Drug Delivery to the Skin - 4 - Flashcards in University Pharmacy

What are the two main types of products which can be delivered to the skin?

Local (applied to skin e.g lidocaine). Systemic (e.g. nicotine patch, entering systemic circulation)

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What are the two types of enhancement strategies?

Chemical (chemical penetration enhancers). Devices (physical enhancement mechanisms)

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State features of toxicology of drugs used in the skin

Theoretical, lack of studies e.g. gallium (initial thought - not able to penetrate the skin due to being charged, but actually forms a neutral complex in the skin)

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Describe features of the mode of action of chemical penetration enhancers (lipid disruption) - (1)

PE disrupts S/C lipid organisation making it more permeable. Produces increase in D, e.g. azone, terpenes, fatty acids (oleic acid). DMSO/Ethanol may just extract lipids

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Describe features of the mode of action of chemical penetration enhancers (lipid disruption) - (2)

Limit of ethanol product (20%) – product will leak out of the skin, alcohol makes lipids more mobile (able to get drugs into the skin)

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Describe features of the mode of action of chemical penetration enhancers (protein modification) - (1)

Interact with keratin opening up the dense protein structure making it more permeable and thus increasing D (probably not that important). May also disrupt protein in membrane. e.g. ionic surfactants, DMSO, urea

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Describe features of the mode of action of chemical penetration enhancers (protein modification) - (2)

(corneocytes) – surfactant may interact with protein (charged amino acids), loose structure, easier penetration into the skin. SDS – anionic surfactant (not suitable for skin, opens up the skin, make proteins more mobile, increases permeability)

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Describe features of the mode of action of chemical penetration enhancers (partitioning promotion) - (1)

Solvent enters S/C changing its solubility properties and thus increasing partitioning. e.g. Water (hydration) PEG, PPG, ethanol, transcutol.

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Describe features of the mode of action of chemical penetration enhancers (partitioning promotion) - (2)

Change the vehicle, allow solvents to enter skin/change solubility (drug penetrates skin, lipid/excipient penetrates, preservatives penetrate, drug in a vehicle if it penetrates into the skin/hydrophilic, makes skin hydrophilic, penetration easier)

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Describe features of the mode of action of chemical penetration enhancers (partitioning promotion) - (3)

Most PEs are combination of above e.g. DMSO. However many irritate and are toxic. DSMO – solvent, application to skin (S/E – foul breath, due to metabolism). If the skin is damaged, some compounds cannot be used

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What are the ideal properties of chemical penetration enhancers? (1)

Pharmacologically inert, non-irritant, non-allergenic, non-toxic, predictable and controllable onset/duration, full recovery of skin following removal, unidirectional, pharmaceutically compatible/acceptable, good solvent, odourless, colourless

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What are the ideal properties of chemical penetration enhancers? (2)

Tasteless and inexpensive

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Describe features of water (1)

Best penetration enhancer. Least toxic. Results in hydration of Stratum corneum. Corneocytes take up water. Makes bilayer more fluid allowing easier penetration of both polar and non-polar drugs

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Describe features of water (2)

Occlusive ointments/impermeable dressings are inert penetration enhancers

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Describe features of water (3)

Cover skin to promote penetration e.g. lidocaine, plaster, bandage placed on skin, more drug enters the skin, skin is more hydrated, natural penetration enhancer (under the bandage)

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Describe features of surfactants (1)

Enhance absorption by a direct effect on the membrane (extract lipids, disrupt lipid bilayer, interacts with keratin). Anionic surfactants are better than cationic which in turn are more effective than non-ionic surfactants

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Describe features of surfactants (2)

Long term use is often harmful. However, the concentrations which are normally used as formulation aids are generally regarded to be safe

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Describe features of fatty acids (oleic acids)

Fluidisation (mobilisation) of intercellular lipids as a result of interaction with lipid domains and thus disruption of the ordered lamellar structures. Less irritancy compared to other PEs

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Describe features of urea (1)

Hydrating agent used to treat scaling conditions e.g psoriasis. Promotes hydration of skin and may exert keratolytic activity. Can be effective but it is difficult to produce stable formulations due to its ability to disrupt hydrogen bonds

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Describe features of urea (2)

Used in formulations with hydrocortisone to improve bioavailability. Helps to break down dead cells of the skin e.g. athlete’s foot

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Describe features of ethanol

Non-polar solvent. MOA (extracts lipids, alters solubility properties of Stratum corneum, solvent drag). Loss on evaporation may increase drug thermodynamic activity. Use in wide range of transdermal drug delivery systems for steroids

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Describe features of propylene glycol

Similar MOA to ethanol. May enhance activity of other PEs. Commonly used in numerous topical formulations.

