TRANSDERMAL DRUG DELIVERY SYSTEM

1. TRANSDERMAL DRUG DELIVERY SYSTEM Dr. Basavaraj K. Nanjwade M. Pharm., PhD KLE University College of Pharmacy BELGAUM-590010, Karnataka, India. E-mail: nanjwadebk@gmail.com Cell No: 00919742431000 KLE College of Pharmacy, Nipani.

2. CONTENTS • Introduction • Objectives of TDDS • Advantages & disadvantages • Mechanism of percutenious absorption • Permeation through skin • Kinetics of transdermal drug delivery system • Factors affecting permeation • Basic components of TDDS • Formulation approaches used in development of TDDS and their evaluation • Permeation enhancer. • References KLE College of Pharmacy, Nipani.

3. TRANSDERMAL DRUG DELIVERY SYSTEM (TDDS) When one hears the words transdermal drug delivery, what comes to mind? More than likely one thinks about a simple patch that one stick onto skin like an adhesive bandage such as nicotine patch. KLE College of Pharmacy, Nipani.

4. Brief History of TDDS • The NDDS may involve a new dosage form e.g., from thrice a day dosage to once a day dosage form or developing a patch form in place of injections. • Throughout the past 2 decades, the transdermal patch has become a proven technology that offers a variety of significant clinical benefits over other dosage forms. • Because transdermal drug delivery offers controlled release of the drug into the patient, it enables a steady blood-level profile, resulting in reduced systemic side effects and, sometimes, improved efficacy over other dosage forms KLE College of Pharmacy, Nipani.

5. Brief History of TDDS • Transdermal drug delivery system was first introduced more than 20 years ago. • The technology generated tremendous excitement and interest amongst major pharmaceutical companies in the 1980s and 90s. • First transdermal patch was approved in 1981 to prevent the nausea and vomiting associated with motion sickness, the FDA has approved, throughout the past 22 years, more than 35 transdermal patch products, spanning 13 molecules. KLE College of Pharmacy, Nipani.

6. INTRODUCTION • Definition: Transdermal drug delivery is defined as a self contained discrete dosage form, which when applied to the intact skin, will deliver the drug at a controlled rate to the systemic circulation. KLE College of Pharmacy, Nipani.

7. POTENTIAL BENEFITS OF TRANSDERMAL DRUG DELIVERY (ADVANTAGES) • Easy to use. • Avoid GIT absorption problems for drugs. • Avoids FP hepatic metabolism of drugs. • More improved and convenient patient compliance. • Rapid termination in case of toxicity is possible. • Self medication is possible. • Reduces frequency of dosing. • Maintains therapeutic level for 1 to 7 days. • Controlled delivery resulting in more reliable and predictable blood levels. KLE College of Pharmacy, Nipani.

8. DISADVANTAGES • Daily dose of more than 10mg is not possible. • Local irritation is a major problem. • Drug requiring high blood levels are unsuitable. • Drug with long half life can not be formulated in TDDS. • Uncomfortable to wear. • May not be economical. • Barrier function changes from person to person and within the same person. • Heat, cold, sweating (perspiring) and showering prevent the patch from sticking to the surface of the skin for more than one day. A new patch has to be applied daily. KLE College of Pharmacy, Nipani.

9. STRUCTURE OF SKIN • Epidermis: • Stratum corneum (Horny cell layer) • Stratum lucidum (Clear layer) • Stratum granulosum ( Granular Layer) • Stratum spinosum (Prickly layer) • Stratum germinativum • Dermis: • Hypodermis or Subcutaneous layer: KLE College of Pharmacy, Nipani.

10. STRUCTURE OF SKIN Epidermis: • The outer layer of skin is made up of Stratified Squamous epithelial cells. • Epidermis is thickest in palms and soles. • The stratum corneum forms the outer most layer (10-15µm thick ) which consists of many layers of compacted , flattened, dehydrated keratinized cells. • Keratin contains cells called as Corneosites. • Stratum corneum layer forms permeability barrier for external environment. KLE College of Pharmacy, Nipani.

11. STRUCTURE OF SKIN • Water content of stratum corneum is around 20%. • The moisture required for stratum corneum is around 10% (w/w) to maintain flexibility and softness. • It consists of Cermides and neutral lipids such as Sterols, free fatty acids and triglycerides. • The stratum corneum is responsible for the barrier function of the skin and behaves as a primary barrier to the percutaneous absorption. KLE College of Pharmacy, Nipani.

