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1.

INTRODUCTION

A transdermal patch is a medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and into the bloodstream. Often, this promotes healing to an injured area of the body. An advantage of a transdermal drug delivery route over other types of medication delivery such as oral, topical, intravenous, intramuscular, etc. is that the patch provides a controlled release of the medication into the patient, usually through either a porous membrane covering a reservoir of medication or through body heat melting thin layers of medication embedded in the adhesive. The main disadvantage to transdermal delivery systems stems from the fact that the skin is a very effective barrier; as a result, only medications whose molecules are small enough to penetrate the skin can be delivered in this method. A wide variety of pharmaceuticals are now available in transdermal patch form. The first commercially available prescription patch was approved by the U.S. Food and Drug Administration in December 1979. These patches administered scopolamine for motion sickness.

2. DEVELOPMENT
Before these patches go into the market, they have to be carefully studied. One way to study these patches are through the use of Franz Diffusion Cell systems. This system is used to study the effects of temperature on the permeated amount of a specific drug on a certain type of membrane, which in this case would be the membrane that is used in the patches. A Franz Diffusion Cell system is composed of a receptor and a donor cell. In many of these research studies the following procedure is used. The donor cell is set at a specific temperature (the

temperature of the environment ), while the receptor cell is set at different one (temperature of the body). Different runs are performed using different temperatures to study the impact of temperature on the release of a certain medicament through a certain type of membrane. Although different concentrations of the medicament are used in this study, they do not affect the amount permeated through the membrane (the process is constant). From Chemical kinetics its concluded that these studies are zero order, since the concentration plays no role in the permeated amount through the membrane. Some pharmaceuticals must be combined with substances, such as alcohol, within the patch to increase their ability to penetrate the skin in order to be used in a transdermal patch. Others can overwhelm the body if applied in only one place, and are often cut into sections and applied to different parts of the body to avoid this, such as nitroglycerin. Many molecules, however, such as insulin, are too large to pass through the skin without it being modified in some way. Several new technologies are being investigated to allow larger molecules to be delivered transdermally.

3. POPULAR USE

The highest selling transdermal patch in the United States is the nicotine patch, which releases nicotine in controlled doses to help with cessation of tobacco smoking. The first commercially available vapour patch to reduce smoking was approved in Europe in 2007.

Two opioid medications used to provide round-the-clock relief for severe pain are often prescribed in patch form: Fentanyl (marketed as Duragesic) and Buprenorphine (marketed as Butrans).

Estrogen patches are sometimes prescribed to treat menopausal symptoms as well as post-menopausal osteoporosis. Other transdermal patches for hormone delivery include the contraceptive patch (marketed as Ortho Evra or Evra) and testosterone patches for both men (Androde) and women (Intrinsa).

Nitroglycerin patches are sometimes prescribed for the treatment of angina in lieu of sublingual pills.

Transdermal scopolamine is commonly used as a treatment for motion sickness. The anti-hypertensive drug clonidine is available in transdermal patch for under the brand name Catapres-TTS

Emsam, a transdermal form of the MAOI selegine, became the first transdermal delivery agent for an antideressant approved for use in the U.S. in March 2006.

Daytrana, the first transdermal delivery agent for the Attention deficit Hyperactive Dsorder (ADHD) drug methylphenidate (otherwise known as Ritalin or Concerta), was approved by the FDA in April 2006.

Vitamin B12 may also be administered through a transdermal patch.Cyanobalamin, a highly stable form of vitamin B12, is compatible with transdermal patching.

Rivastigmine, an Alzhemeirs treatment medication, was released in patch form in 2007, under the brand name Exelon

3. Adverse event

In 2005, the FDA announced that they were investigating reports of death and other serious adverse events related narcotic overdose in patients using Duragestic the fentanyl transdermal patch for pain control. The Duragesic product label was subsequently updated to add safety information in June 2005.[10]

In 2007, Shire and Noven Pharmaceuticals, manufacturers of the Daytrana ADHD patch, announced a voluntary recall of several lots of the patch due to problems with separating the patch from its protective release liner[11]. Since then, no further problems with either the patch or its protective packaging have been reported.

In 2008, two manufacturers of the Fentanyl patch, ALZA Pharmaceuticals (a division of major medical manufacturer johnson&johnson) and Sandoz, subsequently issued a

recall of their versions of the patch due to a manufacturing defect that allowed the gel containing the medication to leak out of its pouch too quickly, which could result in overdose and death[12]. As of March 2009, Sandoz--now manufactured by ALZA--no longer uses gel in its transdermal fentanyl patch; instead, Sandoz-branded fentanyl patches use a matrix/adhesive suspension (where the medication is blended with the adhesive instead of held in a separate pouch with a porous membrane), similar to other fentanyl patch manufacturers such as Mylan and Janssen[13].

In 2009, the FDA announced a public health advisory warning of the risk of burns during MRI scans from transdermal drug patches with metallic backings. Patients should be advised to removed any medicated patch prior to an MRI scan and replace it with a new patch after the scan is complete.[14]

In 2009, an article in Europace journal detailed stories of skin burns that occurred with transdermal patches that contain metal (usually as a backing material) caused by shock therapy from external as well as internal cardioverter defibrillators (ICD)[15].

4. Components
The main components to a transdermal patch are:

Liner - Protects the patch during storage. The liner is removed prior to use. Drug - Drug solution in direct contact with release liner Adhesive - Serves to adhere the components of the patch together along with adhering the patch to the skin

Membrane - Controls the release of the drug from the reservoir and multi-layer patches

Backing - Protects the patch from the outer environment

5. Types of dermal patches


There are five main types of transdermal patches.
Single-layer Drug-in-Adhesive

The adhesive layer of this system also contains the drug. layer not only serves to adhere the various layers together, along with the entire system to the skin, but is also responsible for the releasing of the drug. The adhesive layer is surrounded by a temporary liner and a backing.
Multi-layer Drug-in-Adhesive

The multi-layer drug-in adhesive patch is similar to the single-layer system in that both adhesive layers are also responsible for the releasing of the drug.One of the layers is for immediate release of the drug and other layer is for control release of drug from the reservoir. The multi-layer system is different however that it adds another layer of drug-in-adhesive, usually separated by a membrane (but not in all cases). This patch also has a temporary linerlayer and a permanent backing.
Reservoir

Unlike the Single-layer and Multi-layer Drug-in-adhesive systems the reservoir transdermal system has a separate drug layer. The drug layer is a liquid compartment containing a drug . In this type of system the rate of release is zero order.
Matrix

The Matrix system has a drug layer of a semisolid matrix containing a drug solution or suspension. The adhesive layer in this patch surrounds the drug layer partially overlaying it. Also known as a monolithic device.
Vapour Patch

In this type of patch the adhesive layer not only serves to adhere the various layers together but also to release vapour. The vapour patches are new on the market and they release essential oils for up to 6 hours. The vapour patches release essential oils and are used in cases of decongestion mainly. Other vapour patches on the market are controller vapour patches

that improve the quality of sleep. Vapour patches that reduce the quantity of cigarettes that one smokes in a month are also available on the market.

6. Regulatory aspects
A transdermal patch is classified by the U.S. Food and Drug Administration as a combination product, consisting of a medical device combined with a drug .

