Transdermal Drug Delivery System

ట్రాన్స్‌డెర్మల్ డ్రగ్ డెలివరీ సిస్టమ్

ఉద్దేశించిన అభ్యాస లక్ష్యాలు

ఈ ఉపన్యాసం ముగింపులో విద్యార్థి చేయగలరు:

•    ట్రాన్స్‌డెర్మల్ పారగమ్యతను ప్రభావితం చేసే కారకాలను వివరించండి

•    ట్రాన్స్‌డెర్మల్ డెలివరీ సిస్టమ్ యొక్క భాగాలను చర్చించండి

•    ట్రాన్స్‌డెర్మల్ ప్యాచ్ యొక్క భాగాలను గుర్తించండి

•    వివిధ భాగాల ప్రాముఖ్యతను చర్చించండి

•   Suggest suitable materials for the various components

•   Enlist the approaches for fabrication of TDDS

•   Describe the design of patch in each approach

•   Suggest a suitable design for a drug with given physicochemical properties

•   Explain the need for permeation enhancement methods for transdermal drug delivery

•   Discuss methods employed to improve transdermal permeation of drugs

Transdermal drug delivery system

History

• The first use of transdermal can be found in ancient China, where medicated plasters were slathered on the skin and left to dry

• The method was devised to allow a medication to have direct and constant contact with the skin.

• The first patch certified and accepted by the United States Food and Drug Administration was for a motion sickness patch. It was approved in 1979.

• Nicotine patches rose the profile of transdermal patches in the 1990s when it was approved for patient use.

• Since then, patches have been designed for many medications, including those used to treatment of Alzheimer’s           disease, Parkinsons, and those to administer birth control.

Definition

• Self-contained discrete dosage forms which when applied to the intact skin, deliver the drugs through the skin at a controlled rate to the systemic circulation

Or

• Systems that utilize skin as a site for continuous drug administration into the systemic circulation

Comparison of drug travel- oral v/s transdermal

Transdermal patch – more than a surgical tape

Drug in a transdermal patch

Permeates through the skin

Drug in blood stream

Advantages

• The system avoids the chemically hostile GI environment

• No GI distress or other physiological contraindications of the oral route

• Can provide adequate absorption of certain drugs

• Increased patient compliance

• Avoids first-pass effect

• Allows effective use of drugs with short biological half-life

• Allow administration of drugs with narrow therapeutic windows

• Provides controlled plasma levels of very potent drugs

• Drug input can be promptly interrupted when toxicity occurs

• Self-medication possible

Disadvantages of TDDS

• Varying barrier function of the skin: site to site; person to person; with age…

• Not suitable for drugs requiring high plasma levels

• Adhesive failure

• Skin irritation and sensitization

• May be uncomfortable

• May not be economical

Anatomy of Human Skin

Skin

1.       Epidermis

Ø  Stratum corneum

Ø  Stratum granulosum

Ø  Stratum spinosum

Ø  Stratum lucidum

Ø  Stratum germinativum

2.       Dermis

3.       Subcutaneous tissue

Epidermis

• Outer layer of the skin

• Stratified squamous epithelial cells

• Primary barrier to percutaneous absorption

• Removal of this layers results in increased permeability

• Water content of stratum corneum is around 20%

• The moisture required for stratum corneum is around 10% (w/w) to maintain flexibility and softness

Dermis

• Network of collagen and elastic fibres

• Embedded in mucopolysaccharide matrix

• This network or the gel structure is responsible for the elastic properties of the skin

• Upper portion of the dermis is formed into ridges containing lymphatics and nerve endings

Hypodermis

• Innermost and thickest layer of the skin

• Sheet of the fat containing areolar tissue

• Known as the superficial fascia

• Acts as energy reserve

• Attaches the dermis to the underlying structures

Transdermal permeation routes

1. Transepidermal

Ø  Transcellular /Intracellular

Ø  Paracellular /Intercellular

2. Transfollicular

Transdermal drug permeation

Transepidermal absorption

• Stratum corneum is the main resistance for absorption through this route.

• Permeation involves partitioning of the drug into the stratum corneum.

• Permeation through the skin depends upon the o/w distribution tendencies of the drug.