12. STRUCTURE OF SKIN • It is made up of three layers in thicker parts stratum granulosum, stratum lucidum,stratum spinosum. • Removal of these layers results in increased permeability and water loss. KLE College of Pharmacy, Nipani.

13. STRUCTURE OF SKIN DERMIS: • The dermis is made up of regular network of robust collagen fibers of fairly uniform thickness with regularly placed cross striations . • This network or the gel structure is responsible for the elastic properties of the skin. • It is supplied by blood to convey nutrients, remove waste & regulate body temp. • Drug is well absorbed by this route. • Upper portion of the dermis is formed into ridges containing lymphatics and nerve endings. KLE College of Pharmacy, Nipani.

14. STRUCTURE OF SKIN SUBCUTANEOUS TISSUE: This is a sheet of the fat containing areolar tissue known as the superficial fascia attaching the dermis to the underlying structures . SKIN APPENDAGES: Sweat glands produces sweat of pH 4-6.8 & absorbs drugs, secretes proteins, lipids and antibodies. Its function is to control heat. HAIR FOLLICLES They have sebaceous glands which produces sebum and includes glycerides, cholesterol and squalene. KLE College of Pharmacy, Nipani.

15. Mechanism of absorption through skin Mechanism involved is passive diffusion This can be expressed by FICK’s LAW of DIFFUSION dq = D K A ( c1 – c2 ) dt h dq /dt = rate of diffusion D = diffusion co-efficient K = partition co- efficient A = surface areaof membrane H = thickness of membrane KLE College of Pharmacy, Nipani.

16. Routes of drug absorption through skin • Trans follicular route • Trans epidermal route KLE College of Pharmacy, Nipani.

17. Routes of drug absorption through skin • Trans follicular route: • Fractional area available through this route is 0.1 % • Human skin contains 40-70 hair follicles, 200 to 250 sweat glands on every sq.cm. of skin area. • Mainly water soluble substance are diffused faster through appendages than that of other layers. • Sweat glands and hair follicles act as a shunt i.e. easy pathway for diffusion through rate limiting ST corneum. KLE College of Pharmacy, Nipani.

18. Routes of drug absorption through skin • Trans Epidermal route • Epidermal barrier function mainly resides in horny layer • The viable layer may metabolize, inactivate or activate a prodrug. • Dermal capillary contains many capillaries so residence time of drug is only one minute. • Within stratum corneum molecule may penetrate either transcellularly or intercellular. • Intracellular region is filled with lipid rich amorphous material. KLE College of Pharmacy, Nipani.

19. Routes of drug absorption through skin KLE College of Pharmacy, Nipani.

20. FACTORS AFFECTING TRANSDERMAL PERMEABILITY • Physico chemical properties of parent molecule • Solubility and partition co- efficient • pH condition • Penetrant concentration • Physico chemical properties of drug delivery system • Release characteristic • Composition of drug delivery system • Permeation enhancer used KLE College of Pharmacy, Nipani.

21. Physiological and pathological condition of skin • Lipid film • Skin hydration • Skin temperature • Effect of vehicle • Pathological injury to skin • Biological factors • Skin age • Thickness of S. Corneum • Skin condition KLE College of Pharmacy, Nipani.

22. Solubility and partition co- efficient: • Solubility of a drug influences its ability to penetrate the skin. • pKa is index of solubility of drug in vehicle and ST corneum has influence on transfer of drug from vehicle to skin. • Drug solubility determines concentration presented to absorption site which will effect rate and extent of absorption. • Skin permeation can be enhanced by increasing lipophilic character of drug, so that drug penetrates through STC but not through epidermis due to decreased water solubility. • Drug which is lipid & water soluble is favored. KLE College of Pharmacy, Nipani.

23. pH & penetration concentration: • Moderate pH is favorable because if solutions with high or low pH will result in destruction to the skin. • Higher the concentration of the drug in vehicle faster the absorption. • At higher concentrations than solubility the excess solid drug will function as a reservoir and helps to maintain a constant drug constitution for prolonged period of time. KLE College of Pharmacy, Nipani.

