Lecture 16_ Transdermal Delivery Systems Spring_2024-1 PDF

PHA 339 Understand the process of drug diffusion when applied topically as a transdermal patch Understand the various types of transdermal drug delivery systems Understand various factors that can affect the drug release from such delivery systems Drug delivery through skin in predetermined and cont...

PHA 339 Understand the process of drug diffusion when applied topically as a transdermal patch Understand the various types of transdermal drug delivery systems Understand various factors that can affect the drug release from such delivery systems Drug delivery through skin in predetermined and controlled fashion is called transdermal drug delivery systems (TDDS). TDS is 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. 1st generation TDDS include traditional patches such a clonidine or estrogen 2nd generation TDDS include patches plus some type of enhancement to improve drug delivery ✓ Addition of permeation enhancers 3rd generation TDDS use novel technologies to increase the scope of molecules that can be delivered through the skin ✓ Large molecules, hydrophilic molecules, high drug concentrations Prausnitz, Mark R. and Robert Langer. “Transdermal Drug Delivery.” Nature Biotechnology, Nov 2008: 1261-1268. Physico-chemical and biopharmaceutical aspects of the drugs. Biological/Anatomical, physiological and pathological features of the skin. Percutaneous absorption Characteristics of the delivery system: ✓ formulation ✓adhesive parameters ✓design of the system Diffusion coefficient: Permeation of drug depends on diffusion coefficient of drug. At a constant temperature the diffusion coefficient of drug depends on properties of drug, diffusion medium and interaction between them. Drug concentration: The flux is proportional to the concentration gradient across the barrier and concentration gradient will be higher if the concentration of drug will be more across the barrier. Partition coefficient: The optimal partition coefficient (K) is required. Drugs with high K are not ready to leave the lipid portion of skin. Also, drugs with low K will not be permeated. Molecular size : Drug absorption is inversely related to molecular weight; small molecules penetrate faster than large ones. Temperature and pH: The permeation of drug increase ten folds with temperature variation. The diffusion coefficient decreases as temperature falls. Weak acids and weak bases dissociate depending on the pH and pKa or pKb values. The proportion of unionized drug determines the drug concentration in skin. Skin condition: Diseased state of patient alters the skin conditions. The intact skin is better barrier. Skin hydration: In contact with water the permeability of skin increases significantly. Hydration is most important factor increasing the permeation of skin. Skin age: The young skin is more permeable than older. Children's are more sensitive for skin absorption of toxins. Blood supply: Changes in peripheral circulation can affect transdermal absorption. Regional skin site: Thickness of skin, nature of stratum corneum and density of appendages vary site to site. Delivery of drugs into and through skin requires knowledge of skin and the transport processes across the skin. Skin is the largest and most visible organ in the body. This is the most easily accessible and the most abused as well. Containment of body fluids and tissues Reception of external stimuli Protection from harmful external stimuli Synthesis and metabolism Regulation of body temperature Blood pressure regulation Disposal of biochemical wastes (glandular secretions) Strutre of the Skin Skin Layers Outer epidermis ( squamous epithelium) 50-100 um Lacks blood vessels contains melanocytes Stratum corneum: 10 um- 15-25 layers, 75%-85% proteins, and 10-15% lipids Dermis(or Corium) : Connective tissues 3-5 mm thick Has blood vessels, nerves sweat glands and hair follicle The blood vessels in dermis distribute drugs into the systemic circulation and regulates temperature Hypodermis (Subcutaneous layer) 10 50-100 µm thick (approximately) Consist of irregular scattered cells with large intercellular spaces Mostly carbohydrates, low proteins and lipids Hydrophilic layer and devoid of blood vessels (avascular) Polar drug ( increased permeability) Of the five layers of the epidermis, the most important barrier layer is the outer layer, or stratum corneum (KORne-um). The stratum corneum is made up of dead, keratinized cells called keratinocytes. Cornified multicellular layers (~15-25 layers) 10-20 m thick (thickness depends on the anatomical sites) Consists of 75-85% protein and 15-25% lipids Cells are loose at surface and tightly knit in lower layer Metabolically inactive (dead) Barrier to permeation Region between the epidermis and subcutaneous fatty layer Entire microcirculation serving the skin is in the dermis Network of the sensory nerve present Consists of watery, gelatinous ground substance, mostly collagen fibers Network provides blood supply to the hair follicles, the glandular skin appendages, the subcutaneous fat and the dermis. Local circulation can be turned off and on by vasoconstrictors and vasodilators respectively.  