ABOUT AUTHOR:
Rakesh Kumar Sati
M.Pharm D.I.T Faculty of Pharmacy
Dehradun Uttarakhand
rakeshsatiq.a@gmail.com
ABSTRACT
Transdermal administration of drugs is an another way of administration that can significantly deliver larger molecules in potent quantities that overcome the problem with the oral administration such as poor bioavailability due to first pass metabolism and sometimes responsible for rapid blood level. Drugs that are given by transdermal route may enhance the potency as well as safety of drugs. One such advance has been the development of transdermal patch delivery systems. Transdermal drug technology specialists are continuing to search for new methods that can effectively and painlessly deliver larger molecules in therapeutic quantities to overcome the difficulties associated with the oral route. Transdermal drug delivery system is the system in which the delivery of the active ingredients of the drug occurs by the means of skin. Skin is an effective medium from which absorption of the drug takes place and enters the circulatory system. Various types of transdermal patches are used to incorporate the active ingredients into the circulatory system via skin. The patches have been proved effective because of its large advantages over other controlled drug delivery systems. New transdermal drug delivery system (TDDS) technologies now have been developed that is considered to be helpful in rate controlled delivery of drug that is difficult to administer.
REFERENCE ID: PHARMATUTOR-ART-2034
1.1 INTRODUCTION
Transdermal drug delivery systems (TDDS) are defined as self contained, discrete dosage forms which, when applied to intact skin, deliver the drug(s), through the skin, at a controlled rate to systemic circulation. The Transdermal route of administration is recognized as one of the potential route for the local and systemic delivery of drugs. In comparison to conventional pharmaceutical dosage forms.
TDDS offer many advantages, such as elimination of first pass metabolism, sustained drug delivery, reduced frequency of administration, reduced side effects and improved patient compliance.
Transdermal delivery not only provides controlled, constant administration of the drug, but also allows continuous input of drugs with short biological half-lives and eliminates pulsed entry into systemic circulation, which often causes undesirable side effects. Thus various forms of Novel drug delivery system such as Transdermal drug delivery systems, Controlled release systems, Transmucosal delivery systems etc. emerged. Several important advantages of transdermal drug delivery are limitation of hepatic first pass metabolism, enhancement of therapeutic efficiency and maintenance of steady plasma level of the drug. The first Transdermal system, Transderm-SCOP was approved by FDA in 1979 for the prevention of nausea and vomiting associated with ravel, particularly by sea. The evidence of percutaneous drug absorption may be found through measurable blood levels of the drug, detectable excretion of the drug and its metabolites in the urine and through the clinical response of the patient to the administered drug therapy.2 the common ingredients which are used for the preparation of TDDS are as follows.
DRUG DELIVERY ROUTES ACROSS HUMAN SKIN
Drug molecules in contact with the skin surface can penetrate by three potential pathways: through the sweat ducts, via the hair follicles and sebaceous glands (collectively called the shunt or appendageal route), or directly across the stratum corneum (Fig. 1). The relative importance of the shunt or appendageal route versus
transport across the stratum corneum has been debated by scientists over the years (eg. [5-7]) and is further complicated by the lack of a suitable experimental model to permit separation of the three pathways. In vitro experiments tend to involve the use of hydrated skin or epidermal membranes so that appendages are closed by the swelling associated with hydration. Scheuplein and colleagues [8, 9] proposed that a follicular shunt route was responsible for the presteady-state permeation of polar molecules and flux of large polar molecules or ions that have difficulty diffusing
across the intact stratum corneum. However it is generally accepted that as the appendages comprise a fractional area for permeation of approximately 0.1% [10], their contribution to steady state flux of most drugs is minimal. This assumption has resulted in the majority of skin penetration enhancement techniques being focused on increasing transport across the stratum corneum rather than via the appendages. Exceptions are iontophoretic drug delivery which uses an electrical charge to drive molecules into the skin primarily via the shunt routes as they provide less electrical resistance, and vesicular delivery.
