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Renin Angiotensin Mechanism.

Factors affecting Permeation.

 

Introduction.

  • Transdermal drug delivery systems (TDDS), also known as "patches," are dosage forms that are designed to deliver a therapeutically effective amount of drug through the skin of a patient. 

  • TDD is a painless method of systemic drug delivery that involves applying a drug formulation to intact and healthy skin. 

  • The drug penetrates the stratum corneum first, then the deeper epidermis and dermis, with no drug accumulation in the dermal layer. 

  • When a drug enters the dermal layer, it is available for systemic absorption through the dermal microcirculation. 

  • Transdermal delivery outperforms injectables and oral routes by increasing patient compliance and avoiding first pass metabolism. 

  • Transdermal delivery not only provides controlled, consistent drug administration, but also allows continuous input of drugs with short biological half-lives and eliminates pulsed entry into systemic circulation, which frequently causes undesirable side effects.

Factors affecting Permeation.

  • The main method of transport across mammalian skin is passive diffusion, either at steady state via the trans-epidermal route or, initially, via the trans-appendageal route. 

  • The factors that affect the permeability of the skin are classified into following three categories:

    • Physicochemical properties of the permeate molecule.

    • Physicochemical properties of the drug delivery system.

    • Physiological and pathological condition of the skin.

  1. Physicochemical properties of the permeate molecule:

  • Partition coefficient: 

    •  Drugs possessing both water and lipid solubility are favourably absorbed through the skin. 

    • Transdermal permeability coefficient shows a linear dependence on partition coefficient. 

    • Varying the vehicle may also alter a lipid/water partition coefficient of a drug molecule. 

    • The partition coefficient of a drug molecule may be altered by chemical modification without affecting the pharmacological activity of the drug. 

  • Molecular size: 

    • There is an inverse relationship between transdermal flux and molecular weight of the molecule. 

    • The drug molecules selected as candidates for transdermal delivery tend to lie within a narrow range of molecular weight (100-500 Dalton). 

    • Solubility / Melting point: 

    • Lipophilicity is a desired property of transdermal candidates as lipophilic molecules tend to permeate through the skin faster than more hydrophilic molecules. 

    • Drugs with high melting points have relatively low aqueous solubility at normal temperature and pressure. 

  • PH condition:

    • The pH mainly affects the rates of absorption of acidic and basic drugs whereas unchanged form of drug has better penetrating capacity.

    • Transport of ionizable species from aqueous solutions shows strong pH dependence. 

    • According to the pH partition hypothesis, only the unionised form of the drugs can permeate through the lipid barrier in significant amounts.

  1. Physicochemical properties of the drug delivery system:

  • Vehicle:

    • The affinity of the vehicle for the drug molecules can influence the release of the drug molecule from the carrier.

    • Solubility in the carrier determines the release rate of the drug.

    • The mechanism of drug release depends on whether the drug is dissolved or suspended in the delivery/carrier system and on the interfacial partition coefficient of the drug from the delivery system to skin tissue. 

  • Composition of drug delivery system: 

    • Composition of drug delivery systems may affect not only the rate of drug release but also the permeability of the SC by means of hydration. 

  • Enhancement of transdermal permeation: 

    • Due to the dead nature of the SC the release of the drug from the dosage form is less. 

    • Penetration enhancers can cause the physicochemical or physiological changes in SC and increase the penetration of the drug through the skin.

    • Various chemical substances are found to possess such drug penetration enhancing property.

  1. Physiological and pathological condition of the skin: 

  • Skin age: 

    • Foetal and infant skin appears to be more permeable than mature adult skin and therefore percutaneous absorption of topical steroids occurs more rapidly in children than in adults whereas water permeation has shown to be the same in adults and in children. 

  • Lipid film: 

    • The thin lipid film on skin surface is formed by the excretion of sebaceous glands and cell lipids like sebum and epidermal cell which contain emulsifying agent may provide a protective film to prevent the removal of natural moisturising factor from the skin and help in maintaining the barrier function of the SC. 

  • Skin hydration: 

    • Hydration of SC can enhance transdermal permeability. 

    • The rate of penetration study of salicylic acid through skin with dry and hydrated corneum showed that when the tissues were hydrated, the rate of penetration of the most water-soluble esters increased more than that of the other esters. 

  • Skin temperature: 

    • Raising skin temperature results in an increase in the rate of skin permeation. 

    • Rise in skin temperature may also increase vasodilation of blood vessels, which are in contact with skin leading to an increase in percutaneous absorption. 

  • Cutaneous drug metabolism: 

    • After crossing the SC barrier, some of the drug reaches the general circulation in active form and some of this in inactive form or metabolic form, because of the presence of metabolic enzymes present in the skin layers.

    • It was reported that more than 95% of testosterone absorbed was metabolised as it is present through the skin. 

  • Species differences: 

    • Mammalian skin from different species display wide differences in anatomy in such characteristics as the thickness of SC, number of sweat glands and hair follicles per unit surface area. 

  • Pathological injury to the skin: 

    • Injuries to the skin can cause the disturbance in the continuity of SC and lead to increase in skin permeability.

Commonly asked questions.

  1. Discuss different factors affecting permeation of drug molecules through the skin.
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