E: THE SKIN APPENDAGES Hair follicles Sebaceous glands and sweat glands How the drug applied into skin can reach systemic circulation? Mechanism of Percutaneous Absorption of Drug Through Skin Movement of drug Intercellular channels Stratum Corneum ( 10-15mm thick keratinized layer) Passive diffusion Deeper Epidermal tissue Dermis (Vascularized layer) Drug is available for absorption into general circulation Substances with both aqueous and lipid solubility characteristics are good candidates for diffusion through stratum corneum, epidermis and dermis. 15 EVENTS OF DRUG TRANSPORT ACROSS SKIN FROM TDS TDS (Device) Percutaneous absorption of drug generally results from direct penetration of the drug through stratum corneum (SC). Intercellular diffusion through the Stratum corneum (SC) Transcellular diffusion through the SC Diffusion through aqueousphase sweat ducts Diffusion through oil-phase hair follicles The stratum corneum is often described as a “brick and mortar” structure. Bricks represent the dead; keratinized cells and the mortar represents the lipid bilayers surrounding the cells. Prausnitz, Mark R. and Robert Langer. “Transdermal Drug Delivery.” Nature Biotechnology, Nov 2008: 1261-1268. Transcellular route, or simply passing through both keratinocytes and lipids in what could be visualized as a straight path to the dermis. Intercellular route where the molecule stays in the lipid bilayer and winds around the keratinocytes on its way to the dermis. The most common route of drug penetration is the intercellular route because most drug molecules are more soluble in the lipid environment of the bilayer than in the protein environment of the keratinocytes Permeation Enhancement Techniques Use of Chemicals to enhance permeation: Ethanol, terpenes, propylene glycol, oleic acid, bile acids, dimethyl sulfoxide, azone etc. Iontophoresis: Ions flow diffusively in a medium driven by an applied electric field. Iontophoresis is the process of using small amounts of electrical current to move drugs across the skin and can also be used to enhance penetration of drug molecules through the stratum corneum. The anode will repel positively charged drug molecules. Most drugs are formulated as a salt, for instance fentanyl hydrochloride Drug molecule becomes protonated and takes on a positive charge to the negative charge of the chloride anion. Drug is repelled away from the anode and through the stratum corneum toward the dermis. Fentanyl Hydrochloride Prausnitz, Mark R. and Robert Langer. “Transdermal Drug Delivery.” Nature Biotechnology, Nov 2008: 1261-1268. ENHANCEMENT OF PERCUTANEOUS ABSORPTION Phonophoresis: Use of ultrasound. Sonication causes air pockets in cells to expand and oscillate which disorganizes the lipid bilayers and forms channels through them Microneedles as a penetration enhancer A. Reservoir type B. Matrix type 1.With rate limiting membrane Transderm-scop, Transderm-nitro, Estraderm (Ciba), and Catpress-TTS 2.Without rate limiting membrane (a) With rate limiting adhesive layer: FrandolTM (isosorbide dinitrate), DeponitTM (nitroglycerine) ◦ The drug is uniformly dispersed throughout the hydrophilic or lipophilic matrix. Film Backing Drug/Adhesive Layer This medicated polymer is then molded into a predetermined shape and size. Example: Nitro-Dur (Key Pharm) Protective Liner (removed prior to use) Skin Schematic Drawing of the Matrix (Drug-in-Adhesive) type of patch The principles of both matrix and reservoir systems are used here. The system is fabricated by micro dispersion of drug reservoir, as immobilized microscopic spheres, in the cross-linked polymer matrix. Example: Norgestmet Matrix Reservoir Drug in adhesive Multilaminate Backing Drug Membrane Adhesive Liner / skin 1. The part of the skin where the patch is to applied should be properly cleaned. 2. Patch should not be cut because cutting the patch destroys the drug delivery system. 3. Before applying a new patch, make sure that the old patch is removed from the site. 4. Care should be taken while applying or removing the patch because anyone handling the patch can absorb the drug from the patch. 