The stratum corneum consists of 10-15 layers of corneocytes and varies in thickness from approximately 10-15 μm in the dry state to 40 μm when hydrated [12-14]. It comprises a multi-layered “brick and mortar” like structure of keratin-rich corneocytes (bricks) in an intercellular matrix (mortar) composed primarily of long chain ceramides, free fatty acids, triglycerides, cholesterol, cholesterol sulfate and sterol/wax esters [15]. However it is important to view this model in the context that the corneocytes are not brick shaped but are polygonal, elongated and flat (0.2-1.5 μm thick, 34-46 μm in diameter). The intercellular lipid matrix is generated by keratinocytes in the mid to upper part of the stratum granulosum discharging their lamellar contents into the intercellular space. In the initial layers of the stratum corneum this extruded material rearranges to form broad intercellular lipid lamellae [16], which then associate into lipid bilayers [17, 18], with the hydrocarbon chains aligned and polar head groups dissolved in an aqueous layer (Fig. 2). As a result of the stratum corneum lipid composition, the lipid phase behaviour is different from that of other biological membranes. The hydrocarbon chains are arranged into regions of crystalline, lamellar gel and lamellar liquid crystal phases thereby creating various domains within the lipid bilayers [19]. The presence of intrinsic and extrinsic proteins, such as enzymes, may also affect the lamellar structure of the stratum corneum. Water is an essential component of the stratum corneum, which acts as a plasticizer to prevent cracking of the stratum corneum and is also involved in the generation of natural moisturizing factor (NMF), which helps to maintain suppleness. In order to understand how the physicochemical properties of the diffusing drug and vehicle influence permeation across the stratum corneum and thereby optimise delivery, it is essential to determine the predominant route ofdrug permeation within the stratum corneum. Traditionally it was thought that hydrophilic chemicals diffuse within the aqueous regions near the outer surface of intracellular keratin filaments (intracellular or transcellular route) whilst lipophilic chemicals diffuse through the lipid matrix between the filaments (intercellular route) [9] (see Fig. 2). However, this is an oversimplification of the situation as each route cannot be viewed in isolation. A molecule traversing via the transcellular route must partition into and diffuse through the keratinocyte, but in order to move to the next keratinocyte, the molecule must partition into and diffuse through the estimated 4-20 lipid lamellae between each keratinocyte. This series of partitioning into and diffusing across multiple hydrophilic and hydrophobic domains is unfavourable for most drugs. Consequently, based on more recent data (for example [16, 20-23]) the intercellular route is now considered to be the major pathway for permeation of most drugs across the stratum corneum. As a result, the majority of techniques to optimise permeation of drugs across the skin are directed towards manipulation of solubility in the lipid domain or alteration of the ordered structure of this region
To overcome these difficulties there is need for development of new drug delivery system; which will improve therapeutic efficacy and safety of drugs by more precise (i.e. site specific), spatial and temporal placement within the body there by reducing both the size and number of doses. New drug delivery system are also essential for the delivery of novel, genetically engineered pharmaceuticals (i.e. peptides, proteins) to their site of action, without incurring significant immunogenicity or biological inactivation. Apart from these advantages the pharmaceutical companies recognize the possibility of repattening successful drugs by applying the concepts and techniques of controlled drug delivery system coupled with the increased expense in bringing new drug moiety to the market. (1) One of the methods most often utilized has been Transdermal delivery- meaning transport of therapeutic substances through the skin for systemic effect. Closely related is percutaneous delivery, which is transport into target tissues, with an attempt AVOID systemic effects. (2)
There are two important layers in skin: the dermis and the epidermis. The outermost layer, the epidermis, is approximately 100 to 150 micrometers thick, has no blood flow and includes a layer within it known as the stratum corneum. This is the layer most important to Transdermal delivery as its composition allows it to keep water within the body and foreign substances out. Beneath the epidermis, the dermis contains the system of capillaries that transport blood throughout the body. If the drug is able to penetrate the stratum corneum, it can enter the blood stream. A process known as passive diffusion, which occurs too slowly for practical use, is the only mean to transfer normal drugs across this layer. The method to circumvent this is to engineer the drugs to be water-soluble and lipid soluble. The best mixture is about fifty percent of the drug being each. This is because “Lipid-soluble substance readily pas through the intercellular lipid bi-layers of the cell membranes where as water-soluble drugs are able to pass through the skin because of hydrated intracellular proteins”. Using drugs engineered in this manner much more rapid and useful drug delivery is possible. (3)
Transdermal drug delivery system was first introduced more than 20 years ago. The technology generated tremendous excitement and interest amongst major pharmaceutical companies in the 1980s and 90s. By the mid to late 1990s, the trend of Transdermal drug delivery system companies merging into larger organizations. Transdermal drug deliveries in the text of research articles grow continuously in the transdermal drug delivery 1980s, and have remained constant throughout the past decade. (3)
Innovations in technologies continue to occur at a positive rate, making the technology a fertile and vibrant are a of innovation, research and product development. In the present study, various new development in the field of TDDS are included to improve the release rate and other parameters on need base system and most suitable to the patient. The conventional passive means of applying drugs to skin include the use of vehicles such as ointments, creams, gels and patch technology. More recently, such dosage forms have been developed and/or modified in order to enhance the driving force of drug diffusion (thermodynamic activity) and/or increase the permeability of the skin. These approaches include the use of penetration enhancers, supersaturated systems, hyaluronic acid, prodrugs, liposome’s and other vesicles.
