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Transdermal Drug Delivery Systems : 

Transdermal Drug Delivery Systems Seminar By : Arun kumar, Mpharmacy 2ndsemester, SRR college of pharmaceutical sciences, Valbhapur, Elkathurthy, Karimnagar.

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Introduction Transdermal drug delivery is hardly an old technology, since 1800’s and the technology is no longer just adhesive patches. Due to recent advances in technology and the ability to apply the drug to the site of action without rupturing the skin membrane, transdermal route is becoming a widely accepted route of drug administration. Over the last two decades more than 35 Transdermal patch products have been approved in US. Definition: Transdermal drug delivery system can deliver the drugs through the skin portal to systemic circulation at a predetermined rate and maintain clinically the effective concentrations over a prolonged period of time.

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Potential advantages of TDDS Avoids chemically hostile GI environment (drug degradation in acidic and basic environments is prevented). No GI distress and the factors like Gastric emptying, intestinal motility, transit time, donot effect this route as in oral route. Avoidance of significant presystemic metabolism (degradation in GIT or by the liver) and therefore need lower doses. Allows effective use of drugs with short biological half-life. Allow administration of drugs with narrow therapeutic window because drug levels are maintained within the therapeutic window for prolonged periods of time. Reduced inter and intra patient variability.

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Enhance therapeutic efficacy, reduced fluctuations (rapid blood level spikes-low and high) due to optimization of blood concentration – time profile. Reduction of dosing frequency and enhancement of patient compliance. Provides controlled plasma levels of very potent drugs. Can provide adequate absorption of certain drugs. Avoids the risk and inconveniences of parenteral therapy (Painless method of drug administration). Drug input can be promptly interrupted simply by removal of the patch when toxicity occurs. Provides suitability of self medication.

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Disadvantages of TDDS Drugs that require high blood levels cannot be administered – limited only to potent molecules, those requiring a daily dose of 10mg or less. Transdermal administration is not a means to achieve rapid bolus type drug input, rather it is usually designed to offer slow, sustained drug delivery. Adequate solubility of the drug in both lipophilic and aqueous environments, to reach dermal microcirculation and gain access to the systemic circulation. The molecular size of the drug should be reasonable that it should be absorbed percutaneously.

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Tolerance inducing compounds are not an intelligent choice for this mode of administration unless an appropriate wash out period is programmed in between the dosing regimen. Difficulty of permeation of the drug through human skin –barrier function of the skin. Skin irritation or dermatitis due to excipients and enhancers of drug delivery system used for increasing percutaneous absorption is another major limitation. Adhesive may not adhere well to all types of skin. Uncomfortable to wear. May not be economical.

Cross-section of human skin : 

Cross-section of human skin

Skin Structure and Barrier Properties : 

Skin Structure and Barrier Properties Skin is a multilayered organ complex in both structure and function. Macroscopically ,the outer epidermis and the inner dermis are two distinct layers of the skin. The layers of epidermis are: Stratum Corneum (Horny Layer) Stratum Lucidum(clear layer) Stratum Granulosum (Granular Layer) Stratum Spinosum (Prickly cell Layer) Malpighian Layer (pigment Layer) Stratum Germinativum (regenerative Layer) Epidermis is the outermost layer of the skin, which is approximately 150 micrometers thick. Cells from lowers layers of the skin travel upward during their life cycle and become flat dead cells of the corneum.

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The epidermis is a multilayered structure consisting of viable cells and dead keratinized cells. Stratum corneum :The layer that interacts with the environment is the stratum corneum, or horny layer. The stratum corneum consists of many layers of compact, flat, dehydrated and keratinized cells. These cells are physiologically inactive and are continuously shed with constant replacement from the underlying viable epidermal tissue. The stratum corneum has a water content of only 20% as compared to the normal physiological level of 70%, such as in the physiologically active stratum germinativum (which is the regenerative layer of the epidermis).

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The stratum corneum (10-15μm thick) is the skin’s primary defense layer against invasion .The major lipid classes within the stratum corneum are ceramides, cholesterol, and fatty acids.Their major structural components are aggregates of keratin filaments. All these contribute to tightness and impermeability characteristics of the skin.

