Transdermal Delivery - Lecture Notes

Transdermal Delivery Dr Medha D Joshi Professor and Chair Department of Pharmaceutical Sciences Transdermal Drug Delivery › Facilitates passage of therapeutic quantities of drugs through the skin and into general circulation for their systemic effects – Do not want buildup of drug in dermal...

Transdermal Delivery Dr Medha D Joshi Professor and Chair Department of Pharmaceutical Sciences Transdermal Drug Delivery › Facilitates passage of therapeutic quantities of drugs through the skin and into general circulation for their systemic effects – Do not want buildup of drug in dermal layers of skin › Different than topical – Topical: › Intent is not for drug to get into systemic circulation › Target organ is skin Transdermal Therapeutic Systems (e.g. Patches) › An adhesive medicated patch placed on the skin to deliver its drug through the epidermis › Limitations on ideal candidates for TDD › Penetration enhancers may be part of the formula. › Several chemicals (e.g. ethanol, PG) are capable of increasing SC permeation › Follow manufactures recommendations for placement sites › For a particular patch, size (S.A) determines the amount of drug released over time Percutaneous absorption › “Through the skin” › Direct penetration through stratum corneum – No significant absorption through: › Hair follicles › Sweat glands › Sebaceous glands – Results in: › Measurable blood levels › Detectable excretion of drug or metabolites in urine › Clinical response Skin › pH of the skin is 5.4 to 5.9 › Drugs pass through by passive diffusion › Largest organ › Thickness of skin (epidermis) varies: thick on palms and thin on eyelids Skin Layers 1. Epidermis – Stratum corneum (SC) – Granular layer – Basal layer 2. Dermis 3. Subcutaneous tissue lies beneath skin layers Source: https://en.wikiversity.org/wiki/File:Blausen_0810_SkinAnatomy_01.png Stratum corneum (SC) › Outermost layer made up of dead flattened cells › Brick and mortar structures › Brick = cells and mortar = lipid bilayer › Composed of: – ~ 40% protein (mainly keratin) – ~ 40% water – ~ 20% lipid – Major factor and rate-limiting factor in the 1st step of the absorption process – Behaves as a semi-permeable membrane Granular and Basal Layers › Also part of epidermis – Consist of keratinocytes – Langerhans cells present are part of body defense mechanism › Granular layer lies beneath SC › Basal layer lies beneath granular – Includes melanocytes Dermis › 3-5 mm thick › Consists of: – Matrix of fibrous proteins › Collagen › Elastin › Reticulin – Embedded in a mucopolysaccharide ground substance – Nerves, blood vessels and lymphatics traverse matrix – Eccrine sweat glands, apocrine glands and pilosebaceous units pierce matrix Source: https://en.wikiversity.org/wiki/File:Blausen_0810_SkinAnatomy_01.png Dermis › Blood supply: – Conveys nutrients – Removes waste products – Regulates pressure and temperature – Mobilizes defense forces – Allows for drug absorption › Generous blood volume in the skin acts as a “sink” for diffusing molecules – drug concentration in skin is constantly depleted due to blood flow, allowing more drug molecules to diffuse into the skin from the dosage form Deeper Epidermal Tissues and Dermis › Drug passes through epidermis › Reaches vascularized dermal layer › Becomes available for absorption into the general circulation because of rich vascular network in the dermis Subcutaneous tissue › Provides protective padding › Varies in thickness in body › Some lipophilic drugs accumulate in adipose tissue instead of entering bloodstream Drug Transport Through Skin Drug Transport Through Skin › Passive diffusion › Rate of drug transport across SC follows Fick’s Law of Diffusion › Wherein, = steady state flux across SC › D = diffusion coefficient › ΔC = drug concentration gradient across SC › K = partition coefficient of drug between skin and formulation medium › h = thickness of SC Biological Factors Affecting Drug Absorption Skin condition – Intact, healthy skin is a tough barrier – Can be damaged: › Acids and alkalis › Cuts and abrasions › Dermatitis – Corns, calluses and warts can decrease skin permeability Biological Factors Affecting Drug Absorption Thickness of skin – Absorption is greater when a transdermal medication is applied to skin site with a thin (rather than thick) horny layer not subject to friction or mechanical stresses Good locations: Poor locations: Elbows Upper arm Feet Abdomen Back Buttocks Beltline Biological Factors Affecting Drug Absorption Skin metabolism: – Skin metabolizes: › Steroid hormones › Chemical carcinogens › Some drugs – Could be useful in prodrug delivery Physicochemical Factors affecting Drug Absorption Skin hydration – When water saturates the skin: › The tissue swells, softens and wrinkles › Permeability markedly increases – One of the most important factors in increasing penetration rate of most substances through the skin – Occlusive plastic films may be used to increase drug penetration › Perspiration accumulates  Expected effects of skin delivery systems on horny layer hydration and skin permeability Delivery System Examples/ Constituents Effect on skin hydration Effect on skin permeability Occlusive Dressing Plastic film, unperforated water- Prevents water loss; full hydration Marked increase proof plaster Occlusive Patch Most transdermal patches Prevents water loss; full hydration Marked increase Lipophilic Material Paraffins, fats, oils, waxes, fatty Prevents water loss; may produce Marked increase acids and alcohols, esters, silicones full hydration Absorption/ Anhydrous lipid material plus Prevents water loss; marked Marked increase Emulsifying Base water/oil emulsifiers hydration Water/Oil Emulsion Oily creams Retards water loss; raised Increase hydration Oil/Water Emulsion Aqueous creams May donate water; slight Slight increase? hydration increase Humectants Water-soluble bases, glycerol, May withdraw water; decreased Can decrease or act as glycols hydration penetration enhancer Powder Clays, organics, inorganics, ‘shake’ Aid water evaporation; decreased Little effect on stratum lotions excess hydration corneum Physicochemical Factors affecting Drug Absorption Drug concentration – Drug moves from area of high concentration to low – Transdermal Drug Delivery Systems (TDDS) typically contains more drug than is intended to be delivered to the patient, to maintain concentration gradient Physicochemical Factors affecting Drug Absorption Partition coefficient and solubility of the drug › Drug should have greater physical attraction to the skin than to the vehicle inside the TDDS or ointment/cream base – Aqueous solubility: determines the concentration presented to the absorption site – Partition coefficient: influences the rate of transport across the absorption site – Drugs generally penetrate through the skin better in their un-ionized form – Drug needs adequate lipid and aqueous solubility › Factors can oppose each other › Leads to complications in formulation development Physicochemical Factors affecting Drug Absorption Molecular size of drug – Absorption is inversely proportional to MW – Small molecules penetrate faster – Large molecules penetrate more slowly MW of drug: – MW below 600 Da preferred – Below 800 typically can cross skin membranes Other factors affecting percutaneous absorption Surface area – Apply drug / delivery system to larger area of skin  more chance for absorption › Apply cream or ointment over larger area of skin › Use larger TDDS Other factors affecting percutaneous absorption Duration of contact – In general, longer contact  greater drug absorption – Keep ointment/cream from rubbing off skin before absorption has occurred – TDDS (with drug remaining) left in contact with skin Other factors affecting percutaneous absorption Temperature of the skin – Heat dilates blood vessels therefore increasing the blood circulation and increasing absorption – Similarly use of vasodilators have an effect on percutaneous absorption of drug Conventional Transdermal Formulations Conventional Transdermal Formulations › Examples: – Ointments – Creams – Gels Conventional Transdermal Formulations › Advantages › Disadvantages – Relatively inexpensive and – Relies on patient dexterity easy to manufacture – Variability and poor – Associated with fewer local reproducibility of the skin reactions than patches amount of drug delivered › Lack of adhesive – Product may be transferred from the individual being treated to another individual through accidental skin contact – Messy; affects patient adherence Conventional Transdermal Formulations › Why the variability and poor reproducibility? – Improper application technique – Application of too little or too much product – Removal of the product from application site by rubbing it off on clothes or other surfaces before absorption Conventional Transdermal Formulations › Nitroglycerin ointment – 2% w/w – Used to prevent chronic chest pain caused by heart disease – Dose measured out onto calibrated paper – Must wash hands following application › Ideally, wear gloves › What might happen if caregiver is accidentally exposed? – Less