7. WARNING: This medication is a strong narcotic pain reliever. It should only be used for patients who have been using moderate-to-large amounts of a powerful narcotic medication regularly. Use of this medication by someone who is not regularly taking narcotic pain relievers can cause serious (possibly fatal) breathing problems (e.g., very slow and shallow breathing). used for the relief of acute pain, pain after surgery, or mild pain that lasts only for a short time. You may be at higher risk for addiction if you have abused alcohol Do not increase your dose, use it more frequently. This will lessen the chances of becoming addicted. Do not cut or damage the patch. Broken, cut, or damaged patches ) This medication is not recommended for children under 2 years of age. Make sure your physician knows all the medications you are taking especially, drugs that affect liver enzymes that remove this medication from your body such as azole antifungals (e.g.,intraconazole,keteconazole) macrolide antibiotics (e.g.,erythromycin,clarithromycin troleandomycin), certain HIV medications (protease inhibitors such as ritonavir, nelfinavir), and nefazodone. Avoid eating grapefruit or drinking grapefruit juice while being treated with this medication unless your doctor instructs you otherwise. Grapefruit can increase the amount of this medication in your bloodstream. Consult your doctor or pharmacist for more details. Your physician will want to monitor you more closely or may decrease the dose of

your medications. Do not stop or start any medications without talking with your doctor. (See also Drug Interactions Section) 8. USES: See also the Warning section.Fentanyl patch is used to treat moderate-to-severe chronic pain(e.g.,cancer pain). This medication acts on certain centers in the brain to give you pain relief. It is known as a narcotic pain reliever (opiate-type). 9. HOW TO USE: Read the Patient Information Leaflet and Medication Guide provided by your pharmacist before you start using this medication . Learn how to properly use, store, and discard the patches.The dosage is based on your medical condition, response to therapy, and previous use of narcotics. Do not use more patches or change them more frequently than prescribed.Apply this medication to the skin on a non-irritated, hairless area on your chest, back, or upper arm. The patch is usually changed every 72 hours or as directed by your doctor. Do not apply the patch on burns, cuts, or irritated skin. If needed, clip (do not shave) the hair in the area prior to application. To avoid irritation, use a different area each time and wait at least 3 days before re-using the same area. Remember to remove the old patch before applying a new patch. The used patch should be folded in half with the sticky sides together and discarded properly. For more information, read the Medication Guide.In young children, apply the patch on the upper back. This reduces the chance of your child removing the patch and placing it in the mouth.Before applying the patch, clean the area with water and pat dry. Do not use soap, oils, lotions or alcohol on the application site.Do not use the patch if it appears broken, cut, or damaged. Use the patch immediately after removing it from the sealed package. Peel off the sticky backing, apply the patch to the skin, and press firmly for at least 30 seconds to make sure the patch sticks well, especially around the edges. If your prescribed dose is more than one patch, make sure the edges of the patches do not touch or overlap. Wash your hands after applying the patch.This patch contains a very strong narcotic pain medication. Depending on the manufacturer, the drug may be in the sticky layer, or it may be in a separate layer of gel as well as in the sticky layer. If you accidentally touch the adhesive drug layer to your skin or handle a cut or damaged patch, wash the exposed area with clear water. If you touch the gel or if the gel leaks from the patch, wash the exposed area with plenty of water. Do not use soap, alcohol, or other products to remove the gel. Wear rubber

gloves or use a tissue to remove a cut, damaged or leaking patch. Consult your pharmacist if you have questions.It may take up to 24 hours before you have pain relief. Take immediaterelease narcotic pain medications (e.g.,oxycodone) for acute/breakthrough pain as directed by your doctor. Follow your doctor's or pharmacist's instruction for the safe use of non-narcotic pain relievers (e.g.,acetaminophen,ibuprofen). If you have been using other long-acting narcotic pain medications regularly, check with your doctor or pharmacist since they may need to be stopped before starting this medication.This medication may cause withdrawal reactions, especially if it has been used regularly for a long time or in high doses. In such cases, withdrawal symptoms (such as axniety, irritability, trouble sleeping,diarrhea, or shivering) may occur if you suddenly stop using this medication. To prevent withdrawal reactions, your doctor may reduce your dose gradually. Consult your doctor or pharmacist for more details, and report any withdrawal reactions immediately.If you use this medication for an extended period of time, it may not work as well and you will need a different dose. Talk with your doctor if you think this medication has stopped working well.Inform your doctor if your pain persists or worsens.

10. SIDE EFFECTS: Nausea, vomiting,constipation, confusion, drowsiness,dizziness,dry mouth, sweating, mild itching/redness on the application site, or weakness may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.To prevent constipation, maintain a diet adequate in fiber, drink plenty of water, and exercise. If you become constipated while using this drug, consult your pharmacist for help in selecting a laxative (e.g., stimulant-type and stool softener).Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.Tell your doctor immediately if any of these unlikely but serious side effects occur: in the amount of urine, fast/pounding heartbeat.Tell your doctor immediately if any of slow/irregular/shallow breathing,fainting, mental/mood changes, uncontrolled muscle movements (tremors), change these rare but very serious side effects occur: severe stomach/abdominal pain, slow/irregular heartbeat, seizures, vision changes.A serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction include:rash, itching/swelling

11. PRECAUTIONS: See also the Warning section.Before using this medication, tell your doctor or pharmacist if you are allergic to it; or to other opioid medications.This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: serious breathing problems (e.g., severe asthma or respiratory depression), certain bowel diseases coma (e.g., paralytic ileus), certain brain conditions (e.g., increased intracranial pressure,), intoxication with medications which depress the nervous system or your breathing (CNS/respiratory depressants such as alcohol or

tranquilizers/sedatives).Before using this medication, tell your doctor or pharmacist your medical history, especially of: adrenal gland problems (e.g.,Addissons disease), brain disorders (e.g.,brain tumor,head injury,seizures), difficulty urinating (e.g., enlarged prostate, urethral stricture), lung diseases (e.g.,chronic obstructive pulmonary disease, hypercapnia, hypoxia), heart problems (e.g., slow/irregular heartbeat,low blood pressure),

stomach/intestinal problems (e.g., gallbladder disease, severe constipation), kidney or liver disease, disease of the pancreas (pancreatitis), personal or family history of regular use/abuse of drugs/alcohol/other substances, psychiatric problems (e.g., major depression, toxic psychosis), spinal problem (kyphoscoliosis), underactive thyroid (hypothyroidism).Avoid exposing your skin to direct heat sources such as heating pads, electric blankets, heat lamps, or saunas while wearing fentanyl patch. Tell your doctor immediately if you develop a fever while using this medication. A fever or heat sources may cause more drug to be released into your body and increase the chance of side effects.This drug may make you dizzy or drowsy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely. Avoid alcoholic beverages.To minimize dizziness and lightheadedness, get up slowly when rising from a seated or lying position.Before having surgery, tell your doctor or dentist that you are using this medication.Caution is advised when using this drug in the elderly because they may be more sensitive to its side effects (e.g., slow/shallow breathing).This medication should be used only when clearly needed during pregnacy. Inform your doctor immediately if you are or think you are pregnant. Discuss the risks and benefits with your doctor. This medication should not be started near or at the time of delivery because of possible side effects in the newborn (such as slow/shallow breathing). If prescribed, follow your doctor's instructions closely and do not suddenly stop using this drug. Infants born to mothers who have been using this medication for an extended time may

have withdrawal symptoms such as irritability, abnormal/persistent crying, vomiting, or diarrhea. Tell your doctor immediately if you notice any of these symptoms in your newborn.This medication passes into breast milk and may have undesirable affects on a nursing infant. Breast-feeding while using this drug is not recommended. Consult your doctor before breastfeeding. 12. DRUG INTERACTIONS: See also Warning Section.Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.This drug should not be used with the following medications because very serious interactions may occur: naltrexone,sibutramine, monoamine oxidase inhibitors (e.g., furazolidone, isocarboxazid, linezolid, moclobemide, phenelzine, procarbazine, rasagiline, selegiline, tranylcypromine).Avoid taking MAO inhibitors within 2 weeks before or after treatment with this medication. In some cases a serious, possibly fatal drug interaction may occur.If you are currently using any of these medications, tell your doctor or pharmacist before starting fentanyl.Before using this medication, tell your doctor or pharmacist of all prescription and 14. OVERDOSE: If overdose is suspected, remove the patch. This medicine may be harmful if accidentally swallowed. Contact your local poison control center . Canadian residents should call their local poison control center directly. Symptoms of overdose may include: slow/shallow breathing, excessive drowsiness, persistent dizziness/fainting. 15. NOTES: Do not share this medication with others. It is against the law.This medication has been prescribed for your current condition only. Do not use it later for another condition unless told to do so by your doctor. 16. MISSED DOSE: If you forget to apply a patch, use it as soon as you remember. Do not double the dose to catch up. 17. STORAGE: Store the US product at room temperature below 77 degrees F (25 degrees C) away from light and moisture.Do not store in the bathroom. .Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this

product when it is expired or no longer needed. Consult your pharmacist how to safely discard your product Transdermal patches are becoming more popular and are being developed for everything from contraception to Parkinson's disease. How do they work? Are they effective in getting the medication into you skin? Transdermal patches are considered to be a combination product, which is one that uses a drug as well as a delivery system. The delivery system being the parts of the patch (backing, adhesive etc.) are all important in the transdermal process.

