Pharmaceutical Dosage
Factors Affecting Percutaneous Absorption
Chapter 11: Transdermal Drug Delivery Systems
Topical Dermatological Products
Drugs delivered into the skin for treatment of dermal disorders For local effects Skin as the target organ
Transdermal Products
Drugs delivered through the skin absorption) to the general circulation For systemic effects Skin: not the target organ
(percutaneous
Transdermal Drug Delivery System (TDDS)
Facilitate the passage of therapeutic quantities of drug substances through the skin and into the general circulation for their systemic effects Transderm scop First transdermal (Ciba, now Novartis) approved by the FDA in 1979 Prevents motion sickness, nausea, and vomiting resulting from the use of certain anesthetics
Cadaver Skin Permeation Testing
Evidences of percutaneous drug absorption Measurable blood levels of the drug Detectable excretion of the drug and/or its metabolites in the urine Clinical response of the patient to the therapy Blood concentration needed to achieve (with TDDS) therapeutic efficacy determined by: Comparative analysis of the patient’s response to the drug blood levels Ideal for the drug To migrate through the skin: blood supply without build up in the dermal layers
Stratum Corneum
Skin is composed of: Stratum corneum (the outer layer) Living epidermis Dermis: provide the skin barrier (blockade) layers to penetration by e xternal agents Stratum corneum (keratinized tissue: major rate limiting barrier of TDDS) Behaves as a semipermeable artificial membrane drug molecules penetrate by passive diffusion
Drug Penetration in the Barrier
Drug molecules through the stratum corneum: deeper epidermal tissues: dermis: vascularized dermal layer, Becomes available for absorption into the general circulation Good candidates for diffusion through the stratum corneum, epidermis, and dermis: aqueous and lipid soluble substances
Helps determine the feasibility of a compound to be incorporated into a TDDS
Chemical Enhancers
Evidences of Percutaneous Drug Absorption
Physical and chemical properties of drugs including its molecular weight, solubility, partition coefficient, and dissociation constant, the nature of the carrier vehicle, and the conditioning of the skin Drug concentration Area of application: the larger, the more drug is absorbed Greater physiochemical attraction to the skin than to the vehicle Can permeate skin: with molecular weights ranging from 100 to 800 (ideal molecular weight for TDDS: 400 or less) and adequate lipid and aqueous solubility Hydration of the skin favors percutaneous absorption Site with a thin horny layer than with a thick one The longer the medicated application is permitted to remain in contact with the skin and the greater is the total drug absorption
Chemical skin permeation enhancer: increases skin permeability by damaging or altering the physiochemical nature of the stratum corneum to reduce its diffusion substance Among the alterations of the stratum corneum are: Increased hydration of the stratum corneum Change in the structure of lipids and lipoproteins in the intercellular channels through solvent action or denaturation or both Some drugs inherent capacity to permeate the skin without chemical enhancer. Chemical permeation enhancer: render impenetrable substance useful in TDDS More than 275 chemical compounds have cited as skin penetration enhancers that include: acetone, azone, dimethyl acetamide, dimethly formamide, dimethyl sulfoxide, ethanol, oleic acid, PEG, PG, and sodium lauryl sulfate
Physical Methods to Enhance TDDS
Iontophoresis Delivery of charged chemical compounds across the skin membrane using an applied electrical field Drugs examined: lidocaine, dexamethasone, amino acids, peptides, insulin, verapamil, propanolol, Delivered by rapid injection because of rapid metabolism and poor absorption in oral delivery and from TDDS (large molecular size, ionic character) Enhance TDDS for peptide or protein administration
Different Purposes for In-Vivo Skin Penetration Studies
To verify and quantify: Cutaneous bioavailability of a topically applied drug Systemic bioavailability of a transdermal drug To establish bioequivalence of different topical formulations of the same drug substance To determine the incidence and degree of systemic toxicological risk following topical application of a specific drug or drug product To relate resultant blood levels of drug in human to systemic therapeutic effects
In-Vivo Skin Penetration Studies
Most relevant studies performed in humans and animal models (predictors of human response)
Materials Used In-Vitro Skin Penetration Studies
