Safe and efficient skin drug delivery

Skin, a gate to drug delivery

Many approaches have been developed to overcome the skin barrier properties, including vehicledrug interactions, energy driven methods, vesicles and particles, stratum corneum modification or removal. Among them, combining the use of solubilizer(s) and chemical penetration enhancer(s) in the topical dosage form formulation is a long-established strategy, offering a wide range of possibilities regarding the vehicle: cream, gel, bi-gel, ointment, patch,… and the site of action, i.e. topical or transdermal

Ideal drug properties for skin delivery

The best attributes for a drug to cross the skin barrier are:

• molecular weight < 500 Da to diffuse through the skin.
• melting point < 200°C to dissolve easily in the stratum corneum and have good skin permeability.
• 1 < LogP < 5 for absorption in the hydrolipidic stratum corneum.
• pKa < formulation pH, as ionization of the molecule drastically decreases its absorption.
• drug should be effective at low dose < 20 mg/day.
• drugs with short half-life or high first-pass metabolism are also good candidates for transdermal route instead of the oral route where their degradation is too fast.

Different targets in skin delivery

Depending on the therapeutic effect desired, the site of action of the drug will vary:

• a local action, at different levels of the skin layers: epidermis, dermis or below the ep

Formulating for efficient skin delivery

Three main steps govern drug diffusion from the formulation to the skin:

• Solubility: the formulation must solubilize enough drug to deliver the therapeutic dose at the target site
• Partition: the drug must partition out of the delivery vehicle into the upper layers of the stratum corneum
• Diffusion: the drug molecule diffuses through the stratum corneum mainly via the intercellular path

Formulation development

During formulation development it is critical to use solubilizers that solubilize the therapeutic dose in the vehicle and favor the passive diffusion of the drug, as well as penetration enhancers that will contribute to drug diffusion in the different layers of the skin.

Determine the formulation objectives

• Ensure drug has suitable properties for skin delivery
• Determine the site of action, function of the therapeutic indication
• Choose the most appropriate dosage form among lotion, foam, emulgel, cream, gel, bi-gel, balm, ointment, patch…

Assess drug solubility

• Measure saturation solubility at 32°C
• Test a range of various solubilizers, to increase drug solubility in the formulation
• Test a pool of penetration enhancers with different mode of action, to facilitate diffusion of the drug in the skin

Assess drug permeation

• Use Franz diffusion cells and standardized IVPT protocols
• Test different combinations of solubilizers and penetration enhancers at different ratios
• Select the best combination to deliver the therapeutic dose at the target site

Gattefossé range of solubilizers and penetration enhancers

A pool of penetration enhancers with different modes of action

Our chemical penetration enhancers have different mechanisms of action at the skin level. Used alone or in synergy they provide safe and efficient drug permeation.

Interacting with the aqueous domain

By penetrating in the stratum corneum, the penetration enhancers can change the solubility parameters of the skin and increase the solubility of the drug in the aqueous domain, enhancing the partitioning of the drug from the vehicle to the stratum corneum.

Solvents like water, propylene glycol, ethanol and Transcutol® P act this way. Compared to other solvents, Transcutol® P is less polar. Therefore, ionizable drugs will have an increased permeation in the presence of Transcutol® P.

Interacting with the lipid domain

The penetration enhancers can change the structural organization of the lipid bilayers of the stratum corneum. The site of interaction can be the polar head groups of the lipid leading to fluidization of the intracellular lipids, or the alkyl chain of the lipid inducing disruption of the lipid packing.

Oleic acid is known for interacting with the lipid domain in the skin, causing dermal disruption without irritation. Our oleic-acid-containing excipients provide skin permeation properties in a similar and reversible manner: Labrafil® M 1944 CS, Peceol™ and Plurol® Oleique CC 497.

Opening of tight junctions

Tight junctions are present in the stratum granulosum of the epidermis and constitute the second barrier to molecules on their paracellular passage from outside to inside.

C8-C10 derivatives such as Capryol® 90, Labrafac™ MC60 and Labrasol® are reputed to transiently open the tight junctions.

Fluidizing membranes

The effectiveness of fatty acids as penetration enhancers depends on the fatty acid chain length and the degree of saturation. C12 saturated fatty acids and C18 unsaturated fatty acids are described as being the most efficient penetration enhancers acting by fluidization.

Our Lauroglycol™ co-surfactants contain mainly saturated C12 fatty acids. Our range of excipients containing long chain unsaturated fatty acids (C18:1 and C18:2) consists of: Labrafil® M 1944 CS, Labrafil® M 2125 CS, Plurol® Oleique CC 497, Peceol™ and Maisine® CC.

Synergizing excipients to boost skin drug delivery

The synergy provided by a combination of different penetration enhancers has been widely documented. Using penetration enhancers with different modes of action for greater efficacy is recommended. Their performance needs to be assessed using diffusion cells.

See the full technical brochure on Safe and efficient skin drug delivery here

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Source: Gattefossé, technical brochure Safe and efficient skin drug delivery

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