formulation and characterizatin of transdermal patches by using ...

Abdullah Bin Junaid ., et al. / International Journal of Advances in Pharmaceutical ResearchIJAPRAvailable Online throughwww.ijapronline.orgReview ArticleISSN: 2230 – 7583ANALGESIC THERAPEUTIC TRANSDERMAL DRUG DELIVERY SYSTEMTHOUGH PATCHES*Abdullah Bin JunaidPhD Scholar, Department of Management, Jamia Hamdard, New Delhi, IndiaE-mail: abjs07sid@gmail.comReceived on 25 – 12 - 2011 Revised on 21 – 01- 2012 Accepted on 22– 02 – 2012ABSTRACTTransdermal drug delivery system was introduced to overcome the difficulties of drug delivery through oralroute. A transdermal patch is medicated adhesive patch that is placed on the skin to deliver a specific dose ofmedication through the skin and into the bloodstream. Transdermal dosage forms, though a costly alternative toconventional formulations, are becoming popular because of their unique advantages. Formulated to deliver thedrug at optimized rate into the systemic circulation should adhere to the skin for the expected duration shouldnot cause any skin irritation and/or sensitization, Enhancing bioavailability via bypassing first pass metabolism,Minimizing pharmacokinetic peaks and troughs, Improving tolerability and dosing leads to increase patientcompliance in Continuous delivery.. This review article provides an overview of Transdermal Drug DeliverySystem. Here we discuss the various advantages of this system, methods to enhance penetration through theskin, transdermal patch components and the process to develop these transdermal patchesKey Words: Transdermal Drug Delivery System, Topical drug delivery, Systemic blood circulationINTRODUCTIONIn this new era transdermal drug delivery is asuccessful method to deliver the drug into thebloodstream without pain. This review paper dealswith analgesic drug delivery through patches. Fewof the important clarifications and definitions werediscussed before going into the study oftransdermal pain relief patches. Here we firstdiscuss about the different factors that are involvedfor delivering the drug into the skin when appliedon the skin. The terms we discuss over here arepain, skin; different layers of skin, function of skinand so on since these things plays an important rolein the drug delivery from a transdermal patch intothe skin.PainPain, in the sense of physical pain, is a typicalsensory experience that may be described as theunpleasant awareness of a noxious stimulus orbodily harm (panlab.com). InternationalAssociation for the Study of Pain (IASP) describespain for scientific purpose as "an unpleasantsensory and emotional experience associated withactual or potential tissue damage, or described interms of such damage". Pain is highly subjective tothe individual experiencing it. “Pain is whatever theexperiencing person says it is, existing whenever hesays it does" (Margo McCaffery, 1968). Pain is amajor symptom in many medical conditions,significantly interfering with a person's quality oflife and general functioning. Diagnosis is based oncharacterizing pain in various ways, according toduration, intensity, type (dull, burning or stabbing),source, or location in body. Usually pain stopswithout treatment or responds to simple measuressuch as resting or taking an analgesic, and it is thencalled ‘acute’ pain. But it may also becomeintractable and develop into a condition calledchronic pain, in which pain is no longer considereda symptom but an illness by itself.The two faces of pain: acute and chronicAn unpleasant sensory and emotional experienceassociated with actual or potential tissue damage ordescribed in terms of such damage (InternationalAssociation for the Study of Pain). The two basictypes of pain, acute and chronic, are described asfollows.Acute pain, for the most part, results from disease,inflammation, or injury to tissues. This type of paingenerally comes on suddenly, for example, afterIJAPR / March. 2012/ Vol. 3 / Issue. 3 / 846 - 854 846

