Transdermal Drug Delivery System Introduction.pptx

Introduction to Transdermal Drug Delivery System

1. TRANSDERMAL DRUG DELIVERY SYSTEM (TDDS) Presented by, Jayanth D M.Pharm 1 st year 1 st sem Department of Pharmaceutics College of Pharmacy Madras Medical College, Chennai

2. Contents Definition Advantages and Disadvantages Structure of skin skin permeation pathways Factors affecting transdermal permeation of drugs Barriers for drug permeation Penetration enhancers Basic components of transdermal patches

3. Definition Transdermal drug delivery system is a topically administered dosage form which delivers drugs for systemic effect at a predetermined and controlled rate. A scopolamine-releasing TDD system ( Transderm-Scop ) for 72 hr prophylaxis or treatment of motion-induced nausea is the first approved patch by USFDA in 1979.

4. Advantages By passes hepatic first pass metabolism. In case of emergency, removing the patch at any point of time during therapy can instantly stop drug input. Patient compliance and self administration. Reduced frequency of dosing. Adverse effects are minimized due to steady and optimum blood concentration time profile.

5. Disadvantages Possibility of skin irritation due to one or many of formulation components. Cutaneous metabolism will affect therapeutic performance of the drug. It is feasible for certain potent drugs only. It is not feasible for ionic drugs. Heat, Cold and Sweating prevent the patch from sticking to the surface skin.

6. Structure of Skin The skin is one of the most extensive and readily accessible organs of the human body. The skin of an average adult body covers a surface area of approximately 2m 2 (or 3000 inch 2 ) and receives about one-third of the blood circulating through the body. It serves as a barrier against physical and chemical attacks and shields the body from invasion by microorganisms.

7. Structure of Skin

8. Layers of skin Microscopically the skin is a multilayered organ composed of, anatomically, many histological layers, but it is generally described in terms of three tissue layers, They are, Epidermis Dermis Subcutaneous or Hypodermis

9. Epidermis It is the outermost layer composed of stratified squamous epithelial cells, held together by highly convoluted interlocking bridges which is responsible for skin integrity. Microscopic sections of the epidermis show two main parts: the stratum corneum and the stratum germinativum. Stratum corneum forms outermost layer of epidermis and consist of many layers of compacted, flattened, dehydrated, keratinized cells in stratified layer. Stratum corneum is responsible for the barrier function of the skin (primary barrier for percutaneous absorption).

10. Continuation... It further consist of three layers, namely Stratum spinosum Stratum granulosum Stratum lucidum

11. Dermis and Subcutaneous layer Dermis: It is a thick layer of fibre and elastic tissues (made mostly of collagen, elastin and fibrillin) that gives the skin its flexibility and strength. The dermis contains nerve endings, sweat glands, oil glands, hair follicles and blood vessels. Subcutaneous layer: It is also called as Hypodermis and is composed of loose, textured, white, fibrous connective tissue containing blood and lymph vessels The drug permeation through the skin enter the circulatory system before reaching the Hypodermis.

12. Layer Thickness Composition Epidermis 0.03 – 2.0mm Stratum corneum, Stratum lucidum, Stratum granulosum, Stratum spinosum, and Stratum basale. Dermis 0.5 – 4.0mm Papillary dermis (thin, upper layer) and reticular dermis (thick, lower layer). Hypodermis 1 – 6mm Primarily composed of fat and connective tissue.

13. Layer Cells Present Epidermis Keratinocytes: They produce keratin, a tough protein that helps protect the skin and makes it waterproof. Langerhans Cells: They are immune cells which initiates immune response Merkel Cells: These specialized cells are found in the basal layer of the epidermis and are involved in light touch sensation. Stem cells: Present in stratum basale and constantly renews epidermis Dermis Fibroblasts: T hese cells are responsible for producing the extracellular matrix, which provides structure and support to the dermis. Mast cells: Involves in allergic reaction and inflammation. Macrophages: These are immune cells that engulf and remove cellular debris and pathogens.

14. Skin Permeation Pathways Percutaenous absorption involves passive diffusion of the substances through the skin. A molecule may use two diffusional routes to penetrate normal intact skin, the appendageal route and the epidermal route. There are two major routes for drug permeation through skin, They are, Transcellular Paracellular

15. Transcellular Route Transcellular pathway means transport of molecules across epithelial cellular membrane. These include passive transport of small molecules, active transport of ionic and polar compounds, and endocytosis and transcytosis of macromolecules. It is also termed as Intracellular route. Hydrophilic drugs permeate through skin by this route.

16. Paracellular Route Paracellular pathway means transport of molecules around or between the cells. Tight junctions or similar situations exist between the cells. The principal pathway taken by a permeant is decided mainly by the partition coefficient (log k). It is also termed as Intercellular route. Lipophilic drugs (o/w log k >2) permeants traverse the stratum corneum via the intercellular route. Some drugs permeate through appendageal route i.e. through hair follicles, sebaceous glands, and sweat ducts.