5. The patch should be applied properly to the site of administration. Regardless of the design, most patches are intended to deliver drug into the skin at a constant rate over a designated time period. Since drug diffusion occurs passively according to Fick’s Law, the rate of flux remains constant (zero-order) as long as the concentration gradient across the barrier is unchanged. In other words, there needs to be a significantly large amount of drug in the device in order to maintain a uniform concentration gradient over the duration of patch use. When drug concentrations in the patch are depleted significantly, the drug release rate begins to drop, and the zero-order rate is no longer maintained. Most patches should be removed before reaching this stage. This means there is still a significant amount of drug remaining in the patch after it is ‘used up’ (e.g., Lidoderm Patch is recommended to be worn for 12 hours for treatment of post-herpetic neuralgia). These patches, which deliver about 150 mcg/cm2 of lidocaine over 12 hours of ‘wear’ time, contain 700 mg of the drug in the patch before use, and 665 mg still remain in the patch when removed after 12 hours of use. Similarly, most patches contain at least 95% of the drug after use. This warrants special precautions in handling and disposal of the patch. If a pet or child accidentally ingests the patch, it can be absorbed in lethal doses and prove to be fatal. Thickness of the patch Weight uniformity Percentage Moisture content Percentage Moisture uptake Drug content Uniformity of dosage unit test Shear Adhesion test Peel Adhesion test In vitro drug release studies In vitro skin permeation studies Skin Irritation study Administration of drugs with short half-lives and narrow therapeutic window. Increased patient compliance (less dosing). Risk of overdose is avoided, and the side effects are reduced. Easy termination of the therapy by simple removal of the patch. Self administration possible. Steady state concentration within the therapeutic window can be achieved and maintained. The peaks and troughs associated with conventional dosage form can be avoided. Variability of G.I. absorption is avoided. No first pass effect. 1. Permeability of the drug 1. Size, shape 2. Diffusivity 3. M.P.(melting point) 4. Partitioning 2. Drug or formulation may cause skin irritation or local allergic reaction. 3. Can not administer drug that require high plasma level. Therapeutic TDDS Agent DESIGN, CONTENT COMMENTS Clonidine Catapres-TTS (Boehringer Ingleheim) Four layer patch: 1. Backing of pigmented polyester film 2. Reservoir of clonidine, mineral oil, polyisobutylene, colloidal silicon dioxide 3. Micro porous polypropylene membrane controlling rate of delivery 4. Adhesive formulation of agents Transdermal therapeutic system to delivery therapeutic dose of antihypertensive drug at constant rate for 7 days. TDDS generally applied to hairless or shaven area of upper arm or torso. Estradiol Estraderm (Novartis) Four layer patch: 1. Transparent polyester film. 2. Reservoir of estradiol, alcohol gelled with hydroxpropyl cellulose 3. Ethylene-vinyl acetate copolymer membrane 4. Adhesive formulation of light mineral oil, polyisobutylene Transdermal system to release estradiol continuously. Patch is generally applied to trunk, including abdomen and buttocks, altering sites, twice weekly over a 3 week cycle with dosage frequency adjusted as required Vivelle (Novartis) Three layer patch: 1. Translucent ethylene vinyl alcohol copolymer film 2. Estradiol in matrix of medical adhesive of polyisobutylene, ethyl vinyl acetate copolymer. 3. Polyester release liner, removed prior to application. Use and application similar to Estraderm TDDS. Ansel’s Pharmaceutical Dosage forms and drug delivery systems, Transdermal drug delivery, 9th Edition, Chapter 11 page 299-300 Generic Brand Patch Design Advisability of Cutting Patch Metal Components Advisability of taping Advisability of writing on patch Location Duration Disposal Advisability of exposure to external heat 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. ✓ ✓ ✓ ✓ ✓ ✓ Testosterone (Androderm) Scopolamine (Transderm) Nitroglycerin (Nitro-Dur) Nicotine (Nicoderm) Lidocaine (Lidoderm) Fentanyl (Duragesic) Review Questions Application of an electric field to enhance the penetration of ionic drug through skin membrane is called_______. a. Sonophoresis b. Electrophoresis c. Iontophoresis d. osmosis Review Questions In which type of transdermal transport, the drug molecule stays in the lipid bilayer and winds around the keratinocytes on its way to the dermis. a. Intercellular diffusion b. Active transport c Transcellular pathway d. Electrophoresis Review Questions Application of high frequency ultrasound to enhance the penetration of drug through skin membrane is called_______. a. Sonophoresis b. Electrophoresis c. Iontophoresis d. osmosis Review Questions In which type of TDDS, the drug is uniformly dispersed throughout the hydrophilic or lipophilic matrix. a. Reservoir type b. Reservoir type with rate limiting membrane c. Matrix type d. Microneedle type Review Questions Which is a type of TDDS with reservoir of scopolamine for prevention of nausea. A. Catapress B. Lidoderm C. Transderm-scop D. Estraderm Diffusion is a process by which mass transfer of molecules are brought about by random molecular motion due to a concentration gradient (driving force). Application of Diffusion Process: 1. Passive diffusion of drug in the GI tract. 