Abdullah Bin Junaid ., et al. / International Journal of Advances in Pharmaceutical Researchtrauma or surgery, and may be accompanied byanxiety or emotional distress. The cause of acutepain can usually be diagnosed and treated, and thepain is self-limiting, that is, it is confined to a givenperiod of time and severity. In some rare instances,it can become chronic (MedicineNet.com).Chronic pain is widely believed to representdisease itself. It can be made much worse byenvironmental and psychological factors. Chronicpain persists over a longer period of time than acutepain and is resistant to most medical treatments. Itcan-and often does-cause severe problems forpatients (MedicineNet.com). Pain management isan integral part of treating chronic pain.SKINFigure.1: Various components of skin.The skin is often known as the largest organ of thehuman body. This applies to exterior surface, as itcovers the body, appearing to have the largestsurface area of all the organs. For the average adulthuman, the skin has a surface area of between 1.5-2.0 square meters (16.1-21.5 sq ft.), most of it isbetween 2-3 mm (0.10 inch) thick. The averagesquare inch (6.5 cm²) of skin holds 650 sweatglands, 20 blood vessels, 60,000 melanocytes, andmore than a thousand nerve endings (sedico.net).Skin has pigmentation, or melanin, provided bymelanocytes, which absorb some of the potentiallydangerous ultraviolet radiation (UV) in sunlight. Italso contains DNA repair enzymes which help toreverse UV damage, and people who lack the genesfor these enzymes suffer high rates of skin cancer.One form predominantly produced by UV light,malignant melanoma, is particularly invasive,causing it to spread quickly, and can often bedeadly. Human skin pigmentation varies amongpopulations in a striking manner. This has led to theclassification of people on the basis of skin color(en.wikipedia.org)Functions of SkinSkin performs the following functions:1. Protection: an anatomical barrier frompathogens and damage between the internal andexternal environment in bodily defense;Langerhans cells in the skin are part of theadaptive immune system2. Sensation: contains a variety of nerve endingsthat react to heat and cold, touch, pressure,vibration, and tissue injury; see somatosensorysystem and haptics.3. Heat regulation: the skin contains a bloodsupply far greater than its requirements whichallows precise control of energy loss byradiation, convection and conduction. Dilatedblood vessels increase perfusion and heat losswhile constricted vessels greatly reducecutaneous blood flow and conserve heat.Erector pili muscles are significant in animals.4. Control of evaporation: the skin provides arelatively dry and impermeable barrier to fluidloss. Loss of this function contributes to themassive fluid loss in burns.5. Aesthetics and communication: others see ourskin and can assess our mood, physical stateand attractiveness.6. Storage and synthesis: acts as a storage centerfor lipids and water, as well as a means ofsynthesis of vitamin D by action of UV oncertain parts of the skin.7. Excretion: sweat contains urea, however itsconcentration is 1/130th that of urine, henceexcretion by sweating is at most a secondaryfunction to temperature regulation.8. Absorption: Oxygen, nitrogen and carbondioxide can diffuse into the epidermis in smallamounts, some animals using their skin fortheir sole respiration organ. In addition,medicine can be administered through theskin, by ointments or by means of adhesivepatch, such as the nicotine patch oriontophoresis. The skin is an important site oftransport in many other organisms.9. Water resistance: The skin acts as a waterresistant barrier so essential nutrients aren'twashed out of the body.Skin LayersSkin is composed of three primary layers:The epidermis, which provides waterproofingand serves as a barrier to infection;The dermis, which serves as a location for theappendages of skin; andThe hypodermis (subcutaneous adipose layer).Different types of skin (pehp.org).Oily Skin: Oily skin is caused by overactivity ofthe sebaceous glands. Oily skin is thick with largepores and has a greater tendency to develop acne,but not wrinkles. Most people who have oily skinalso have oily hair.IJAPR / March. 2012/ Vol. 3 / Issue. 3 / 846 - 854 847

