transdermal drug delivery system

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Transdermal Drug Delivery Systems : 

Transdermal Drug Delivery Systems Presented By : Y.Jairam kumar M.pharmacy Seminar By : Y.Jairam kumar M.pharmacy 2ndsemester, K LR Pharmacy college

CONTENTS : 

CONTENTS INTRODUCTION ADVANTAGES & DISADVANTAGES STRUCTURE OF SKIN FACTORS AFFECTING PERCUTANEOUS ABSORPTION BASIC COMPONENTS OF TDDS APPROACHES USED IN DEVELOPMENT OF TDDS EVALUATION OF TDDS CONCLUSION REFERENCES

Slide 3: 

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.

Slide 4: 

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.

Slide 5: 

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. The molecular size of the drug should be reasonable that it should be absorbed percutaneously. Skin irritation or dermatitis due to excipients and enhancers of drug delivery system used for increasing percutaneous absorption is another major limitation.

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)

Slide 8: 

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. 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.

Slide 9: 

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 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.

Slide 10: 

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

Slide 11: 

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

Slide 12: 

Malpighian Layer: The basal cells also include melanocytes which produce and distribute the melanin granules to the keratinocytes required for pigmentation. 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.

Slide 13: 

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 Where 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 Physico-chemical properties of penetrant -Thick ness(hs) -Permeant diffusion coefficient(Dss) -Partition coefficient(ks) Between membrane & external phases expressed as Ps= ks Dss / hs Membrane flux J = APS (CP –CR) Combined both the equations J/A=DS KS (CP –CR) / hS Physiological & pathological conditions of skin -Most physiological factor is the hydration state of stratum corneum -In hydration state decreases the skin barrier properties and increase permeability. EX: Esters of salicylic acid.

Physicochemical properties of drug delivery system : 

Physicochemical properties of drug delivery system Organic solvents and surface active agents can also alter the permeability of skin and enhance the percutaneous absorption The release of drug from the delivery vehicle depends on its affinity to the vehicle. The pH of the vehicle can influence the rate of release of the drug from the drug delivery systems The composition of drug delivery system not only affects the rate of drug release, but also the permeability of stratum corneum by affecting hydration, mixing with skin lipids

Chemical permeation enhancers : 

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.

Slide 20: 

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, fatty acids oleicacid and lauric acid. Miscellaneous - Lecithin, sodium deoxycholate, L-amino acid,acidphosphatase,phospholipase

Slide 21: 

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.

Electrically Assisted methods : 

Electrically Assisted methods 1.Ultrasound (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.

Slide 24: 

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

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.

Basic components of TDDS : 

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

DRUG: : 

DRUG: The choice of drug is critical in the successful development of a transdermal product IDEAL PROPERTIES OF DRUG:- It should be non irritant Molecular size should be less than 1000 daltons It should not metabolized in the skin It should not bind to skin proteins Dose of the drug should be less Drug should have low melting point

Drug properties : 

Drug properties Dose deliverable : <10mg/day Aqueous solubility : >1mg/ml Lipophilicity : 10< ko/w <1000 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

Slide 34: 

POLYMER MATRIX: Polymers controls the release of the drug from the device IDEAL PROPERTIES OF POLYMER MATRIX: The polymer must allow the diffusion of the drug substance at desirable rate No loss of mechanical strength should be seen after combined with drug No interaction with other materials It should not decompose on storage or during the life of the device The polymer and its decomposed product should be nontoxic The cost of the polymer should not be excessively high

PERMEATION ENHANCERS : 

PERMEATION ENHANCERS Lipophilic Solvents : Increase the permeation of lipophilic drugs Ex: DMSO, DMF, Dimethoxy acetamide, glycerol, propylene glycol Surfactants: Increase the permeation of hydrophilic drugs. Ex: SLS, Dioctyl sulfosucccinate Two component systems : Ex:oleic acid &propylene glycol

Adhesive : : 

Adhesive : Characteristics of adhesive:- ►It should not cause irritation,sensitization or imbalance in the normal skin flora ►It should adhere to the skin strongly ►It should be easily removable ►It should have intimate contact with the skin at both macroscopic & microscopic levels Ex:-Acrylic adhesives silicon adhesives

Slide 37: 

BACKING MEMBRANE: It is flexible and provide good bond to the drug reservoir Prevent drug from leaving the dosage form through the top

DIFFERENT COMPONENTSOF TDDS DEVICE : 

DIFFERENT COMPONENTSOF TDDS DEVICE

TRANS DERMAL DEVICES : 

TRANS DERMAL DEVICES It can be classified into 4 types 1) Membrane-moderated type 2) Adhesive diffusion controlled type 3) Matrix dispersion type 4) Micro reservoir type

MEMBRANE MODERATED TYPE : 

MEMBRANE MODERATED TYPE

The intrinsic rate of drug release from this type of system dQ/dt=CR/1/Pm +1/PaFor micro porous membrane is essentially some of the permeability coefficient. For simultaneous permeation across the pores and polymeric material Pa=Ka/m.Da/ha Pm=Km/r.Dm/hm combine the both equations dQ/dt= Km/r. Ka/m. Da. Dm Km/r. Dm. ha +Ka/m.Da/hm EX; Transderm scop, Transderm nitro : 

The intrinsic rate of drug release from this type of system dQ/dt=CR/1/Pm +1/PaFor micro porous membrane is essentially some of the permeability coefficient. For simultaneous permeation across the pores and polymeric material Pa=Ka/m.Da/ha Pm=Km/r.Dm/hm combine the both equations dQ/dt= Km/r. Ka/m. Da. Dm Km/r. Dm. ha +Ka/m.Da/hm EX; Transderm scop, Transderm nitro

ADHESIVE DIFFUSION CONTROLLED TYPE : 

ADHESIVE DIFFUSION CONTROLLED TYPE

Rate of drug release; dq/dt=(Ka/r.Da/ha)Cr ka/r= partition coefficient of drug from reservoir layer to the rate controlled adhesive layer EX; Deponite system, Verapamil : 

Rate of drug release; dq/dt=(Ka/r.Da/ha)Cr ka/r= partition coefficient of drug from reservoir layer to the rate controlled adhesive layer EX; Deponite system, Verapamil

MATRIX DISPERSION TYPE : 

MATRIX DISPERSION TYPE

The rate of drug release; dq/dt=(Acp.Dp/2t)1/2Cp is equals to Cr. At steady state Q vs t1/2 Q/ t1/2=[(2A-Cp)CpDp]1/2 EX; Nitrodur, Verapamil : 

The rate of drug release; dq/dt=(Acp.Dp/2t)1/2Cp is equals to Cr. At steady state Q vs t1/2 Q/ t1/2=[(2A-Cp)CpDp]1/2 EX; Nitrodur, Verapamil

MICRO RESERVOIR TYPE : 

MICRO RESERVOIR TYPE

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.

Slide 51: 

Transdermal patches available in the market

Slide 52: 

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 now it is increased to $21.5 billion in the year 2010 and it is expected to $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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