Transdermal Drug Delivery

Systems
Dr O Hanbali

Drug in Formulation (Tablets, Capsules)

Release of Drug

Site of Drug Administration (Drug in GIT)
Absorption of Drug

Distribution

Drug in Circulation
Elimination

Non Target Site

Drug in Target (or receptor) Site

Urine, Stool, …

Sustained Drug Action 2. Targeting Drug Action . Approaches for CDDS: 1.Controlled Drug Release A technique or method in which active chemicals are made available to a specified target at a rate and duration designed to accomplish a specific effect. Localized Drug Action 3.

. and effective controlled-release in its most patient friendly form. more convenient.Introduction to Transdermal Drug Delivery Easier.

The skin separates the vital organs from the external environment. Acts as a thermostat in maintaining body temperature Plays a role in the regulation of the blood pressure.Skin The skin of an average adult body covers a surface area of approximately 2 m2 and receives about one-third of the blood circulating through the body. heat) . microbial and radiological attack.g. It also serves as a food reserve and as a sensory organ transmitting external environmental information (e. chemical. pain. Protects against physical.

Schematic representation of the horny layer and suggested routes for drug transport Intercellualr and Transcelluar Diffusion Low Molecular weight drugs+Lipophilic .

Possible routes for drug entry through the skin Intra.and Transappenageal Diffusion Ionic + Large Polar Penetrant .

Transdermal Drug Delivery (TDD) Diffusion of the medication (drug) through skin into the systemic circulation for distribution and therapeutic effect Introduction to Transdermal Drug Delivery .

Introduction to Transdermal Drug Delivery .

Therapies That Use Transdermal Delivery of Drugs Therapy Motion Sickness Anti-angina Hypertension Smoking Cessation Hormone Replacement Therapy Drug Delivered by TDD Scopolamine Nitroglycerine Clonidine Nicotine Estradiol Estradiol/Progestin Testosterone Fentanyl Lidocaine Pain Management Introduction to Transdermal Drug Delivery .

Narrow therapeutic window .Poor oral absorption .Advantages of TDD Systems Reduces first-pass effect and GI incompatibility Sustains therapeutic drug levels Permits self-administration Non-invasive (no needles or injections) Improves patient compliance Reduces side effects Allows removal of drug source & Termination of further administration.A very short half-life . if necessary Administration of drugs with: .

Skin irritation.  Melting point  Introduction to Transdermal Drug Delivery .Limitations of TDD Systems Poor diffusion of large molecules. Limited By: Dose of the drug.  Molecular weight of drug.  Crystalline state.

Stratum Corneum is the barrier in TDD (Rate limiting step) Introduction to Transdermal Drug Delivery .

Permeability Coefficient Is the Critical Predictor of Transdermal Delivery Transport = Flux = (mg/cm2/sec) = J=P x A x (Cd – Cr) Permeability Coefficient = P = D x K (cm/sec) h A = Surface area of patchWhere D = Diffusivity of drug in membrane (skin) K = Partition coefficient (patch/skin) C = Concentration in donor or receptor patch or skin) h = Thickness of membrane (skin) .

0 and 4] Toxicology profile (non-irritating and non-sensitizing to skin) .Attributes of a Passive TDD Drug Candidate Daily dose (< 20 mg/day) Half-life (10 hours or less) Molecular weight (< 500 daltons) Melting point (< 200 oC) Skin permeability Lipid solubility [partition coefficient (Log P) between –1.

Patch size. Wear period. Desired drug delivery profile. etc. Packaging. Patch cost. . . appearance. Patch disposal. Ease of application. comfort.TDD System Design Factors Therapeutic indication. duration.Dose level. Application site. shape. Skin adhesion profile.

incorporates drug and excipients in drug-in-adhesive TDD systems. Membrane: moderates rate of drug release. Adhesive: maintains contact with patient’s skin. Liner: protects patch during storage. is removed prior to application.TDD Patches: A System of Components Components must be chemically and physically compatible. . Drug formulation may or may not include excipients Backing: provides protection from external factors during application period.