Abdullah Bin Junaid ., et al. / International Journal of Advances in Pharmaceutical ResearchDry Skin: Dry skin is caused by underactivity ofthe sebaceous glands, environmental conditions, ornormal aging. Dry skin is usually thinner and moreeasily irritated. There is a greater tendency todevelop wrinkles, but not acne.Balanced Skin: Balanced skin is neither oily nordry. It is smooth and has fine texture ––with fewproblems. However, it has a tendency to becomedry as a result of environmental factors and aging.Combination Skin: Combination skin consists ofoily regions -- often on the forehead and around thenose –– and regions that are balanced or dry.Transdermal PatchesThe first transdermal patch was approved by theFDA in 1979. It was a patch for the treatment ofmotion sickness. In the mid-1980s, thepharmaceutical companies started the developmentof a nicotine patch to help smokers quit smoking,and within a few months at the end of 1991 andbeginning of 1992 the FDA approved four nicotinepatches (originaldrugs.com).A careful inspection of these patches is done beforethey go into the market. Franz Diffusion CellSystem is an effective method to study the workingmechanism of transdermal patches. By this methodthe effect of temperature was studied onpermeability of a drug through a certain membrane.A Franz diffusion Cell system consists of a donorcell and a receptor. The process followedresearchers in their study is that the donor cell waskept on body temperature and the receptor cell waskept at environmental temperature. Till now oralroute of drug administration is the most commondrug delivery route. Oral route has someadvantages but among the disadvantages is the poorbioavailability which is due to first passmetabolism which leads to less absorption of thedrug into the blood stream which then creates needof a high dose or more frequent dosing.(http://en.wikipedia.org).Advantages and disadvantages of transdermaldrug deliveryTransdermal drug delivery systems offer severalimportant advantages over more traditionalapproaches, including:longer duration of action resulting in areduction in dosing frequencyIncreased convenience to administer drugswhich would otherwise require frequent dosingimproved bioavailabilitymore uniform plasma levelsreduced side effects and improved therapy dueto maintenance of plasma levels up to the end ofthe dosing intervalflexibility of terminating the drugadministration by simply removing the patchfrom the skinImproved patient compliance and comfort vianon-invasive, painless and simple applicationSome of the greatest disadvantages totransdermal drug delivery are:possibility that a local irritation at the site ofapplicationErythema, itching, and local edema can becaused by the drug, the adhesive, or otherexcipients in the patch formulationBASIC COMPONENTS OF T. D. D. S (BakerRW et al., 1989)1. Polymer MatrixPolymer is a substance that controls the release ofthe drug from the patch.a) Polymers from natural origin: These consists ofWaxes, Gelatin, Cellulose derivatives, Proteins,Zein, Starch, Gum and its derivatives Naturalrubber etc.b) Synthetic Elastomers: These include Hydrinrubber, silicone rubber, Acrylonitrile,Styrenebutadieine rubber, Polybutadieine etc.c) Polymers from synthetic origin: These arePolyvinyl chloride, Polypropylene, Polyamide,Polyvinyl alcohol, Polyacrylate etc.2. DrugA transdermal drug delivery system can be madesuccessful by the correct selection of the drug.Some of the desired properties of a drug to beincluded in a transdermal patch are as follows:Physicochemical properties1. The molecular weight of the drug shouldapproximately be less than 1000 daltons.2. Affinity for lipophilic phases as well ashydrophilic phase is an important criterion thatmust be fulfilled by the drug.3. Melting point of the drug should be low.Having all these properties the drug must be nonirritating, potent and should have short half life.3. Permeation Enhancers (Cal K et al, 2000)The main function of these substances is to increasepermeability through skin. These compounds canbe classified under the following categories.a). SolventsThese compounds swallow the polar pathway andhence increase the penetration.For example: Methanol, ethanol, dimethylsulfoxide, methyl sulfoxide, 2 pyrrolidone etc.Mechanism of permeation enhancer (Sheth &Mistry, 2011)These are the chemical compounds that increasepermeability of stratum corneum so as to attainhigher therapeutic level of drug. Permeationenhancers interact with structural components ofIJAPR / March. 2012/ Vol. 3 / Issue. 3 / 846 - 854 848

