Passive delivery of protein drugs through transdermal route

Figures & data

Figure 1. Physical techniques of transdermal drug delivery.

Figure 2. Different penetration pathways across the skin (the upper right corner shows the channel formed by intercellular lipid matrix).

Figure 3. Strategies for passive delivery of proteins.

Table 1. Various classes of CPEs and their mechanism of action.

Class of CPEs	Examples	Mechanism of action	Ref.
Solvents	Protic: Ethanol, propylene glycol	They alter the solubility properties of the tissue with a consequent improvement for drug distribution into the membrane. Creates a greater driving force for permeation by the rapid permeation of ethanol, or evaporative loss of volatile solvent from the donor phase forming supersaturated state.	[19]
	Aprotic: Dimethyl sulphoxide (DMSO), Dimethyl formamide (DMF), Dimethyl acetamide (DMA)	They distort the packing geometry of intercellular lipids by interacting with intercellular lipids preferably hydrophilic head groups, DMSO, in particular, has shown to alter the keratin filaments geometry from α helical to β sheet, a finding consistent in numerous results, however the exact role of conversion in permeability enhancement is yet to be understood.
Fatty acids	Oleic acid, linoleic acid and lauric acid	Induce discrete lipid domain called as pools within SC bilayer lipids which creates a change in permeability barrier of lipids thus facilitating permeation of hydrophilic molecules through the membrane.	[20]
Terpenes	Monoterpenes: Menthol, eucalyptol (1,8cineole) Sesquiterpenes: nerolidol, α-bisabolol	Change the solvent nature of the SC and hence facilitates partitioning of drug across the tissue. Drug diffusivity through the membrane is also altered consequently affecting penetration.	[21]
Surfactants	Dodecyl betaine, sodium lauryl sulphate (SLS), cetyltrimethylammonium bromide	They solubilize lipids within the SC enhancing the fluidity of the lipid layer. They get swelled at the SC and interact with intercellular keratin altering permeability characteristics.	[21]
Azones	–	They get absorbed into the bilayer lipids of the SC to destroy the packing arrangement and consequently increasing the fluidity of the lipid layer. The enhanced fluidity provides favourable environment for the transport of peptide and protein drugs.	[19]
Pyrrolidones Carbamic acid derivatives dioxolones and dioxanes derivatives called as soft enhancement of percutaneous absorption (SEPA)	N-methyl-2-pyrrolidone (NMP) and 2-pyrrolidone (2P) Transkarbam 12 SEPA 0009 (2-n-nonyl1,3-dioxolanes) (ND)	They generate “reservoirs” within skin membranes altering solvent nature of the membrane. Thus, formed reservoirs act as source of penetrant and provide opportunity for prolonged release over the period of time. The carbon dioxide released in presence of acidic pH of skin disrupts the lipid geometry. The disruption is mainly carried due to change in hydrogen bonding to polar head group of lipids and conformational change in the structure of Transkarbam 12. They reversibly alter the lipid structure of SC, thereby increasing the fluidity of membrane for permeation.	[22] [23] [24]

Figure 4. Peptide mediated transport mechanisms for transdermal permeation.

Table 2. Widely explored CPPs.

CPP	Source	Sequence of peptides	Length	Ref.
Penetratin	Protein derived from Drosophila Antennapedia homeo domain	RQIKIWFQNRRMKWKK	16	[36]
Tat	Protein from human immunodeficiency virus I	CGRKKRRQRRRPPQC	15	[37]
p-VEC	Derived from murine vascular endothelial cadherin	LLIILRRRIRKQAHAHSK-amide	18	[38]
MAP	Model peptide	KLALKLALKALKAALKLA-amide	18	[37]
Arg7	Model peptide	RRRRRRR	7	[39]
MPG	Peptide derived from fusion sequence of HIV-1 gp41 protein coupled to peptide derived from the nuclear localization sequence of SV40 T-antigen	GALFLGFLGAAGSTMGAWSQPKSKRKV	27	[40]
Transportan	Minimal active part of galanin (amino acids 1–12) coupled to mastoparan via Lys	GWTLNSAGYLLGKINLKALAALAKISIL-amide	28	[41]
SynB1	Protegrin-I	RGGRLSYSRRRFSTSTGR	18	[42]
SynB3	Protegrin-I	RRLSYSRRRF	10	[42]

Figure 5. Transport mechanism of transfersomes: (i) movement of transfersomes through adsorption mechanism and (ii) transport of transfersomes using osmotic gradient mechanism.

Figure 6. Schematic illustration of hyaluronic acid modified transfersomes for drug delivery towards lymphatics through the transdermal route.

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