24. FACTORS AFFECTING TRANSDERMAL PERMEABILITY • Physico-chemical properties of drug delivery system • Release characteristic • Solubility of drug in vehicle determines the release rate. Composition of drug delivery system • It not only effects the rate of drug release but also the permeability of STC by means of hydration mixing with skin lipids. Example methyl salicylate is more lipophilic than its parent acid (Salicylic acid). When applied to skin from fatty vehicle methylsalicylate yielded higher absorption. KLE College of Pharmacy, Nipani.

25. FACTORS AFFECTING TRANSDERMAL PERMEABILITY Physiological and pathological condition of skin Lipid film: It acts as protective layer to prevent removal of moisture from skin. Defeating of this film will decrease TD absorption. Skin hydration: It can be achieved by covering skin with plastic sheeting, which leads to accumulation of sweat, condensed water vapors, increase hydration and increase porosity. KLE College of Pharmacy, Nipani.

26. FACTORS AFFECTING TRANSDERMAL PERMEABILITY Effect of vehicle: A vehicle can influence absorption by its effect on physical state of drug and skin. Example greases, paraffin bases are more occlusive while water in oil bases are less. Humectants in bases will dehydrate the skin and decrease percutaneous absorption. KLE College of Pharmacy, Nipani.

27. FACTORS AFFECTING TRANSDERMAL PERMEABILITY Biological factors: Skin age: Skin of foetus, young ones and elders is more permeable than adult tissue. Skin metabolism: Viable epidermis is metabolically active than dermis. If topically applied drug is subjected to biotransformation during permeation local and systemic bioavailability is affected. KLE College of Pharmacy, Nipani.

28. BASIC COMPONENTS OF TRANSDERMAL DRUG DELIVERY SYSTEM COMPONENT OF TRANSDERMAL DEVICE INCLUDE: 1) POLYMER MATRIX 2) THE DRUG 3) PERMEATION ENHANCER 4) OTHER EXCEPIENTS KLE College of Pharmacy, Nipani.

29. Basic components of Transdermal drug delivery KLE College of Pharmacy, Nipani. 29

30. POLYMER MATRIX Following criteria to be considered in selection a polymer: • Molecular weight, physical of polymer must allow diffusion of drug at desired rate. • Polymer must be non-reactive, inert, non-toxic, easy to manufacture, inexpensive. • It should not decompose on storage of the device & not deteriorate when large amount of active ingredient is in corporated into it. KLE College of Pharmacy, Nipani.

31. LIST OF POLYMERS USED NATURAL POLYMERS: Cellulose derivatives, Zein, Gelatin, Shellac, Waxes, Gums & Natural rubber SYNTHETIC ELASTOMER POLYBUTADIENE: Polysiloxane, Silicon rubber, Nitrile, Acrylonitryle, Butyl rubber, Styrene butadiene rubber. SYNTHETIC POLYMER Poly vinyl alcohol, Poly vinyl chloride, Polyethylene, Poly propylene, Poly urea, PVP, Polymethacrylate KLE College of Pharmacy, Nipani.

32. DRUG For successful developing transdermal delivery, drug should be chosen with great care physicochemical properties 1. Mol. wt. less than 1000 Daltons 2. Affinity for both lipophilic & hydrophilic phase 3. Drug should have low melting point KLE College of Pharmacy, Nipani.

33. BIOLOGICAL PROPERTIES • It should be potent with daily dose of few mg/ day. • Half life of drug should be short. • Non irritant to skin. • Drug prone to ‘first pass effect’ and which degrade in GIT are ideal candidate. KLE College of Pharmacy, Nipani.

34. Ideal properties of drug candidate KLE College of Pharmacy, Nipani.

35. PERMEATION ENHANCERS • These are the agents which promote the skin permeability by altering the skin as a barrier to the flux of desired penetrant. • Flux J across the skin can be given by J= D. dc/dx D= diffusion coefficient C= concentration x=Spatial coordinate • D is function of size, shape, flexibility of diffusing drug molecule KLE College of Pharmacy, Nipani.

36. Activity of penetration enhancers • Interaction with the polar head groups of lipid via hydrogen and ionic bonding • Change in hydration sphere of lipids and affect the packing at the head region • Increase volume of the aqueous layer swelling and hydration • Protein modification- open up the dense keratin structure and make it more permeable KLE College of Pharmacy, Nipani.