expensive than patch Conventional Transdermal Formulations › Hormone replacement products – Testosterone, estrogens, progesterone – Frequently compounded in past; compounding volume will likely decrease with implementation of USP – Some products available commercially Conventional Transdermal Formulations › AndroGel – Testosterone 1% (w/w) – Applied to shoulders, upper arms, or stomach › Areas that can be covered by a short sleeve t-shirt › Prevents product from transferring to others › Let dry before putting on shirt › Wash hands following application › Do not shower or swim for 4-6 hours Conventional Transdermal Formulations › EstroGel – Estradiol 0.06% (w/w) – Hydroalcoholic gel › Contains Carbopol – Packaged as metered dose pump › Each pump administers 0.75 mg estradiol – Apply to 1 arm, from wrist to shoulder › Dries in 2-5 minutes › Wash hands thoroughly to avoid spread of medication Conventional Transdermal Formulations › EvaMist – Estradiol transdermal spray – Underwent safety review by FDA – boxed warning added re: unintentional secondary exposure › Reports of unintended exposure to children and animals › Why this system but not other transdermal estrogens? Transdermal Drug Delivery Systems General Design Features of TDDS › Individually packaged and sealed to preserve and protect until use › Composed of a number of layers, including: 1. Impermeable backing layer 2. Drug reservoir or matrix system 3. Rate-controlling membrane 4. Adhesive layer 5. Release liner / protective cover / peel-back liner Rate-controlling mechanism › Device: – If the drug is delivered to the stratum corneum at a rate less than the absorption capacity › Skin: – If the drug is delivered to the skin area at saturation level TDDS Layers 1. Impermeable backing membrane: – Blocks passage of: › Drug from the system › Influences from outside environment (including moisture) › Moisture from the skin – Helps hydrate the skin, enabling increased drug penetration – 2-3 mm thick – Made from: › Transparent or pigmented polymer film TDDS Layers 2. Either a drug reservoir or a matrix system: – Stores and releases the drug at the skin site – Information about the differences in upcoming slide 3. A release membrane (sometimes called rate- controlling membrane) – May or may not be present 4. A release liner – Removed before application – Enables drug release TDDS Layers 5. An adhesive layer – Maintains contact with skin after application – Must be pressure-sensitive › Able to adhere to the skin with minimal pressure › Remain in place for the intended period of wear – Should: › Be non-irritating › Allow easy peel-off after use › Be compatible with other system components Failure of adhesive layer › Many failures reported to the FDA › Patch no longer attached to the patient › Leads to: – Decreased absorption / clinical effects – Accidental overdose in children who pick up the patch › Cost implications: – Patch needs to be replaced if adhesive stability is poor Types of TDDS Matrix Systems 43 Types of TDDS: Matrix › Matrix systems – AKA monolithic – Drug dispersed in matrix that lies between backing and adhesive layers, or within adhesive itself › Matrix controls rate of drug release › Drug and matrix are dissolved or blended together, cast as the matrix, and dried › The gelled matrix is produced in sheets or cylinders and cut to size Types of TDDS: Matrix › Matrix systems Types of TDDS: Matrix › Matrix systems – Classified by amount of drug present with regard to its equilibrium solubility and steady state concentration gradient at the stratum corneum 1. Without an excess of drug 2. With an excess of drug Types of TDDS: Matrix › Matrix systems 1. Without an excess of drug › Drug maintains saturation at stratum corneum only as long as the level of drug in the device exceeds the solubility limit of the stratum corneum › As matrix concentration drops below skin concentration, the transport of drug from the device to the skin gradually declines Types of TDDS: Matrix › Matrix systems 2. With an excess of drug › Drug reserve ensures continued drug saturation at the stratum corneum › Rate of drug delivery decreases more slowly than in TDDS without excess drug › Most TDDS are designed this way – Drug-releasing capacity beyond the time frame recommended for replacement – Ensures continuous drug availability and absorption – Used TDDS replaced on schedule with fresh ones Types of TDDS Reservoir Devices Types of TDDS: Reservoir › Reservoir Systems – AKA membrane-controlled systems – Designed to contain: › A drug reservoir or “pouch”, usually in liquid or gel