PERCUTANEOUS ABSORPTION

Definition:Percutaneous Absorption: The term percutaneous absorption covers the entire process by which a drug applied to the outer surface of the skin is taken up into the systemic circulation. This requires penetration into the layers of the skin with subsequent permeation across each layer and finally uptake into the capillary blood vessels in the upper region of the dermis.Description: It is necessary to consider both the structure of the membrane and the interactions of the three components – membrane, penetrant and vehicle to determine the physical and chemical factors which assist or hinder the process and is elaborated in the following Fig.

Percutaneous drug absorption results from direct penetration through the stratum corneum, followed by passing through the epidermal tissues and into the dermis.

FORMULATION CONSIDERATION FOR DERMATOLOGICAL PREPARATIONS:

When formulators develop dermatological preparations for optimum bioavailability, they employ two main methods of approach either singly or combined.

1. The first scheme formulates the vehicle or device so that the drug has the maximum tendency to leave the base and to partition into the skin. The scientist does not intend that the vehicle components should affect the physicochemical properties of the SC. Thus the vehicle design promotes drug release by simply optimizing the chemical potential of the medicament. However, most of vehicles tend to change the nature of the SC by hydrating it. 2. The alternative strategy incorporates into the formulation materials known as penetration enhancers which are chemicals entering into the skin, dynamically and reversibly altering it to enhance the penetration of drug.Example of penetration enhancers includes: Dimethyl sulfoxide (DMSO), propylene glycol, 2-pyrrolidone etc.

Simplified multilayer model of skin

PROCESS OF PERCUTANEOUS ABSORPTION:

The phenomenon of percutaneous absorption (or skin permeation) can be visualized as consisting of a series of steps in sequence; sorption of a penetrant molecule onto the surface layers of SC, diffusion through it and the viable epidermis and finally, at the papillary layer of the dermis. The molecule is taken up into the microcirculation for subsequent systemic distribution. The viable tissue layers and the capillaries are relatively permeable and the peripheral circulation is rapid. The SC acts as a passive diffusion medium, but not an inert. No active transport process has been shown to be involved in skin permeation.

Model of percutaneous absorption

ADVANTAGES AND DISADVANTAGES OF TDDSAdvantages of transdermal drug delivery as compared to conventional oral administrations are:1. Avoidance of the gastrointestinal tract2. First-pass metabolism in the liver3. Improved patient compliance.Disadvantages of transdermal drug delivery include:1. Localized cutaneous reactions2. Systemic toxicity3. Time required for drug diffusion

ROUTES OF PENETRATION

The major barrier to percutaneous absorption resides in the outer skin horny layer (SC), and there are two main routes of permeation through this layer:

1 - Transappendageal route through (A) Hair follicles (B) Sweat glands(C) Sebaceous glands and(D) pilosebaceous apparatus 2-Transepidermal route across intact SC (A) Via Intercellular lipids (between the cells)and (B) Via keratinized cells or transcellular (across the cells).Epidermal appendages i.e., hair follicles, sebaceous glands and sweat glands are scattered sparsely throughout the skin.Their cross-sectional area 0.1-1% of the skin area. Sweat glands are of two types eccrine and apocrine. Little evidence regarding eccrine glands’ role in cutaneous permeability. Hair follicles cover 1/1000 of total surface roughly.Thus epidermis represents an area 100-1000 times more than other routes of entry.Between transepidermal and transappendageal the former is the principle portal of entry for the drugs absorbed through both the pathways as pilosebaceous units offer relatively smaller absorbing surface.For substances absorbed primarily by transepidermal route, penetration is rapid but lesser than GIT absorption and always followed by some degree of pilosebaceous penetration.

