% drug in 60% PG | |||||
13.6 | 19.0 | Adefovir | 2% drug in PB pH 4.8 | |||||
- | 8.7 | Indomethacin | 2% drug in 60% PG | |||||
L-Proline | L-Pro2 | 40.0 | 70.3 ± 7.7 | Theophylline | 5% drug in 60% PG | 68.2 ± 11.5 µM IC50—HaCaT) | 182.6 ± 6.7 µM IC50—3T3 | [60] |
47.0 | 6.54 ± 0.87 | Hydrocortisone | 2% drug in 60% PG | |||||
β-Alanine | | 5.87 | 240.55 ± 21.06 | Tenofovir | 2% drug in 4 % HPMC | 80 % viability for Hep G2, MCF 7 and A549 cells, at 100 µg/mL | [81] | |
Serine | | 1.87 | 37.08 ± 1.85 | Tetracaine | 2.5% drug in 1 % HPMC and HP-β-CD | 100 % HEK cells viability at 0.14 µM | [49] | |
2.96 | 5.74 ± 0.74 | Ropivacaine | 2.5% drug in 1 % HPMC | |||||
Glycine-Histidine | Pal-GH | 7.2 | 17.7 ± 1.3 | Metronidazole | 1% drug in gel formed with 5 % enhancer | ------------------------- | [82] | |
L-Leucine | | 7.14 | 851.47 ± 69.49 | Fluorouracil | 0.5% drug in water | 177 ± 14 µM TC50—HaCaT | 387 ± 19 µM TC50—3T3 | [83] |
2.28 | 29.92 ± 5.33 | Hydrocortisone | 0.1% drug in water |
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Pereira, R.; Silva, S.G.; Pinheiro, M.; Reis, S.; Vale, M.L.d. Current Status of Amino Acid-Based Permeation Enhancers in Transdermal Drug Delivery. Membranes 2021, 11, 343. https://doi.org/10.3390/membranes11050343
Pereira R, Silva SG, Pinheiro M, Reis S, Vale MLd. Current Status of Amino Acid-Based Permeation Enhancers in Transdermal Drug Delivery. Membranes. 2021; 11(5):343. https://doi.org/10.3390/membranes11050343
Chicago/Turabian StylePereira, Rui, Sandra G. Silva, Marina Pinheiro, Salette Reis, and M. Luísa do Vale. 2021. "Current Status of Amino Acid-Based Permeation Enhancers in Transdermal Drug Delivery" Membranes 11, no. 5: 343. https://doi.org/10.3390/membranes11050343