• Lipophilic drug concentrate in and diffuse with relative ease.

• Permeation through the dermis is through the interlocking channels of the ground substance

Transcellular route

•   Direct route -Path of shortest distance

• Drugs cross the skin by directly passing through both the phospholipids membranes and the cytoplasm of the dead keratinocytes that constitute the stratum corneum

• Drugs must cross the lipophilic membrane of each cell, then the hydrophilic cellular contents containing keratin, and then the phospholipid bilayer of the cell one more time

• Series  of  steps  is  repeated  numerous  times  to  traverse  the  full thickness of the stratum corneum

Paracellular / intercellular route

• Pass through the small spaces between the cells of the skin

• More tortuous

• Thickness of the stratum corneum is only about 20 µm, the actual diffusional path of most molecules crossing the skin is on the order of 400 µm

• The 20-fold increase in the actual path of permeating molecules greatly reduces the rate of drug penetration

Transfollicular absorption

• The skin appendages (sebaceous and eccrine glands) are considered as shunts for by passing the stratum corneum.

• Follicular route is important for permeation because the opening of the follicular pore is relatively large and sebum aids in the diffusion of the penetrant.

• Partitioning into the sebum followed by the diffusion to the depths of the epidermis is the mechanism

Transdermal drug permeation

Clearance by local circulation

The earliest point of entry of drugs into the systemic circulation is within the papillary plexus in the upper epidermis

Factors Affecting Transdermal Permeation

Biological factors

Age

Blood flow

Site of patch application / stratum corneum thickness

Skin metabolism

Presence of hair follicles

Injury or trauma to the skin

Hydration of the skin

Effect of humidity and temperature

Chronic use of certain drugs

Skin hydration

Physicochemical factors

Diffusion coefficient

Drug concentration

Partition coefficient

Molecular size and shape

Skin age

➢ the young skin is more permeable than older

➢ Children are more sensitive for skin absorption of toxins

➢ Advancing age causes epidermis to atrophy

➢ Dermoepidermal junctions flatten – dermis thins

➢ Irritant and allergic interaction reactions are weaker in older individuals

Blood flow

➢ Changes in peripheral circulation can affect transdermal absorption

➢ Blood flow limits the absorption of the drug from the dermis

➢ Vasoconstrictor drug administered through other routes can significantly affect blood flow to the dermis hence dermal clearance of the drug into the general circulation

Site of application

➢ Thickness of skin, nature of stratum corneum and density of appendages vary site to site

➢ Variations in stratum corneum thickness, the number of sebaceous glands, and hydration status can all affect absorption

➢ Regional permeability: nail < < palm/sole < trunk/extremities < face/scalp < < scrotum

Skin metabolism

• Skin metabolizes steroids, hormones, chemical carcinogens and some drugs

• Skin metabolism determines efficacy of drug permeated through the skin

• If the penetrating drug is subject to biotransformation during skin permeation local and systemic bioavailability can be affected drastically

Hair follicles

• Hair follicles and sweat glands could provide shunt routes for drugs and chemicals through the stratum corneum

• Hair follicles are considerable weak spots in our protective sheath against certain hydrophilic drugs and may allow a fast delivery of topically applied substances

• Surface area of the follicular epithelium can be seen as a considerable enlargement of the skin surface

• Hair follicles can act as a relevant reservoir for topically applied substances and that nanoparticles and liposomes at a size of 300–750 nm preferentially penetrate into the hair follicles

Injury or trauma to the skin

• Changes in the integrity of skin affects transepidermal water loss (TEWL)

• Increased percutaneous absorption is characteristic in patients with inflamed eczematous skin

Hydration of the skin

• In contact with water the permeability of skin increases significantly

• Permeability of the stratum corneum is substantially higher in hydrated state

• Skin occlusion with wraps or impermeable plastic films prevents the loss of surface water from the skin and this causes increased level of hydration in the stratum corneum thereby decreasing the protein network density and the diffusional path length

• Occlusion of the skin surface also increases skin temperature by 2-3oC resulting in increased molecular motion and skin penetration

Chronic use of certain drugs

• Long term use of keratolytics like salicylic acid results in increased drug penetration

Humidity and temperature

• The permeation of drug increase ten folds with temperature variation

• The diffusion coefficient decreases as temperature falls

• Heat increases skin permeability

• Increased body fluid circulation

• Increased blood vessel wall permeability, rate-limiting membrane permeability, and drug solubility

Skin hydration

• In contact with water the permeability of skin increases significantly.

