SWATI S.UGHADE M¶PHARM 1st YEAR ` ` ` ` Introduction Permeation through skin Factors affecting permeation Basic components of transdermal drug delivery system ` ` 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. or Transdermal drug delivery system are topically administered medicaments in the form of patches that deliver drugs for systemic effects at a predetermined and controlled rate. ` ` ` ` A transdermal drug delivery device , is a device which provides an alternative route for administering medication. These devices allow for pharmaceuticals to be delivered across the skin barrier. In theory, transdermal patches work very simply. A drug is applied in a relatively high dosage to the inside of a patch, which is worn on the skin for an extended period of time. ` ` Through a diffusion process, the drug enters the bloodstream directly through the skin. Since there is high concentration on the patch and low concentration in the blood, the drug will keep diffusing into the blood for a long period of time, maintaining the constant concentration of drug in the blood flow. intestinal motility. No GI distress and the factors like Gastric emptying. . Avoidance of significant presystemic metabolism (degradation in GIT or by the liver) and therefore need lower doses.` ` ` Potential advantages of TDDS avoids chemically hostile GI environment (drug degradation in acidic and basic environments is prevented). do not effect this route as in oral route. transit time. This approach to drug delivery offers many advantages over traditional methods . Allow administration of drugs with narrow therapeutic window because drug levels are maintained within the therapeutic window for prolonged periods of time.` ` ` ` Allows effective use of drugs with short biological half-life. . Reduced inter and intra patient variability. rapid notification of medication in the event of emergency. . as well as the capacity to terminate drug effects rapidly via patch removal. Multi-day therapy with a single application.` ` The patch also permits constant dosing rather than the peaks and valleys in medication level associated with orally administered medications. are all further advantages of this route. ` ` ` ` ` ` Enhance therapeutic efficacy. . Drug input can be promptly interrupted simply by removal of the patch when toxicity occures. Can provide adequate absorption of certain drugs. Reduction of dosing frequency and enhancement of patient compliance. Avoids the risk and inconveniences of parenteral therapy (Painless method of drug administration). Provides suitability of self medication. reduced fluctuations (rapid blood level spikes-low and high) due to optimization of blood concentration ± time profile. Provides controlled plasma levels of very potent drugs. The molecular size of the drug should be reasonable that it should be absorbed percutaneously. rather it is usually designed to offer slow. Transdermal administration is not a means to achieve rapid bolus type drug input. . sustained drug delivery. those requiring a daily dose of 10mg or less.` ` ` ` Disadvantages of TDDS Drugs that require high blood levels cannot be administered ± limited only to potent molecules. to reach dermal microcirculation and gain access to the systemic circulation. Adequate solubility of the drug in both lipophilic and aqueous environments. Along with these limitations the high cost of the product is also a major drawback for the wide acceptance of this product. The adhesives may not adhere well to all types of skin and may be uncomfortable to wear.` ` ` However this system has its own limitations in which the drug that require high blood levels cannot be administered and may even cause irritation or sensitization of the skin. . ` ` ` ` 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. Uncomfortable to wear. . Skin irritation or dermatitis due to excipients and enhancers of drug delivery system used for increasing percutaneous absorption is another major limitation. . . The outermost layer. This is the layer most important to transdermal delivery as its composition allows it to keep water within the body and foreign substances out.` ` ` ` There are two important layers in skin: the dermis and the epidermis. is approximately 100 to 150 micrometers thick. the epidermis. has no blood flow and includes a layer within it known as the stratum corneum. is the only means to transfer normal drugs across this layer.