Abdullah Bin Junaid ., et al. / International Journal of Advances in Pharmaceutical Researchstratum corneum that is proteins and lipids. Theyalter protein and lipid packaging of stratumcorneum thus chemically modifying barrierfunction leading to increased permeability.Classification of penetration enhancersTerpenes (essential oils): E.g. Nerodilol, menthol,1 8cineol, limonene, carvone etc.Pyrrolidones: E.g. N‐methyl‐2‐pyrrolidone (NMP),azone etc.Fatty acids and esters: E.g. Oleic acid, linoleicacid, lauric acid, capric acid etc.Sulfoxides and similar compounds: E.g. Dimethylsulfoxide (DMSO), N, Ndimethyl formamide.Alcohols, Glycols, and Glycerides: E.g. Ethanol,Propylene glycol, Octyl alcohol etc.Miscellaneous enhancers: E.g. Phospholipids,Cyclodextrins, Amino acid derivatives, Enzymesetc.b) SurfactantsThese substances enhance the polar pathway ofhydrophilic drugs. The polar head and hydrocarbonchain exerts the surfactant property and affect thepenetration of the drug.Examples include: Sodium lauryl sulphate,Pluronic F127, Dioctyl sulphosuccinate, sodium mstaurocholate, sodium tauroglycocholate etc.c) Other chemicals include N, N-dimethyl-mtoluamide,urea, calcium thioglycolate, a hydratingagent, anticholinergic agents etc.IJAPR / March. 2012/ Vol. 3 / Issue. 3 / 846 - 854 849

Abdullah Bin Junaid ., et al. / International Journal of Advances in Pharmaceutical Research4. Other excipientsa) Adhesives: (Sheth and Mistry, 2011)So far an adhesive which is pressure sensitive is usedto clip the transdermal patch to the skin which can belocated either on the back or on the face of thedevice.There are certain criteria to be fulfilled by theadhesive and these are:It should adhere insistently to the skin is easy toremove.There should not be any residue on skin after itsremoval.There should not be any allergy or itching to theskin.Face adhesive also have to fulfil certain criteria like:The drug enhancer and the excipients should exertphysical as well as chemical compatibility.There should be steady penetration of the drug theskin and into the blood stream.b) Backing membrane: (Sheth & Mistry, 2011)These membranes are flexible and offer a good bongto drug reservoir. These membranes also protect thedrug from the leakage from the top. This is made upof impermeable substances like plastic backing withabsorbent pad metallic plastic laminate pad etc thatgives protection to the drug during the use.CLASSIFICATION OF TRANSDERMALPATCHESTransdermal patches are basically of four types.These are as follows:1. Single-layer Drug-in-AdhesiveIn this type of patches the drug is directly in contactwith the skin-containing adhesive.However in this type there is incorporation of amembrane between two distinct drug-in-adhesivelayers or addition of multiple drug-in-adhesive layersunder a single backing film.3. Drug reservoir-in-AdhesiveIn this type of system there is an introduction of aliquid section that contains a drug solution or asuspension separated but a semi-permeablemembrane and adhesive. The adhesive adhere to theskin and can either be included as a continues layerbetween release liner and the membrane.4. Drug Matrix-in-AdhesiveThis system not only works as fixer to the skin butalso works as a foundation that contains drug and allother excipients under the baking film. The drugrelease depends on the diffusion rate across the skinin this type of system.2. Multi-layer Drug-in-AdhesiveIn this type of system the drug is incorporateddirectly into the adhesive and that is why it is similarto single-layer drug-in-adhesive.The characteristic of Matrix system is that it consistsof a semisolid matrix that contain a drug solution andthat solution is in direct contact with the release liner.The component that is responsible for adhesion to theskin is incorporated in an overlay and forms aconcentric configuration around the semisolid matrixWorking of Transdermal PatchesTransdermal patches are considered to be acombination product, which is one that uses a drug asIJAPR / March. 2012/ Vol. 3 / Issue. 3 / 846 - 854 850

Abdullah Bin Junaid ., et al. / International Journal of Advances in Pharmaceutical Researchwell as a delivery system. The delivery system beingthe parts of the patch (backing, adhesive etc.) are allimportant in the transdermal process. Transdermalpatches are available to help quit smoking, to easemotion sickness, to provide oral contraception or toinfuse hormones into the blood stream to alleviatesymptoms of menopause. Transdermal patches areconsidered to be parenteral and are diffused throughintact skin structures. The patch adheres to the skinand delivers the medication through the blood stream.Some pharmaceuticals must be combined withsubstances, such as alcohol within the patch toincrease their ability to penetrate the skin in order tobe used in a transdermal patch. The molecules of themedication must be small enough to pass through theskin. There are five crucial parts to the transdermalpatch which enable the success of the