• Hydration is most important factor increasing the permeation of skin.

• So use of humectant is done in transdermal delivery.

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

Diffusion coefficient

• Penetration 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

• 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 for good action

• Drugs with high K are not ready to leave the lipid portion of skin

• Drugs with low K will not be permeated

Molecular size and shape

• Drug absorption is inversely related to molecular weight

• Small molecules penetrate faster than large ones

Kinetics of Transepidermal Permeation

• The release of a therapeutic agent from a TDDS applied to the skin surface and its transport to the systemic circulation involves the following steps:

– Dissolution within and release from the formulation

– Partitioninginto the outermost layer of the skin, SC

– Diffusion through the SC

– Partitioningfrom the SC into the aqueous viable epidermis

– Diffusionthrough the viable epidermis and into the upper dermis

– Uptake into the local capillary network and eventually the systemic circulation

A Multilayer Skin Model Showing Sequence of Transdermal Permeation of Drug for Systemic Delivery

•   Trandermal permeation can be possible if the drug possesses certain physico-chemical properties. The rate of permeation across the skin (dQ / dt) is given by:

dQ/dt=Ps(Cd-Cr)   -------------- Eq. 1

Where, Cd = concentration of skin penetrant in the donar compartment (e.g., on the surface of stratum corneum)

Cr = concentration in the receptor compartment (e.g., body) respectively

Ps = the overall permeability constant of the skin tissue to the penetrant

Ps=KsDss/hs-----------Eq. 2

• Ks is the partition coefficient for the interfacial partitioning of the penetrant molecule from a solution medium or a transdermal therapeutic system onto the stratum corneum

• Dss is the apparent diffusivity for the steady state diffusion of the penetrant molecule through a thickness of skin tissues

• hs is the overall thickness of skin tissues

Components of a TDDS

The components of the transdermal drug delivery system include –

•   The drug

•    Polymer matrix or matrices

•   The permeation enhancers

•   Drug reservoir components

•   Backing laminate

•   Rate controlling membrane

•   Adhesive

•   Release liner

Desirable properties of drugs in TDDS

Physicochemical properties

• Solubility

• Melting point

• Molecular weight

• pH

• Hydrogen bonding

Biological properties

• Potent

• Half life

• Irritancy

• Stability

• Tolerance

• Binding

• Metabolism

Physicochemical properties of the drug

• Should have some degree of solubility in both oil and water (ideally greater than 1 mg/ml)

• Should have melting point less than 200°F

• Molecular weight of less than 1000 Daltons

• A saturated aqueous solution of the drug should have a pH value between 5 and 9

• Drugs highly acidic or alkaline in solution are not suitable for TDD; because they get ionized rapidly at physiological pH

• Hydrogen bonding groups should be less than 2

Biological properties of the drug

• Drug should be very potent, i.e., it should be effective in few mgs per day (ideally less than 25 mg/day)

• Should have short biological half life

• Should be nonirritant and non-allergic to human skin

• Should be stable when in contact with the skin

• Should not stimulate an immune reaction to the skin

• Tolerance to drug must not develop under near zero order release profile of transdermal delivery

• Should not get irreversibly bound in the subcutaneous tissue

• Should not get extensively metabolized in the skin

Polymer

• Integral and foremost important component of transdermal drug delivery systems

• Mechanism of drug release depends upon the physicochemical properties of the drug and polymer used in the manufacture of the device

• Molecular weight, glass transition temperature, chemical functionality of polymer must allow diffusion and release of the specific drug

• The polymer should permit the incorporation of a large amount of drug

• The polymer should not react, physically or chemically with the drug

• The polymer should be easily manufactured and fabricated into the desired product and inexpensive

• The polymer must be stable and must not decompose in the presence of drug and other excipients used in the formulation, at high humidity conditions, or at body temperature

• Polymers and its degradation products must be non-toxic

• No single material may have all these attributes; e.g., cosolvents such as ethanol, propylene glycol, PEG 400 could be added to increase drug solubility

Polymers in TDDS

Techniques employed to modify the polymer properties and thus drug release rates

• Cross linked polymers: The higher the degree of cross linking, the denser the polymer and slower the diffusion of drug molecules through the matrix.