` ` ` Beneath the epidermis. it can enter the blood stream. which occurs too slowly for practical use. If the drug is able to penetrate the stratum corneum. the dermis contains the system of capillaries that transport blood throughout the body. . A process known as passive diffusion. much more rapid and useful drug delivery is possible. The best mixture is about fifty percent of the drug being each.` ` ` ` The method to avoid this is to engineer the drugs be both water-soluble and lipid soluble. Using drugs engineered in this manner. This is because ³Lipid-soluble substances readily pass through the intercellular lipid bi-layers of the cell membranes whereas water-soluble drugs are able to pass through the skin because of hydrated intracellular proteins´. . . but they are considered rather insignificant. Sweat ducts and hair follicles are also paths of entry. relatively impermeable membrane which usually provides the rate limiting step in transdermal drug delivery system.` ` The stratum corneum develops a thin. tough. 1% of total surface). but it is considered to be of minor importance because of relatively smaller area (less than 0. whereas the nonpolar molecules dissolve and diffuse through the nonaqueous lipid matrix of the stratum corneum. . The transappendageal route transports substances via the sweat glands and the hair follicles with their associated sebaceous glands.` ` ` ROUTES OF PENETRATION Under normal circumstances. the predominant route is through the intercellular spaces within the hydrated stratum corneum. abdomen. . chest/back. and upper arms/legs shows intermediate permeability. There are numerous differences among patient groups as well as between various regions of the body.` ` ` ` ` FACTORS AFFECTING PERMEABILITY OF STRATUM CORNEUM Human skin is not all the same. The most permeable areas are the mucous membranes and eyelids while face/head. The least permeable areas are the palmar surfaces and nails. age and ethnicity. .Mechanisms of drug permeation Hydrophilic drugs permeates by Intercellular pathway and Lipophilic drugs permeates by Intracellular (Transcellular) mechanism. Diffusion of drug from rate limiting membrane to stratum corneum.` ` ` ` ` ` The various steps involved in transport of drug from patch to systemic circulation are as follows Diffusion of drug from drug reservoir to the rate controlling membrane. Sorption by stratum corneum and penetration through viable epidermis. Uptake of drug by capillary network in the dermal papillary layer. Effect on target organ. . ` ` ` ` ` ` ` 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 = PA C 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 C is the drug concentration gradient across the skin . e.e. Ps is the overall permeability coefficient of the skin tissue to the penetrant. . on the surface of stratum corneum and in the receptor compartment i. The rate of permeation across the skin is given by: dQ/dt = Ps ( Cd ± Cr )««««««««(1) ` where Cd and Cr are the concentration of the skin penetrant in the donor compartment i.` ` This permeation can be possible only if the drug possesses certain physiochemical properties. body respectively . .` ` This permeability coefficient is given by the relation Ps = KsDss / hs where Ks is the partition coefficient for the interfacial partitioning of the penetrant molecule from a solution medium or a transdermal therapeutic system on to the stratum corneum. Dss is the apparent diffusivity for the steady state diffusion of the penetrant molecule through a thickness of skin tissues and hs is the overall thickness of skin tissues. The equation becomes: . From equation (1) it is clear that a constant rate of drug permeation can be obtained only when Cd >> Cr i. the drug concentration at the surface of the stratum corneum Cd is consistently and substantially greater than the drug concentration in the body Cr.e.Dss and hs are constant under given conditions the permeability coefficient Ps for a skin penetrant can be considered to be constant.` ` As Ks . e. . either constant or greater than the rate of skin uptake Ra .` ` ` The equation becomes: dQ/dt = Ps Cd And the rate of skin permeation is constant provided the magnitude of Cd remains fairly constant throughout the course of skin permeation. For keeping Cd constant the drug should be released from the device at a rate Rr i. the drug concentration on the skin surface Cd is maintained at a level equal to or greater than the equilibrium solubility of the drug in the stratum corneum Cs .