Skin penetration may be tested in vitro using: Various skin tissues (human or animal) in a diffusion cell Using human skin: limited because of difficulties of procurement, storage, expense, and variation in permeation Animal skin: shown to be effective like shed snakeskin (Elaphe obsolete, black rat snake) which is nonliving, pure stratum corneum, hairless and similar to human skin but slightly less permeable Living Skin Equivalent (LSE) Test Skin (Organogenesis Inc.) Product developed as an alternative for dermal absorption studies An organotypic culture of human dermal fibroblasts in a collagen-containing matrix and stratified epidermis composed of human epidermal keratinocytes
Diffusion Systems and Principle Utilized
Diffusion cell systems Employed in vitro to quantify the release rates of drugs from topical preparations Skin membranes or synthetic membranes employed as barriers to the flow of drug and vehicle to stimulate the biologic system
The Transderm-Nitro System Comprises of Four Layers
Monolithic system Incorporate a drug matrix layer between backing and frontal layers Drug matrix layer Composed of polymeric material
A tan-colored backing layer (aluminized plastic) that is impermeable to nitroglycerin A drug reservoir or matrix system containing nitroglycerin adsorbed on lactose, colloidal silicon dioxide, and silicon medical fluid An ethylene-vinyl acetate copolymer membrane that is permeable to nitroglycerin A layer of hypoallergenic silicon adhesive: a protective peel strip that is removed from the adhesive surface prior to use
Different Layers of the Transdermal Drug Delivery System
Two Categories of the TDDS
Controls the rate at which the drug is released for percutaneous absorption 2 types either with or without an excess of drug with regard to its equilibrium solubility and steady: state concentration gradient at the stratum corneum As the concentration of the drug in the device diminishes below the skin’s saturation limit Transport of drug from device to skin declines Most TDDs designed to contain an excess of drug Drug-releasing capacity beyond the time frame recommended for replacement Membrane-controlled transdermal system Designed to contain drug reservoir or pouch (in liquid or in gel form, a rate controlling membrane) Backing, adhesive, and protecting layers Examples of this technology: TransdermNitro (Novartis) and Transderm-Scop (Novartis) Advantage over monolithic systems: release rate of drug remains constant when the drug solution in the reservoir remains saturated Prepared by preconstruction of the delivery unit filling the drug reservoir: sealing or lamination Continuous process Serves as a rate-controlling mechanism or factor: Drug delivery device o If the drug is delivered to the stratum corneum at a rate less than the absorption capacity Skin o If the drug is delivered to the skin area to
Sonophoresis Studied as a means to enhance TDDS Influence integrity of stratum corneum and thus affect penetrability Agents examined: hydrocortisone, lidocaine, and salicylic acid in such formulations as gels, creams and lotions
Occlusive or blockade backing membrane Protects the system from environmental entry and from loss of drug from the system or moisture from skin Drug reservoir or matrix system Stores and releases the drug at the skin site Release liner Removed before application and enables drug release
Adhesive layer Maintains contact application
with
the
skin
after
Backing Layer
Must be occlusive To retain the skin moisture and hydrate the site of application for increase drug penetration Used as backing liners Transparent or pigmented films of propylene, polyethylene, and polyofelin
Examples of Transdermal Drug Delivery Systems
Adhesive Layer
Must be pressure sensitive Adheres to the skin with minimal pressure and remains in place for intended period of wear Should be non-irritating, permit unimpeded drug flux to the skin, compatible with all other systems, allow easy peel-off after use Commonly used as adhesive: polybutyl acrylate
Different Design Objectives of TDDS
Deliver the drug to the skin for percutaneous absorption at therapeutic levels at an optimal rate Contain medicinal agents having necessary physiochemical characteristics to release from the system, and partition to the stratum corneum Occlude the skin to ensure one w ay flux of drug into the stratum corneum Have a therapeutic advantage over other dosage forms and drug delivery systems No irritation or sensitize the skin Adhere well to the patient’s skin and have size, appearance, and site placement that encourage acceptance
Advantages of TDDS
