SWATI S.

UGHADE MPHARM 1st YEAR

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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.

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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.

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, do not effect this route as in oral route. Avoidance of significant presystemic metabolism (degradation in GIT or by the liver) and therefore need lower doses.

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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. This approach to drug delivery offers many advantages over traditional methods .

The patch also permits constant dosing rather than the peaks and valleys in medication level associated with orally administered medications. Multi-day therapy with a single application, rapid notification of medication in the event of emergency, as well as the capacity to terminate drug effects rapidly via patch removal, are all further advantages of this route.

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 occures. Provides suitability of self medication.

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.

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. The adhesives may not adhere well to all types of skin and may be uncomfortable to wear. Along with these limitations the high cost of the product is also a major drawback for the wide acceptance of this product.

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. Uncomfortable to wear.

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There are two important layers in skin: the dermis and the epidermis. The outermost layer, the epidermis, is approximately 100 to 150 micrometers thick, has no blood flow and includes a layer within it known as the stratum corneum. This is the layer most important to transdermal delivery as its composition allows it to keep water within the body and foreign substances out.

Beneath the epidermis, the dermis contains the system of capillaries that transport blood throughout the body. If the drug is able to penetrate the stratum corneum, it can enter the blood stream. A process known as passive diffusion, which occurs too slowly for practical use, is the only means to transfer normal drugs across this layer.

The method to avoid this is to engineer the drugs be both water-soluble and lipid soluble. The best mixture is about fifty percent of the drug being each. This is because Lipid-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. Using drugs engineered in this manner, much more rapid and useful drug delivery is possible.

The stratum corneum develops a thin, tough, relatively impermeable membrane which usually provides the rate limiting step in transdermal drug delivery system. Sweat ducts and hair follicles are also paths of entry, but they are considered rather insignificant.

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ROUTES OF PENETRATION Under normal circumstances, the predominant route is through the intercellular spaces within the hydrated stratum corneum, 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, but it is considered to be of minor importance because of relatively smaller area (less than 0.1% of total surface).

FACTORS AFFECTING PERMEABILITY OF STRATUM CORNEUM Human skin is not all the same. There are numerous differences among patient groups as well as between various regions of the body, age and ethnicity. The most permeable areas are the mucous membranes and eyelids while face/head, chest/back, abdomen, and upper arms/legs shows intermediate permeability. The least permeable areas are the palmar surfaces and nails.

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

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. Diffusion of drug from rate limiting membrane to stratum corneum. Sorption by stratum corneum and penetration through viable epidermis. Uptake of drug by capillary network in the dermal papillary layer. Effect on target organ.

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Skin permeability kinetics : Ficks First Law of Diffusion : Percutaneous absorption of most drugs is a passive-diffusion process that can be described by Ficks 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 (g/hr) A is area of the skin P is the effective permeability coefficient C is the drug concentration gradient across the skin

This permeation can be possible only if the drug possesses certain physiochemical properties. 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.e. on the surface of stratum corneum and in the receptor compartment i.e. body respectively . Ps is the overall permeability coefficient of the skin tissue to the penetrant.

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.

As Ks ,Dss and hs are constant under given conditions the permeability coefficient Ps for a skin penetrant can be considered to be constant. From equation (1) it is clear that a constant rate of drug permeation can be obtained only when Cd >> Cr i.e. the drug concentration at the surface of the stratum corneum Cd is consistently and substantially greater than the drug concentration in the body Cr. The equation becomes:

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.e. either constant or greater than the rate of skin uptake Ra .

i.e Rr >> Ra Since Rr >> Ra , 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. Cd>>Cs. Therefore a maximum rate of skin permeation is obtained and is given by the equation: (dQ/dt)m = PsCs

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. .

It includes : ` Skin related factors ` Environmental factors ` Drug related factors : 1. Physicochemical factors 2. Biological factors
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Region of application of the patch Hydration: Hydrated skin is more permeable than dry skin. Pathological conditions Broken or irritated skin: Drugs can more easily bypass the stratum corneum , increases permeability. Temperature: Warmer skin is more permeable.

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Temperature Exposure to air Exposure to light

1. 2. 3. 4. 5. 6. 7. 8.

Physicochemical factors : Solubility Molecular size Lipophilicity Ionisation of the drug Melting point Partition coefficient Diffusipon coefficient Drug concentration

Higuchi postulated that ,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; J = EDA/KL where E represents the thermodynamic activity of the drug in the vehicle K - effective activity concentration of the drug in the membrane D -diffusivity A -cross sectional area L -thickness of the membrane

Generally molecules of <500 Da are absorbed through skin Solute molecular weight ,the only significant determinant of the dermal blood clearance of the solute.

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An empirical formula proposed by Guy & Potts explains the relationship between the lipophilicity ,size & skin permeability of the molecule : Log Pss = -6.3 + 0.71 log K oct/water - 0.061  MW Pss - permeability coefficient at steady state K oct/water - partition coefficient between the octanol & water phase

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Anionic drug are relatively less permeable than cationic & nonionic drugs. Ion pair mechanism : Eg. Lignocaine paired with counter ion nitrate , mesylate or bromide

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Reduction in melting point have direct effect on solubility in skin lipids so increase transdermal permeation . A binary eutectic mixture Eg. Terpenes with ibuprofen

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Dose of the drug Skin condition Skin age Blood flow species differences Elimination half life of the drug

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The components of transdermal devices include: 1. Polymer matrix or matrices. 2. The drug 3. Permeation enhancers 4. Other excipients 5. Backing laminates 6. Release liner

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1.Polymer Matrix The Polymer controls the release of the drug from the device. Possible useful polymers for transdermal devices are: a) Natural Polymers: e.g. Cellulose derivatives, Zein, Gelatin, Shellac, Waxes, Proteins, Gums and their derivatives, Natural rubber, Starch etc.

b) Synthetic Elastomers: e.g. Polybutadieine, Hydrin rubber, Polysiloxane, Silicone rubber, Nitrile, Acrylonitrile, Butyl rubber, Styrenebutadieine rubber, Neoprene etc. c) Synthetic Polymers: e.g. Polyvinyl alcohol, Polyvinyl chloride, Polyethylene, Polypropylene, Polyacrylate, Polyamide, Polyurea, Polyvinylpyrrolidone, Polymethylmethacrylate, Epoxy etc.