form › A rate-controlling membrane › Backing, adhesive, and protecting layers – A small amount of drug is frequently placed in the adhesive layer › Initiates prompt absorption Types of TDDS: Reservoir › Reservoir Systems (Transderm-Nitro) Provides a more consistent drug release as compared to monolithic systems Types of TDDS: Reservoir › Reservoir Systems – Made by either: › Pre-constructing the delivery unit, filling the reservoir, and sealing › Lamination process (continuous process of construction, dosing and sealing) Types of TDDS: Reservoir › Reservoir Systems –Micro-reservoir systems › Subcategory › Contain several small reservoirs of drug enclosed between backing and rate-controlling membrane, rather than one large reservoir Transderm Scop® A comparison Practice Question › Which of the following statements regarding membrane-controlled transdermal systems is true? – LO 2 – a. Can result in contact dermatitis after application to the skin – b. Might contain some drug within the adhesive layer for “immediate” delivery – c. Often result in a more consistent drug delivery as compared to monolithic systems – d. b & c – e. All of the above Drugs Available in TDDS Not an all-inclusive list Transdermal Scopolamine (FYI) › First TDDS on the market › Indication: – Prevention of motion sickness › Products available: – Transderm Scōp › 72 hour duration › Type of system: – Reservoir Transdermal Nitroglycerin (FYI) › Indication: – Management of angina › Products available: – Minitran: 4 strengths available – Nitro-Dur: 6 strengths available – Various generic manufacturers › Daily dosing › Type of system: – Matrix Transdermal Estradiol (FYI) › Indication: – Hormone replacement therapy – May be given on continuous basis in patients without intact uterus – Typically given on cyclic basis (3 weeks on, 1 week off) in patients with an intact uterus – Several products available › Some combination products with norethindrone › All matrix systems except Estraderm › Dosed once or twice weekly Transdermal Contraceptives (FYI) › Indication: – Contraception › Products available: – Ortho Evra, Xulane (estradiol / norelgestromin) › Dosing: – 1 patch per week for 3 weeks – 1 week patch-free › Type of system: – Matrix Transdermal Testosterone (FYI) › Indication: – Hormone replacement therapy › Products available: – Androderm: 2 strengths › Once nightly dosing › Type of system: – Reservoir Transdermal Clonidine (FYI) › Indication: – Hypertension › Products available: – Catapres-TTS: 3 strengths › 7 day duration › Type of system: – Reservoir Transdermal Fentanyl (FYI) › Indication: – Pain management › Products available: – Duragesic: 5 strengths › 72 hour duration › Type of system: – Matrix Transdermal Buprenorphine (FYI) – Approved June 2010 in US › Available in Europe since 2001 › Indication: – Management of moderate to severe chronic pain › Products available: – Butrans: 5 strengths › 7 day duration › Type of system: – Matrix Transdermal methylphenidate (FYI) › Indication: – Treatment of ADHD › Products available: – Daytrana: 4 strengths › 9-hour wear period – why? › Type of system: – Matrix Transdermal Nicotine (FYI) › Indication: – Smoking cessation › Once daily dosing › 3 step products › Products available: – Nicoderm: reservoir system Transdermal Rivastigmine (FYI) › Indication: – Alzheimer’s disease › Once daily dosing › Products available: – Exelon: 2 strengths › Type of system: – Matrix Transdermal selegiline (FYI) › Indication: – Major depressive disorder › Products available: – Emsam: 3 strengths › Once daily dosing › Type of system: – Matrix Transdermal oxybutynin (FYI) › Indication: – Treatment of urge incontinence › Products available: – Oxytrol, Oxytrol for Women › Twice weekly dosing › Type of system: – Matrix Transdermal Lidocaine (FYI) › Indication: – Relief of pain associated with postherpetic neuralgia › Painful condition caused by the varicella zoster virus (herpes zoster = shingles) › Products available: – Lidoderm › Applied daily › Type of system: – Reservoir Transdermal Rotigotine (FYI) › Indication: – Moderate to severe restless legs syndrome – Parkinson's disease › Products available: – Neupro › Applied daily › Type of system: – Matrix Transdermal Ibuprofen (FYI) › Product currently in development – Medherent’s TEPI patch: Phase III studies approved – Already available in UK (Nurophen®, approved 2016) › Contains high load of ibuprofen a consistent drug release profile › Through the skin for as long as 12 hours › For treatment of conditions such as back pain, arthritis and neuralgia › Matrix type Other