The Challenge of Nanovesicles for Selective Topical Delivery for Acne Treatment: Enhancing Absorption Whilst Avoiding Toxicity

Figures & data

Table 1 Examples of the Most Commonly Prescribed Topical Acne Treatments

Molecule	Trademarks	Pharmaceutical Class	Side Effects
Benzoyl peroxide	Benzac^® Clean Gel; Panoxyl^®	Antimicrobial	Redness, desquamation, bleaches hair and clothes
Clindamycin	Dalacin-T^®; Zindaclin^® Treclin^® (combined with tretinoin)	Antibiotic	Resistance overgrowth of Gram-negative bacteria, irritation, itching
Erythromycin	Eryacne^® Zineryt^® (combined with zinc acetate)	Antibiotic	Resistance and overgrowth of Gram-negative bacteria
Clindamycin + benzoyl peroxide	BenzaClin^®; Duac^® Acanya^®	Antibiotic + Antimicrobial	Resistance, redness, desquamation
Erythromycin + benzoyl peroxide	Benzamycin^TM	Antibiotic + Antimicrobial	Resistance, redness, desquamation
Dapsone	Aczone^®	Antibiotic/anti-inflammatory	Dryness, erythema
Azelaic acid	Finacea^®	Antimicrobial	Burning, stinging and tightness of the skin
Tretinoin	Avita^®; Retin-A^®, Ketrel^®	Retinoid	Erythema, scaling, burning, flare
Terazotene	Zorac^®	Retinoid	Erythema, scaling, burning, flare
Adapalene	Differin^®, Tactuo^TM, Epiduo^TM (combined with benzoyl peroxide)	Retinoid	Irritation, erythema, peeling, dryness

Figure 1 Schematic representation of the advantages of nanomedicine in acne treatment compared to conventional therapies.

Figure 2 Schematic representation of liposomes and liposomal-like vesicles.

Table 2 Summary of the Main Features of Nanovesicles in Use or Under Development for Acne Treatment

Nanocarriers	Composition/Description	Advantages	Disadvantages	Some Delivered Anti-Acne Active Ingredients
Liposomes^Citation24–Citation26,Citation28–Citation30,Citation34–Citation38,Citation40–Citation43,Citation50	Spherical vesicles, characterized by a phospholipid bilayer (made of dipalmitoyl phosphatidylcholine, hydrogenated soya lecithin, fatty alcohol polyglycol ether, cholesterol, dicetylphosphate) and an aqueous core	Controlled drug release; decreased skin irritation; reduced side effects of free drug; formulation versatility; increased drug solubilization; drug protection from light and oxygen	Poor stability due to lipid peroxidation and accumulation in the upper skin layers; limited permeation through skin	Clindamycin; retinoic acid; benzoyl peroxide; tea tree oil
Niosomes^Citation22,Citation44–Citation48,Citation50,Citation51	Vesicles containing non-ionic surfactant bilayer (such as cetyl alcohol, decyl glucoside, Brij, polysorbates, spans, poloxamers, alkyl polyglucoside surfactants) enclosing an aqueous cavity	Greater vesicle stability; non-toxic nature and lower cost than liposomes; improved drug permeation through the stratum corneum and higher skin retention	Inability to reach the deeper skin layers	Retinoic acid; terazotene
Etho^Citation30,Citation50,Citation52–Citation55,Citation69^–^Citation72	Elastic nanosystems containing phospholipids, high amount of ethanol, and water	Excellent flexibility; ability to passage through stratum corneum; high loading capacity for lipophilic drugs; relatively simple and inexpensive to manufacture	Skin irritation due to high concentration of alcohol and poor skin penetration	Azelaic acid
Ultraderformable vesicles^Citation18,Citation49,Citation52,Citation56–Citation62,Citation64–-^Citation68	Deformable vesicles due to the presence of edge activator (such as sodium cholate, sodium deoxycholate, Span 80, Tween 80 and dipotassium glycyrrhizinate)	High deformability; ability to destabilize skin lipid organization; increased permeation into the deeper skin layers	Mechanism of action is still not clear; conflicting information on their ability to reach the systemic circulation	Adapalene; benzoyl peroxide; retinoic acid; photosensitizer
LeciPlex^Citation31,Citation73	Vesicular nanocarrier containing a combination of phospholipids and cationic surfactants (such as didodecyldimethyl ammonium bromide, cetyltrimethylammonium bromide)	Enhanced skin deposition	Few studies on human skin have been performed	Azelaic acid
Invasomes^Citation31,Citation50,Citation52,Citation73	Flexible carriers made of phosphatidylcholine, terpenes (such as limonene, cineole, fenchone, citral) and ethanol	Enhanced drug percutaneous permeation, thus guaranteeing faster activity	Irritation and toxicity may occur as a function of the used penetration enhancers. Mechanism of skin permeation not completely clear; few available studies	Dapsone; azelaic acid; curcumin

Note: Data from references.^{6,11,13,18,30,62}

Figure 3 Topical treatment using liposomes or deformable vesicles. Both the carriers are able to deliver hydrophobic and hydrophilic compounds.

Figure 4 Confocal laser scanning micrographs of the interaction between ultradeformable vesicles labeled with rhodamine and Colo-38 cells using: (A) Hoechst filter and (B) TRITC filter; and (C) superimposition of figures. Reprinted with permission from Cosco D, Paolino D, Maiuolo J, et al. Ultradeformable liposomes as multidrug carrier of resveratrol and 5-fluorouracil for their topical delivery. Int J Pharm. 2015;489(1–2):1–10. Copyright © 2015 with permission from Elsevier Ltd.⁵⁶

Figure 5 Representation of a generic ethosomal formulation using freeze–fracture electron microscopy. Reprinted with permission from Paolino D, Lucania G, Mardente D, Alhaique F, Fresta M. Ethosomes for skin delivery of ammonium glycyrrhizinate: In vitro percutaneous permeation through human skin and in vivo anti-inflammatory activity on human volunteers. J Control Release. 2005;106(1–2):99–110. Copyright © 2005 with permission from Elsevier Ltd.⁷⁰

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