medication tobe distributed into the bloodstream. There is the liner,the drug, the adhesive, the membrane and thebacking. The liner is removed prior to use andprotects the patch while it is not in use. Drug comesin contact with the liner and is the solution which isexposed to the skin. The adhesive binds thecomponents of the patch together while keeping itadhered to the skin. The membrane controls therelease time for the drug and is often used in manydifferent layers to release a certain amount at a time.The backing is the part that is exposed to the air, andprotects the drug at all times. All of these parts workas the sum of the whole to infuse the medication intothe bloodstream, through the skin. This is a noninvasive way to treat many diseases and disorders. Inaddition to the aspects of each patch - there are fourtypes of transdermal patches.Regulatory aspectsA transdermal patch is classified by the U.S. Foodand Drug Administration as a combination product,consisting of a medical device combined with a drugor biological product that the device is designed todeliver. Prior to sale in the United States, anytransdermal patch product must apply for and receiveapproval from the Food and Drug Administration,demonstrating safety and efficacy for its intendeduse. The first FDA approved Transdermal Drug Patchwas in the year 1979. Since then, the transdermaldrug delivery systems have come a long way. Figure7 gives a chronology of the events in the field oftransdermal technology along with the approvals thatwere obtained at every stage of this chronology. TheFDA regulation process for Transdermal drugdelivery system is very stringent. Transdermal DrugDelivery system is a combinational device as definedin 21 CFR § 3.2(e) by Food and DrugAdministration. Transdermal drug delivery systemhave to undergo premarket approval (PMA) andhence requires substantial evidence includingbiomechanical testing, animal testing, clinical trialsstudies before the transdermal patch can get approvalfor use in the market. The most recent approval in thefield of transdermal drug delivery system was theapproval of Nuepro patch for treatment ofParkinson’s disease (Josh, 2008.)In the case of Passive transdermal drug deliverysystem, the factor that requires consideration isensuring that the drug in the drug-reservoir or thedrug-in-adhesive is present and being delivered in astable as well as controlled form. It is also importantto understand the reactivity of the drug on the skinand ensure that the material used for manufacturingthe transdermal patch do not have an adverse reactionon the skin, for instance itching, inflammation, etc.The patch also needs to be kept on from several hoursto, in some cases, several days (e.g., contraceptivepatch) and hence the properties of the patch like thetype of polymers, adhesives used in the making alsoneed special consideration. The material used formaking the patch is polymers. There are varioustypes of polymeric materials that are utilized for theconstruction of transdermal drug delivery system.The following section in the paper describes thepolymeric materials along with their properties thatare used in the making of transdermal drug deliverysystem.The future of transdermal drug deliveryTransdermal drug delivery is theoretically ideal formany injected and orally delivered drugs, but manydrugs cannot pass through the skin because of skin'slow permeability. Pharmaceutical companies developnew adhesives, molecular absorption enhancers, andpenetration enhancers that will enhance skinpermeability and thus greatly expand the range ofdrugs that can be delivered transdermally. Two of thebetter-known technologies that can help achievesignificant skin permeation enhancement areiontophoresis and phonophoresis (sonophoresis).Iontophoresis involves passing a direct electricalcurrent between two electrodes on the skin surface.Phonophoresis uses ultrasonic frequencies to helptransfer high molecular weight drugs through theskin. A newer and potentially more promisingtechnology is micro needle-enhanced delivery. Thesesystems use an array of tiny needle-like structures toopen pores in the stratum corneum and facilitate drugtransport. The structures are small enough that theydo not reach the nerve endings, so there is nosensation of pain. These systems have been reportedto greatly enhance (up to 100,000 fold) thepermeation of macromolecules through skin.IJAPR / March. 2012/ Vol. 3 / Issue. 3 / 846 - 854 851