Transdermal patches are available to help quit smoking, to ease motion sickness, to provide oral contraception or to infuse hormones into the blood stream to alleviate symptoms of menopause. Transdermal patches are considered to be parenteral and are diffused through intact skin structures.

The patch adheres to the skin and delivers the medication through the blood stream. Some pharmaceuticals must be combined with substances, such as alcohol within the patch to increase their ability to penetrate the skin in order to be used in a transdermal patch. The molecules of the medication must be small enough to pass through the skin.

There are five crucial parts to the transdermal patch which enable the success of the medication to be distributed Drugs can be delivered across the skin to have an effect on the tissues adjacent to the site of application (topical delivery) or to have an effect after distribution through the circulatory system (systemic

delivery). While there are many advantages to delivering drugs through the skin the barrier properties of the skin provide a significant challenge. By understanding the mechanisms by which compounds cross the skin it will be possible to devise means for improving drug delivery"

Since 1979 transdermal patches have been in use and are available in a wide variety of treatments. Since many oral medications harm the liver, transdermal medications have proven to be less harsh on the effects of the liver and effective in transmission and treatment.into the bloodstream. There is the liner, the drug, the adhesive, the membrane and the backing. The liner is removed prior to use and protects the patch while it is not in use. Drug comes in contact with the liner and is the solution which is exposed to the skin. The adhesive binds the components of the patch together while keeping it adhered to the skin. The membrane controls the release time for the drug and is often used in many different layers to release a certain amount at a time. The backing is the part that is exposed to the air, and protects the drug at all times. All of these parts work as the sum of the whole to infuse the medication into the bloodstream, through the skin.

This is a non invasive way to treat many diseases and disorders. In addition to the aspects of each patch - there are four types of transdermal patches. These four types are: Single layer

18. INTRODUCTION OF TRANSDERMAL DRUG SYSTEM.

18.1 Abstract: With the advent of new era of pharmaceutical dosage forms, transdermal drug delivery system (TDDS) established itself as an integral part of novel drug delivery systems.

Transdermal patches are polymeric formulations which when applied to skin deliver the drug at a predetermined rate across dermis to achieve systemic effects. Transdermal dosage forms, though a costly alternative to conventional formulations, are becoming popular because of their unique advantages. Controlled absorption, more uniform plasma levels, improved bioavailability, reduced side effects, painless and simple application and flexibility of terminating drug administration by simply removing the patch from the skin are some of the potential advantages of transdermal drug delivery. Development of controlled release transdermal dosage form is a complex process involving extensive efforts. This review article describes the methods of preparation of different types of transdermal patches viz., matrix patches, reservoir type, membrane matrix hybrid patches, drug-in-adhesive patches and micro reservoir patches. In addition, the various methods of evaluation of transdermal dosage form have also been reviewed. Transdermal drug delivery is the non-invasive delivery of medications from the surface of skin-the largest and most accessible organ of human body- through its layers, to the circulatory system. TDDS offers many advantages over conventional injection and oral methods. It reduces the load that the oral route commonly places on the digestive tract and liver. It enhances patient compliance and minimizes harmful side effects of a drug caused from temporary overdose. Another advantage is convenience, especially notable in patches that require only once weekly application. Such a simple dosing regimen can aid in patient adherence to drug therapy. Designing and development of transdermal patches can be described as state of the art. The development of TDDS is multidisciplinary activity that encompasses fundamental feasibility studies starting from the selection of drug molecule to the demonstration of sufficient drug flux in an ex vivo and in vivo model followed by fabrication of a drug delivery system that meets all the stringent needs that are specific to the drug molecule (physicochemical and stability factors), the patient (comfort and cosmetic appeal), the manufacturer (scale up and manufacturability) and most important the economy1. 18.2 Transdermal Permeation Earlier skin was considered as an impermeable protective barrier, but later investigations were carried out which proved the utility of skin as a route for systemic administration2. Skin is the most intensive and readily accessible organ of the body as only a fraction of millimeter of tissue separates its surface from the underlying capillary network. The various steps involved in transport of drug from patch to systemic circulation are as follows3-4:

1. Diffusion of drug from drug reservoir to the rate controlling membrane. 2. Diffusion of drug from rate limiting membrane to stratum corneum. 3. Sorption by stratum corneum and penetration through viable epidermis. 4. Uptake of drug by capillary network in the dermal papillary layer. 5. Effect on target organ. 18.3 Basic Components Of TDDS

Polymer matrix / Drug reservoir Drug Permeation enhancers Pressure sensitive adhesive (PSA) Backing laminates Release liner Other excipients like plasticizers and solvents

Polymer matrix / Drug reservoir: Polymers are the backbone of TDDS, which control the release of the drug from the device. Polymer matrix can be prepared by dispersion of drug in liquid or solid state synthetic polymer base. Polymers used in TDDS should have biocompatibility and chemical compatibility with the drug and other components of the system such as penetration enhancers and PSAs. Additionally they should provide consistent and effective delivery of a drug throughout the products intended shelf life and should be of safe status5. Companies involved in the field of transdermal delivery concentrate on a few selective polymeric systems. For example, Alza Corporation mainly concentrates on ethylene vinyl acetate (EVA) copolymers or microporous polypropylene and Searle Pharmacia concentrates on silicon rubber6. Similarly Colorcon, UK uses HPMC for matrix preparation for propranolol transdermal delivery and Sigma uses ethylcellulose for isosorbide dinitrate matrix7-9. The polymers utilized for TDDS can be classified as2-3:

Natural Polymers: e.g. cellulose derivatives, zein, gelatin, shellac, waxes, gums, natural rubber and chitosan etc10.

Synthetic Elastomers: e.g. polybutadiene, hydrin rubber, polyisobutylene, silicon rubber, nitrile, acrylonitrile, neoprene, butylrubber etc.

Synthetic Polymers: e.g. polyvinyl alcohol, polyvinylchloride, polyethylene, polypropylene, polyacrylate, polyamide, polyurea, polyvinylpyrrolidone, polymethylmethacrylate etc.

The polymers like cross linked polyethylene glycol11, eudragits12, ethyl cellulose, polyvinylpyrrolidone13 and hydroxypropylmethylcellulose14 are used as matrix formers for TDDS. Other polymers like EVA15, silicon rubber and polyurethane16 are used as rate controlling membrane. Drug: The transdermal route is an extremely attractive option for the drugs with appropriate pharmacology and physical chemistry. Transdermal patches offer much to drugs which undergo extensive first pass metabolism, drugs with narrow therapeutic window, or drugs with short half life which causes non- compliance due to frequent dosing. The foremost requirement of TDDS is that the drug possesses the right mix of physicochemical and biological properties for transdermal drug delivery17-18. It is generally accepted that the best drug candidates for passive adhesive transdermal patches must be non ionic, of low molecular weight (less than 500 Daltons), have adequate solubility in oil and water (log P in the range of 1-3), a low melting point (less than 200C) and are potent (dose in mg per day)19. Table 1 enlists the currently available drugs for transdermal delivery. In addition drugs like rivastigmine for alzheimers and parkinson dementia, rotigotine for parkinson, methylphenidate for attention deficit hyperactive disorder and selegiline for depression are recently approved as TDDS. Permeation Enhancers: These are the chemical compounds that increase permeability of stratum corneum so as to attain higher therapeutic levels of the drug candidate20. Penetration enhancers interact with structural components of stratum corneum i.e., proteins or lipids. They alter the protein and lipid packaging of stratum corneum, thus chemically modifying the barrier functions leading to increased permeability21. Over the last 20 years, a tremendous amount of work has been directed towards the search for specific chemicals, combination of chemicals, which can act as penetration enhancers. Some of the permeation enhancers have been enlisted in Table 2.