information regarding TDDS Advantages of TDDS 1. Produce more uniform blood levels than conventional release oral products – Can maintain plasma levels over longer duration – Reduces adverse effects 2. Extend the activity of drugs having short half-lives – Improve compliance Advantages of TDDS 3. Avoid GI absorption problems 4. Avoid first pass effect 5. Alternate to oral route: patients experiencing nausea/vomiting 6. Non-invasive, convenient, user friendly – No pain associated with administration 7. Easy to identify medication in emergencies 8. Drug therapy may be terminated rapidly – Remove patch Disadvantages of TDDS 1. Only relatively potent drugs may be used – Due to skin impermeability 2. Contact dermatitis may result – Some patients have adhesive sensitivity MRI / TDDS Safety › Some patches have metallic components in the backing layer – Can overheat and cause burns if subjected to MRI scan – Metallic components in release liner not an issue › Not present during scan – removed when patch is applied to the patient – If TDDS is applied to a site outside of the transmit RF coil, the patient should not be at risk General Clinical Considerations 1. Absorption may vary according to site of application – Counsel on importance of: › Using the recommended site › Rotating locations so skin can regain its normal permeability characteristics 2. Skin sites may be reused after 1 week General Clinical Considerations 3. Apply to clean, dry, hairless skin – Wet or moist skin: can accelerate drug penetration beyond that which is intended – Oily skin: can affect patch adhesion – Broken skin: too much drug absorption – Calloused skin: too little drug absorption – Hair should be carefully cut › Do not wet-shave or use depilatory agent › These methods could remove outer layers of stratum corneum › Could increase rate and extent of absorption General Clinical Considerations 4. Do not use skin lotions at the application site – Affects skin hydration – Can alter partition coefficient between drug in the system and the skin – Could prevent patch from adhering properly 5. Press system firmly against the skin site for about 10 seconds – Need uniform contact for proper adhesion – If it dislodges, may try to reapply – If it doesn’t stick, a new patch may be used General Clinical Considerations 6. Avoid touching the adhesive layer when applying – Some drug may be present in this layer – Wash hands following application – Do not rub eyes or mouth 7. Systems may be left on while showering, bathing or swimming General Clinical Considerations 8. Do not place at sites subject to rubbing from clothing – Belt line, etc. 9. Wear system for the full period of time stated in the package directions 10.If skin irritation results, consult with physician 11.After removal, fold systems in half with adhesive layer together – Systems contain residual drug: only 3% of total drug content is absorbed from the lidocaine patch (Lidoderm) – Discard in manner safe to children and pets Percutaneous Absorption Models 85 In vivo studies › Most relevant when conducted in humans › Animal models may be used: – Weanling pig – Rhesus monkey – Hairless rat – Mouse In vivo studies › Used to: 1. Determine bioavailability 2. Establish bioequivalence of different formulations of the same drug 3. Determine toxicologic risk 4. Relate blood levels after transdermal administration to systemic therapeutic effects In vitro studies › Diffusion cell – Human skin – Animal skin – Epidermal cells – Dermal cells › Employed in vitro to quantify the release rates of drugs from transdermal preparations In vitro studies › Diffusion cell – Skin is clamped into cell – Investigators measure compound passing from stratum corneum side through to a fluid bath – Determines if drug can pass through In vitro studies In vitro studies › Limited because of: – Difficulty in obtaining material – Storage – Expense – Variability in permeation – Animal skins are more permeable than human skin In vitro studies › Excised human skin: – Sources: › Autopsies › Amputations › Cosmetic surgery › Human cadaver In vitro studies › Alternative test materials: – Shed black rat snake skin › Nonliving › Pure stratum corneum › Hairless › Similar to human skin, but slightly less permeable In vitro studies: commercially available human skin equivalents SkinEthic RHE (Reconstructed Human keratinocytes cultured on an inert polycarbonate filter at the air-liquid Human Epidermis) interface in chemically defined medium Episkin Human keratinocytes cultured on a collagen base which permit terminal differentiation and