TDD Patch Construction (Technologies) Four Major Transdermal Systems Polymer Membrane Permeation Controlled TDDS. Microreservoir Dissolution Controlled TDDS. Drug Reservoir Gradient Controlled TDDS. Polymer Matrix Diffusion Controlled TDDS. .

Silicone  fluid. .g polyisobutylene.  Rate controlling Membrane: Microporous. adhesive. hypoallergic. Drug Reservoir : • dispersed on solid polymer matrix e. Nonporous.Polymer Membrane Permeation Controlled TDDS. eg. Ethylene-Vinyl acetate copolymer.  Suspended in unleachable viscous liquid medium eg. Silicone adhesive. drug compatible. Adhesive Layer: Thin layer. Eg. Dissolved in solvent.

. The component responsible for skin adhesion is incorporated in an overlay and forms a concentric configuration around the semisolid matrix.Polymer Matrix Diffusion Controlled TDDS. The Matrix system design is characterized by the inclusion of a semisolid matrix containing a drug solution or suspension which is in direct contact with the release liner.

The Multi-layer Drug-inAdhesive is similar to the Single-layer Drugin-Adhesive in that the drug is incorporated directly into the adhesive. the multi-layer encompasses either the addition of a membrane between two distinct drug-in-adhesive layers or the addition of multiple drug-inadhesive layers under a single backing film . However.Drug Reservoir Gradient Controlled TDDS.

Microreservoir Dissolution Controlled TDDS Suspend drug in aqueous solution of water drug solubilizer eg. Homogeneously disperse drug with controlled aqueous high shear mechanical force ( unstable thermodynamically). . Stabilize by immediate crosslinking the polymer chain insitu. PEG.

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Improvement of Skin Permeability Physical Approach: Stripping of stratum corneum.  Iontophoresis.  Hydration of stratum corneum.  .  Phonophoresis.  Thermal Energy.  Chemical Approach: Synthesis of lipophilic analogs (prodrugs).  Coadministration of skin permeation enhancer  Biochemical Approach: Synthesis of bioconvertable prodrugs  Coadministration of skin metabolism inhibitors.  Delipidization of stratum corneum.

increasing the permeation rate by several times.they facilitate the permeation of the actives through the skin. This is very important with respect to the feasibility of a system. for example No pharmacological activity High stability Predictable and repeatable results Full compatibility with the other ingredients and components No toxicity or allergic reactions Good release from the formulation Good general characteristics (odor. because most of the actives do not enter the skin in the required dosage from a relatively small area. Sometimes a combination of ingredients is needed to create the correct enhancement effect.Penetration Enhancers This term refers to an entire family of chemically different substances that all share a common characteristic . color and low price) .

Establishing a drug reservoir within the stratum corneum (Implants). Increasing the solubility of the active. Optimising the thermodynamic activity of the drug in the vehicle and/or skin. . Increasing the drug diffusivity in the stratum corneum.The increase in skin permeation is created by: Causing reversible damage to the stratum corneum.

fatty acids and related structures Fatty acid esters Fatty acids Miscellaneous compounds and groups Amines and amides Complexing agents . belonging to the following categories: Ionic compounds Dimethyl sulfoxide and related compounds Azone and related compounds Solvents and related compounds Fatty alcohols. One review found that more than 275 chemical compounds were cited as skin penetration enhancers.Enhancers belong to several different classes.

Ultrasound drug permeation (Ultrasonic) .

Iontophoresis It is a process that facilitate the transport of ionic species by application of physiologically acceptable electrical current. Check how this works?! .

Additional Development Stages In vitro skin permeation studies Franz-Diffusion Cell .

Additional Development Stages Clinical evaluation  Formulation and manufacturing scale-up  Stability studies  Analytical evaluation  Regulatory submission and approval  .

and improve comfort and wear Patch designs with specialized drug delivery profiles Patches with features that aid in application and use User and environmentally-friendly packaging designs .Transdermal System Design: What’s Ahead? Delivery of larger molecules using enhanced passive and active delivery systems Materials and formulations to reduce skin irritation. enhance the adhesion profile.

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