MECHANISM OF PERCUTANEOUS ABSORPTION:The cornified inert layer of epidermis, SC appears to provide the rate-limiting step to transdermal drug absorption and permeation of the skin depends on diffusion; therefore, the hydration of the skin will affect drug permeability. Absorption via the transdermal route primarily occurs by passive diffusion through stratum corneum. The rate ofdiffusion is dependant on:• Permeability coefficient of the drug (Kp)• Applied concentration of the drug (C)• Surface area of the skin exposed to the drug (A)• Thickness of the epidermis (h)

STAGES IN PERCUTANEOUS ABSORPTION: -Diagrammatic representation of the sequential steps involved in percutaneous absorption 1. Partitioning2. Diffusion3. Partitioning4. Diffusion5. Capillary uptake

APPLICATION OF PERCUTANEOUS ABSORPTION:

(1) Surface treatment: The care for the skin surface mainly by using cosmetic application, by forming a protective layer, or by attacking bacteria and fungi. (sunscreens, barriers that hinder moisture loss, antimicrobials and insect repellents).(2) Stratum corneum treatment: The main therapies aimed at the horny layer (Stratum Corneum) improve emolliency by raising water content or stimulating sloughing (keratosis, exfoliants such as salicylic acid ). (3)Skin appendage treatment: Antiperspirants (aluminium) reduce hyperhydrosis of the sweat glands. Depilatory, Topical antibiotics, Antifungals, Exfolients for acne treatment. (4) Viable epidermis and dermis treatment: We can treat many diseases provided that the preparation efficiently delivers drug to the receptor (antiinflammatory, anesthetic, antihistamine). (5) Systemic treatment via percutaneous absorption: In recent years considerable scientific work has led the route being used to treat several conditions by means of transdermal patches (e.g. motion sickness (hyoscine), angina (nitroglycerin).

PROCESSES FOR PERCUTANEOUS ABSORPTION OF A TRANSDERMAL DRUG DELIVERY SYSTEM:

Absorption of drug from a TDDS into the systemic circulation may be occurred as passage through consecutive skin layers /or barriers and involves the following steps as shown in

1. Release from the formulation;2. Penetration into the SC and permeation/diffusion through it;3. Partitioning from SC into VE before reaching the capillaries located in the dermis.These layers have different barrier properties thus, showing different permeabilities and during diffusion process, the drug can be enzymatically degraded or bound to skin components, thus decreasing the overall permeation.Drug partitioning into the SC is the first limiting factor as for most of the formulations the drug diffuses rapidly in the vehicle. At the formulation/skin interface, the drug partitioning into the membrane is highly dependent on the relative solubility of the drug in the components of the delivery system and in the SC. After partitioning into the SC, the drug diffuses through the SC, at a rate determined by the diffusivity within it.In the deepest layers of the SC, the drug undergoes a second partitioning step at the SC/VE interface. As a result, for highly hydrophobic drugs, the VE constitutes the major barrier for drug absorption, as the drug has to partition into the more hydrophilic nature of the VE. The dermis is also hydrophilic in nature. However, once the drug reaches the deepest layers of the VE, the high vasculature of the dermis allows rapid distribution of the drug into the systemic circulation.

Schematic representation of the processes involved in the absorption of substances through the skin.

PRINCIPLES OF PERCUTANEOUS DRUG ABSORPTION (For 8 marks question)

1. Drug absorption through the skin

Any substance that come into contact with the skin surface can penetrate the stratum corneum, permeate the skin strata and diffuse into the underlying tissues or become absorbed into the dermal blood supply and hence the systemic circulation as shown in Figure below. Drug absorption through the skin can be manipulated in order to deliver drug or substance to:i. the skin surface (e.g. cosmetics, sunscreens, insect repellents).ii. targeted skin layers (e.g. corticosteroids to treat localised skin disorders).iii. underlying tissues (e.g. non steroidal anti-inflammatory agents to treat muscular inflammation).iv. the systemic circulation (e.g. oestradiol to treat symptoms of menopause, nicotine to aid smoking cessation, glyceryl trinitrate for the treatment of angina pectoris and fentanyl for the treatment of chronic cancer-related pain).However, TDD also has limitations, which are mainly related to the biological, physicochemical and pharmacokinetic aspects of percutaneous absorption . For instance, due to the efficient barrier properties of the stratum corneum there will be a characteristic lag time prior to the accumulation of adequate plasma drug concentrations and the onset of therapeutic action. Thus, TDD is not suitable for acute conditions where a rapid therapeutic effect is desired.The partitioning of a drug into the SC and its subsequent diffusion through this integument are critical determinants of percutaneous drug absorption.