37. Backing membrane They are flexible and provide a good bond to the drug reservoir, prevent the drug from leaving the dosage form through top. It is an impermeable membrane that protects the product during the use on the skin. Contains formulation throughout shelf-life and during wear period Must be compatible with formulation (non adsorptive) Printable E.g.: Metallic plastic laminate , plastic backing with adsorbent pad adhesive foam pad. KLE College of Pharmacy, Nipani. 37

38. Schematic Skin absorption of drug KLE College of Pharmacy, Nipani. 38

39. DRUG IN TARGET TISSUE LOCALIZED DRUG IN DELIVERY SYSTEM PHARMACOLOGICAL RESPONSE RELEASE TOPICAL DRUG IN SKIN SECRETION FLUIDS, SWEAT, SEBUM, pH 4.5--5.5 DISTRIBUTION ABSORPTION TRANSDERMAL DRUG IN BLOOD CIRCULATION ELIMINATION Topical application-absorption & action of drugs SYSTEMIC KLE College of Pharmacy, Nipani.

40. FORMULATION APPROACHES FOR DEVELOPMENT OF TRANSDERMAL DRUG DELIVERY SYSTEM KLE College of Pharmacy, Nipani.

41. TYPES OF FORMULATION • PLATFORM FOR THE DRUG: • Liquids • Semisolids : ointments and gels • Non flowing material That is … • Polymeric film or rubbery gels and • Solid-state platform KLE College of Pharmacy, Nipani.

42. TYPES OF PLATFORM • MONOLITH : slabs, reservoir, vehicle, film, polymer matrix • FILMS : • Natural or synthetic • Porous and non porous • ADHESIVES: viscoelastic materials which remains permanently tacky • E.g. Natural or synthetic rubber, polyacrylates and silicon elastomer KLE College of Pharmacy, Nipani.

43. 1. POLYMER MEMBRANE PERMEATION CONTROLLED SYSTEM KLE College of Pharmacy, Nipani.

44. 1. POLYMER MEMBRANE PERMEATION CONTROLLED SYSTEM • RCM made up of EVA copolymer • A thin layer of drug compatible, hypoallergenic adhesive polymer e.g. Silicon or polyacrylet adhesive may be applied to the external surface. • Rate of drug release affect by varying the polymer composition, permeability coefficient and thickness of rate limiting membrane and adhesive. KLE College of Pharmacy, Nipani.

45. 1. POLYMER MEMBRANE PERMEATION CONTROLLED SYSTEM • Accidental breakage of the rate controlling membrane can result in dose dumping or a rapid release of the entire drug content. E.g. • Nitroglycerine releasing trans dermal system for once a day medication for angina KLE College of Pharmacy, Nipani.

46. 1. POLYMER MEMBRANE PERMEATION CONTROLLED SYSTEM • Scopolamine-releasing transdermal system for 72 hr. prophylaxis of motion sickness. • Clonidine releasing transdermal system for 7 day therapy of hypertension. • Estradiol-releasing transdermal system for treatment of menopausal syndrome for 3-4 days. KLE College of Pharmacy, Nipani.

47. = 1. POLYMER MEMBRANE PERMEATION CONTROLLED SYSTEM • The intrinsic rate of the drug release from this type of drug delivery system is defined by dq CR dt 1/pm + 1/pa KLE College of Pharmacy, Nipani.

48. 1. POLYMER MEMBRANE PERMEATION CONTROLLED SYSTEM • Pm and pa respectively defined as…. pm km/r . Da hm ka/m . Da ha = pa = KLE College of Pharmacy, Nipani.

49. 1. POLYMER MEMBRANE PERMEATION CONTROLLED SYSTEM • Where, • Km/r and ka/m are the partition coefficient for the interfacial partitioning of the drug from reservoir to the membrane and from the membrane to adhesive layer respectively. • Dm and Da are diffusion coefficient and • hm and ha are the thickness KLE College of Pharmacy, Nipani.

50. 1.POLYMER MEMBRANE PERMEATION CONTROLLED SYSTEM • Substituting the pm and pa equation in equation 1 dq km/r . Ka/m . Dm . Da dt km/r. Dm. ha + ka/m . Da . hm • Which define the intrinsic rate of drug release from a membrane moderated drug delivery system. = cr KLE College of Pharmacy, Nipani.