Transdermal Drug Delivery Systems

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Transdermal Drug Delivery Systems

• Dr O Hanbali

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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
Urine, Stool,
Drug in Target (or receptor) Site
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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
• Sustained Drug Action
• Localized Drug Action
• Targeting Drug Action

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Introduction to TransdermalDrug Delivery
Easier, more convenient, and effective
controlled-release in its most patient friendly
form.
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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)

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Schematic representation of the horny layer and
suggested routes for drug transportIntercellualr
and Transcelluar DiffusionLow Molecular weight
drugsLipophilic
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Possible routes for drug entry through the
skinIntra- and Transappenageal DiffusionIonic
Large Polar Penetrant
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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
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Introduction to Transdermal Drug Delivery
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Therapies That Use Transdermal Delivery of Drugs
Introduction to Transdermal Drug Delivery
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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

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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
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Stratum Corneum is the barrier in TDD (Rate
limiting step)
Introduction to Transdermal Drug Delivery
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Permeability Coefficient Is the Critical
Predictor of Transdermal Delivery

• Transport Flux (mg/cm2/sec)
• JP x A x (Cd Cr)
• Permeability Coefficient P D x K (cm/sec)
• 
  h
• Where A Surface area of patch
• 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)

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Attributes of a Passive TDD Drug Candidate

• Daily dose (lt 20 mg/day)
• Half-life (10 hours or less)
• Molecular weight (lt 500 daltons)
• Melting point (lt 200 oC)
• Skin permeability
• Lipid solubility
  partition coefficient (Log P)
  between 1.0 and 4
• Toxicology profile
• (non-irritating and non-sensitizing to skin)

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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.

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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.

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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.

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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.

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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.
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Drug Reservoir Gradient Controlled TDDS.

• The Multi-layer Drug-in-Adhesive is similar to
  the Single-layer Drug-in-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-in-adhesive layers under a single
  backing film

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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 cross-linking the polymer
  chain in-situ.

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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.

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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)

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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.

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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

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Ultrasound drug permeation(Ultrasonic)
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Iontophoresis

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

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Additional Development Stages

• In vitro skin permeation studies

Franz-Diffusion Cell
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Additional Development Stages

• Clinical evaluation
• Formulation and manufacturing scale-up
• Stability studies
• Analytical evaluation
• Regulatory submission and approval

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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