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Describe features of azone (1)

1-dodecylazacycloheptan-2-one. Laurocapram. Mwt 281.49. Clear, colourless, odourless liquid. Melting point >7 degrees Celsius. Log P =6.2, smooth, oily, non-greasy feel. miscible with most organic solvents - alcohols, ketones, hydrocarbons

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Describe features of azone (2)

LD50 in the rate of >9g/Kg. Stable > 7 years. Pharmacologically inert, non-irritant. Enhanced penetration of both hydrophobic and hydrophilic drugs. Optimum concentrations of azone that can be used in formulations are in the range of 1 –3%

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Describe features of azone (3)

Partitions into lipid bilayer, disrupts, increasing diffusivity. Had some mild toxicity

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Describe features of DMSO (1)

One of the earliest penetration enhancers. Aprotic solvent. Colourless liquid with good solvent properties. Promotes absorption of a wide range of compounds. Denatures keratin. Interacts with polar head groups of lipids, distorting bilayer

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Describe features of DMSO (2)

Main problem that a concentration of 60% required to induce effect and at this level it produces erythema and wheals. Metabolised to produce dimethylsulphide (foul taste/breath), also has a smell itself. Dimethylsulphide also used

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Describe features of pro-drugs (1)

Lipophilic (or hydrophilic in some cases) moieties attached to parent compound. Alter physicochemical properties of drug (formulation/absorption optimised). Pro-drug may be enzymatically converted in skin or in systemic circulation

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Describe features of pro-drugs (2)

Approach commonly used commercially and academically e.g. betamethasone-17-valerate, clindamycin phosphate

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Describe features of pro-drugs (3)

Vitamin D – not absorbed very well, very oily, doesn’t get into skin, very hydrophobic (stuck in stratum corneum), cannot get into systemic circulation. Change chemistry of molecule, add functional group, removed from enzymes in the skin

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Describe features of pro-drugs (4)

Variation in metabolism of prodrugs in patients

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Describe features of ion pairs (1)

Charged species do not readily penetrated Stratum corneum. Formation of ion pair with oppositely charged species, neutralising charge. Formation of salt (e.g. lidocaine HCl), use of counter ion (e.g. salicyates with amines), coacervation

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Describe features of ion pairs (2)

Ion pairs – ionised molecules (e.g. Fe, charged molecule – difficult to get into the body, comes out of the skin very slowly, develop ion pair for neutralisation). Diethylamine – diclofenac. Beclomethasone (dipropionate – group removed in metabolism)

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Describe features of eutectics

Mixture of 2 components that don't interact to form new compound but at certain ratio, inhibit crystallisation of one another e.g. lower m.p. EMLA - eutectic mixture of lidocaine and prilocaine. Penetration enhancers being investigated

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Describe features of supersaturated systems (thermodynamic option) - 1

dM/dt = aD/γh. For maximum penetration the drug should be at highest TA. In saturated solution - dissolved molecules are in equilibrium with solid

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Describe features of supersaturated systems (thermodynamic option) - 2

Saturated drug systems in miscible co-solvents can be combined to create a drug formulation at n-fold its saturation concentration. Can also occur by evaporation of solvent from system upon application to skin

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Describe features of supersaturated systems (thermodynamic option) - 3

Supersaturated systems – change saturation (change vehicle, change solubility of ionised drug based on pKa). Increased degree of saturation, increase amount transported (plot)

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Describe features of liposomes (1)

Lipid vesicles fully enclose an aqueous volume. Phospholipids with/without cholesterol. Hydrophilic drugs trapped within aqueous regions. Lipophilic drugs in lipid bilayer. Most commonly manufactured by solvent evaporation and rehydration

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Describe features of liposomes (2)

Classified according to method of preparation, size, lamellarity. MLV (0.1-10 nm). SUV (20-50 nm). LUV (150-500 nm). 1-10 nm gap between skin cells. Biodegradeable, non-immunogenic

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What are the benefits of liposomes?

Get drug across stratnum corneum. Decrease systemic absorption of drug. Formation of reservoirs of drug in S/C and epidermis. Protect drug from degradation. Increase drug loading in certain formulations

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What is the mode of action of liposomes? (1)

Still under debate. Liposomes not believed to cross S.corneum intact. Phospholipids may be acting as PEs. May fuse with skin surface, increase driving force for drug permeation. Liposomes may penetrate into S.corneum

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What is the mode of action of liposomes? (2)

Fuse with lipids releasing payload, producing drug reservoir. May also penetrate via follicles. DaunoXome, AmBisome. Topically unsuccessful (Pervaryl lipogel 1% econazole nitrate) - due to formulation instability/cost

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Describe features of transferosomes (1)

Highly controversial. Contain phospholipid (4-10%) with surfactant (10-20% sodium cholate/deoxycholate) and ethanol (3-10%). Surfactant acts as edge activator (flexibility). 200-400 nm in diameter and squeeze through pores between cells of 20 nm

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Describe features of transferosomes (2)

Driving force is xerophobia (tendency to avoid dry surroundings) e.g. 20% hydration at top of S. corneum to 100% at basement membrane (gradient may not be linear). Formulations must be applied as finite dose under non-occluded conditions

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Describe features niosomes

Similar to liposomes but are prepared mainly from non-ionic surfactants e.g. sucrose ester surfactants, polyoxyethylene alkyl ether surfactants. Lower toxicity than ionic surfactants and phospholipids. MOA might be similar to liposomes/less effective

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Describe features of ethosomes

Comprised of phospholipids but contain high levels (e.g. 30%) of alcohol (mainly ethanol). Creates a soft vesicle with some flexibility. MOA believed to be a combination of ethanol and more flexible vesicle

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Drug Delivery to the Skin - 4

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