• Polymer blends:Polymers have been blended on varying ratios to combine the advantages of the individual polymers.

• Plasticizers:Plasticizers have been known to reduce the stiffness of the polymer backbone, thereby increasing the    diffusion characteristics of the drug.

Penetration enhancers

• Compounds, which promote skin permeability by altering stratum corneum the as a barrier to the flux of a desired

• Resistance of skin to diffusion of drugs has to be reduced in order to allow drug molecules to cross skin and to maintain therapeutic levels in blood.

• They can modify the skin’s barrier to penetration either by interacting with the formulation that applied or with the skin itself.

• Pharmacologically inert, nontoxic, non-allergenic, non-irritating and ability to act specifically, reversibly and for   predictable duration

• Should not cause loss of body fluids, electrolytes or other endogeneous materials

Ex: Terpenes, Terpenoids, Pyrrolidones

Solvents like alcohol, Ethanol, Methanol

Surfactants like Sodium Lauryl sulfate, Pluronic F127, Pluronic F68

Drug reservoir components

• It must be compatible with the drug

• Must allow for drug transport at the desired rate

• Drug reservoir must possess the desired viscosity attributes to ensure reliable manufacturing process

• Must possess the desired adhesive and cohesive properties to hold the system together

Backing laminates

• Primary function is to provide support

• Should be able to prevent drug from leaving the dosage form through top

• Must be impermeable to drugs and permeation enhancers

• Should allow moisture vapour transmission rate

• Must have optimal elasticity, flexibility, and tensile strength

•   Must be chemically compatible with the drug, enhancer, adhesive and other excipients

•   Must be relatively inexpensive and must allow printing and adhesive lamination

•   Composed of

– Pigmented layers

– An aluminium vapor coated layer

– A plastic film (polyethylene, polyvinyl chloride, polyester)

– A heat seal layer

Rate controlling membrane

• Rate controlling membranes in transdermal devices govern drug release from the dosage form

Adhesive layer

• For fastening of transdermal devices to the skin

• A pressure sensitive adhesive

• Positioned on the face or in the back of device

• Should not cause irritation, sensitization or imbalance in the normal skin flora during its contact with the skin.

Classes of polymers evaluated for potential adhesive applications in

TDDS include:

➢ Polyisobutylene type pressure sensitive adhesives

➢ Acrylic type pressure sensitive adhesives

➢ Silicone type pressure sensitive adhesives

Release liners

• The release liner has to be removed before the application of transdermal system

• Prevents the loss of the drug that has migrated into the adhesive layer during storage

• Helps to prevent contamination

• Composed of

– A base layer, which may be nonocclusive or occlusive

– Release coating layer made of silicon or Teflon.

• Other materials include polyesters, foil, Mylar and metallized laminate

Approaches to Transdermal Therapeutic Systems

• Membrane permeation controlled systems

• Adhesive dispersion controlled systems

• Matrix dispersion type systems

• Microreservoir system

Membrane permeation controlled systems

• The drug reservoir is totally encapsulated in a shallow compartment moulded from

– A drug – impermeable metallic plastic laminate

– Rate controlling polymeric membrane which may be microporous or non-porous.

– Drug can be in the form of solution, suspension, gel or dispersion in polymer matrix in the reservoir compartment

• The rate of drug release from this type of TDDS can be tailored by varying the composition of polymer, permeability coefficient, thickness of the rate limiting membrane & adhesive.

• On the outer surface of polymeric membrane, a thin layer of adhesive polymer is applied

Membrane permeation controlled systems…

Name	Drug	Remarks
Transderm-nitro	Nitroglycerine	For once a day medication in angina pectoris.
Transderm-scop	Scopolamine	For 72 hrs. prophylaxis of motion sickness
Catapress	Clonidine	delivers clonidine at an approximately constant rate for 7 days
Estraderm	Estradiol	Nominal rate of estradiol release 50 micrograms/day

Adhesive Dispersion Type TDDS

• In this type, the drug reservoir is prepared by directly dispersing the drug in an adhesive polymer

• Then this medicated adhesive polymer is spread over a flat sheet of drug impermeable backing membrane

• The drug reservoir layer is then covered by a non-medicated rate controlling polymer of constant thickness to produce an adhesive diffusion controlling DDS

Example: Isosorbide dinitrate-releasing Transdermal therapeutic system (Frandol tape) for once a day medication of angina pectoris.