Avoid: Gastrointestinal absorption difficulties First-pass effect Inconvenience of parenteral therapy Substitute for oral administration of medication Provide extended: Therapy with a single application Activity of drugs having a short half- life through the reservoir of drug in the therapeutic delivery system and its controlled release Drug therapy may be terminated rapidly by removal of the application from the surface of the skin Identified easily and rapidly in emergencies
Disadvantages of TDDS
Only relatively potent drugs are suitable candidates for transdermal delivery Some patients develop contact dermatitis at the site of application
Transdermal Scopolamine (transderm scop system) Patch is worn (at least 4 hours before the anti nausea effect effect is required) in a hairless hairless area area behind the ear Prevents motion sickness, nausea and vomiting resulting from the use of certain anesthetics and analgesics used in surgery Transdermal Nitroglycerin For prophylactic treatment of angina When taken sublingually: relatively low dose, short plasma half-life, high peak plasma levels, and inherent side effects Examples: Deponit (Schawarz), Minitram (3M Pharmaceuticals), Nitro-Dur (Key), and Transderm-Nitro Transderm-Nitro (Novartis) Transdermal Clonidine (Catapres TTS) First trandermal system for hypertension Transdermal Nicotine (Nicotrol) As adjunct in smoking cessation programs Effective aid in quitting smoking Provides sustain blood levels of nicotine replacement therapy Transdermal Estradiol Treatment of moderate to severe vasomotor symptoms associated with menopause, female hypogonadism, female castration, primary ovarian failure, and atrophic conditions caused by deficient endogenous estrogen production (atrophic vaginitis and kraurosis vulvae) Examples: Vivelle (Novartis) Transdermal Testosterone For optimal absorption, applied to clean, dry scrotal skin that has been dry-shaved Placed on the scrotum (stretching the scrotal skin with one hand and pressing the adhesive side of the TDDS against the skin with the other hand, holding it in place for about 10 seconds) Androderm TDDS: applied nightly to a clean, dry unbraded area of the skin of the back, abdomen, upper arms, or thighs
Other Transdermal Therapeutic Systems
Include: Diltiazem, isosorbide dinitrade, propranolol, nifedipine, mepindolol, and verapamil, cardiovascular agents Levonorgestrel with estradiol for hormonal contraception Physostigmine and xanomeline for Alzheimer’s disease therapy Naltrexone and methadone for substance addiction Buspirone for anxiety Bupropion for smoking cessation Papaverine for male impotence
General Clinical Considerations in the Use of TDDSs
Percutaneous absorption varies with the site of application Applied to clean, dry skin: relatively free of hair and not oily, irritated, inflamed, broken, or callused Use of skin lotion: avoided at the application site: affect skin hydration and can alter the partition coefficient between the drug and the skin Should not be physically altered by cutting since it destroys the integrity of the system Should be removed from its protective package or backing Placed at a site not subjected to being rubbed off by clothing or movement Worn for full period stated in the products instructions The patient or caregiver should clean the hands thoroughly before and after applying TDDS. In case of sensitivity or intolerance, the patient should seek revaluation TDDS should be folded in half: cannot be reused
Crystal Reservoir Technology
Resulted in smaller patches with a more controlled and sustained drug release
Single Layer Drug-in-Adhesive
Backing Drug-in-adhesive Liner
Multilayer Drug-in-Adhesive Drug-in-Adhesive
Backing Drug-in-adhesive Membrane Drug-in-adhesive Liner
Drug Reservoir-in-Adhesive
Backing Drug Membrane Adhesive Liner
Drug Matrix-in-Adhesive
Backing Adhesive Drug liner
Therapeutic Agent Clonidine
Estradiol
TDDS Catapres-TTS (Boehringer Ingelheim)
Estraderm (Novartis)
Design and Content
Comments
Four layer patch: (a) Backing of pigment polyester film (b) Reservoir of clonidine, mineral oil, polyisobutylene, colloidal silicone dioxide (c) Microporous polypropylene membrane controlling rate of delivery (d) Adhesive formulation of agents Four layer patch: (a) Transparent polyester film (b) Reservoir of estradiol, alcohol gelled with hydroxypropyl cellulose, (c) Ethylene vinyl acetate copolymer membrane (d) Adhesive formulation of light mineral oil, polyisobutylene
Transdermal therapeutic system to deliver therapeutic dose of antihypertensive drug at constant rate for 7 days. TDDS generally applied to hairless or shave are of upper arm or torso