Pressure sensitive adhesives: A PSA is a material that helps in maintaining an intimate contact between transdermal system and the skin surface. It should adhere with not more than applied finger pressure, be aggressively and permanently tachy, exert a strong holding force. Additionally, it should be removable from the smooth surface without leaving a residue37-38. 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. For matrix systems with a peripheral adhesive, an incidental contact between the adhesive and the drug and penetration enhancer should not cause instability of the drug, penetration enhancer or the adhesive. In case of reservoir systems that include a face adhesive, the diffusing drug must not affect the adhesive. In case of drug-in-adhesive matrix systems, the selection will be based on the rate at which the drug and the penetration enhancer will diffuse through the adhesive. Ideally, PSA should be physicochemically and biologically compatible and should not alter drug release40. Backing Laminate: While designing a backing layer, the consideration of chemical resistance of the material is most important. Excipient compatibility should also be considered because the prolonged contact between the backing layer and the excepec may cause the additives to leach out of the backing layer or may lead to diffusion of excipients, drug or penetration enhancer through the layer. However, an overemphasis on the chemical resistance may lead to stiffness and high occlusivity to moisture vapor and air, causing patches to lift and possibly irritate the skin during long wear. The most comfortable backing will be the one that exhibits lowest modulus or high flexibility, good oxygen transmission and a high moisture vapor transmission rate41-42. Examples of some backing materials are vinyl, polyethylene and polyester films. 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. It is therefore regarded as a part of the primary packaging material rather than a part of dosage form for delivering the drug. 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.

Other excipients: Various solvents such as chloroform, methanol, acetone, isopropanol and dichloromethane are used to prepare drug reservoir14,44. In addition plasticizers such as dibutylpthalate, triethylcitrate, polyethylene glycol and propylene glycol are added to provide plasticity to the transdermal patch45-46. 18.4 Preparation Of Different Types Of Transdermal Patches: Several system designs have been used in development and fabrication of TDDSs. The systems that have been introduced in market can be classified into following types43,47: Matrix type Reservoir type Membrane matrix hybrid Micro reservoir type Drug in adhesive type 18.4.1 Matrix Type Transdermal Patch(s): Drug reservoir is prepared by dissolving the drug and polymer in a common solvent. The insoluble drug should be homogenously dispersed in hydrophilic or lipophillic polymer. The required quantity of plasticizer like dibutylpthalate, triethylcitrate, polyethylene glycol or propylene glycol and permeation enhancer is then added and mixed properly. The medicated polymer formed is then molded into rings with defined surface area and controlled thickness over the mercury on horizontal surface followed by solvent evaporation at an elevated temperature. The film formed is then separated from the rings, which is then mounted onto an occlusive base plate in a compartment fabricated from a drug impermeable backing. Adhesive polymer is then spread along the circumference of the film48-49. Some examples of matrix patches prepared by solvent evaporation method mentioned in literature are given in Table 3. Commonly used polymers for matrix are cross linked polyethylene glycol, eudragits, ethyl cellulose, polyvinylpyrrolidone and hydroxypropylmethylcellulose. The dispersion of drug particles in the polymer matrix can be accomplished by either homogenously mixing the finely ground drug particles with a liquid polymer or a highly

viscous base polymer followed by cross linking of polymer chains or homogenously blending drug solids with a rubbery polymer at an elevated temperature50. The matrix system is exemplified by the development of Nitro-Dur. Advantages of matrix patches include absence of dose dumping, direct exposure of polymeric matrix to the skin and no interference of adhesive. Design of matrix type patch is shown in Figure 1. 18.4.2 Reservoir Type Transdermal Patch(s): The drug reservoir is made of a homogenous dispersion of drug particles suspended in an unleachable viscous liquid medium (e.g. silicon fluids) to form a paste like suspension or gel or a clear solution of drug in a releasable solvent (e. g. ethanol). The drug reservoir formed is sandwiched between a rate controlling membrane and backing laminate54. The rate controlling membrane can be nonporous so that the drug is released by diffusing directly through the material, or the material may contain fluid filled micropores in which case the drug may additionally diffuse through the fluid, thus filling the pores. In the case of nonporous membrane, the rate of passage of drug molecules depends on the solubility of the drug in the membrane and the thickness of membrane. Hence, the choice of membrane material is dependent on the type of drug being used. By varying the composition and thickness of the membrane, the dosage rate per unit area of the device can be controlled. Mostly EVA, ethyl cellulose, silicon rubber and polyurethanes are used to prepare rate controlling membranes1,55-57. EVA is used most frequently to prepare rate controlling membrane in transdermal delivery systems because it allows the membrane permeability to be altered by adjusting vinyl acetate content of polymer. Polyurethane membranes are suitable especially for hydrophobic polar compounds having low permeability through hydrophobic polymers such as silicon rubber or EVA membrane58. Liang et al., (1990) studied controlled release of scopolamine through EVA membrane in transdermal patch formulations and release rates were compared with uncontrolled reservoirs. It was found that an EVA membrane patch released scopolamine at a constant rate for more than 72 hours56. Krishna and Pandit (1994) prepared three transdermal formulations containing propranolol hydrochloride in a hydrophilic polymer matrix, one without rate controlling membrane and other two with EVA rate controlling membranes of different thickness. It was found that

increased thickness of EVA led to greater retention of the drug in device and zero order profile was observed with EVA57. Rate controlling membrane may be prepared by solvent evaporation method or compression method. In case of solvent evaporation method, polymer is dissolved in solvent with or without plasticizer. Then the solution is poured on the horizontal surface and left for evaporation of solvent in order to obtain a thin film. Examples of preparation of rate controlling membrane by solvent evaporation method are shown in Table 4. In case of compression method, polymer is compressed with required force at high temperature for specific period of time59. Drugs that require relatively high doses or greater permeation enhancement, such as testosterone, use liquid reservoir systems. But the application of enhancers and adhesive technologies has allowed many drugs that were initially administered in liquid reservoirs to be used as matrix type systems e.g. estradiol, nicotine, nitroglycerine60. The main advantage of reservoir type patches is that this patch design can provide a true zero order release pattern to achieve a constant serum drug level. Examples of marketed preparations are Duragesic, Estradem and Androderm. Figure 2 illustrates the design of reservoir type of patch. 18.4.3 Membrane matrix hybrid type patch(s): This is the modification of reservoir type transdermal patch. The liquid formulation of the drug reservoir is replaced with a solid polymer matrix (e.g. polyisobutylene) which is sandwiched between rate controlling membrane and backing laminate43. Examples of marketed preparations are Catapress and TransdermScop. 18.4.4 Micro reservoir type transdermal patch(s): The drug reservoir is formed by suspending the drug solids in an aqueous solution of water miscible drug solubilizer e.g. polyethylene glycol. The drug suspension is homogenously dispersed by a high shear mechanical force in lipophillic polymer, forming thousands of unleachable microscopic drug reservoirs (micro reservoirs). The dispersion is quickly stabilized by immediately cross linking the polymer chains in-situ which produces a medicated polymer disc of a specific area and fixed thickness. Occlusive base plate mounted between the medicated disc and adhesive form backing prevents the loss of drug through the

backing membrane61-62. This system is exemplified by development of Nitrodisc. Micro reservoir type transdermal system is shown in Figure 3. 18.4.5 Drug in adhesive type transdermal patch(s): The drug and other selected excipients, if any, are directly incorporated into the organic solvent based pressure sensitive adhesive solution, mixed, cast as a thin film and dried to evaporate the solvents, leaving a dried adhesive matrix film containing the drug and excipients. This drug in adhesive matrix is sandwiched between release liner and backing is different from single layer in that it adds another layer of drug-in-adhesive, usually separated by a membrane. Some examples of suitable pressure sensitive adhesives are polysiloxanes, polyacrylates and polyisobutylene. These pressure sensitive adhesives are hydrophobic in nature and are prepared as solutions of polymer dissolved in organic solvents. Hence, this type of system is preferred for hydrophobic drugs as it is to be incorporated into organic solvent based hydrophobic adhesive63. Rachel et al., (2004) prepared drug in adhesive patches of green tea extract and it was observed that major catechins and caffeine extracted from green tea were successfully delivered transdermally from drug-in-adhesive patches64. Kannikkanan et al., (2004) prepared and evaluated monolithic drug in adhesive type transdermal patches of melatonin and used eudragit E100 as adhesive polymer65. Lake and Pinnock (2000) proved that once a week drug in adhesive patch of estrogen is more patient compliant as compared to twice a week reservoir patch. Characteristics of drug in adhesive patch may account for improved patient compliance due to ease of remembering once weekly patch application, improved cosmetic acceptance and better adhesion66. Examples of marketed preparations of drug-in-adhesives patches are Climara, Nicotrol and Deponit. Design of this system is shown in Figure 4. 18.5 Evaluation Of Transdermal Patches Development of controlled release transdermal dosage form is a complex process involving extensive research. Transdermal patches have been developed to improve clinical efficacy of the drug and to enhance patient compliance by delivering smaller amount of drug at a predetermined rate. This makes evaluation studies even more important in order to ensure their desired performance and reproducibility under the specified environmental conditions.