Abdullah Bin Junaid ., et al. / International Journal of Advances in Pharmaceutical ResearchGlobal Overview of the Active Transdermal DrugDelivery MarketTransdermal delivery can nonetheless be viewed in apositive light as a highly attractive route of drugadministration. The major challenge of technologiesthat enable, for example, inhalable and oral delivery,is to deliver sufficient quantities of the drug to theinaccessible surface through which it crosses into theblood. For systemic delivery, inhalers andformulations for inhalation must incorporateadvanced designs to allow deposition in the deeplung. Oral technologies must protect the drug fromthe harsh environment in the stomach just so that itreaches the epithelium intact. In contrast, transdermalformulations can be applied directly to the surface themedication is intended to cross, the skin. The densecapillary bed close beneath the surface tantalizinglysuggests easy access to the systemic circulation.Furthermore, patches can readily be designed torelease active ingredient over extended periods andthus confer many of the benefits of implants or depotinjections, but without the need for an invasiveprocedure to position a foreign device. Indeed,patients can interrupt dosing from a patch if requiredsimply by removing it. The potential benefits oftransdermal delivery have spurred several companiesto overcome the challenges the skin presents as abarrier by developing active transdermal deliverytechnologies. These systems use energy to enhancethe extent and rate at which pharmaceuticalcompounds cross the 10- to 20-micrometer dead layerof the skin, the stratum corneum, which representsthe major barrier. The companies developing activetransdermal systems aim to open up the transdermalmarket to the delivery of products that werepreviously considered undeliverable via this route.REFERENCES1. Action-on-pain.co.uk, Different types of pain,viewed 29 December 2011, 2. Ahfs, Nitroglycerin transdermal, viewed 20December 2011,3. Aggarwal, G Development, fabrication andevaluation of transdermal drug delivery system -A review, viewed 28 December 2011,4. Basak, S Transdermal patches: what pharmacistsneed to know, viewed 02 January 2012,5. Bhowmik, D et. al, Recent advances intransdermal drug delivery system, viewed 04January 2012,6. Cloe, A About transdermal patches, viewed 25December 2011,7. Deardorff, W Types of back pain: acute pain,chronic pain, and neuropathic pain, viewed 03January 2012, 8. Department of health and human service, Caremanagement guidelines: pain management,viewed 28 December 2011,9. Dermadoctor.com, P a t c h t e c h n o l o g y i ns k i n c a r e , v i e w e d 0 7 J a n u a r y2 0 1 2 ,< http://www.dermadoctor.com/article_patchtechnology-in-skin-care_256.html>10. Dhiman, S Transdermal patches: a recentapproach to new drug delivery system, viewed 06January 2011,11. Epec project, Pain management, viewed 01January 2012,12. Eustice, C Transdermal drug patches, includingthose for arthritis pain, must be removed beforemri, viewed 23 December 2011,13. Gagné, J The different kinds of pain, viewed 24December 2011,14. Internist extra, Chronic pain management, viewed30 December 2011,15. Josh, K Transdermal drug delivery systems andtheir use of polymers, viewed 23 December 2011,16. Macintyre, P et. al, Acute pain management:scientific evidence, viewed 26 December 2011,IJAPR / March. 2012/ Vol. 3 / Issue. 3 / 846 - 854 852

Abdullah Bin Junaid ., et al. / International Journal of Advances in Pharmaceutical Research17. Medical news today, What is pain? What causespain?, viewed 03 January 2012,18. Morrow, T Transdermal patches are more thanskin deep, viewed, 05 January 2012,19. Pasero, C McCaffery, M The lidocaine patch,viewed 29 December 2011,20. Saroha, K et. al, Transdermal patch: a discretedosage form, viewed 27 December 2011,21. Shreeraj, 2008, Transdermal drug deliverytechnology revisited: recent advances, viewed 28December22. Sheth, N Mistry, R Formulation and evaluation oftransdermal patches and to study permeationenhancement effect of eugenol, viewed 03January 2012, 23. Somers, L Transdermal patches: how do theywork? viewed 22 December 2011,24. Writer, T Duragesic transdermal pain patch:be very, very careful..., viewed 24 December2011,

Abdullah Bin Junaid ., et al. / International Journal of Advances in Pharmaceutical ResearchCALLFORPAPERSwww.ijapronline.orgIJAPR / March. 2012/ Vol. 3 / Issue. 3 / 846 - 854 854