Transdermal drug delivery system (2)


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Transdermal drug delivery system (2)

  2. 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. 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. 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. 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. 6. Fig. 1 Basic diagram of skin structure.
  7. 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. 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. 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. 10. Fig. 2. Process of transdermal permeation.
  11. 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. 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. 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. 14. VI. Development of the Transdermal Therapeutic SystemA. Transdermal Penetration of Drugs 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. 15. 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)
  16. 16. 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)
  17. 17.  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
  18. 18. 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
  19. 19. 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
  20. 20. Fig. 3. Types of transdermal delivery devices.
  21. 21.  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
  22. 22. Table 1 Transdermal Controlled- Release Products and DevicesDrug Trade Name Type of Devices IndicationScopolamine Transderm-Scop Reservoir Motion sicknessNitroglycerine Transderm-Nitro Reservoir Angina Nitro-Dur Monolithic Nitrodisc MonolithicEstradiol Estraderm Reservoir and Hormone ethanol treatment enhancer
  23. 23. Table 2 Transdermal Products under DevelopmentDrug Trade name Producer-MarketerMinocycline Sunstar American Cyanamide, TakedaEstradiol+Noret Estracombi Ciba-Geigy, Alzahisterone TISDHEA PharmedicFentanylTriamcinolone Whitby Pharm.acetonide
  24. 24.  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-β-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.
  25. 25. Fig. 4. Schematic diagram illustrating the principles of iontophoresis.
  26. 26. 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)
  27. 27. 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
  28. 28.  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
  29. 29. 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)
  30. 30.  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
  31. 31. THANK YOU