Skin Penetration Enhancers

1) Solvents - H2O - Alkyl Esters - Dimethyl Sulfoxide (DMSO) - Dimethyl Acetamide, DMFormamide (DMA and DMF) - Azone - Pyrrolidone Derivatives

2) Fatty Acids3) Surfactant4) Terpenes5) Phospholipids (liposomes)

Solvents1) H2O (most natural P.E)

- At normal relative humidity (RH), water content of S.C is 15-20 %, soaking or occlusion can increase H2O content up to 300-400 %.

- Mechanism:

1)H2O can act as plasticizer increase elasticity and permeability of the skin.2) Swelling and softening S.C develops multiple folds 37% in SA.3) Aqeous solvation of intercellular lipids

diffusion coefficient.

Solvents (H2O)

• It’s anticipated polar cmp. would have greater solubility relative to non polar cmp. in hydrated S.C than dehydrated S.C, so the effect of H2O is mainly on the polar drugs.

Effect of hydration on the percutaneous absorption of glycol slicylate

Table 1. Effect of hydration on the in vivo penetration of salicylate

derivatives (esters) Ethyl Salicylate

Methyl Salicylate

Glycol Salicylate

Relative urinary exc. rate

2.0 3.2 9.0

Water solubility 0.03 0.08 1.27

PC 1170 343 7.7

Solvents (H2O)

• We noticed that S.C hydration aided the absorption of glycol salicylate more than methyl or ethyl salicylate which is consistent with such anticipation

• How Hydration of S.C can be achieved:1) Soaking, but not practical.2) Occlusion with plastic film3) Vehicle effect:- Fats and oils decrease water loss because they are

impermeable (ointment, w/o emulsion)- Humectants (glycerol, propylene glycol, sorbitol) at low

RH may withdrew H2O from skin- Ethanol may dry S.C- Powders SA for H2O evaporation

Solvents (H2O)

Solvents

2) Alkyl Esters:• Examples: Ethyl acetate and Propyl acetate

• Mechanism: Unclear, some evidence suggests they might extract lipids from S.C leading to in the diffusion resistance.

- Considered as safe penetration enhancers by the FDA

• Problems1) More volatile than ethanol, accordingly, packing design should be

directed to prevent evaporation upon storage and application.2) Hydrolyzable and thus should be remained anhydrous upon storage.

Upon application, hydrolysis is not a problem.

Solvent3) DMSO (Dimethyl Sulfoxide)

• Characteristic: organic solvent, miscible with water and common organic solvents, has low Mwt which allow for its quick penetration into the deep layers of the skin.

• Mechanism:- Capable of H-bond formation with cellular components such as protein and interact

with them and may alter conformation and association of proteins leading to unfold or expand protein chains.

- At high concentration: 1) it has a high osmotic activity, which distorts the laminated structure of SC and thus

forms channels within the matrix. 2) SC may hold large amount of DMSO. In effect, the solvent become the membrane

phase (barrier phase), and since most drugs are more soluble in DMSO than in H2O high conc. of the drug is attained conc. gradient in the SC, which would further promote the percutaneous absorption of the drug.

So,

Solvents similar to |DMSO

Dimethyl Acetamide (DMA)

DMFormamide (DMF)

- Organic solvents, promote permeability in the skin which appears to be very similar to those produced by DMSO. However, they haven’t been studied as DMSO.

- They have the same mechanism as DMSO.

2-pyrrolidone

5-Dimethyl-2-pyrollidone

5-methyl-2-pyrrolidone

Solvents

5) Azone

Characteristic:- Colorless, Odorless, Liquid- Pharmacologically inert, devoid of S/E (Irritation,

sensitivity or photo toxicity)- Potential enhancers for wide variety of drugs

mainly lipophilic ones, since they are lipophilic (alkyl chain=non polar, Lactam=polar)

- Compatible with most organic solvents

Solvents (Azone)

• Mechanism:

It has alkyl chain and more polar lactam grouping. Lactam grouping is expected to interact with the polar head of the structured lipid layer, while the alkyl chain would interact with the alkyl chain region of lipids leading to a decrease in rigidity of lipids and consequently increase in fluidity and diffusivity of lipids.

- Melting of lipids in the skin is lowered by azone.

Fatty Acids

• Oliec acid

- Mechanism: in the fluidity of lipids penetration across membrane.