reconstruction of the epidermis with a functional stratum corneum Epiderm Neonatal human-derived epidermal keratinocytes (NHEK) cultured to form a multi-layered, highly differentiated model of the human epidermis EpidermFT Neonatal human-derived dermal fibroblasts (NHFB) and NHEK co-cultured to form a multi-layered, highly differentiated model of the human dermis and epidermis StrataTest Full-thickness skin model using a near-diploid human keratinocyte cell line, NIKS Epidermal Skin Test 1000 Reconstructed epidermal model made from primary human keratinocytes; it (EST1000) comprises a fully differentiated epidermis with viable and cornified cell layers Advanced Skin Test 2000 Full-thickness dermal equivalent based on embedded fibroblasts with an (AST2000) epidermal layer of keratinocytes on top. Source: Pharmaceutics. 2012 Mar; 4(1): 26–41. In vitro studies › Alternative test materials: – Other materials designed to mimic intercellular lipids of the stratum corneum › Cellulose acetate › Silicone rubber › Isopropyl myristate – Disadvantage: › Not as complex as human skin › Care must be taken before extrapolating to a clinical situation Percutaneous Absorption Enhancers Chemical Absorption Enhancers › Increase skin permeability by: – Reversibly damaging the skin, or – Altering the physicochemical nature of the stratum corneum to reduce its diffusional resistance › Increase hydration of the stratum corneum › Change the structure of the lipids and lipoproteins in the intercellular channels through solvent action or denaturation Chemical Absorption Enhancers › Selection should be based on: – Efficacy – Dermal toxicity – Physicochemical compatibility with other components – Biocompatibility with other components Chemical Absorption Enhancers › Examples: – Ethanol – Polyethylene glycol – Propylene glycol – Fatty acids – Esters – Mineral oil – Urea Active Transdermal Drug Delivery Systems Active TDDS or Physical absorption enhancers › Energy is spent to enhance permeation of drugs through skin › Drug penetration rate and extent is not dependent on the concentration gradient › Hydrophilic, protein, and peptide drugs can be delivered using these techniques Transdermal Lidocaine and Tetracaine › Indication: – Topical local analgesia for superficial dermatological procedures › Products available: – Synera › Prior to procedure, apply to intact skin for 30 minutes › Heat-activated patch system – Contains a heating element (activated by contact with air after removal from protective pouch › Type of system: – Reservoir Physical Absorption Enhancers: Iontophoresis (IP) – AKA electromotive drug administration (EMDA) – Involves the delivery of charged chemical compounds across the skin using an applied electrical current – Ions cross through: › Pores (main route) › Disrupted stratum corneum – Based on the principle of “like repels like” Physical Absorption Enhancers: Iontophoresis › Ionized drug solution is placed in an electrode of the same charge › Current is applied › Drug is repelled from electrode into the skin Physical Absorption Enhancers: Iontophoresis › Drug-containing electrode = active › Non-drug containing electrode = passive › Consists of: – Battery – Microprocessor controller – Drug reservoir – Electrodes › Improvement in batteries and electronics have led to smaller, more efficient IP patches Physical Absorption Enhancers: Iontophoresis https://www.youtube.com/watch?v=Ix4eUr4DOwA Physical Absorption Enhancers: Iontophoresis › Delivery is complex › Depends on: – Interaction between drug and vehicle (electrolyte or buffer) – Partitioning of drug between vehicle and skin – Diffusion through a highly heterogeneous membrane under the influence of: › Chemical potential gradient › Electrical potential gradient Physical Absorption Enhancers: Iontophoresis Variables affecting the process include: 1. Current – Continuous current: › Electrochemical polarization develops › Magnitude of effective current across the skin decreases – Pulsatile current: › Skin can depolarize during the off phase › Delivery is improved Physical Absorption Enhancers: Iontophoresis 2. Physicochemical factors of the drug – Charge – In general: › Positive ions  favor transport › Negative ions  less transport, due to electrostatic repulsion across negatively charged skin membrane Physical Absorption Enhancers: Iontophoresis 2. Physicochemical factors of the drug – Size › Smaller  more mobile › Larger can still cross – Structure – Hydrophilicity › Should be water-soluble – Should be low-dose Physical Absorption Enhancers: Iontophoresis 3. Formulation