However, the amount of drug that can be delivered using these methods is still limited since the barrier properties of the skin are not fundamentally changed and as such, with the exception of patches, the majority are used to treat localized skin diseases where systemic absorption is not required. Thus, while new passive technologies typically offer an improvement in dose control, patient acceptance and compliance compared to more traditional semisolid formulations, they do not have the potential to widen the applicability of Transdermal drug delivery unlike active Transdermal drug delivery technologies.
Transdermal drug technology specialists are continuing to search for new methods that can effectively and painlessly deliver larger molecules in therapeutic quantities to overcome the difficulties associated with the oral route. Transdermal Drug Delivery System is the system in which the delivery of the active ingredients of the drug occurs by the means of skin. Skin is an effective medium from which absorption of the drug takes place and enters the circulatory system. Various types of Transdermal patches are used to incorporate the active ingredients into the circulatory system via skin. The patches have been proved effective because of its large advantages over other controlled drug delivery systems. This review article covers a brief outline of various components of Transdermal patch, applications of Transdermal patch, their advantages, disadvantages, when the Transdermal patch are used and when their use should be avoid and some of the recent development in the field along with the latest patents in this field.
Association of Pharmaceutical Scientists. Even though scientists and engineers with high interest continue to this day to publish Transdermal related scientific papers in great numbers, it is intriguing to find such continued interest while only 10 or so new drugs utilizing Transdermal technology have been introduced during these past 20 years.
A Transdermal drug delivery device, which may be of an active or a passive design, is a device which provides an alternative route for administering medication. These devices allow pharmaceuticals to be delivered across skin barrier. In theory Transdermal patches work very simply. A drug is applied in a relatively high dosage to the inside of a patch, which is worn on the skin for an extended period of time. Through a diffusion process, the drug enters the blood stream directly through the skin. Since there is high concentration on the patch and low concentration in the blood, the drug keep diffusing in to the blood for a long period of time, maintaining the constant concentration of drug in blood flow.
Today drugs administered through skin patches include scopolamine (for motion sickness), estrogen (for menopause and to prevent osteoporosis after menopause), nitroglycerin (for angina), and 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), and aroma patches, and patches that measure sunlight exposure.
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1.3 TRANSDERMAL DRUG DELIVERY SYSTEM
1.3.1 DEFINITION
Transdermal drugdelivery systems are topically administered medicaments in the form of patches that deliver drugs for systemic effects at a predetermined and controlled rate.(1) Transdermal drug delivery has made an important contribution to medical practice, but has yet to fully achieve its potential as an alternative to oral delivery and hypodermic injections.
First-generation Transdermal delivery systems have continued their steady increase in clinical use for delivery of small, lipophilic, low-dose drugs.
Second-generation delivery systems using chemical enhancers, noncavitational ultrasound and iontophoresis have also resulted in clinical products; the ability of iontophoresis to control delivery rates in real time provides added functionality.
Third-generation delivery systems target their effects to skin's barrier layer of stratum corneum using microneedles, thermal ablation, microdermabrasion, electroporation and cavitational ultrasound. Microneedles and thermal ablation are currently progressing through clinical trials for delivery of macromolecules and vaccines, such as insulin, parathyroid hormone and influenza vaccine. Using these novel second- and third-generation enhancement strategies, Transdermal delivery is poised to significantly increase its impact on medicine.
Interest in Transdermal has increased on several fronts over the past several years technology companies have generated additional clinical data demonstrating the potential advanced Transdermal technology, pharmaceutical companies there become more aggressive in exploring alternate formulations to extend patent.
1.3.2 ADVANTAGES AND DISADVANTAGES OF TRANSDERMAL DRUG DELIVERY (13)
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.
* Patches after defined dosage period.
* Limited number of drugs is used by transdermal system.
1.3.3 PROPERTIES THAT INFLUENCE TRANSDERMAL DELIVERY(14)
* Release of the medicament from the vehicle.
* Penetration through the skin barrier.
* Activation of the pharmacological response.
