Breaking Through, Part II: Chemical Ingredient Delivery*

*Adapted with permission from M Rule, K Saliesh, T Haw-Yueh, H Zhai and HI Maibach, Percutaneous penetration enhancers: An Overview, in Handbook of Cosmetic Science and Technology, 4th edn, CRC Press, Boca Raton, FL (2014) pp 141–156

Biochemical means of penetration enhancement include the use of pro-drug molecules,¹ chemical modification,² enzyme inhibition,³ and vesicular systems or colloidal particles.⁴ While the previous column discussed physical means for the active and passive delivery of chemicals through skin, this installment focuses on examples of chemical approaches, which are gaining acceptance for the delivery of chemicals into skin.

Colloidal Particles

Among the various chemical strategies used, special formulation approaches—based mainly on the usage of colloidal carriers—are perhaps the most promising. Liposomes, i.e., phospholipid-based artificial vesicles, and niosomes, which are nonionic surfactant vesicles, are widely used to enhance drug delivery across skin. In addition, proliposomes and proniosomes, which are converted to liposomes and niosomes upon hydration, are also used in transdermal drug delivery.⁵

Generally, these colloidal carriers are not expected to penetrate into viable skin. Most reports cite a localizing effect, whereby the carriers accumulate in the stratum corneum (SC) or other upper skin layers. However, a new type of liposome, called a transferosome, has been introduced, which is believed to penetrate deeper and intact.^{6, 7}

Transferosomes: Transferosomes consist of phospholipids, cholesterol and additional “edge activators”—i.e., surfactant molecules such as sodium cholate. Transferosome inventors state that 200–300 nm transferosomes are ultra-deformable and squeeze through pores less than one-tenth of their diameter, and are thus able to penetrate intact into skin. The penetration of these colloidal particles works best under in vivo conditions and requires a hydration gradient from the skin surface toward the viable tissues to encourage skin penetration under non-occluded conditions.

Ethosomes: In addition, ethosomes, which are liposomes high in ethanol content (up to 45%), penetrate skin and enhance compound delivery into deep skin strata or even systematically. Their suggested mechanism is that ethanol fluidizes both ethosomal lipids and lipid bilayers in the SC, allowing the soft, malleable vesicles to penetrate through the disorganized lipid bilayers.⁸

Surfactant interactions: In recent years, new information on the interactions between surfactants and the skin has been reported, which explains their utility in these delivery systems. Once a surfactant contacts the skin, it binds to the skin’s deeper proteins by denaturing the surface proteins, causing the stratum corneum to swell. This disorganizes the intercellular lipids of the skin—i.e., the fluid lipids and removal of the calcium ions or surrounding ions, causing a reduction of corneocyte adhesion—leading to accessibility of deeper proteins.⁹

Mechanisms of action: Six potential mechanisms of action for colloidal carriers have been proposed:¹⁰

1. Penetration by a free drug process—i.e., the drug releases from the vesicle then penetrates skin independently;
2. Penetration of the SC by intact liposomes;
3. Enhancement due to the release of lipids from carriers and interaction with the SC lipids;
4. Improved drug uptake by skin;
5. Different enhancement efficiencies to control drug input; and
6. The role of protein, which requires elaboration.

Once a surfactant contacts skin, it binds to deeper proteins by denaturing surface proteins, causing the SC to swell.

Chemical Penetration Enhancers

Substances that help promote drug diffusion through the SC and epidermis are referred to as penetration enhancers (PEs), accelerants, adjuvants or sorption promoters.¹¹ PEs have been extensively studied given their advantages, such as design flexibility with formulation chemistry and patch application over large areas. PEs improve drug transport by reducing the resistance of the SC to drug permeation. To date, no existing chemical penetration enhancer has proven to be perfect.

In particular, the efficacy of PEs toward the delivery of high-molecular weight drugs remains limited. Attempts to improve enhancement by increasing the potency of enhancers inevitably lead to compromised safety; indeed, achieving sufficient potency without irritancy has proven challenging.

Nano-structured lipid carriers, nanoemulsions and oil solutions are receiving increased attention for advantages such as ease of manufacturing, thermodynamic stability, enhanced drug solubilization and increased drug permeation rate.¹²

For example, Tsai and colleagues created a hesperetin-carrying microemulsion that showed improved permeation in comparison to non-microemulsion aqueous solutions.¹²A similar oil-based nano-carrier system of ropinirole, used to treat Parkinson’s Disease, was found to have good pharmacokinetic features, with potential to replace oral dosage forms; it also showed sufficient manipulation of the stratum corneum barrier.¹³

The solubility of microemulsions and nanoemulsions is the reason for their increased permeation for improved drug delivery. This is due to the partitioning of the drug between the internal oil phase and external aqueous phase.¹⁴ An increase in drug solubility within the external phase will progress the partitioning effect from the internal to the external phase; thus, the drug will be able to diffuse easier to be discharged.¹⁴

In relation, emulsifiers can explain increased skin permeation due to enhanced partitioning of the actives into skin.¹⁵ Micelles and liquid crystalline phases affect the solubility properties of active ingredients, in turn changing their thermodynamic movement.¹⁵ Otto confirmed that emulsifiers arranged in liquid crystalline structures in the water phase enhanced the skin penetration of active ingredients.¹⁵

