MAXIMIZING THE BIOAVAILABILITY OF DRUGS APPLIED TO SKIN

Drug or prodrug selection

Log P obat penting?? initial concentration in the first layer of membrane Log P<< prodrug with an optimal partition coefficient Mecanism: After absorption and diffusion to the viable tissues, enzymes convert the prodrug to the active species Ex.: topical steroidal anti-inflammatory drugs, naltrexone, nalbuphine, buprenorphine, bblockers and other drugs

Chemical potential adjustment

The maximum skin penetration rate obtained when a drug is at its highest thermodynamic act. (supersaturated sol.) Supersaturated solutions can occur due to evaporation of solvent/mixing of cosolvents They suggested that the complex mixture of fatty acids, cholesterol, ceramides, etc. in the stratum corneum may provide an antinucleating effect thereby stabilizing the supersaturated system.

Hydration
Water content of the s.c. is 15 to 20% of the dry weight but can vary according to humidity of the external environment Water opens up the compact layer of the horny layer swell and open the structure of the s.c leading to an increase in penetration. Alter permeant solubility and thereby modify partitioning from the vehicle into the membrane. Moisturizing factors, occlusive films, hydrophobic ointments and transdermal patches enhance skin bioavailability

Ultrasound (phonophoresis)
The ultrasonic energy disturbs the lipid packing in the intercellular spaces of the s.c by: a. heating increase the fluidity of the stratum corneum lipids as well directly increase the diffusivity of molecules through the skin barrier b. cavitation the formation and subsequent collapse of gas bubbles in a liquid effects enhances drug penetration into the tissue ultrasound can push particles through by pressure increase in the skin, although only slightly

Phonophoresis

Iontophoresis
A small electric current is applied to the skin enable penetration of charged molecules into the skin A drug reservoir is placed on the skin under the active electrode with the same charge as the drug A grounding electrode is positioned elsewhere on the body The active electrode effectively repels the active substance and forces it into the skin Transport is driven by electrical repulsion from driving electrode

Contrary to iontophoresis, electroosmosis can be used to transport uncharged and larger molecules When an electric field is applied to a charged skin membrane and causes a solvent flow across this membrane This stream of solvent carries along with it dissolved molecules Enhances the penetration of neutral and especially polar substances

Iontophoresis

Iontophoresis
IonsysTM (Fentanyl)

Vyteris Lidosite

Electroporation
Requires a large voltage treatment for a short period of 10 s to 100 ms Produces transient hydrophilic pores (aqueous pathways on the lipid bilayers) across the skin barrier Flux increases of up to 10 000-fold have been obtained for charged molecules Electroporation may combine with iontophoresis to enhance the permeation of peptides such as vasopressin, LHRH (luteinizing hormonereleasing hormone), neurotensin and calcitonin

Electroporation

Needle array
The s.c can be simply bypassed by an injection, and one development of this approach is a device consisting of 400 microneedles to insert drug just below the barrier. The feel to the skin is rather like a cat's tongue, or sharkskin The solid silicon needles (coated with drug) or hollow metal needles (filled with drug solution) penetrate the horny layer without breaking and without stimulating nerves in the deeper tissues The technique may also be combined with iontophoresis.

Penetration enhancers
a. The material should be pharmacologically inert b. Not interacting with receptors c. Non-toxic, non-irritating and non-allergenic. d. The action should be immediate and the effect (onset & duration) should be predictable and controllable e. Upon removal of the material, the skin should immediately and fully recover its normal barrier property f. The enhancer shouldnt cause loss of body fluids, electrolytes or other endogenous materials

g. It should be compatible with a wide range of drugs and excipients h. The substance should be a good solvent for drugs i. The material should be cosmetically acceptable (good spreadability and skin 'feel'). j. The chemical should formulate into all the variety of preparations used topically. k. It should be odourless, tasteless, colourless and inexpensive.

 Water Sulphoxides (especially dimethylsulphoxide) and their analogues Pyrrolidones Fatty acids and alcohols Azone and its derivatives Surfactants - anionic, cationic and nonionic Urea and its derivatives Alcohols and glycols Essential oils, terpenes and derivatives Synergistic mixtures.

Complexes
Complexation of drugs with cyclodextrins has been used to enhance aqueous solubility and drug stability. Cyclodextrins of pharmaceutical relevance contain 6, 7 or 8 dextrose molecules (a-, b-, g-cyclodextrin) bound in a 1,4- configuration to form rings of various diameters The ring has a hydrophilic exterior and lipophilic core in which appropriately sized organic molecules can form non-covalent inclusion complexes resulting in increased aqueous solubility and chemical stability

Liposomes and transfersomes

Liposomes are colloidal particles formed as concentric biomolecular layers that are capable of encapsulating drugsconsisting of phospholipids and cholesterol For example, the flux of oestradiol has been increased 20-fold using a variety of liposomes. The same vesicles increased 10-fold the deposition of this hormone within the stratum corneum.

 Transfersomes are vesicles composed of phospholipids as their main ingredient with 1025% surfactant (such as sodium cholate) and 310% ethanol. The surfactant molecules act as edge activators, conferring ultradeformability on the transfersomes, which reportedly allows them to squeeze through channels in the stratum corneum that are less than one-tenth the diameter of the transfersome

 liposomes are too large to pass through pores of less than 50 nm in size, transfersomes up to 500 nm can squeeze through to penetrate the stratum corneum barrier spontaneously Data indicate that as much as 50% of a topical dose of a protein or peptide (such as insulin) penetrates the skin in vivo in 30 minutes.