These studies are predictive of transdermal dosage forms and can be classified into following types:

Physicochemical evaluation In vitro evaluation In vivo evaluation

Upon the success of physicochemical and in vitro studies, in vivo evaluations may be conducted. 18.6 Physicochemical Evaluation: Thickness: The thickness of transdermal film is determined by traveling microscope12, dial gauge, screw gauge55 or micrometer67 at different points of the film. Uniformity of weight: Weight variation is studied by individually weighing 10 randomly selected patches and calculating the average weight. The individual weight should not deviate significantly from the average weight53. Drug content determination: An accurately weighed portion of film (about 100 mg) is dissolved in 100 mL of suitable solvent in which drug is soluble and then the solution is shaken continuously for 24 h in shaker incubator. Then the whole solution is sonicated. After sonication and subsequent filtration, drug in solution is estimated spectrophotometrically by appropriate dilution48. Content uniformity test: 10 patches are selected and content is determined for individual patches. If 9 out of 10 patches have content between 85% to 115% of the specified value and one has content not less than 75% to 125% of the specified value, then transdermal patches pass the test of content uniformity. But if 3 patches have content in the range of 75% to 125%, then additional 20 patches are tested for drug content. If these 20 patches have range from 85% to 115%, then the transdermal patches pass the test. Moisture content: The prepared films are weighed individually and kept in a desiccators containing calcium chloride at room temperature for 24 h. The films are weighed again after a specified interval until they show a constant weight. The percent moisture content is calculated using following formula68.

% Moisture content = Initial weight Final weight X 100 Final weight Moisture Uptake: Weighed films are kept in a desiccator at room temperature for 24 h. These are then taken out and exposed to 84% relative humidity using saturated solution of Potassium chloride in a desiccator until a constant weight is achieved. % moisture uptake is calculated as given below68. % moisture uptake = Final weight Initial weight X 100 Initial weight Flatness: A transdermal patch should possess a smooth surface and should not constrict with time. This can be demonstrated with flatness study. For flatness determination, one strip is cut from the centre and two from each side of patches. The length of each strip is measured and variation in length is measured by determining percent constriction. Zero percent constriction is equivalent to 100 percent flatness. % constriction = I1 I2 X 100 I1 I2 = Final length of each strip I1 = Initial length of each strip Folding Endurance: Evaluation of folding endurance involves determining the folding capacity of the films subjected to frequent extreme conditions of folding. Folding endurance is determined by repeatedly folding the film at the same place until it break. The number of times the films could be folded at the same place without breaking is folding endurance value13. Tensile Strength: To determine tensile strength, polymeric films are sandwiched separately by corked linear iron plates. One end of the films is kept fixed with the help of an iron screen and other end is connected to a freely movable thread over a pulley. The weights are added gradually to the pan attached with the hanging end of the thread. A pointer on the thread is (1)

used to measure the elongation of the film. The weight just sufficient to break the film is noted. The tensile strength can be calculated using the following equation69. Tensile strength= F/a.b (1+L/l) (2)

F is the force required to break; a is width of film; b is thickness of film; L is length of film; l is elongation of film at break point In another study, Tensile strength of the film was determined with the help of texture analyzer70. The force and elongation were measured when the films broke. 18.7 Water vapor transmission studies (WVT): For the determination of WVT, Rao et al., (1997) weighed one gram of calcium chloride and placed it in previously dried empty vials having equal diameter. The polymer films were pasted over the brim with the help of adhesive like silicon adhesive grease and the adhesive was allowed to set for 5 minutes. Then, the vials were accurately weighed and placed in humidity chamber maintained at 68 % RH. The vials were again weighed at the end of every 1st day, 2nd day, 3rd day up to 7 consecutive days and an increase in weight was considered as a quantitative measure of moisture transmitted through the patch45. In other reported method, desiccators were used to place vials, in which 200 mL of saturated sodium bromide and saturated potassium chloride solution were placed. The desiccators were tightly closed and humidity inside the desiccator was measured by using hygrometer. The weighed vials were then placed in desiccator and procedure was repeated69,71. WVT = W/ ST (3)

W is the increase in weight in 24 h; S is area of film exposed (cm2); T is exposure time Microscopic studies: Distribution of drug and polymer in the film can be studied using scanning electron microscope. For this study, the sections of each sample are cut and then mounted onto stubs using double sided adhesive tape. The sections are then coated with gold palladium alloy using fine coat ion sputter to render them electrically conductive. Then the sections are examined under scanning electron microscope72.

Adhesive studies: The therapeutic performance of TDDS can be affected by the quality of contact between the patch and the skin. The adhesion of a TDDS to the skin is obtained by using PSAs, which are defined as adhesives capable of bonding to surfaces with the application of light pressure. The adhesive properties of a TDDS can be characterized by considering the following factors73:

Peel Adhesion properties: It is the force required to remove adhesive coating from test substrate. It is tested by measuring the force required to pull a single coated tape, applied to substrate at 180 angle. The test is passed if there is no residue on the substrate. Minghetti et al., (2003) performed the test with a tensile testing machine Acquati model AG/MC 1 (Aquati, Arese, Italy )74.

Tack properties: It is the ability of the polymer to adhere to substrate with little contact pressure. Tack is dependent on molecular weight and composition of polymer as well as on the use of tackifying resins in polymer75-78.

Thumb tack test: The force required to remove thumb from adhesive is a measure of tack. Rolling ball test: This test involves measurement of the distance that stainless steel ball travels along an upward facing adhesive. The less tacky the adhesive, the further the ball will travel. Quick stick (Peel tack) test: The peel force required breaking the bond between an adhesive and substrate is measured by pulling the tape away from the substrate at 90 at the speed of 12 inch/min. Probe tack test: Force required to pull a probe away from an adhesive at a fixed rate is recorded as tack.

Shear strength properties or creep resistance : Shear strength is the measurement of the cohesive strength of an adhesive polymer i.e., device should not slip on application determined by measuring the time it takes to pull an adhesive coated tape off a stainless plate. Minghetti et al., (2003) performed the test with an apparatus

which was fabricated according to PSTC-7 (pressure sensitive tape council) specification74. In vitro release studies: Drug release mechanisms and kinetics are two characteristics of the dosage forms which play an important role in describing the drug dissolution profile from a controlled release dosage forms and hence their in vivo performance79. A number of mathematical model have been developed to describe the drug dissolution kinetics from controlled release drug delivery system e.g., Higuchi80, First order81, Zero order82 and Peppas and Korsenmeyer model83. The dissolution data is fitted to these models and the best fit is obtained to describe the release mechanism of the drug. There are various methods available for determination of drug release rate of TDDS.

The Paddle over Disc: (USP apparatus 5/ PhEur 2.9.4.1) This method is identical to the USP paddle dissolution apparatus, except that the transdermal system is attached to a disc or cell resting at the bottom of the vessel which contains medium at 32 5C84

The Cylinder modified USP Basket: (USP apparatus 6 / PhEur 2.9.4.3) This method is similar to the USP basket type dissolution apparatus, except that the system is attached to the surface of a hollow cylinder immersed in medium at 32 5C49.