Interestingly, a recent study by Degim found that multi- and double-walled carbon nanotubules also have permeation effects, similar to drug carriers.¹⁶ While their penetration enhancement is through absorption and subsequent desorption, i.e., a depot effect, the carbon nanotubules did not penetrate the skin. However, Degim gave the nanotubules a high loading to enhance the transdermal penetration of especially hydrophobic drugs.¹⁶

Additional information has been published on the advantages of nanostructured lipid carriers. Using idbenone (IDB), a comparative study was made between nanostructured lipid carriers (NLCs), nano-emulsions and oil solutions in order to determine which improved chemical stability and enhanced skin delivery. NLCs significantly improved the chemical stability of IDB, as well as skin permeation and formulation stability, compared with NE and oil solution.¹⁷

The increasing understanding of mechanisms of penetration should accelerate the development of passive and active enhancers for use with active cosmetic ingredients.

NLCs will continue to progress in the transdermal field and can effectively be used as carriers for topical drugs. For instance, a chemical complex of arginine and chitosan was formed to see what value it may hold as a penetration enhancer for the drug adefovir—an acyclic nucleoside phosphonate used as a broad-spectrum antiviral that is highly effective against herpes-, retro- and hepadviruses.¹⁸ Here, N-arginine chitosan (N-Arg-CS) proved its potential as a novel transdermal enhancer,¹⁸ offering an alternative method to disrupt the molecular protein side-chains within the stratum corneum, in turn creating specific methods for enhancement.

Conclusion

All in all, the increasing understanding of mechanisms of penetration, along with widespread use of penetration enhancers, should accelerate the development of both passive and active—physical and chemical—enhancers for use with active cosmetic ingredients.

For more on this subject, the Dragicevic textbooks referenced provide detailed summaries of this rapidly expanding literature.^19–23

References

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2. A Boucaud et al, Effect of sonication parameters on transdermal delivery of insulin to hairless rats, J Control Release 81 (1–2) 113–119 (2002)
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6. K Morimoto et al, Effects of proteolytic enzyme inhibitors on enhancement of transdermal iontophoretic delivery of vasopressin and analogue in rats, Int J Pharm 81 119 (1992)
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9. MD Planas et al, Noninvasive percutaneous induction of topical analgesia by a new type of drug carrier and prolongation of local pain insensitivity by anesthetic liposomes, Anesth Analg 75 615–621 (1992)
10. BW Barry, Novel mechanisms and devices to enable successful transdermal drug delivery, Eur JPharm Sci 14 101–104 (2001)
11. G Cevc, Transfersomes, liposomes and other lipid suspensions on the skin: Permeation enhancement, vesicle penetration and transdermal drug delivery, Crit Rev Ther Drug Career Syst 13 257–388 (1996)
12. E Touiton et al, Ethosomes-novel vesicular carriers for enhanced delivery: characterization and skin penetration properties, J Control Rel 65 403–418 (2000)
13. Som et al, Status of surfactants as penetration enhancers in transdermal drug delivery, J Pharm Bioallied Sci 4(1) 2–9 (2012)
14. WR Pfister, S Dean and ST Hsieh, Permeation enhancers compatible with transdermal drug delivery systems. I, Selection and formulation considerations, Pharm Tech 8 132 (1990)
15. Tsai et al, In vitro permeation and in vivo whitening effect of topical hesperetin microemulsion delivery system, Int J Pharm 388 1–2 257–62 (2010)
16. Azeem et al, Oil based nanocarrier system for transdermal delivery of ropinirole: A mechanistic, pharmacokinetic and biochemical investigation, Int J Pharm 422 1–2 436–44 (2012)
17. Abdullah et al, In vitro permeation and in vivo anti-inflammatory and analgesic properties of nanoscaled emulsions containing ibuprofen for topical delivery, Int J Nanomedicine 6 387–96 (2011)
18. Otto et al, Effect of emulsifiers and their liquid crystalline structures in emulsions on dermal and transdermal delivery of hydroquinone, salicylic acid and octadecenedioic acid, Skin Pharmacol Physiol 23 5 273–82 (2010)
19. N Dragicevic and HI Maibach, Percutaneous penetration enhancers, chemical methods, in Penetration Enhancement: Modification of the Stratum Corneum, vol 1, Springer, Berlin (2016)
20. N Dragicevic and HI Maibach, Percutaneous penetration enhancers, chemical methods in Penetration Enhancement: Drug Manipulation Strategies and Vehicle Effects, vol 2, Berlin, Springer (2016)
21. N Dragicevic and HI Maibach, Percutaneous penetration enhancers, chemical methods, in Penetration Enhancement: Nanocarriers, vol 3, Springer, Berlin (2016)
22. N Dragicevic and HI Maibach, Percutaneous penetration enhancers, chemical methods, in Penetration Enhancement, vol 4, Springer, Berlin (2016)
23. N Dragicevic and HI Maibach, Percutaneous penetration enhancers, chemical methods, in Penetration Enhancement, vol 5, Springer, Berlin (2016)