` i.e.i. Therefore a maximum rate of skin permeation is obtained and is given by the equation: (dQ/dt)m = PsCs . Cd>>Cs.e Rr >> Ra Since Rr >> Ra . . .` ` From the above equation it can be seen that the maximum rate of skin permeation depends upon the skin permeability coefficient Ps and is equilibrium solubility in the stratum corneum Cs. Thus skin permeation appears to be stratum corneum limited. Physicochemical factors 2.It includes : ` Skin related factors ` Environmental factors ` Drug related factors : 1. Biological factors ` . Temperature: Warmer skin is more permeable. . Pathological conditions Broken or irritated skin: Drugs can more easily bypass the stratum corneum . increases permeability.` ` ` ` ` Region of application of the patch Hydration: Hydrated skin is more permeable than dry skin. ` ` ` Temperature Exposure to air Exposure to light . 2. 3.1. 5. 7. Physicochemical factors : Solubility Molecular size Lipophilicity Ionisation of the drug Melting point Partition coefficient Diffusipon coefficient Drug concentration . 8. 6. 4. J = EDA/KL where E represents the thermodynamic activity of the drug in the vehicle K .` Higuchi postulated that .effective activity concentration of the drug in the membrane D -diffusivity A -cross sectional area L -thickness of the membrane .provided the vehicle containing the permeating chemical does not affect the membrane .the drug flux (J) for an idealised system could be expressed in the terms of the thermodynamic activity of the penetrating agent in the vehicle by the following equation. the only significant determinant of the dermal blood clearance of the solute. .` ` Generally molecules of <500 Da are absorbed through skin Solute molecular weight . ` ` ` ` An empirical formula proposed by Guy & Potts explains the relationship between the lipophilicity .061 MW Pss .permeability coefficient at steady state K oct/water .3 + 0.size & skin permeability of the molecule : Log Pss = -6.71 log K oct/water .0.partition coefficient between the octanol & water phase . Lignocaine paired with counter ion nitrate . Ion pair mechanism : Eg. mesylate or bromide .` ` ` Anionic drug are relatively less permeable than cationic & nonionic drugs. Terpenes with ibuprofen .` ` ` Reduction in melting point have direct effect on solubility in skin lipids so increase transdermal permeation . A binary eutectic mixture Eg. ` ` ` ` ` ` Dose of the drug Skin condition Skin age Blood flow species differences Elimination half life of the drug . Release liner . Polymer matrix or matrices.` ` ` ` ` ` ` The components of transdermal devices include: 1. 2. Backing laminates 6. Other excipients 5. Permeation enhancers 4. The drug 3. Gelatin. Shellac. Proteins. Possible useful polymers for transdermal devices are: a) Natural Polymers: e. Gums and their derivatives. . Waxes.` ` ` ` ` 1. Zein. Cellulose derivatives.g. Starch etc.Polymer Matrix The Polymer controls the release of the drug from the device. Natural rubber. Polymethylmethacrylate. Polyvinyl alcohol. Polybutadieine. Polypropylene. Nitrile. Polyvinylpyrrolidone. Styrenebutadieine rubber.g. Epoxy etc. Polysiloxane.g. Polyacrylate. Polyvinyl chloride. Polyethylene. Polyurea. Polyamide. Silicone rubber. Butyl rubber. . Acrylonitrile.b) Synthetic Elastomers: e. c) Synthetic Polymers: e. Neoprene etc. Hydrin rubber. The following are some of the desirable properties of a drug for transdermal delivery.Drug For successfully developing a transdermal drug delivery system .` 2. . the drug should be chosen with great care. having short half life and be non irritating. . 2.` Physicochemical properties 1. The drug should have affinity for both ± lipophilic and hydrophilic phases. The drug should have low melting point . Along with these properties the drug should be potent. The drug should have a molecular weight less than approximately 1000 daltons. 3. Extreme partitioning characteristics are not conducive to successful drug delivery via the skin. These may conveniently be classified under the following main headings: .` ` ` 3.Permeation Enhancers These are compounds which promote skin permeability by altering the skin as a barrier to the flux of a desired penetrant. laurocapram (Azone). miscellaneous solvents ± propylene glycol. silicone fluids. N-methyl. Examples include water alcohols ± methanol and ethanol. 