The reciprocating disc: (USP apparatus 7) In this method patches attached to holders are oscillated in small volumes of medium, allowing the apparatus to be useful for systems delivering low concentration of drug. In addition paddle over extraction cell method (PhEur 2.9.4.2) may be used85.

Diffusion Cells e.g. Franz Diffusion Cell and its modification Keshary- Chien Cell: In this method transdermal system is placed in between receptor and donor compartment of the diffusion cell. The transdermal system faces the receptor compartment in which receptor fluid i.e., buffer is placed. The agitation speed and temperature are kept constant. The whole assembly is kept on magnetic stirrer and solution in the receiver compartment is constantly and continuously stirred throughout the experiment using magnetic beads. At predetermined time intervals, the receptor fluid is removed for analysis and is replaced with an equal volume of fresh receptor fluid. The concentration of drug is determined spectrophotometrically46,86.

The pH of the dissolution medium ideally should be adjusted to pH 5 to 6, reflecting physiological skin conditions. For the same reason, the test temperature is typically set at 32C (even though the temperature may be higher when skin is covered). PhEur considers 100 rpm a typical agitation rate and also allows for testing an aliquot patch section. The latter may be an appropriate means of attaining sink conditions, provided that cutting a piece of the patch is validated to have no impact on the release mechanism. The dissolution data obtained is fitted to mathematical models in order to ascertain the release mechanism85. In vitro permeation studies: The amount of drug available for absorption to the systemic pool is greatly dependent on drug released from the polymeric transdermal films. The drug reached at skin surface is then passed to the dermal microcirculation by penetration through cells of epidermis, between the cells of epidermis through skin appendages87. Usually permeation studies are performed by placing the fabricated transdermal patch with rat skin or synthetic membrane in between receptor and donor compartment in a vertical diffusion cell such as franz diffusion cell or keshary-chien diffusion cell. The transdermal system is applied to the hydrophilic side of the membrane and then mounted in the diffusion cell with lipophillic side in contact with receptor fluid. The receiver compartment is maintained at specific temperature (usually 325C for skin) and is continuously stirred at a constant rate. The samples are withdrawn at different time intervals and equal amount of buffer is replaced each time. The samples are diluted appropriately and absorbance is determined spectrophotometrically. Then the amount of drug permeated per centimeter square at each time interval is calculated. Design of system, patch size, surface area of skin, thickness of skin and temperature etc. are some variables that may affect the release of drug. So permeation study involves preparation of skin, mounting of skin on permeation cell, setting of experimental conditions like temperature, stirring, sink conditions, withdrawing samples at different time intervals, sample analysis and calculation of flux i.e., drug permeated per cm2 per second55. Preparation of skin for permeation studies: Hairless animal skin and human cadaver skin are used for permeation studies. Human cadaver skin may be a logical choice as the skin model because the final product will be used in humans. But it is not easily available. So,

hairless animal skin is generally favored as it is easily obtained from animals of specific age group or sex. Intact Full thickness skin: Hair on dorsal skin of animal are removed with animal hair clipper, subcutaneous tissue is surgically removed and dermis side is wiped with isopropyl alcohol to remove residual adhering fat. The skin is washed with distilled water. The skin so prepared is wrapped in aluminum foil and stored in a freezer at -20C till further use. The skin is defrosted at room temperature when required. Separation of epidermis from full thickness skin: The prepared full thickness skin is treated with 2M sodium bromide solution in water for 6 h. The epidermis is separated by using a cotton swab moistened with distilled water. Then epidermis sheet is cleaned by washing with distilled water and dried under vacuum. Dried sheets are stored in desiccators until further use88-89. In vivo Studies In vivo evaluations are the true depiction of the drug performance. The variables which cannot be taken into account during in vitro studies can be fully explored during in vivo studies. In vivo evaluation of TDDS can be carried out using: Animal models Human volunteers Animal models Considerable time and resources are required to carryout human studies, so animal studies are preferred at small scale90. The most common animal species used for evaluating transdermal drug delivery system are mouse, hairless rat, hairless dog, hairless rhesus monkey, rabbit, guinea pig etc. Various experiments conducted lead us to a conclusion that hairless animals are preferred over hairy animals in both in vitro and in vivo experiments4,91. Rhesus monkey is one of the most reliable models for in vivo evaluation of transdermal drug delivery in man92.

Human models The final stage of the development of a transdermal device involves collection of pharmacokinetic and pharmacodynamic data following application of the patch to human volunteers. Clinical trials have been conducted to assess the efficacy, risk involved, side effects, patient compliance etc. Phase I clinical trials are conducted to determine mainly safety in volunteers and phase II clinical trials determine short term safety and mainly effectiveness in patients. Phase III trials indicate the safety and effectiveness in large number of patient population and phase IV trials at post marketing surveillance are done for marketed patches to detect adverse drug reactions. Though human studies require considerable resources but they are the best to assess the performance of the drug93. Skin irritation studies: White albino rats, mice or white rabbits are used to study any hypersensitivity reaction on the skin13,53. Mutalik and Udupa (2005) carried out skin irritation test using mice. The mice were divided into 5 groups, each group containing 6 animals. On the previous day of the experiment, the hair on the backside area of mice were removed. The animals of group I was served as normal, without any treatment. One group of animals (group II, control) was applied with marketed adhesive tape (official adhesive tape in USP). Transdermal systems (blank and drug loaded) were applied onto nude skin of animals of III and IV groups. A 0.8% v/v aqueous solution of formalin was applied as standard irritant (group V). The animals were applied with new patch/ formalin solution each day up to 7 days and finally the application sites were graded according to a visual scoring scale, always by the same investigator. The erythema was as follows: 0 for none, 1 for slight, 2 for well defined, 3 for moderate and 4 for scar formation. The edema scale used was as follows: 0 for none, 1 for slight, 2 for well defined, 3 for moderate and 4 for severe. After visual evaluation of skin irritation, the animals were sacrificed and skin samples were processed for histological examination. The results of this study showed that the prepared systems (both blank and drug loaded) and USP adhesive tape produced negligible erythema and edema. While standard irritant, formalin produced severe edema and erythema. The histopathologic examination of the skin also indicated that adhesive tape and prepared patches produced mild inflammation and edema49. Stability studies: The stability studies are conducted to investigate the influence of temperature and relative humidity on the drug content in different formulations. The transdermal formulations are subjected to stability studies as per ICH guidelines94.

Regulatory requirements: A transdermal patch is classified by U.S. Food and Drug Administration (FDA) as a combination product, consisting of a medical device combined with drug or biologic product that the device is designed to deliver. Prior to sale, any transdermal patch product must receive approval from FDA, demonstrating safety and efficacy for its intended use89. 18.9 Conclusion: Since 1981, transdermal drug delivery systems have been used as safe and effective drug delivery devices. Their potential role in controlled release is being globally exploited by the scientists with high rate of attainment. If a drug has right mix of physical chemistry and pharmacology, transdermal delivery is a remarkable effective route of administration. Due to large advantages of the TDDS, many new researches are going on in the present day to incorporate newer drugs via the system. A transdermal patch has several basic components like drug reservoirs, liners, adherents, permeation enhancers, backing laminates, plasticizers and solvents, which play a vital role in the release of drug via skin. Transdermal patches can be divided into various types like matrix, reservoir, membrane matrix hybrid, micro reservoir type and drug in adhesive type transdermal patches and different methods are used to prepare these patches by using basic components of TDDS. After preparation of transdermal patches, they are evaluated for physicochemical studies, in vitro permeation studies, skin irritation studies, animal studies, human studies and stability studies. But all prepared and evaluated transdermal patches must receive approval from FDA before sale. Future developments of TDDSs will likely focus on the increased control of therapeutic regimens and the continuing expansion of drugs available for use. Transdermal dosage forms may provide clinicians an opportunity to offer more therapeutic options to their patients to optimize their care.