2.Drug For successfully developing a transdermal drug delivery system , the drug should be chosen with great care. The following are some of the desirable properties of a drug for transdermal delivery.

Physicochemical properties 1. The drug should have a molecular weight less than approximately 1000 daltons. 2. The drug should have affinity for both lipophilic and hydrophilic phases. Extreme partitioning characteristics are not conducive to successful drug delivery via the skin. 3. The drug should have low melting point . Along with these properties the drug should be potent, having short half life and be non irritating.

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3.Permeation Enhancers These are compounds which promote skin permeability by altering the skin as a barrier to the flux of a desired penetrant. These may conveniently be classified under the following main headings:

a)Solvents : These compounds increase penetration possibly by following the polar pathway and/or by fluidizing lipids. Examples include water alcohols methanol and ethanol; alkyl methyl sulfoxides dimethyl sulfoxide, alkyl homologs of methyl sulfoxide dimethyl acetamide and dimethyl formamide ; pyrrolidones 2 pyrrolidone, N-methyl, 2-purrolidone; laurocapram (Azone), miscellaneous solvents propylene glycol, glycerol, silicone fluids, isopropyl palmitate.

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b) Surfactants These compounds are proposed to enhance polar pathway transport, especially of hydrophilic drugs . The ability of a surfactant to alter penetration is a function of the polar head group and the hydrocarbon chain length. Anionic Surfactants: e.g. Dioctyl sulphosuccinate, Sodium lauryl sulphate, Decodecylmethyl sulphoxide etc. Nonionic Surfactants: e.g. Pluronic F127, Pluronic F68, etc

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Bile Salts: e.g. Sodium ms taurocholate, Sodium deoxycholate, Sodium tauroglycocholate Biary system: These systems apparently open up the heterogeneous multilaminate pathway as well as the continuous pathways. e.g. Propylene glycol-oleic acid and 1, 4-butane diollinoleic acid.

c) Miscellaneous chemicals These include urea, a hydrating and keratolytic agent; N, N-dimethyl-m-toluamide; calcium thioglycolate; anticholinergic agents. These include eucalyptol, di-o-methyl--cyclodextrin and soyabean casein.

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4.Other excipient : Pressure sensitive adhesives: A PSA is a material that helps in maintaining an intimate contact between transdermal system and the skin surface. Eg. Polyacrylates, polyisobutylene and silicon based adhesives are widely used in TDDSs39. The selection of an adhesive is based on numerous factors, including the patch design and drug formulation.

Ideally, PSA should be physicochemically and biologically compatible and should not alter drug release40. systems should fulfill the following criteria

(i)Should adhere to the skin aggressively, should be easily removed. (ii)Should not leave an unwashable residue on the skin. (iii) Should not irritate or sensitize the skin.

The face adhesive system should also fulfill the following criteria. (i)Physical and chemical compatibility with the drug, excipients and enhancers of the device of which it is a part. (ii) Permeation of drug should not be affected. (iii) The delivery of simple or blended permeation enhancers should not be affected.

5. Backing membrane: Backing membranes are flexible and they provide a good bond to the drug reservoir, prevent drug from leaving the dosage form through the top, and accept printing. It is impermeable substance that protects the product during use on the skin e.g. metallic plastic laminate, plastic backing with absorbent pad and occlusive base plate (aluminium foil), adhesive foam pad (flexible polyurethane) with occlusive base plate (aluminium foil disc) etc.

Backing Laminate: While designing a backing layer, the consideration of chemical resistance of the material is most important. Examples of some backing materials are vinyl, polyethylene and polyester films.

6. 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. ` However, as the liner is in intimate contact with the delivery system, it should comply with specific requirements regarding chemical inertness and permeation to the drug, penetration enhancer and water. Typically, release liner is composed of a base layer which may be non-occlusive (e.g. paper fabric) or occlusive (e.g. polyethylene, polyvinylchloride) and a release coating layer made up of silicon or teflon. ` Other materials used for TDDS release liner include polyester foil and metallized laminates38, 43.

Chien, YW, Novel drug delivery systems, Drugs and the Pharmaceutical Sciences, Vol.50, Marcel Dekker, New York, NY;1992;797 Banker, G. S and Rhodes, C. T Modern pharmaceutics, third edition, New York, Marcel Dekker, inc,. 1990. Jain.N.K, Controlled and novel drug delivery ,first edition, CBS publishers and distributors, New Delhi.1997. Brahmankar.D.M, Jaiswal.S.B, Biopharmaceutics and pharmacokinetics A Teatise. Vallabh Prakashan, Delhi1995,335-371.

Transdermal drug delivery system/introduction http://www.controlled/ release drug delivery systems.com Ryan D. Gordon, and Tim A. Peterson, transdermal drug delivery , drug delivery technology, www.drugdeliverytechnology.com www.biomed.brown.edu/Courses/BI108.