17. Transport of drug from patch to systemic circulation It involves the following steps, Diffusion of drug from drug reservoir to the rate controlling membrane. Diffusion of drug from rate limiting membrane to stratum corneum. Sorption by stratum corneum and permeation through viable epidermis. Uptake of drug by capillary network in the dermal papillary layer. Effect on target organ

18. Factors Description Skin condition Intact skin is better barrier than diseased skin. Skin age Skin of young ones is more permeable than older ones. Blood supply Changes in peripheral blood circulation can affect transdermal permeation. Regional skin site Thickness of skin, nature of stratum corneum, and density of appendages vary site to site. Skin metabolism Skin metabolizes steroids, hormones, chemical carcinogens and some drugs. Species differences The skin thickness, density of appendages, and keratinization of skin vary species to species, so affects the penetration. Biological factors affecting transdermal permeation

19. Factors Description Temperature Permeation of drug increases ten folds with increase in temperature pH Weak acids and weak bases dissociate depending on the pH and pKa or pKb values. The proportion of unionized drug determines the drug concentration in skin. Drug concentration The flux is proportional to the concentration gradient across the barrier Partition coefficient The optimal K, partition coefficient is required for good action. Drugs with high K are not ready to leave the lipid portion of skin. Also, drugs with low K will not be permeated. Molecular size & Shape Drug absorption is inversely related to molecular weight; small molecules penetrate faster than large ones. Physiochemical factors affecting drug permeation

20. Barrier for Drug Permeation Stratum corneum, the outermost layer of the epidermis, which acts as a protective barrier against external substances, including drugs. It acts as a rate limiting step, acts as a passive but non-inert diffusive medium. It consist of 10-15 layers of corneocytes which acts as barrier for penetration. It consist of alternate hydrophilic and hydrophobic regions which effectively prevent the passage of many molecules. Thickness of the Stratum corneum ranges from 10 – 30µm.

21. Penetration Enhancers Physical means Chemical means Iontophoresis Electroporation Sonophoresis Microneedles Iontophoresis Microneedle Array Patch (IMPA) Fatty acids: Oleic acid Sulfoxides: Dimethyl Sulfoxide (DMSO) Alcohols: Ethanol Glycols: Propylene glycol Pyrrolidones: N-Methyl-2-Pyrrolidone (NMP) Surfactants: Sodium dodecyl sulphate

22. Mechanism of Chemical Penetration Enhancers Penetration enhancers may act by one or more of three main mechanisms Disruption of the highly ordered structure of stratum corneum lipid. Interaction with intercellular protein. Improved partition of the drug, coenhancer or solvent into the stratum corneum.

23. Ideal Characteristics They should be non-toxic, non-irritating and non-allergenic. They would ideally work rapidly; the activity and duration of effect should be both predictable and reproducible. They should not produce any pharmacological activity within the body. They should allow therapeutic agents into the body whilst preventing the loss of endogenous materials from the body i.e. Unidirectional. When removed from the skin, barrier properties should return both rapidly and fully to normal.

24. Chemical Penetration Enhancers Sulphoxide: It acts by denaturing protein and, on application to human skin, it changes the intercellular keratin conformation from α helical to ß sheet. Pyrrolidones: It partition into the stratum corneum and alters the solvent nature of membrane. Fatty acids: It interacts and modifies the lipid domain of stratum corneum. Terpenes: It modify the solvent nature of the stratum corneum, thus improving drug partitioning into the tissue.

25. Components of Transdermal Patch Polymer matrix/Drug reservoir Drug Penetration enhancer Pressure sensitive adhesive Backing laminate Release liner Other excipients

26. Polymer matrix/Drug reservoir: It is the backbone of TDDS which controls the release of drug from the device. Polymers used should be biocompatible and chemically compatible with the drug and other components Example: HPMC and Ethyl cellulose. Drug: The drug should posses good physiochemical and pharmacokinetic properties. Penetration enhancers: To increase permeability of stratum corneum, so as to attain higher therapeutic levels of drug. Pressure sensitive adhesive: It maintains an intimate contact between patch and the skin surface. Example: Polyacrylates, Polyisobutylene and silicone based adhesives. Components of Transdermal Patch

27. Parameters Properties Dose Less than 20mg/day Half life Less than 10 hours Molecular weight Less than 500 Daltons Partition coefficient 1-4 Aqueous solubility Greater than 1mg/mL pH 5-9 Skin Permeation Coefficient Greater than 0.5 × 10 -3 cm/hr Skin reaction Non-irritant & Non-sensitizing Oral Bioavailability Low Ideal properties of drug candidates for TDDS

28. Backing laminate The primary function of backing laminate is to provide support. Ideal Characteristics It should be chemical resistant and excipient compatible because the prolonged contact between backing layer and excipients may cause the additives to leach out or may lead to diffusion of excipients, drugs through the layer. It should have low moisture vapour transmission rate. It should have optimum elasticity, flexibility and tensile strength. Examples: Aluminium vapour coated layer Plastic film (Polyethylene, Polyester)

29. During storage release liner prevents the loss of drug that has migrated into the adhesive layer and contamination. It is therefore regarded as a part of primary packing material. It is composed of base layer which may be non-occulsive (paper fabric) or occulsive (polyethylene and PVP), and a release coating layer made of silicon or Teflon. Other excipients Solvents to prepare drug reservoir: Chloroform, Methanol, Acetone etc. Plasticizers: Dibutyl-phthalate, polyethylene glycol. Release Liner

30. Examples of Drugs approved by USFDA for TDDS

31. References Yie.W.Chien; Novel Drug Delivery System; Second Edition; e-book PDF. Sabine Szunerits & Rabah Boukherroub 2018; Heat: A Highly Efficient Skin Enhancer for Transdermal Drug Delivery; Frontiers in Bioengineering and Biotechnology; Volume:06; Article:15. Md.Intakhab Alam.et.al 2013; Type, Preparation and Evaluation of Transdermal Patches: A Review; World Journal of Pharmacy and Pharmaceutical Sciences; Volume:02; Issue:04; Page no: 2199-2233.

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