Drug delivery technologies are now receiving considerable attention from pharmaceutical companies. The main purpose of developing alternative drug delivery technologies is to increase efficiency and safety of drug delivery and provide more convenience for the patient. Substantial research conducted during the past several years has lead to the development of technologies that meet the requisite criteria for delivering the drug through a non-invasive route. One of such technologies is transdermal drug delivery.

Transdermal drug delivery is the non-invasive delivery of medications from the surface of the skin - the largest and most accessible organ of the human body - through its layers, to the circulatory system. Medication delivery is carried out by a patch that is attached to the body surface. Transdermal patch is a medicated adhesive pad that is designed to release the active ingredient at a constant rate over a period of several hours to days after application to the skin. It is also called skin patch. A skin patch uses a special membrane to control the rate at which the drug contained within the patch can pass through the skin and into the bloodstream. The first transdermal patch was approved by the FDA in 1979. It was a patch for the treatment of motion sickness. In the mid-1980s, the pharmaceutical companies started the development of a nicotine patch to help smokers quit smoking, and within a few months at the end of 1991 and beginning of 1992 the FDA approved four nicotine patches. Today drugs administered through skin patches include scopolamine (for motion sickness), estrogen (for menopause and to prevent osteoporosis after menopause), nitroglycerin (for angina), lidocaine to relieve the pain of shingles (herpes zoster). Non-medicated patches include thermal and cold patches, weight loss patches, nutrient patches, skin care patches (therapeutic and cosmetic), aroma patches, and patches that measure sunlight exposure. 18. 10 Advantages and disadvantages of transdermal drug delivery Transdermal drug delivery systems offer several important advantages over more traditional approaches, including:

longer duration of action resulting in a reduction in dosing frequency Increased convenience to administer drugs which would otherwise require frequent dosing

improved bioavailability more uniform plasma levels reduced side effects and improved therapy due to maintenance of plasma levels up to the end of the dosing interval

flexibility of terminating the drug administration by simply removing the patch from the skin

Improved patient compliance and comfort via non-invasive, painless and simple application

Some of the greatest disadvantages to transdermal drug delivery are:


possibility that a local irritation at the site of application Erythema, itching, and local edema can be caused by the drug, the adhesive, or other excipients in the patch formulation

The main components of a transdermal patch are: Transdermal patch may include the following components:

Liner - Protects the patch during storage. The liner is removed prior to use. Drug - Drug solution in direct contact with release liner Adhesive - Serves to adhere the components of the patch together along with adhering the patch to the skin

Membrane - Controls the release of the drug from the reservoir and multi-layer patches

Backing - Protects the patch from the outer environment

19. Types of transdermal patches


There are four main types of transdermal patches: 19.1 Single-layer Drug-in-Adhesive In this system the drug is included directly within the skin-contacting adhesive. In this type of patch the adhesive layer is responsible for the releasing of the drug, and serves to adhere the various layers together, along with the entire system to the skin. The adhesive layer is surrounded by a temporary liner and a backing. 19.2 Multi-layer Drug-in-Adhesive

The Multi-layer Drug-in-Adhesive is similar to the Single-layer Drug-in-Adhesive in that the drug is incorporated directly into the adhesive. The multi-layer system adds another layer of drug-in-adhesive, usually separated by a membrane. This patch also has a temporary linerlayer and a permanent backing. 19.3 Reservoir The transdermal system design includes a liquid compartment containing a drug solution or suspension separated from the release liner by a semi-permeable membrane and adhesive. The adhesive component of the product can either be as a continuous layer between the membrane and the release liner or as a concentric configuration around the membrane.Reservoir 19.4 Matrix The Matrix system has a drug layer of a semisolid matrix containing a drug solution or suspension, which is in direct contact with the release liner. The adhesive layer in this patch surrounds the drug layer partially overlaying it. 19.5 The future of transdermal drug delivery Transdermal drug delivery is theoretically ideal for many injected and orally delivered drugs, but many drugs cannot pass through the skin because of skin's low permeability. Pharmaceutical companies develop new adhesives, molecular absorption enhancers, and penetration enhancers that will enhance skin permeability and thus greatly expand the range of drugs that can be delivered transdermally. Two of the better-known technologies that can help achieve significant skin permeation enhancement are iontophoresis and phonophoresis (sonophoresis). Iontophoresis involves passing a direct electrical current between two electrodes on the skin surface. Phonophoresis uses ultrasonic frequencies to help transfer high molecular weight drugs through the skin. A newer and potentially more promising technology is micro needle-enhanced delivery. These systems use an array of tiny needle-like structures to open pores in the stratum corneum and facilitate drug transport. The structures are small enough that they do not reach

the nerve endings, so there is no sensation of pain. These systems have been reported to greatly enhance (up to 100,000 fold) the permeation of macromolecules through skin. OriginalDrugs.compatches and natural health products

Types of transdermal patches

delivery of medication through the skin's surface. They are used to treat everything from smoking addiction to hormone imbalances. Doctors prefer the transdermal route for some medications to prevent the gastrointestinal symptoms caused by certain drugs. Direct delivery of the medication into the bloodstream also makes transdermal patches a popular choice for patients. There are many types of transdermal patches available. 19.6 Scopolamine Patch -approved medication to be used as a transdermal patch in 1979. Scopolamine prevents motion sickness by interfering with the chemical signals in the brain that trigger vomiting and nausea. Scopolamine can cause blurry vision and pupil dilation if it comes into contact with your eyes, so wash your hands thoroughly after pressing it onto the skin behind your ear. Be aware that elderly people sometimes have a negative reaction to scopolamine, such as increased agitation and drowsiness. 19.7 Fentanyl Patch -based narcotic used for severe chronic pain. MedicineNet.com reports that it works by altering chemicals in the brain's pain control center. Fentanyl patches are time-released and work best when placed on the upper torso. Do not take other pain medications when using a fentanyl transdermal patch unless your doctor tells you to. The

Food and Drug Administration has issued several warnings about fentanyl patches due to various reported deaths and complaints of serious adverse reactions. Always administer fentanyl patches exactly as prescribed by your doctor, and immediately report any unusual reactions such as hallucinations and difficulty breathing. As with other opiate medications, fentanyl can cause physical dependence in some people. 19.8 Nicotine Patch

Most countries require warning labels on tobacco products. Nicotine transdermal patches are marketed under several different brand names, and have helped many people quit smoking. Nicotine is the addictive ingredient in smoking products, and nicotine patches work by delivering a small, controlled amount of nicotine into the bloodstream on a time-released schedule. Use nicotine patches as part of a smoking cessation program under the direction of your doctor. Do not use tobacco products while wearing a nicotine patch, because it can cause toxic levels of nicotine in your blood. Always consult your doctor before using nicotine transdermal patches. 19.9 Hormonal Patches

symptoms of menopause, such as hot flashes and vaginal dryness. It is also sometimes prescribed as osteoporosis prevention therapy for women experiencing menopause or postmenopause. According to the U.S. National Library of Medicine, estrogen patches carry a serious warning for increased risk of endometrial cancer, stroke, heart attack, breast cancer and dementia. The birth control transdermal patch uses female hormones to prevent ovulation. Because the birth control patch contains estrogen and progestin hormones, it also carries the same risks as the estrogen patch. Always use the lowest dose of hormones needed to prevent unwanted side effects.