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Stratum Corneum (topmost 15 μm layer) is the main barrier

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Stratum Lucidum: In the palm of the hand and sole of the foot, a zone forms a thin, translucent layer immediately above the granule layer. The cells are non-nuclear. Stratum Granulosum: This layer is above the keratinocytes. They manufacture  the basic staining particle, the keratinohylline granules. This keratogenous or transitional zone is a region of intense biochemical activity and morphological change. Stratum Spinosum: The cells of this layer are produced by morphological and histochemical alteration of the cells basal layers as they moved upward. The cells flatten and their nuclei shrink. They are interconnected by fine prickles and forms intercellular bridges- the desmosomes. These links maintain the integrity of the epidermis

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Malpighian Layer: The basal cells also include melanocytes which produce and distribute the melanin granules to the keratinocytes required for pigmentation - a protective measure against radiation. Stratum Germinativum: Basal cells are nucleated, columnar. Cells of this layer have high mitotic index and constantly renew the epidermis and this proliferation in healthy skin balances the loss of dead horny cells from the skin surface.. The human skin contains the dermis, approximately 2-3 mm thick, forms the bulk of the skin. The dermis contain a network of blood vessels, lymph vessels,hair follicles, sweat glands & sebaceous glands – skin appendages.

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Beneath the dermis is the hypodermis, which is primarily composed of fibroblasts and adipocytes - sub cutanious fatty tissues. Bulbs of hair project into these fatty tissues. The hypodermis binds skin to the underlying structures, in addition to serving as a thermo regulator and a cushion to internal organs against trauma. The skin is interspersed with hair follicles and associated sebaceous glands and sweat glands. Collectively these are referred to as skin appendages. On an average of 10-70 hair follicles and 200-500 sweat ducts per square centimeter are present on the skin surface. These skin appendages occupy only 0.1% of the total human skin surface.

1.Through stratum corneum 2.Transfollicular 3.Through sweat gland : 

1.Through stratum corneum 2.Transfollicular 3.Through sweat gland Pathways of drug penetration

Mechanisms of drug permeation : 

Mechanisms of drug permeation Hydrophilic drugs permeates by Intercellular pathway and Lipophilic drugs permeates by Intracellular (Transcellular) mechanism.

Skin permeability kinetics : 

Skin permeability kinetics Fick’s First Law of Diffusion Percutaneous absorption of most drugs is a passive-diffusion process that can be described by Fick’s first law of diffusion dQ/dt = JT = PAΔC JT is the total flux transported through a unit area of skin per unit time in steady state (µg/hr) A is area of the skin P is the effective permeability coefficient ΔC is the drug concentration gradient across the skin

Factors affecting percutaneous absorption : 

Factors affecting percutaneous absorption Physicochemical factors Biological factors Formulation factors

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Physicochemical factors of penetrant/drug Partition coefficient Solubility Ionization / pKa Molecular size and weight Stability or half-life

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Biological factors PH of the environment Area of application Age, Sex, Race Condition of the skin Integrity and Thickness of stratum corneum Pathological conditions of skin Hydration Metabolism Temperature

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Formulation factors Vehicle-solubility of the drug Lipophilicity of the solvent PH of the vehicle Composition of drug delivery system Surfactants

Drug properties : 

Drug properties Dose deliverable : ≤ 10mg/day Aqueous solubility : >1mg/ml Lipophilicity : log P (1-3) Molecular size : < 500 Daltons Melting point : < 200°C Drug should not be an irritant to skin. The drug should not stimulate an immune reaction in the skin. Along with these properties the drug should be potent, having short half life

Strategies for the enhancement of drug permeability : 

Strategies for the enhancement of drug permeability

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Drug vehicle interactions 1.Prodrugs The prodrug approach has been investigated to enhance transdermal delivery of drugs with unfavourable partition coefficients. The prodrug design strategy generally involves addition of a pro-moiety to increase partition coefficient and solubility to increase the transport of the drug in the stratum corneum. Upon reaching the viable epidermis, esterases release the active drug by hydrolysis thereby optimizing concentration in the epidermis.

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2.Ion-pairs Charged drug molecules do not readily partition into or permeate through human skin. Formation of lipophilic ionpairs has been investigated to increase stratum corneum penetration of charged species. This strategy involves adding an oppositely charged species to the charged drug, forming an ion-pair in which the charges are neutralized so that the complex can partition into and permeate through the stratum corneum. The ion-pair then dissociates in the aqueous viable epidermis releasing the parent charged drug that can diffuse within the epidermal and dermal tissues.