Surfactants

• We have 3 types of surfactants:- Anionic: irritant- Cationic: also irritant, not compatible with many drugs

- Non Ionic: less irritant and less toxic than ionic, so it’s the mainly surfactant used.

Surfactant

Hydrophobic part: alkyl, aryl, alkyl phenol, polyoxypropylene

Hydrophilic part: Sorbitol, sucrose, glycerol, PEG, poloxyethylene

The 2 parts are bonded by ester or ether linkage.

Table 1. Examples of surfactantsTrade name

Chemical structure Chemical name

Span® 20

Sorbitan monolaurate

TWEEN® 20

Polyoxyethylenesorbitan monolaurate

Sucrose monolaurate

Polyoxyethylene 8 stearate

Brij® 97

Polyoxyethylene 10 oleyl ether (C18-1E10)

Ethylene glycol monooctyl ether

Triton® X-100

4-(1,1,3,3-Tetramethylbutyl)phenyl-polyethylene glycol

Ethylene glycol monododecyl ether

P;oaxamer or pluronic

Polyoxyethylene-polyoxypropylene

Surfactants (non ionic)

• Mechanism: They penetrate to lipids relaxation of the ordered structure

of SC lipids facilitate diffusion through existing channels and probably create new ones.

• Factors affecting their enhancement:

1) Concentration: 2 effects (CMC)

- Below CMC: they are free to penetrate into membrane inc. permeability. Also the drug is free.

- Above CMC: Solubilization of the drug by micelle thermodynamic activity driving force for drug absorption.

*Possible profiles for the effect of surfactants on transdermal permeation

• With permeation enhancement

• With no permeation enhancement

Surfactants

2) Chain Length of Hydrophilic and hydrophobic groups:

- There is optimum length that can be determined.

Case 1: oxyethylene chain length

is constant and the change is in alkyl chain length ( same hydrophilic part but changing the hydrophobic part of the surfactant)

Case 2: Ethylene oxide chain length is changing (hydrophilic part) while alkyl chain length is the same (hydrophobic part)

3) HLB (Hydrophilic-Lipophilic Balance)

Related to above point

Terpenes

• Terpene: Compound that is constituent of volatile oil (essential oil)

- Oil or oil component can be used.

- Ex: Menthol, pinene, cineol, limonene, euculyptus oil……

• Mechanism: acts mainly on lipid structure change the packing of lipids intermolecular forces

fluidity diffusion coefficient.- Due to their high PC, they don’t have significant interaction

with proteins.

Terpenes• To show these effects, DSC was

done before and after treatment with terpenes

- T2 and T3: lipids melting, either in two stages (biphasic), or lipid melting (T2) followed by disruption of protein-lipid complex at cell membrane (T3)

- T4: protein denaturation at higher temp. of lipids melting.

The figure suggest that only shift in lipid melting with no effect on protein denaturation which is consistent with the above proposed mechanism.

Phospholipids (liposomes)

• Liposomes are phospholipid bilayer encapsulating the polar drug in the aq environment and the lipophilic drugs in the lipid bilayer.

Phospholipids (liposomes)• Mechanism: liposomes may penetrate the skin (same as carriers), From conventional vehicle, free drug should be released before its available

for absorption. However in liposomes, the drug does not have to be released. Liposomes vehicles are readily miscible with skin surface lipids, they may penetrate taking the drug into deep layers. Thus even polar drugs incorporated inside the aqueous compartment can be delivered inside the liposome to deep layers of the skin. Accordingly, Liposomes are useful for drugs that doesn’t penetrate the skin in the free forms.

• when they reach the dermis the encapsulated drug is not available for absorption, only the free drug is, this due to the large size of liposomes. Accordingly, liposomes can serve as depot, as slow release vehicle inside the dermis. They can maintain high conc. in the skin than conventional vehicles.

• Liposomes also supplement skin surface lipids, excellent potential for hydrating the horny layer (not the main mechanism)

• Liposomes offer protection against metabolism by enzymes drug clearance. (not the main mechanism)

Phospholipids (liposomes)

Phospholipids (liposomes)

• Liposomes may provide lipids for lipoidal channels improve continuity facilitate movement of lipophilic drugs liposomes are more advantages and successful for lipophilic drugs than hydrophilic ones with respect to this mechanism.

• Liposomes may rupture at skin surface or during penetration leading to the release of free drug

• Small liposomes are more likely to penetrate than large ones.