factors – Drug concentration › Increasing concentration usually results in increased delivery – pH › Buffer ions will compete with the drug for the delivery current, esp. most buffer systems are composed of small molecules › Use larger molecules to maintain pH (ethanolamine:ethanolamine HCl) instead of HCl and NaOH Physical Absorption Enhancers: Iontophoresis 3. Formulation factors – Ionic strength › Drugs delivered by iontophoresis are generally potent and present in small amounts › Increase in ionic strength will increase competition for available current – Viscosity 4. Biological factors – Thickness of the skin – Permeability of the skin – Presence of pores on skin surfaces Physical Absorption Enhancers: Iontophoresis › Advantages: – Control delivery rates by varying: › Current density › Pulsed voltage › Drug concentration › Ionic strength – Allows large, charged molecules to be delivered to patient – Avoids: › GI incompatibility › Erratic absorption › First pass metabolism Physical Absorption Enhancers: Iontophoresis › Advantages: – Reduces adverse effects – Reduces inter-patient variability – Avoids continuous injection and infusion risks: › Infection › Inflammation › Fibrosis – Enhances patient compliance with a convenient and non-invasive therapeutic regimen Physical Absorption Enhancers: Iontophoresis › Disadvantages: – Can lead to skin irritation at high current densities › Burns may result if improperly placed › May be minimized by lowering the current – Less problem with newer units – Operated by battery packs instead of household current – Lag time between administration and drug reaching blood stream Physical Absorption Enhancers: Iontophoresis – Previously available: › Lidocaine IP products for the needle-phobic – Lidocaine (LidoSite , NumbyStuff ) › Topical anesthetic › Marketed only to doctors / hospitals; no products currently still on market › Why? Physical Absorption Enhancers: Iontophoresis – IONSYS : › Fentanyl iontophoretic transdermal system › Indication: – Short term management of acute post-operative pain › Schedule II drug › Patient-controlled system › Provides on-demand delivery for 24 hours or 80 doses › Should only be used with hospitalized patients › Must titrate drug to acceptable level (minimum effective dose) on IV fentanyl before initiating treatment Physical Absorption Enhancers: Iontophoresis – Device consists of: › Plastic top housing – 3 volt lithium battery – Electronic components › Bottom housing – Hydrogel containing drug, excipients – Skin adhesive Physical Absorption Enhancers: Iontophoresis Physical Absorption Enhancers: Iontophoresis › Other uses of IP: – Iontophoresis of pilocarpine › Induce sweating in diagnosis of cystic fibrosis – Practiced since the 1930’s – Still most useful test – Increased Cl- in sweat diagnostic for CF – Topical delivery of fluoride to teeth – Dexamethasone › Anti-inflammatory agent › Delivered directly into joints Physical Absorption Enhancers: Iontophoresis › Uses of IP: – Commonly used with drugs for veterinary use: › NSAIDs › Corticosteroids › Anti-inflammatory agents › Antibiotics › Local anesthetics – Being investigated for protein delivery Physical Absorption Enhancers: Sonophoresis › Sonophoresis – AKA Phonophoresis, ultrasound – Transport drug across skin using high frequency ultrasound › Drug is mixed with coupling agent – Gel (usually) – Ointment – Cream › Ultrasonic energy is transferred from the phonophoresis device to the skin, through this coupling agent Physical Absorption Enhancers: Sonophoresis › Thought to disrupt the lipids in the stratum corneum › Increases skin penetrability › Example: – Hydrocortisone (1-10%) Physical Absorption Enhancers: Sonophoresis › Formulation factors: – Vehicle must be smooth and non-gritty › Will be rubbed by the head of the transducer – Should have relatively low viscosity › Makes application easier › Improves movement of the transducer head during the ultrasound process – Air should not be incorporated › Air bubbles may disperse the ultrasound waves Photodynamic Therapy Photodynamic Therapy 1. Light-activated drug is applied topically or injected intravenously 2. Drug accumulates in the affected tissue 3. Low power light is delivered through the PDT device and focused on the affected tissue 4. Light activates photo-reactive drug, releasing agents that destroy only affected cells. Photodynamic Therapy › Most applications use light waves in the visible light spectrum – 350-800 nm range Photodynamic Therapy › Advantages: – Avoids first pass effect – Causes minimal damage to healthy tissues