3.Eutectic Systems : 

3.Eutectic Systems The melting point of a drug influences solubility and hence skin penetration. According to solution theory, lower the melting point, greater the solubility of a material in a given solvent, including skin lipids. The melting point of a drug delivery system can be lowered by formation of a eutectic mixture, which is a binary system. At a constant ratio, the components inhibit the crystallization process of each other, such that the melting point of the two components in the mixture is less than that of each component alone.

4.Vehicle – Saturated and Supersaturated Solutions : 

4.Vehicle – Saturated and Supersaturated Solutions The maximum skin penetration rate is obtained when a drug is at its highest thermodynamic activity as is the case in a supersaturated solutions. Supersaturated solutions can occur due to evaporation of solvent or by mixing of cosolvents.

Vesicles and Particles : 

Vesicles and Particles 1.Transfersomes: These are vesicles composed of phospholipids as their main ingredient with 10-25% surfactant (such as sodium cholate) and 3-10% ethanol. The surfactant molecules act as “edge activators", conferring ultradeformability on the transfersomes, which reportedly allows them to squeeze through channels in the stratum corneum that are less than one-tenth the diameter of the transfersome.

2.Ethosomes : 

2.Ethosomes These are liposomes with high alcohol content capable of enhancing penetration to deep tissues and the systemic circulation. It is proposed that alcohol fluidizes the ethosomal lipids and stratum corneum bilayer lipids thus allowing the soft, malleable ethosomes to penetrate through the disorganized lipid bilayers.

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3.Liposomes The most effective liposomes are reported to be those composed of lipids similar to stratum corneum lipids, which are most likely to enter stratum corneum lipid lamellae and fuse with endogenous lipids. 4.High Velocity Particles –needle less injection Transdermal delivery is achieved by firing the liquid or solid particles at supersonic speeds through the outer layers of the skin using a suitable energy source. The mechanism involves forcing compressed gas (helium) through the nozzle, with the resultant drug particles entrained within the jet flow reportedly traveling at sufficient velocity for skin penetration.

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Needle-free Jet Injectors

Advantages : 

Advantages Pain-free delivery — particles are too small to trigger pain receptors on the skin. Improved efficacy and bioavailability. Targeting to a specific tissue, such as a vaccine delivered to epidermal cells. Accurate dosing and Overcomes needle phobia. Safety — the device avoids skin damage or infection from needles or splash back of body fluids. The PowderJect system fires solid particles (20–100µm) through stratum corneum into lower skin layers, using a supersonic shock wave of helium gas. Intraject is a development of the vaccine gun designed to deliver liquids through skin without using needles.

Stratum corneum modified : 

Stratum corneum modified 1.Hydration Hydration of stratum corneum increases rate of most (but not all) substances, water opens up the compact structure of horny layer. Moisturizing factors, occlusive films, hydrophobic ointments and transdermal patches all enhance drug bioavailability into skin.

2.Chemical permeation enhancers : 

2.Chemical permeation enhancers A substance that will increase the permeability of the epithelial barrier by modifying its structure also termed as accelerants or sorption promoters-can enhance drug flux. Ideal Penetration Enhancer Non-toxic, non-irritating, non-allergenic. Immediate onset of increased permeability. Immediate recovery of normal barrier properties upon removal (reversible). Physically and Chemically compatible with a wide range of drugs.

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Solvents - Ethanol, acetone, polyethylene glycol, glycerol, propylene glycol, dimethyl sulfoxide Surfactants - Brij30, brij72, Pluronic, Sodium lauryl sulphate, Span 20, Tween 80. Azones - N- Acyl hexahydro-2-oxo-1H-azepines, N-Alkylmorpholine-2,3-diones. Terpenes - Limonene, Carvone Fatty alcohols - Lauryl alcohol, linolenyl alcohol, oleic and fatty acids acid and lauric acid. Miscellaneous - Lecithin, sodium deoxycholate, L-amino acid, acid phosphatase,phospholipase & calonase

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Lipid action The enhancer disrupts stratum corneum lipid organization, making the drug permeable. The accelerant molecules jump into the bilayer, rotating, vibrating and translocating, forming microcavities and increasing the free volume available for drug diffusion. e.g. Azone, Terpenes, Fatty acids, DMSO and Alcohols. Protein modification Ionic surfactants, decylmethylsulphoxide and DMSO interact well with keratin in corneocytes, opening up the dense protein structure, making it more permeable, thus increasing drug diffusion.

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Partitioning promotion Many solvents enter stratum corneum, change its solution properties by altering the chemical environment, and thus increase partitioning of a second molecule into the horny layer. e.g. Ethanol, Azone, Propylene glycol, DMSO. Many chemical enhancers combine these three LPP mechanisms.

