Transdermal drug delivery systems provide several advantages over oral drug administration, including avoidance of first-pass metabolism, controlled drug levels over time, and increased patient compliance. The structure of the skin, particularly the stratum corneum layer, influences drug permeation rates. Optimization of drug formulations includes the use of penetration enhancers to increase the drug's ability to partition into the skin. Examples of drugs delivered via transdermal patches include scopolamine for motion sickness, nitroglycerin for angina, and estradiol for hormone therapy.

1. Transdermal Drug Delivery

2. Transdermal Drug Delivery The structure of Human Skin Theoretical advantages of the transdermal route Optimization of percutaneous absorption Development of the transdermal therapeutic system Examples of transdermal applications Other transdermal systems Recent advances

3. I. Introduction Transdermal permeation (percutaneous absorption) The passage of substance from the outside of the skin through its various layers into the bloodstream Advantages of transdermal delivery system The system avoids the chemically hostile GI environment No Gi distress or other physiological contraindications of the oral route Can provide adequate absorption of certain drugs Increased patient compliance Avoids first-pass effect Allows effective use of drugs with short biological half-life Allow administration of drugs with narrow therapeutic windows Provides controlled plasma levels of very potent drugs Drug input can be promptly interrupted when toxicity occurs

4. Disadvantages of TDS Drug that require high blood levels cannot be administered Adhesive may not adhere well to all types of skin Drug or drug formulation may cause skin irritation or sensitization Uncomfortable to wear May not be economical Consideration of TDS development Bioactivity of drug Skin characteristics Formulation Adhesion System design Factors influence the permeation of drugs Skin structure and its properties The penetrating molecule and its physical-chemical relationship to skin and the delivery platform The platform or delivery system carrying the penetrant The combination of skin, penetrant, and delivery system

5. II. The Structure of Human Skin Human skin The stratified avascular cellular epidermis An underlying dermis of connective tissue Stratum corneum or horny layer Rate-limiting or slowest step in the penetration process Transport mechanism Transepidermal pathway across the horny layer either intra- or intercellularly Via hair folicles and sweat glands (the appendageal route)

6. Fig. 1 Basic diagram of skin structure.

7. Factor influence the transdermal route Time scale of permeation (steady-state vs. transient diffusion) Physicochemical properties of penetrant (pKa, molecular size, stability, binding affinity, solubility, partition coefficient) Integrity and thickness of stratum corneum Density of sweat glands and folicles Skin hydration Metabolism Vehicle effects Stable preparation of TDS Correct partition coefficient relative to the drug reservoir, device membrane and skin layers Rate-controlling membrane : low flux (skin act as a sink) Impermeability of stratum corneum : individual patient ’ s skin control drug input and significant biological variability

8. Partition into skin Prodrugs with low melting points Penetration-enhancing substances Microenviornment of the skin surface Light, oxygen, bacteria Change in skin flora with maceration and irritation of the skin – sweat gland ineffective Enzyme (80 to 90% as efficient as in the liver) Hydrolytic, oxidative, reductive and conjugative reaction Incorporate enzyme inhibitors

9. III. Theoretical Advantages of the Transdermal Route Variables associated with GI absorption First-pass effect Changes in pH Gastric emptying, intestinal motility and transit time Activity of human and bacterial enzymes Influence of food Percutaneous administration Control administration and limit pharmacological action Minimize pulse entry of a drug into the bloodstream Not deliberately provide a control on/off action Skin membranes : slow-response system with prolonged lag time

10. Fig. 2. Process of transdermal permeation.

11. IV. Optimization of Percutaneous Absorption Formulation of dermatological preparations Vehicle or device to maximize drug partition into the skin Incorporate penetration enhancer into formulation Enhancers Phamacologically inert, not interacting with receptors Neither toxic, irritating nor allergenic The onset of enhancer activity and the duration of effect : predictable and controllable Skin : immediate and full recovery Promote penetration without problems of loss of body fluids, electrolytes or other endogeneous materials Compatible with drug and adjuvants & A suitable solvent for drug Spread well on the skin &Formulate into cream, ointment, gel, lotion, suspension, aerosol, etc Odorless, tasteless, colorless, inexpensive