20. Transdermal Patches Are More Than Skin Deep


The simply designed transdermal patch has undergone a dramatic transformation over the past decade. In its strictest sense, all transdermal systems attempt to create a balance between a number of key factors including size of patch or coverage area, concentration of the drug, duration of therapeutic drug level, and use of an enhancer. The advantages of transdermal delivery are obvious even delivery of a therapeutic level of drug is painless, the patient does not need to inject himself, there are no bulky delivery devices to manage or dangerous needles to dispose of, and there are few or no gastrointestinal effects from the drug itself. Peak plasma levels of the drug are reduced, leading to decreased side effects. In addition, transdermal delivery is useful for those drugs that have a high first pass effect through the liver, have poor oral uptake, need frequent administration, or that interact with stomach acid. The first pass effect results in the destruction of a significant amount of the drug. Drugs absorbed through the skin, however, enter the general circulation directly avoiding the liver, with less total drug absorption occurring. These benefits have not been lost on clinicians. As a result, the patch business is growing at a healthy annual revenue rate of 12 percent with a current worldwide market of about $3 billion, with the U.S. making up 56 percent of the market. Unless you are in the transdermal patch business, you will not be aware of the advances under development. 20.1 Humble beginnings The first transdermal systems were simply pieces of plastic dipped into a drug that was dissolved in alcohol. The plastic had an adhesive around the edges. Although revolutionary in their day, they created a significant number of skin reactions, more often than not fell off, and had a number of other limitations. These problems gave a lasting negative impression of the whole sector. The next generation still in use today uses a "drug in the adhesive" model. This is a significant improvement, as the skin irritation is diminished and in many cases eliminated. The adhesive serves two functions: It is the glue that keeps the patch attached to the skin, and it acts as the suspension that holds the drug. But it creates a major challenge: The concentration of the drug within the adhesive directly affects the "stickiness" of the adhesive.

Thus, if there is a need for large quantities of drug, either the size of the patch must be increased or the patch needs to be reapplied more frequently. Basically, the patch would not stick, as it would be primarily made up of the drug. 20.2 Next generation patches Third generation patches have solved some of these issues by using an acrylic reservoir that holds the drug. Silicon adhesive is added to create a semisolid suspension of microscopic, concentrated drug cells. Now, fourth generation transdermal systems involve the addition of an enhancer a mechanism to increase the permeability of the skin and in some of the technology, a mechanism to time the delivery and create bolus dosing. There are a number of enhancers to drug delivery. These include iontophoresis, ultrasound, chemicals including gels, microneedles, sonophoresis, lasers, and electroporatic methods. Some delivery systems avoid the patch altogether. These use a gel that is rubbed into the skin. This method, mastered by Antares Pharma, tailors the kinetic profile of the drug to the gel. CombiGel consists of a hydro alcoholic gel containing a combination of enhancers. This gel is totally invisible and is designed to be rapidly absorbed through the skin. The first transdermal testosterone gel for men, released in 2000, used this approach. The gel was fraught with challenges, including cost, irritancy, delivery efficacy, cosmetic issues, smell, and color. Many other drugs will soon be delivered using this method. 20.3 Nanotechnology gaining hold Another enhancer that is gaining advancement is microneedles. Why should a needle that is a few inches long be used to deliver a drug that is only a few atoms large? This technology combines the advantage of a needle and the transdermal patch. The devices are dime-sized pieces of polymer with hundreds of hollow microneedles between 100 and 1,000 micrometers long. These small needles penetrate the top layers of skin and allow the drug to pass through with ease. This size of needle does not penetrate deeply enough to stimulate the nerves and hence ... no pain! This technology can be combined with an electronically controlled micropump that delivers the drug at specific times or upon demand. Once approved by the FDA, these devices would

allow the patient or physician to control the time and dose of the drug being delivered. These devices have the potential to place drugs precisely into the area where special immune cells reside, making these drugs capable of modulating the immune system, with relative ease. Alza is using a slightly different variation on the use of needles. The company has developed the patented Macroflux transdermal technology that uses microprojections to create superficial pathways through the dead skin barrier. The tips of the projections contain active drug a quick bolus. Interestingly, the Alza Web site displays a study where human growth hormone, a rather large protein, was able to reach therapeutic levels hours after the application of the patch. 20.4 Pain relief Pain relief routinely benefits from transdermal patch technology. Most of the readers are aware of the Duragesic patch. There are several others now on the market. One is Lidoderm, a lidocaine 5 percent patch, which is used for post herpetic neuralgia. Other exciting advancements in pain control include the E-Trans fentanyl HCl patch. This credit card-size patch is an active delivery device that has a self-contained battery that delivers pulses of fentanyl HCl, a strong narcotic. This mimics the use of intravenous self-controlled analgesic systems that are very expensive, cumbersome, and require considerable nursing care. A study just published in the Journal of the American Medical Association demonstrated that this patch does the job about as well as conventional intravenous devices. Alza is hoping for approval in 2004. Finally, SonoPrep offers a topical anesthetic system with an ultrasound enhancer. This system uses a small ultrasound generator to transport 4 percent lidocaine HCl into the skin in an area just big enough to place a catheter into a vein or artery. It anesthetizes the area in less than a minute and can allow for prolonged application for several hours.
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These advances will revolutionize the delivery of many drugs, enhancing the application of nanotechnology and giving new options to patients needing biologic drugs. Soon, pol
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21. PICTURE

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REFERENCE
1. ^ Segal, Marian. "Patches, Pumps and Timed Release: New Ways to Deliver Drugs". Food and Drug Administration. Archived from the original on 2007-02-10. http://web.archive.org/web/20070210094825/http://www.fda.gov/bbs/topics/consumer/CON0 0112.html. Retrieved 2007-02-24. 2. ^ "FDA approves scopolamine patch to prevent peri-operative nausea". Food and Drug Administration. 1997-11-10. Archived from the original on 2006-12-19. http://web.archive.org/web/20061219210229/http://www.fda.gov/bbs/topics/ANSWERS/AN S00834.html. Retrieved 2007-02-12. 3. ^ Prausnitz M, Langer R. Transdermal drug delivery. Nature Biotechnology. Volume 26, Number 11, Pages 1261-1268, November 2006 4. ^ Nachum Z, Shupak A, Gordon CR (2006). "Transdermal scopolamine for prevention of motion sickness : clinical pharmacokinetics and therapeutic applications". Clinical Pharmacokinetics 45 (6): 54366. PMID 16719539. 5. ^ Berner B, John VA (February 1994). "Pharmacokinetic characterisation of transdermal delivery systems". Clinical pharmacokinetics 26 (2): 12134. doi:10.2165/00003088199426020-00005. PMID 8162656. 6. ^ First Databank Inc.. "Clonidine - Transdermal (Catapres-TTS) side effects, medical uses, and drug interactions". http://www.medicinenet.com/clonidine-transdermal/article.htm. Retrieved 2010-09-28. 7. ^ Peck, Peggy (2006-03-01). "FDA Approves First Antidepressant Transdermal Patch". http://www.medpagetoday.com/Psychiatry/Depression/2764. Retrieved 2010-09-28. 8. ^ Cabray, Matthew (2006-04-12). "Transdermal Patch Approved For Treatment Of ADHD". http://www.medicalnewstoday.com/articles/41333.php. Retrieved 2010-09-28. 9. ^ Peck, Peggy (2007-07-10). "Medical News: FDA Approves Rivastigmine Patch for Alzheimer's Disease". http://www.medpagetoday.com/ProductAlert/Prescriptions/6119. Retrieved 2011-03-10. 10. ^ "FDA ALERT (07/2005): Narcotic Overdose and Death". Food and Drug Administration. 2005-07-15. Archived from the original on 2007-02-20. http://web.archive.org/web/20070220083526/http://www.fda.gov/cder/drug/InfoSheets/HCP/f entanylHCP.htm. Retrieved 2007-02-24. 11. ^ Megget, Katrina (2007-09-05). "ADHD Transdermal Patches Withdrawn". http://www.inpharmatechnologist.com/Materials-Formulation/ADHD-transdermal-patches-withdrawn. Retrieved 2010-09-28. 12. ^ Silverman, Ed (2008-02-12). "J&J and Sandoz Recall Fentanyl Patches". http://www.pharmalot.com/2008/02/jj-and-sandoz-recall-fentanyl-patches/. Retrieved 201009-28. 13. ^ As stated on the packaging and labels of Sandoz-branded Fentanyl Transdermal System products, revised March 2009. 14. ^ "FDA Public Health Advisory: Risk of Burns during MRI Scans from Transdermal Drug Patches with Metallic Backings". http://www.fda.gov/cder/drug/advisory/transdermalpatch.htm. Retrieved March 9, 2009.[dead
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15. ^ Brown, MR: "Analgesic patches and defibrillators: a cautionary tale", Europace,2009 Nov;11(11):1552-3

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