Stratum corneum bypassed or removed : 

Stratum corneum bypassed or removed 1.Microneedle array Microneedles are somewhat like traditional needles, but are fabricated on the micro scale. They are generally one micron in diameter and range from 1-100 microns in length. Microneedles have been fabricated with various materials such as metals, silicon, silicon dioxide, polymers, glass,etc. Stratum corneum can be bypassed by a device of 400 microneedles which insert drug just below the barrier. Flux increases up to 100-1000-fold. Hollow microneedles could be used to remove fluid from the body for analysis such as blood glucose measurements.

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2. Stratum corneum ablation/abrasion The abrasion technique involves the direct removal or disruption of the upper layers of the skin to facilitate the permeation of topically applied medicaments. Some of these devices are based on techniques employed by dermatologists for superficial skin resurfacing termed as microdermabrasion which are used in the treatment of acne, scars, hyperpigmentaion and other skin blemishes. Microdermabrasion uses a stream of aluminium oxide crystals and dermabrasion employs a motor-driven abrasive fraise or cylinder.

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. Microscissuining is a process which creates microchannels in the skin by eroding the impermeable outer layers with sharp microscopic metal granules. Laser ablation applies high powered pulses(laser radiation) to vapourise a section of the horny layer so as to produce permeable skin regions.

3.Follicular delivery : 

3.Follicular delivery The pilosebaceous unit (hair follicle, hair shaft and sebaceous gland) provides a route that bypasses the intact stratum corneum.The sebaceous gland cells are more permeable than corneocytes and thus drugs can reach the dermis by entering the follicle (bypassing stratum corneum), passing through the sebaceous gland or penetrating the epithelium of the follicular sheath. The rich blood supply aids absorption, even though the shunt route cross-sectional area is small. Colloidal particles, such as liposomes and analogues and small crystals target the hair follicle. In general, particles >10 μm remain on the skin surface, those 3–10 μm concentrate in the follicle and when <3μm they penetrate follicles and stratum corneum alike.

Electrically Assisted methods : 

Electrically Assisted methods 1.Ultrasound (Phonophoresis / Sonophoresis) Used originally in physiotherapy and sports medicine, applies a preparation topically and massages the site with an ultrasound source. The ultrasonic energy (at low frequency) disturbs the lipid packing in stratum corneum by cavitation. Sonicators operating at frequencies in the range of 20kHz to 3MHz are available commercially and can be used for Sonophoresis. Therapeutic ultrasound (1–3MHz) - for massage, Low-frequency ultrasound (23-40kHz) - in dentistry, High-frequency ultrasound (3–10 MHz) - diagnostic purposes.

Enhanced Transdermal Permeation by Cavitation of stratum corneum upon application of Ultrasound. : 

Enhanced Transdermal Permeation by Cavitation of stratum corneum upon application of Ultrasound.

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Ultrasound to Enhance Skin Permeability

2.Iontophoresis : 

2.Iontophoresis The electrical driving of charged molecules into tissue, passes a small direct current (approximately 0.5 mA/cm2) through a drug containing electrode in contact with the skin. The most popular electrodes are based on the silver/silver chloride redox couple. Three main mechanisms enhance molecular transport: Charged species are driven primarily by electrical repulsion from the driving electrode. Flow of electric current may increase the permeability of skin and Electroosmosis may affect uncharged molecules and large polar peptides. Limitations: Hair follicle damage is possible.

3.Electroporation : 

3.Electroporation Skin electroporation (electropermeabilization) creates transient aqueous pores in the lipid by application of high voltage of electrical pulses of approximately 100–1000 V/Cm for short time(milliseconds). These pores provide pathways for drug penetration that travel straight through the horny layer. This technology has been successfully used to enhance the skin permeability of molecules with differing lipophilicity and size including biopharmaceuticals with molecular weights greater that 7kDA..

4.Magnetophoresis : 

4.Magnetophoresis Magnetophoresis is a novel approach in enhancing drug delivery across biological barriers. Benzoic acid, a diamagnetic substance, was selected as a drug candidate. The influence of magnetic field strength on diffusion flux was determined and was found to increase with increasing applied strength.

5.Photomechanical waves : 

5.Photomechanical waves A drug solution, placed on the skin and covered by a black polystyrene target, is irradiated with a laser pulse. The resultant photomechanical wave stresses the horny layer and render the stratum corneum more permeable to macromolecules via a possible transient permeabilisation effect due to the formation of transient channels and enhances drug delivery. However ,this new technique does not yet seem to have produced any human clinical data.