Matrix dispersion type TDDS

Preparation of a drug polymer blend

Then pasted on to an occlusive base plate in a compartment fabricated from a drug impermeable plastic backing

Adhesive polymer is then spread along the circumference to form a strip of adhesive rim around the medicated disc

Matrix dispersion type TDDS

Microreservoir type TDDS

• A combination of reservoir and matrix diffusion type drug delivery system.

• A drug reservoir is formed by first suspending the solid drug in an aqueous solution of water soluble polymer. This drug suspension is homogenously dispersed in a lipophilic polymer by high energy dispersion technique.

• This forms the microscopic spores of drug reservoir which are supported over an occlusive pad and are thermodynamically unstable

• Stabilization by cross linking the polymer chain in-situ using cross linking agent

• It can be further coated with a layer of biocompatible polymer to improve the drug release

Permeation Enhancement Methods

Physical Enhancement Techniques

1. Stature Based

Microneedles

2. Electrically Based

Iontophoresis

Electroporation

Ultrasound

Photomechanical wave

3. Velocity Based

Jet Propulsion

Microneedles - Microporation

Basic design of microneedle delivery system devices. Needles with or without hollow centre channels are placed onto the skin surface so that they penetrate the SC and epidermis without reaching the nerve endings present in the upper epidermis.

• Involves the use of micro needles that are applied to the skin

• They pierce only the SC and increase skin permeability

• Uses needles that are 10 to 200 μm in height and 10 to 50 μm in width

• Micro needles do not stimulate the nerves, so the patient does not experience pain or discomfort

• They are usually drug coated projections of solid silicon or hollow, drug filled metal needles

Improving Transdermal Permeation

Iontophoresis

• Process of enhancing the permeation of topically applied therapeutic agents through the skin by the application of electric current

• Drug is applied under an electrode of the same charge as the drug

• An indifferent counter electrode is positioned elsewhere on the body

• Active electrode effectively repels the active substance and forces it into the skin

Sonophoresis

• Involves the use of ultrasonic energy to enhance skin penetration of active substances

• Low frequency regimes (20 KHz < f <100 KHz)

• Mechanism of transdermal skin permeation involves the disruption of the SC lipids by the formation of gaseous cavities, thus allowing the drug to pass through the skin

• Several antibiotics have been delivered through this technique

Electroporation

• Application of short (microsecond or millisecond), high voltage (50-1000 volts) pulses to the skin

• Mechanism of penetration is the formation of transient pores due to electric pulses

• Allow the passage of macromolecules from the outside of the cell to the intracellular space via a combination of processes such as diffusion and electrophoresis

• Macromolecules that have been delivered by electroporation include: insulin,vaccines, oligonucleotides and microparticles

Magnetophoresis

• Application of a magnetic field which acts as an external driving force to enhance the diffusion of a diamagnetic solute across the skin

• Exposure to magnetic field might induce structural alterations in the skin

• Magnetophoresis can be combined with chemical permeation enhancers for enhanced drug permeation

Jet propulsion

Needle free injectors

• Technique involves firing the liquid or solid particles at supersonic speeds through the SC

• A pain-free method of administration of drugs to the skin

Mechanism involves

• Forcing compressed gas such as helium or nitrogen through the nozzle with the resultant drug particles entrained within the jet flow, reportedly traveling at sufficient velocity for skin penetration

Injection without needles – Dermal powder jet

Thermal ablation

• Thermal ablation selectively heats the skin surface to generate micron-scale perforations in the stratum corneum.