Photodynamic Therapy › Disadvantages: – Current laser light used cannot pass through more than ~ 3 cm of tissue › Limits areas that may be treated – Makes skin and eyes sensitive to light for 6+ weeks following treatment – Other adverse effects: › Nausea / vomiting › Metallic taste in mouth Photodynamic Therapy › Uses: – Cancer diagnosis – abnormal cells take up compound differently than normal cells – Cancer therapy › Primarily used to treat tumors on or just under skin, or on the lining of internal organs using endoscopes and fiber optic catheters › Light exposure must be timed carefully so that it occurs when most of the sensitizing agent has left healthy cells but is still present in cancer cells Photodynamic Therapy › Non-cancer uses: – Age-related macular degeneration – Psoriasis – Actinic Keratoses – Other disease states being investigated › In clinical trials for severe acne  Photodynamic Therapy: Approved Products Brand name Generic name Indications How administered Levulan Aminolevulinic acid – Actinic keratosis Admixed immediately prior to use Kerastick® ALA Warty overgrowths of skin Crush glass ampule to allow solid Found on sun-exposed and liquid components to mix; areas of face and scalp shake for 3 minutes to dissolve Kaposi’s sarcoma and other drug carcinomas (unlabeled) Applied to target lesions Severe acne (unlabeled) 14-18 hours later, patient is illuminated under appropriate light Treated skin cells die and slough off Photofrin® Porfimer sodium Esophageal cancer IV injection of drug Endobronchial non-small cell Illumination with laser lights 40-50 lung cancer hours later Barrett’s esophagus (pre- cancerous condition)  Photodynamic Therapy: Approved Products Brand name Generic name Indications How administered Cysview® Hexaminolevulinate HCl Cytoscopic visualization of Instilled into bladder; bladder bladder cancers not visible evacuated 1-3 hours later under white light Examined under white and blue light within 30 minutes; lesions fluoresce red under blue light Visudyne® Verteporfin Age-related macular Drug administered via peripheral IV; degeneration travels to target cells via lipoproteins Psoriasis (unlabeled) Activated by shining red light into Psoriatic and rheumatoid patient’s eye 15 minutes later arthritis (unlabeled) Other Techniques 137 Microporation › Creation of micropores in the stratum corneum › Created by – Electroporation – Microneedles – Ultrasound – Radiofrequency and laser › Targeted to disrupt or bypass the stratum corneum › Currently under development › Under various stages of FDA approval Electroporation › High voltage pulse is applied to the skin for short period › Leads to increased permeability of stratum corneum › Formation of pores which close shortly after pulse ends Microneedle or Microprojection based devices › Tiny drug coated projections or needles are used to pierce top layer of skin and make superficial holes for transport of drug › Needles are too small to reach nerve endings and elicit pain response › Instead, patients feel the texture of sandpaper or a cat's tongue › They can deliver proteins, nanoparticles, and both small and large molecules through the skin. ZP Patch Technology ZP Patch Technology ZP Patch Technology ZP Patch Technology › Originally known as Macroflux by Alza Corp › Platform technology in various stages of clinical trials – ZP-PTH for osteoporosis – ZP-Glucagon for severe hypoglycemia – ZP-Triptan for migraine – GLP-1 for diabetes Needle free injections: velocity based techniques › Uses high velocities to force particles across stratum corneum › This device pushes drug molecules into the skin by creation of high velocity jet (>100 m/s) of compressed gas (usually helium) that accelerates through the nozzle of the device carrying drug particles with it › Inability to deliver drugs over longer periods of time; however, well suited for vaccination Lidocaine Powder for injection › Powder Intradermal Injection System – Used on intact skin to provide topical local analgesia › Indications – Prior to venipuncture or peripheral intravenous cannulation, in children 3–18 years of age – Prior to venipuncture in adults SUMAVEL® DosePro® SUMAVEL® DosePro® (sumatriptan injection) by Zogenix is indicated in adults for (1) the acute treatment of migraine, with or without aura, and (2) the acute treatment of cluster headache. Which dosage form would you prefer? › Sumatriptan for migraine – Sumavel Dosepro (jet injector) – Imitrex injection system › Lidocaine for local analgesia – Zingo (jet injector) – One of the previously marketed IP patches › Why?