2. Transport of drugs through polymeric membrane. 3. Percutaneous absorption of drugs Receiver Compartment Cd C1 C2 Donor Compartment h Cr Cross sectional area = S Thickness = h Concentration in the membrane on the donor side = C1 Concentration in the membrane on the receptor side = C2 Concentration in the donor side = Cd Concentration in the receptor side = Cr Assumptions 1. Steady state exists 2. No aqueous boundary layer exists Since C1 and C2 are difficult to measure, Cd and Cr are generally monitored. If the partition coefficient = K = C1/ Cd or K = C2/ Cr Under Sink Condition Cr  0 dM DSK (Cd − Cr ) = dt h Where, P =DK/h = Permeability Coefficient (cm/sec) dM DSKCd = = PSCd dt h M = PSCd t Why called a diffusion coefficient? Not a constant ?? Ordinarily "D" doesn't remain constant Can be changed at higher concentration, temperature, pressure, solvent properties, chemical nature of the diffusant etc. Therefore, it is called diffusion coefficient rather than constant. Amount Released (mg) Nonsteady state Steady State tL = lag time Time (hours) In the early stage, the curve is nonlinear (nonsteady state condition). At a later time, the diffusion is constant, and the curve is linear (steady state condition) Lag time (tL): The point of interaction of the extrapolated steady state portion of the curve and the time axis. This is the time required for a penetrant to establish a uniform concentration gradient within the membrane. 2 h tL = 6D h = thickness of the membrane and D = Diffusion Coefficient Skin/membrane preparation Diffusion cell assembly Donor and receptor phases assembly Periodic sampling of receptor Maintenance of sink conditions Analysis of samples Plotting of the data Calculation of the flux Flux: The amount of material (M) passing through a membrane of unit cross-section (S) in unit time (t) is known as flux (J). J= dM g Sdt cm 2 sec Fick's 1st law Flux is proportional to the concentration gradient (dc/dx) J dc dx J = −D dc dx M dM/dt dM DSK (Cd − Cr ) = dt h Time *Derivation in additional slides Equations: Diffusion of drugs DSK (Cd − Cr ) dM = dt h Cd = Concentration in the donor side; Cr = Concentration in the receiver (receptor) side Under sink Condition: dM dt tL = = DSKCd h 2 h 6D tL = Lag Time ; h = Thickness of a membrane; D = Diffusion Coefficient Permeability = P = DK/h D = Diffusion coefficient; K = Partition coefficient; h = Thickness of the membrane Practice Problem: The permeability of a drug through a polymer membrane is 1.01 x 10-5 cm/sec. Its diffusion coefficient is 4.23 x 10-7 cm2/sec. If the thickness of the membrane used in this study is 0.085 cm, calculate its partition coefficient of the drug. Permeability = where DK h D = diffusion coefficient K = partition coefficient h = thickness P = D= h = K= 1.01 x 10-5 cm/sec 4.23 x 10-7 cm2/sec 0.085 ? Pxh 1.01 x 10 -5 x 0.085 (cm/ sec x cm) K = = D 4.23 x 10 -7 ( cm 2 / sec ) K = 2.03 Practice Problem: In a diffusion study through human skin, the lag time of a drug was found to be 50 minutes. If the thickness of the skin is 0.085cm, what is the diffusivity of the drug? 2 t lag h = 6D t lag = lag time = 50 minutes h = thickness of the skin = 0.085 cm D = Diffusivity 2 (0.085 )2 h D = = = 0.000024 cm2/ min 6 x t lag 6 x 50 Practice Problem: The lag time of Methadone, a drug used in the treatment of heroin addiction, at 25 C through a silicon membrane transdermal patch was calculated to be 5 min. The thickness of the membrane was 0.01 cm. Calculate the permeability coefficient of the drug at 25 C if K = 10.5. The permeability coefficient is given by DK/h. Therefore, the first thing to determine is the diffusion coefficient D. Using the lag time equation: D = h2/6tl D= (0.01)2/ (6x300) = 5.5 x 10 -8 cm2/sec Using the permeability coefficient equation (P=DK/h) = (5.5 x 10 -8 cm2/sec) x (10.5) / 0.01 cm = 5.8 x 10 -8 cm/sec Correct Answer : 5.8 X 10 -8 cm/sec Practice Problem: The lag-time of butyl paraben for diffusion across a 0.085 cm thick membrane is 47.5 minutes. Calculate D for butyl paraben. 2 2 t = h /6D, or D = h /6t L L 47.5 minutes = 47.5 x 60 = 2850 seconds D = (0.085)2/(6x2850) = 4.23 x 10-7 cm2/sec Pharmaceutics: Basic Principles and Application to Pharmacy Practice by Dr Dash ▪ Chapter 11- Semi solid dosage forms Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems; ▪ Chapter 11- Transdermal Drug Delivery Systems Diffusion of drugs Flux: The amount of material (M) passing through a membrane of unit cross-section (S) in unit time (t) is known as flux (J). dM g J= Sdt cm 2 sec Fick's 1st law Flux is proportional to the concentration gradient (dc/dx) dc J dx dc J = −D dx dM dc  (C − C1  = − D = − D 2  Sdt dx  h   C − C2  J = D 1   h  C1 C2 K= = Cd Cr J= dM DSK (Cd − Cr ) = dt h