12. V. The Theory for Penetration-Enhancer Activity 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 Alter the packing of the lipid tails  disorder and traverse by a lipid-like penetrant

13. Solvents DMSO, propylene glycol, ethanol Partition coefficient elevate drug concentration in the skin Cosolvent Azone (1-dodecylazacycloheptane-2-one) Cis-unsaturated oleic acid Additive : PG  increase solubilizing ability for lipid-like materials Flip over to insert between the hydrophobic groups of the membrane lipids  increasing fluidity of lipid Interaction mechanism of solvents and surfactants with proteins Interaction with polar groups Relaxation of binding forces and alterations in helix conformations Pore route formation

14. VI. Development of the Transdermal Therapeutic System Transdermal Penetration of Drugs by Percutaneous absorption via diffusion Transcellular penetration through stratum corneum Intercellular penetration through stratum corneum Transappendageal penetration including the subaceous pathway and aqueous pathway of the salty sweat glands

15. Types of Transdermal Systems Transdermal systems are used for delivery of analgesics (fentanyl), hormone replacement therapies (estradiol and testosterone) and medications for angina (nitroglycerin), hypertension (clonidine), and motion sickness (scopolamine). Transdermal systems that deliver nicotine for use in smoking cessation are also available. In Japan and in parts of Europe, systems that incorporate antiinflammatory drugs (flurbiprofen and ketaprofen) and monoamine oxidase inhibitors such as selegiline have also been introduced. In this section, a review of a selected group of systems is provided with an emphasis on product characteristics and the clinical performance measures of safety, efficacy, reliability, and acceptability of drug treatment

16. B. Formulation Platform for the drug A liquid : well-constrained A semisolid : ointment, semisolid gel A non-flowing material Polymeric film or rubbery gels Solid-state platform Combination Types of platform Monolith, slabs, reservoirs, vehicles, films, polymer matrix Films : nature (natural or synthetic), structure (porous or nonporous)

17. C. Adhesion Adhesion Good skin contact Good bonding between laminating layers Properties of pressure-sensitive adhesives Adhesive-cohesive properties Peel strength Tack and creep quality of adhesive Occlusive (serve as barrier such as vinyl, PE, polyester film) Nonocclusive (allow water and gases to flow through films)

18. Pressure-sensitive adhesive ASTM (American Society for Testing and Materials) definition : viscoelastic material which remains permanently tacky Remove from a surface without leaving a residue Natural or synthetic rubbers, polyacrylates, silicone Release liner (release paper, peel-away strip) Sheet that serve as a protectant or carrier for an adhesive film (easily removed) Paper, polystyrene or polyester films with coating of silicone, long-chain branched polymers, chromium complex, fluorochemicals or various hard polymers

19. D. Bioactivity Trandermal drug delivery Minimize the fluctuating levels of drug in the blood Provide drug level within the limits of the therapeutic windows Pharmacokinetic view Prolonged steady-state blood levels by adjusting drug loading, vehicle components, and surface area

20. VII. Examples of Transdermal Applications Monolithic systems Nitrodur and Nitrodisc Manufacture drug reservoir with polymer with subsequent casting and drying Punch from sheet or sliced cylinder Assembled with the system backing, peripheral adhesive and protective liner Membrane-controlled transdermal system Transderm-Nitro, Transderm-Scop Form-fill-seal from lamination process

21. Fig. System Controlled Drug Delivery System

22. Fig. 3. Types of transdermal delivery devices.

23. Hormones Estradiol and progesterone Avoid hepatic metabolism Cardiovascular drugs Hypertension and angina Betablockers : timolol, propranolol Hepatic metabolism of propranolol Analgesics Control of chronic pain by transdermal therapy Antihistamines Treatment of allergy Chlorpheniramine Maintain histamine-receptor antagonism while reducing CNS side effects such as drowsiness Central nervous system drugs Physostigmine : cholinesterase inhibitors To inhibit breakdown of acetylcholine by 30 to 40% over 4d