Diagrammatic representation of some of the processes involved in the absorption of substances through the skin.

2. Transport pathways through the stratum corneum

The stratum corneum is not continuous, but pierced by hair follicles and sweat glands, there are three potential routes of drug transport across the stratum corneum: transappendageal, transcellular or intercellular.The contribution of the skin appendages (the transappendageal pathway) to transdermal transport remains controversial. As the hair follicles only occupy 0.1% of the total skin area and drug diffusion along the sweat pores would be against an outward aqueous flow, it is thought that this route may only be of minor significance . On the other hand, the transappendageal pathway dominated transport during the early stages of

drug permeation whereas bulk diffusion through the SC predominate during the latter stages. Although it is possible that thetransappendageal route offers an alternative pathway for a permeating molecule, it is generally accepted that diffusion through the bulk of the stratum corneum dominates during the latter stages of skin transport.It has been proposed that the uptake of relatively hydrophilic solutes (with a log octanol/water partition coefficient (log KOCT/W) < 3) is governed by the intracorneocyte protein domain while more lipophilic solutes (log KOCT/W > 3) reside preferentially in the intercellular lipid domain. It must be borne in mind, however, that in order for a drug to penetrate the corneocytes, it must associate with thecornified cell envelope (the lipid monolayer is significantly more hydrophobic than the intercellular lipid lamellae and the scaffold of proteins are highly insoluble) as well as the tightly-packed intra-corneocyte keratin intermediate filaments.As these components are likely to make the corneocytes very dense and almost impermeable to solute transport , it is thought that the corneocytes act as mechanical barriers that increase the diffusional path-length of solutes .

Potential transport pathways through the stratum corneum

3. Mechanism of permeation enhancement

However, in order to determine the mechanism responsible for drug permeation enhancement, the non-interactive contribution of the formulation must be controlled. In other words, the thermodynamic activity has to be the same. There are two types of contribution of the formulation for the solute flux.1. Interactive mechanisms relate to the interactions between the vehicle and SC, resulting in barrier property alterations, such as, lipid fluidity, extraction, membrane solubility, or protein modification.2. Non-interactive mechanisms are the strategies to enhance the drug permeation without affecting the barrier properties, very often this mechanism relates to the thermodynamic activity of the solute within the vehicle applied.In the literature, the pre-treatment of skin membranes with PG (propylene glycol) in vitro for 12 h prior to the application of a solvent deposited dry drug film (100 μl of a 0.3% solution in acetone:ethanol 1:1 v/v), has been shown to increase the penetration of 5- fluorouracil and oestradiol by 12-9 fold respectively, compared with untreated skin.

Mechanism action of PG A - untreated skin; B - pretreated with PG

FACTORS INFLUENCING DRUG PERCUTANEOUS ABSORPTION:

Parameters Factors Affecting

1. Drug Compound: Molecular weight

Water/lipid partition coefficient Ionization Molecular size Solubility

2. Formulation: Volatility/occlusionConcentration/thermodynamic activityDistribution in the SCExcipientsPenetration enhancers

3. Skin:SpeciesAge, sex, raceAnatomical siteTemperatureSkin condition (disease) and hydration of the SC

Metabolism4. Application:

Skin area dose (film thickness)Total skin area in contact with formulationDuration of exposureRepeated application

Physiological factors

Skin condition – Intact skin is a barrier – Damaged skin more permeable – Diseased skin usually more permeable Skin age - babies and children – greater area/weight than adult- absorb more drug e.g. steriod - premature infants- no stratum corneum - e.g. the use of topical caffeine for breathing Difficulties.Regional skin site - wide variation e.g face to foot Skin metabolism - The skin contains a variety of enzymes that are capable of metabolising both endogenous chemicals (such as hormones and steroids) and foreign substances that come into contact with it

