Biopharmaceutics Transdermal 2 Flashcards
How can skin permeation be enhanced (drug/vehicle properties)?
Drug selection (lipophilic preferable)
Pro-drug (for hydrophilic, charged drugs, conversion to ester to neutralise)
Ion pair complexes (to neutralise highly charged drugs)
Chemical potential (thermodynamic methods to make the drug more thermodynamically favourable for drug absorption)
Eutectic systems
Liposome or vesicle-based formulations (smaller particles and surrounded by lipids)
What characteristics achieve optimal permeability?
Low MW - higher diffusion
Low MP - better solubility
Where a drug does not possess the ideal physicochemical properties, what is needed?
Manipulation of the SC to enhance diffusion
How can the SC be manipulated?
Hydration
Lipid fluidisation
Powered electrical devices (iontophoresis, phonophoresis, electroporation)
Name 2 drugs that show good skin permeability.
Nicotine
Nitroglycerine
Maximum skin penetration is achieved when the drug…
Has the highest thermodynamic activity (when its at its highest concentration in the formulation compared to the skin) e.g. when in a supersaturated solution
How is a supersaturated solution produced?
By dissolving as much of the drug as you can into a solvent and then evaporating the solvent or mixing with co-solvents so you still have the same amount of drug, just in a lesser amount of solvent
How does this apply in practice (supersaturation)?
Evaporation of solvent from the warm surface of the skin, resulting in supersaturation, occurs in most topically applied formulations
Creates a steep concentration gradient from the skin to the underlying tissue
What role does the presence of water have to play (in supersaturation and absorption)?
If water is absorbed from the skin into the vehicle, it can act as an anti-solvent
This can increase the thermodynamic activity of the drug by 5-10 times
How does water act as an anti-solvent?
In a topical formulation, the drug is most likely to be lipophilic dissolved in something like an alcohol
The presence of water acts an an anti-solvent as the drug is hydrophobic and so it prevents the drug from dissolving, making the solution more supersaturated
Which in turn increases the thermodynamic activity of the drug and helps to achieve maximum skin penetration
Supersaturated solutions are inherently what?
Unstable
How can the stability of supersaturated solutions be increased?
Incorporation of anti-nucleating agents to prevent recrystallisation and improve stability
How does the SC act to stabilise supersaturated drug solutions?
Complex mixtures of FA’s, cholesterol and ceramides in the SC may provide an anti-nucleating effect
What can be said about the structure of crystals, and how this influences their MP and solubility?
Crystals have a highly organised structure and so it takes a lot of energy to disrupt and break down that structure, resulting in a higher MP and poor solubility
What is a eutectic mixture?
Involves mixing 2 components, that at a certain ratio, inhibit crystallisation of each other, thus the MP of both compounds is decreased
What is the result of formulating as a eutectic mixture?
Lower the MP of both solid components and increase solubility, this is favourable for drug permeability across the skin
How does MP influence solubility and skin penetration?
The lower the drugs MP, the greater the solubility in a given organic solvent, including skin lipids
MP’s can be reduced to below or around skin temp. to enhance solubility
Aside from lowering MP, how else do eutectic mixtures enhance skin penetration?
Often contain penetration enhancers as the second component, these help disrupt the SC and enhance penetration
E.g. ibuprofen with terpenes
How can permeation enhancer activity be expressed?
Enhancement ratio (ER) = drug permeability coefficient after enhancer treatment / drug permeability coefficient before enhancer treatment