24. Table 1 Transdermal Controlled-Release Products and Devices Drug Trade Name Type of Devices Indication Scopolamine Transderm-Scop Reservoir Motion sickness Nitroglycerine Transderm-Nitro Reservoir Angina Nitro-Dur Monolithic Nitrodisc Monolithic Estradiol Estraderm Reservoir and ethanol enhancer Hormone treatment

25. Table 2 Transdermal Products under Development Drug Trade name Producer-Marketer Minocycline Sunstar American Cyanamide, Takeda Estradiol+Norethisterone Estracombi TIS Ciba-Geigy, Alza DHEA Pharmedic Fentanyl Triamcinolone acetonide Whitby Pharm.

26. Drug development using TTS Ketoprofen, 5-Fu, metoprolol, terodiline, primaquine, ibuprofen, piconol, nitrendipine, diclofenac, corticosteroids, sandimune (cyclosporine A), fluazifopbutyl, glyceryl trinitrate, azo-profen esters, methotrexate, medroxyprogesterone acetate, levonorgestrel, mepindolol, oxycodone, prostaglandins, 9-  - D -arabinofuranosyladenine (Ara-A) Iontophoresis Built-in battery layer Comparable in size to a normal transdermal patch The Lectro Patch, General Medical Co. Treatment time : 20 min Recommended maximum current : 4mA Lidocaine (local anesthesia), dexamethasone (arthritis), hydrocortisone (arthritis), acetic acid (calcified tendinitis) etc.

27. Fig. 4. Schematic diagram illustrating the principles of iontophoresis.

28. VIII. Other Transdermal Systems Lectec Co. A solid-state, hydrophilic reservoir system Health-Chem Co. Transdermal laminar system Elan Co. Absorbed from bracelets by electrical impulses Molecular Biotech Co. Proplastic membrane (molecular sponge)

29. IX. Recent Advances Rolf Amphoteric enhancers : SLS, lauryl amine oxide, Azone decylmethylsulfoxide, lauryl ethoxylate, octanol PSA (pressure sensitive adhesives) Adhesive matrix, multilaminated PSA matrix Adverse interaction between the drug, exicipents, cosolvents and permeation enhancers in reservoir and matrix-type system Silicone PSA : tack, adhesion, cohesive strength Polydimethylsioxane PSA : biocompatibility and high permeability

30. Actiderm (Bristol Myers Squibb) Path with no drug as occlusive dressing Placed over topically applied corticosterids to enhance efficacy by promoting hydration of the stratum corneum Laminated reservoir system by Hercon Steady-state blood levels for extended periods Two or four layers, including a backing membrane, the drug reservoir, a rate-controlling membrane, and an adhesive Ketobemidone and carbonate ester prodrug Prodrug with isopropyl myristate, ethanol and ethanol-water readily penetrate the skin Enzymatic conversion, high solubility of prodrug in polar and apolar solvents

31. X. Conclusion Critical parameter in designing a TDS Drug stability, physical stability of the formulation, irritation and sensitization properties, preservation and esthetic acceptability Vehicle affect drug bioavailability Maximizing drug penetration into skin Two mechanism that manipulate the diffusion of a drug across the skin Change the degree of interaction between drug and vehicle (drug ’ s thermodynamic activity) Changes in the stratum corneum that will affect its diffusional resistance (vehicle-barrier interaction )

32. Transdermal therapy 70% or more of all drugs : potentially delivered by TDS Limitation : drug potency, skin permeability, topical reaction, cutaneous metabolism, delivery by small volume of skin Further TTS : use of prodrug, penetration enhancer and specific nontoxic enzyme inhibitors Peptide delivery biotechnology Penetration enhancer and iontophoresis