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,

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. Approaches for CDDS: 1. Sustained Drug Action 2. Localized Drug Action 3. Targeting Drug Action

Introduction to Transdermal

Drug Delivery

Easier, more convenient, and effective controlled-release in its most patient friendly form.

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. The skin separates the vital organs from the external environment, Protects against physical, chemical, microbial and radiological attack, Acts as a thermostat in maintaining body temperature Plays a role in the regulation of the blood pressure. It also serves as a food reserve and as a sensory organ transmitting external environmental information (e.g. pain, heat)

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

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, if necessary Administration of drugs with: - A very short half-life - Narrow therapeutic window - Poor oral absorption

Limitations of TDD Systems

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

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)

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 1.0 and 4] Toxicology profile (non-irritating and non-sensitizing to skin)

TDD System Design Factors

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

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. Membrane: moderates rate of drug release. Adhesive: maintains contact with patients skin; incorporates drug and excipients in drug-in-adhesive TDD systems. Liner: protects patch during storage; is removed prior to application.

TDD Patch Construction (Technologies)

Four Major Transdermal Systems

Polymer Membrane Permeation Controlled TDDS. Polymer Matrix Diffusion Controlled TDDS. Drug Reservoir Gradient Controlled TDDS. Microreservoir Dissolution Controlled TDDS.

Polymer Membrane Permeation Controlled TDDS.

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

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 component responsible for skin adhesion is incorporated in an overlay and forms a concentric configuration around the semisolid matrix.

Drug Reservoir Gradient Controlled TDDS.

The Multi-layer Drug-inAdhesive is similar to the Single-layer Drugin-Adhesive in that the drug is incorporated directly into the adhesive. However, 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

Microreservoir Dissolution Controlled TDDS

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

Improvement of Skin Permeability

Physical Approach:
Stripping of stratum corneum. Hydration of stratum corneum. Iontophoresis. Phonophoresis.
Thermal Energy.

Chemical Approach:
Synthesis of lipophilic analogs (prodrugs). Delipidization of stratum corneum. Coadministration of skin permeation enhancer

Biochemical Approach:
Synthesis of bioconvertable prodrugs Coadministration of skin metabolism inhibitors.

Penetration Enhancers
This term refers to an entire family of chemically different substances that all share a common characteristic - they facilitate the permeation of the actives through the skin, increasing the permeation rate by several times. This is very important with respect to the feasibility of a system, 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, 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, color and low price)

The increase in skin permeation is created by:

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

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

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

Transdermal System Design: Whats Ahead?

Delivery of larger molecules using enhanced passive and active delivery systems Materials and formulations to reduce skin irritation, enhance the adhesion profile, 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