Physicochemical ParametersPhysicochemical Attraction of DrugMolecular Weight of DrugHydration of SkinTemperature & pHDrug ConcentrationsDiffusion coefficientPartition coefficientArea of ApplicationsContact Time

IDEAL MOLECULAR PROPERTIES FOR DERMAL/ PERCUTANEOUS ABSORPTION OF A DRUG A low molecular weight (generally less than 500 Daltons)

An adequate solubility in oil and water A balanced partition coefficient A low melting point Potent drug (maximum 50 mg/day)

PERMEATION PATHWAYS FOR PERCUTANEOUS ABSORPTIONS OF POLAR AND NON-POLAR DRUGS

Polar (hydrophilic) Path through corneocytes with their desmosomal connections.This route is believed to be hydrophilic in natural, it is composed of aqueous region surrounded by polar lipids that create the walls of

microchannels. 3-10 corneocytes create a columns that form a cluster. Corneocytes edges inside each cluster were found to intercalate extensively, but neighboring cluster were separated by gaps of a few micrometers.

Nonpolar (lipophilic) Path Agents dissolve in and diffuse through the lipid matrix between the protein filaments.

• Hydrophilic drugs and ions undergo absorption through the polar pathways of the skin.• The polar or porous pathways includes the deformities in the lipid bilayers and appendegial pathways or shunt

pathway. it is also thought to be the route by which water evaporates through the skin.• The dry skin is positively charged at physiological pH, thus negatively charged molecules may diffuse more rapidly

across the skin than negatively charged molecules followed by non-ionic molecules.• For most lipophilic molecules (MW <500 Da) , the predominant pathway is via the lipid domains.• The drug needs to partition through the lipid region of the intercellular space or the transcellular lipids to diffuse

across the SC.

METHODS OF MAXIMIZING THE BIOAVAILIBILITY OF DRUG THROUGH SKIN:• Drug or pro drug selection• Hydration• Ultrasounds(phonophoresis)• Ionophoresis • elctroporation • Stratum corneum removal• Micro-needle array• Chemical penetration enhancers

LAWS BEHIND PERCUTANEOUS TRANSPORTPercutaneous flux is directly proportional to the concentration gradient and, therefore, transport across the skin occurs primarily by passive diffusion.Fick’s first law: the diffusion flux along direction x is proportional to the concentration gradient.

At steady state, the flux due to passive diffusion through skin may be described by Fick’s 1st lawJ = kp X ∆a

J = flux of the permeant (moles/cm2s)kp = permeability coefficient of the permeant through the membrane (cm/s)∆a = activity gradient across the membrane (moles/cm3)kp is the inverse of the “resistance”, which the membrane offers to solute transport, and is defined by kp = KD / hK = membrane-aqueous phase partition coefficient of the soluteD = diffusion coefficient of the solute in the membrane (cm2/s)h = diffusion path length through the membrane

Fick’s Law of Diffusion:

dQ = (DAKP) (C1-C2) dt hWhere, dQ/dt - rate of diffusion

D - diffusion coefficient A - surface area of membrane Kp – partition coefficient h - membrane thickness C1 - C2 = concentration difference for solute Generally, C1>>C2

SKIN PERMEATION ENHANCERSSkin penetration enhancers are molecules which reversibly remove the barrier resistance of the stratum corneum. They allow drugs to penetrate more readily to the viable tissues and thus enter the systemic circulation. Enhancement of skin penetration by these molecules is achieved via modification of stratum corneum by either hydration or by acting on the SC lipids and keratin, partitioning and solubility effects.

Example: sulphoxides (such as dimethylsulphoxide, DMSO), Azones (e.g. laurocapram), pyrrolidones (for example 2-pyrrolidone, 2P), alcohols and alkanols (ethanol, or decanol), glycols (for example propylene glycol, PG, a common

excipient in topically applied dosage forms), surfactants (also common in dosage forms) and Terpenes (in generally recognized as safe list). Because of increased risk of toxicity many of these chemicals are now not in use as skin permeation enhancers.