Transdermal system to release 12b-estradiol continuously. Patch is generally applied to trunk, including abdomen and buttocks, alternating sites twice a weekly over 3-week cycle with dosage frequency adjusted as required
Vivelle (Novartis)
Three-layer patch: Use and application similar to Estraderm (a) Translucent ethylene vinyl alcohol TDDS copolymer film (b) Estradiol in matrix of medical adhesive of poly isobutylene, ethylene vinyl acetate copolymer (c) Polyester release liner, removed prior to application
Climara (Berlex )
Three-layer patch: (a) Translucent polyethylene film (b) Acrylate adhesive matrix containing estradiol (c) Protective liner of siliconized or fluoropolymer-coated polyester film, removed prior to use Four layer patch: (a) Backing layer of polyester film (b) Reservoir of fentanyl, alcohol gelled with hydroxyethyl cellulose (c) Rate controlling ethylene-vinyl acetate copolymer membrane (d) Fentanyl containing silicone adhesive Multilayer round patch: (a) Aluminized backing film (b) Pressure sensitive acrylate adhesive (c) Methacrylic acid copolymer solution of nicotine dispersed in pad of nonwoven viscose, cotton (d) Acrylate adhesive layer (e) Protective aluminized release liner that overlies adhesive layer, removed prior to use
Fentanyl
Duragesic (Janssen)
Nicotine
Habitrol (Nivartis Consumer)
Nicoderm CQ (SmithKline Beecham Consumer)
Multilayer rectangular patch: (a) Occlusive backing of aluminum, polyester, ethylene-vinyl acetate copolymer (b) Reservoir of nicotine in ethylene-vinyl acetate copolymer matrix (c) Rate-controlling polyethylene membrane (d) Polyisobutylene liner, removed prior to application
Nicotrol
Multilayer rectangular patch:
Use and application similar to Estraderm TDDS and system may be applied weekly
Transdermal therapeutic system providing continuous 72 hour systemic delivery of potent opioid analgesic and indicated in patients with chronic pain requiring opioid analgesia
Transdermal therapeutic system providing continuous release systemic delivery of nicotine to aid smoking smoking cessation. Patched somewhat vary in nicotine content and dosing schedules.
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(McNeil Consumer)
(a) Outer backing of laminated polyester film (b) Rate-controlling adhesive nonwoven material, nicotine (c) Disposable liner, removed prior to use
Prostep (Lederie)
Multilayer round patch: (a) Beige foam tape acrylate adhesive (b) Backing foil gelatin low density polyethylene coating (c) Nicotine gel matrix (d) Protective foil with well (e) Release liner removed prior to use Three-layer system: (a) Covering foil (b) Nitroglycerin matrix with polyisobutylene adhesive, plasticizer, release membrane (c) Protective foil, removed prior to use Nitroglycerin in gel like matrix of glycerin water , lactose polyvinyl alcohol, povidone, sodium citrate sealed in polyester, foil, polyethylene laminate Four-layer patch: (a) Backing layer of aluminized plastic (b) Reservoir of nitroglycerin absorbed on lactose, colloidal silicone dioxide, ilicone medical fluid (c) Ethylene-vinyl acetate copolymer membrane (d) Silicone adhesive Four Layer patch: (a) Backing layer of aluminized polyester film (b) Reservoir of scopolamine, mineral oil, polyisobutylene (c) Microporous polypropylene membrane for rate delivery of scopolamine (d) Adhesive of polyisobutylene, mineral oil, scopolamine Three-layer patch: (a) Backing layer of polyethylene terephthalate (b) Matrix film layer of testosterone, ethylene-vinyl actetate copolymer (c) Adhesive strips of polyisobulylene, colloidal silicone dioxide
Nitroglycerin
Deponit (Schwarz Pharma)
Nitroglycerin
Nitro- Dur (Key)
Nitroglycerin
TransdermNitro (Novartis)
Scopolamine
Transderm Scop (Novartis Consumer)
Testosterone
Testoderm (Alza)
Adroderm (SmithKline Beecham)
Five-layer patch: (a) Backing film of ethylene-vinyl acetate copolymer, polyester laminate (b) Reservoir of testosterone, ,alcohol, glycerin, glyceryl monoleate, methyl laureate gelled with acrylic acid copolymer (c) Microporous polyethylene membrane (d) Acrylic adhesive (e) Adhesive polyester laminate
Continuous release of drugs over 3 days to prevent nausea, vomiting of motion sickness. Patch is placed behind ear. For repeated administration, first patch is removed and second placed behind other ear. Also approved to prevent nausea of certain anesthetics and analgesics during surgery. Patch is placed on scrotum in treatment of testosterone deficiency
Patch is placed on back, abdomen, upper arms, or thighs for treatment of testosterone deficiency
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