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Controlled Heat Aided Drug Delivery(CHADD) System Heat increases skin temperature that leads to increase in microcirculation and blood vessel permeability, thus facilitating drug transfer to the systemic circulation. Drug solubility, both in the patch formulation and within the skin increase with a rise in temperature. A technology known as Controlled Heat-aided Drug Delivery system was developed and the CHADD system contains a small heating unit that can be placed on top of a traditional patch. An oxidation reaction within the unit provides heat at a limited intensity and duration.

Basic components of TDDS : 

Basic components of TDDS Drug Polymer matrix Penetration enhancers Other Excipients Rate controlling membrane Adhesive Release liner Backing membrane

Types of Transdermal delivery devices : 

Types of Transdermal delivery devices

Transdermal matrix system : 

Transdermal matrix system Rate controlling factors Drug concentration in polymer matrix Chemical nature of polymer matrix Geometry of device Polymers: PVC, PVP, Ethylene vinylacetate, microporous polypropylene. Initially the drug is released rapidly, then rate declines as matrix is depleted. Advantages: Sleeker and thinner, daily or multiple-day Applications. Appropriate for drugs that penetrate readily and/or have low dosage requirements.

Transdermal reservoir system : 

Transdermal reservoir system Rate controlling factors Membrane thickness Membrane permeability Polymers: Cellulosic esters, polyamides or PVC. Advantages: Used when matrix systems cannot penetrate skin and drugs require significant penetration enhancement and/or high dosage levels.

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Release liners Protects the skin-contacting adhesive during storage. Substrate carries a very thin release coating. Provides low energy surface for ease of removal. e.g.: polyester or polystyrene based films. Backing material Contains formulation throughout shelf life and during wear period. They have laminate structure. They must be compatible with the formulation (nonadsorptive). They are occlusive and completely water impermeable in nature. e.g.: Poly urethane films, Ethyl vinyl acetate, Poly olefins. Adhesive layer Acrylic copolymers, polyisobutylene and polysiloxane.

Evaluation of TDDS : 

Evaluation of TDDS Content, Content uniformity. In vitro release Vs Ex vivo permeation of active and penetration enhancer – difussion cells. Residual solvent, residual monomer Release liner peel, adhesion. Mechanical properties Moisture absorption & Moisture loss Microbiology Pouch integrity

Franz Diffusion Cell : 

Franz Diffusion Cell Skin: Rat abdominal, Rabbit, Porcine, Human cadaver

Mechanical properties evaluation by ultra tester : 

Mechanical properties evaluation by ultra tester

Moisture absorption & Moisture loss studies : 

Moisture absorption & Moisture loss studies Moisture absorption study: Saturated solution of Alcl3 (79.50% RH)/ 3 days. Moisture loss study: Patches were placed in a desiccator containing Cacl2 at 40oC/24 hr.

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Transdermal patches available in the market

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Marketed Products of Modified Transdermal Drug Delivery Technologies

Conclusion : 

Conclusion Transdermal drug delivery technologies are becoming one of the fastest growing sectors within the pharmaceutical industry. Advances in drug delivery systems have increasingly brought about rate controlled delivery with fewer side effects as well as increased efficacy and constant drug delivery. The market value for transdermal delivery was $12.7 billion in 2005, and is expected to increase to $21.5 billion in the year 2010 and $31.5 billion in the year 2015 – suggesting a significant growth potential over the next 10 years.

References : 

References Controlled drug delivery –concepts and advances – by S.P.Vyas R.K.Khar. Encyclopedia of pharmaceutical technology -third edition edited by James Swarbrick volume-4 Microsphere Technology and Applications by Diane J. Burgess and Anthony J. Hickey. Controlled and Novel drug delivery edited by N.K.Jain reprint 2007 Encyclopedia of controlled drug delivery volume 2 encyclopedia of controlled drug delivery Asian Journal of Pharmaceutical and Clinical Research transdermal drug delivery system: a review p. k.gaur,s. mishra, s. purohit, k. dave..

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European Journal of Pharmaceutical Sciences Review -Novel mechanisms and devices to enable successful transdermal drug delivery by B.W. Barry. Transdermal drug delivery- penetration enhancement techniques- Heather A.E. Benson. Microneedles : The option for painless delivery by Geeta M Patel.