• Transiently heating the skin’s surface to hundreds of degrees for microseconds to milliseconds

• Localizes heat transfer to the skin surface without allowing heat to propagate to the viable tissues below

• This spares these tissues from damage or pain

• Mechanistically, thermal ablation may involve rapidly vaporizing water in the stratum corneum

• Resulting volumetric expansion ablates micron-scale craters in the skin’s surface

• Skin heating has been achieved using ohmic microheaters and radio-frequency ablation

Microdermabrasion

• A final way to remove the stratum corneum barrier employs abrasion by microdermabrasion or simply using sandpaper.

• Microdermabrasion is a widely used method to alter and remove skin tissue for cosmetic purposes

• Shown to increase skin permeability to drugs, including lidocaine and 5-fluorouracil

• Vaccine delivery across the skin has also been facilitated by skin abrasion using sandpaper

Commercially Available Transdermal Patches

• Nicotine patch

Nicotine patch helps to give up smoking by relieving the desire to smoke, and some of the unpleasant effects which smokers experience when they stop smoking

• Transdermal scopolamine patches

• Hormone patch

• Clonidine patches for hypertension

• Testosterone patches

• Fentanyl patches

• Nitroglycerine patches

Summary

• Self-contained discrete dosage forms which when applied to the intact skin, deliver the drugs through the skin at a controlled rate to the systemic circulation

Transdermal patch – more than a surgical tape

Drug in blood

Permeates Stream through the skin

Drug in a transdermal patch

Anatomy of Human Skin

1. Epidermis

·         Stratum corneum

·         Stratum granulosum

·         Stratum spinosum

·         Stratum lucidum

·         Stratum germinativum

2. Dermis

3. Subcutaneous tissue

Transdermal permeation routes

1. Transepidermal

·         Transcellular /Intracellular

·         Paracellular /Intercellular

2. Transfollicular

Factors Affecting Transdermal Permeation

Biological factors

Age

Blood flow

Site of patch application / stratum corneum thickness

Skin metabolism

Presence of hair follicles

Injury or trauma to the skin

Hydration of the skin

Effect of humidity and temperature

Chronic use of certain drugs

స్కిన్ హైడ్రేషన్

భౌతిక రసాయన కారకాలు

వ్యాప్తి గుణకం

ఔషధ ఏకాగ్రత

విభజన గుణకం

పరమాణు పరిమాణం మరియు ఆకారం

ట్రాన్స్‌పిడెర్మల్ పెర్మియేషన్ యొక్క గతిశాస్త్రం…

•    ఔషధం నిర్దిష్ట భౌతిక-రసాయన లక్షణాలను కలిగి ఉంటే ట్రాండర్మల్ పారగమ్యం సాధ్యమవుతుంది. చర్మం అంతటా పారగమ్యత రేటు (dQ / dt) దీని ద్వారా ఇవ్వబడింది:

dQ/dt=Ps(Cd-Cr)    ------------- Eq. 1

Ps=KsDss/hs------------Eq. 2

• భాగాలు - ఔషధ, పాలిమర్, అంటుకునే, విడుదల లైనర్, బ్యాకింగ్ మాంబ్రేన్

• పాలిమర్ -  డ్రగ్ మ్యాట్రిక్స్/ రేట్ కంట్రోలింగ్ మెమ్బ్రేన్, బ్యాకింగ్ మెమ్బ్రేన్

• సూత్రీకరణలో పెర్మియేషన్ పెంచేవి  - చర్మం అంతటా ఔషధ ప్రవాహాన్ని పెంచడానికి

విధానాలు

• మెమ్బ్రేన్ పెర్మియేషన్ కంట్రోల్డ్ సిస్టమ్స్

• అంటుకునే వ్యాప్తి నియంత్రిత వ్యవస్థలు

• మ్యాట్రిక్స్ డిస్పర్షన్ టైప్ సిస్టమ్స్

• మైక్రోరిజర్వాయర్ వ్యవస్థ

ఫిజికల్ ఎన్‌హాన్స్‌మెంట్ టెక్నిక్స్

1. పొట్టితనాన్ని బట్టి

మైక్రోనెడిల్స్

2. ఎలక్ట్రికల్ బేస్డ్

అయోంటోఫోరేసిస్

ఎలెక్ట్రోపోరేషన్

అల్ట్రాసౌండ్

ఫోటోమెకానికల్ వేవ్

3. వేగం ఆధారంగా

జెట్ ప్రొపల్షన్

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