2-purrolidone. alkyl methyl sulfoxides ± dimethyl sulfoxide. alkyl homologs of methyl sulfoxide dimethyl acetamide and dimethyl formamide . glycerol. pyrrolidones ± 2 pyrrolidone. isopropyl palmitate. .a)Solvents : These compounds increase penetration possibly by following the polar pathway and/or by fluidizing lipids. Nonionic Surfactants: e. etc . Dioctyl sulphosuccinate.g. Decodecylmethyl sulphoxide etc.` ` ` ` ` b) Surfactants These compounds are proposed to enhance polar pathway transport. Sodium lauryl sulphate. Pluronic F68. especially of hydrophilic drugs . Pluronic F127.g. The ability of a surfactant to alter penetration is a function of the polar head group and the hydrocarbon chain length. Anionic Surfactants: e. Propylene glycol-oleic acid and 1.g. Sodium tauroglycocholate Biary system: These systems apparently open up the heterogeneous multilaminate pathway as well as the continuous pathways. Sodium deoxycholate. 4-butane diollinoleic acid.` ` ` ` Bile Salts: e. Sodium ms taurocholate.g. e. . anticholinergic agents. N-dimethyl-m-toluamide. N. a hydrating and keratolytic agent.` c) Miscellaneous chemicals These include urea. . calcium thioglycolate. di-o-methyl-ß-cyclodextrin and soyabean casein. These include eucalyptol. polyisobutylene and silicon based adhesives are widely used in TDDSs39.Other excipient : Pressure sensitive adhesives: A PSA is a material that helps in maintaining an intimate contact between transdermal system and the skin surface. including the patch design and drug formulation. Polyacrylates.` ` ` ` 4. . Eg. The selection of an adhesive is based on numerous factors. (iii) Should not irritate or sensitize the skin. (ii)Should not leave an unwashable residue on the skin. PSA should be physicochemically and biologically compatible and should not alter drug release40. .` Ideally. should be easily removed. systems should fulfill the following criteria ` ` ` (i)Should adhere to the skin aggressively. . (i)Physical and chemical compatibility with the drug.` The face adhesive system should also fulfill the following criteria. (iii) The delivery of simple or blended permeation enhancers should not be affected. (ii) Permeation of drug should not be affected. excipients and enhancers of the device of which it is a part. plastic backing with absorbent pad and occlusive base plate (aluminium foil). . and accept printing.g. metallic plastic laminate. adhesive foam pad (flexible polyurethane) with occlusive base plate (aluminium foil disc) etc. Backing membrane: Backing membranes are flexible and they provide a good bond to the drug reservoir. It is impermeable substance that protects the product during use on the skin e. prevent drug from leaving the dosage form through the top.5. the consideration of chemical resistance of the material is most important. polyethylene and polyester films. Examples of some backing materials are vinyl.Backing Laminate: While designing a backing layer. . g. it should comply with specific requirements regarding chemical inertness and permeation to the drug.6. paper fabric) or occlusive (e. Release Liner: During storage the patch is covered by a protective liner that is removed and discharged immediately before the application of the patch to skin. polyvinylchloride) and a release coating layer made up of silicon or teflon. 43. ` However. release liner is composed of a base layer which may be non-occlusive (e.g. ` Other materials used for TDDS release liner include polyester foil and metallized laminates38. . polyethylene. penetration enhancer and water. as the liner is in intimate contact with the delivery system. Typically. Novel drug delivery systems. Biopharmaceutics and pharmacokinetics A Teatise. New York. New York. Marcel Dekker. C. Brahmankar. 1990. Jaiswal.B.N. Drugs and the Pharmaceutical Sciences.K. Jain. Delhi1995.797 Banker.M.first edition. New Delhi. third edition. S and Rhodes.S. Vallabh Prakashan. Vol. CBS publishers and distributors.1992.` ` ` ` Chien.50.1997. Marcel Dekker. inc. T Modern pharmaceutics.D.335-371. Controlled and novel drug delivery .. G. . NY. YW. drug delivery technology.com Ryan D.` Transdermal drug delivery system/introduction http://www.brown.com www. Gordon.drugdeliverytechnology.edu/Courses/BI108. ` ` ` . www. transdermal drug delivery . Peterson. and Tim A.biomed.controlled/ release drug delivery systems. . .