1.3.4 KINETICS OF TRANSDERMAL PERMEATION(15)
Knowledge of skin permeation kinetics is vital to the successful development
of Transdermal therapeutic systems. Transdermal permeation of a drug involves the following steps:
1. Sorption by stratum corneum.
2. Penetration of drug through viable epidermis.
3. Uptake of the drug by the capillary network in the dermal papillary layer.
This permeation can be possible only if the drug possesses certain physiochemical properties.
The rate of permeation across the skin is given by
dQ
------ = Ps (Cd – Cr) ... …….. (1)
dt
where Cd and Cr are the concentration of the skin penetrant in the door compartment i.e. on the surface of stratum corneum and in the receptor compartment i.e. body respectively. Ps is the overall permeability coefficient of the skin tissue to the penetrant. This permeability coefficient is given by the relationship:
DssKs
Ps = -------------
hs
where Ks is the partition coefficient for the interfacial partitioning of the penetrant molecule from a solution medium or a Transdermal therapeutic system on to the stratum corneum, Dss is the apparent diffusivity for the steady state diffusion of the penetrant molecule through a thickness of skin tissues and hs is the overall thickness of skin tissues. As Ks, Dss and hs are constant under given conditions permeability coefficient Ps for a skin penetrant can be considered to be constant. From equation (1) it is clear that a constant rate of drug permeation can be obtained only when Cd >> Cr i.e. the drug concentration at the surface of the stratum corneum Cd is consistently and substantially greater than the drug concentration in the body Cr. The equation becomes
dQ
------- = Ps Cd
dt
And the rate of skin permeation is constant provided the magnitude of Cd remains fairly constant throughout the course of skin permeation. For keeping Cd constant the drug should be released from the device at a rate Rr i.e. either constant or greater than the rate of skin uptake Ra i.e. Rr >> Ra.
Since Rr >> Ra, the drug concentration on the skin surface Cd is maintained at a level equal to or greater than the equilibrium solubility of the drug in the stratum corneum Cs i.e. Cd >> Cs. Therefore a maximum rate of skin permeation is obtained and is given by the equation:
(dQ/dt)m = PsCs
From the above equation it can be seen that the maximum rate of skin permeation depends upon the skin permeability coefficient PS and equilibrium solubility in the stratum corneum CS. Thus skin permeation appears to be stratum corneum limited.
1.3.5 BASIC COMPONENTS OF TRANSDERMAL DRUG DELIVERY SYSTEMS (15)
The components of Transdermal devices include:
1. Polymer matrix or matrices
2. The drug
3. Permeation enhancers
4. Other excipients
1. Polymer Matrix
The Polymer controls the release of the drug from the device.
Possible useful polymers for Transdermal devices are:
a)Natural Polymers:
E.g. Cellulose derivatives, Zein, Gelatin, Shellac, Waxes, Proteins, Gums and their derivatives, Natural rubber, Starch etc.
b) Synthetic Elastomers:
E.g.Polybutadieine, Hydrin rubber, Polysiloxane, Silicone rubber, Nitrile, Acrylonitrile, Butyl rubber, Styrenebutadieine rubber, Neoprene etc.
c)Synthetic Polymers:
E.g. Polyvinyl alcohol, Polyvinyl chloride, Polyethylene, Polypropylene, Polyacrylate, Polyamide, Polyurea, Polyvinylpyrrolidone, Polymethylmethacrylate, Epoxy etc.
2. Drug
For successfully developing a Transdermal drug delivery system, the drug should be chosen with great care. The following are some of the desirable properties of a drug Transdermaly delivery.
Physicochemical properties:
1. The drug should have a molecular weight less than approximately 1000 daltons.
2. The drug should have affinity for both – lipophilic and hydrophilic phases. Extreme partitioning characteristics are not conducive to successful drug delivery via the skin.
3. The drug should have low melting point.
Along with these properties the drug should be potent, having short half life and be none irritating.
3. Permeation Enhancers
These are compounds which promote skin permeability by altering the skin as a barrier to the flux of a desired penetrant.
These may conveniently be classified under the following main headings:-
a) Solvents
These compounds increase penetration possibly by swallowing the polar pathway and/or by fluidizing lipids. Examples include water alcohols – methanol and ethanol; alkyl methyl sulfoxides – dimethyl sulfoxide, alkyl homologs of methyl sulfoxide dimethyl acetamide and dimethyl formamide; pyrrolidone – 2 pyrrolidone, N-methyl, 2-purrolidone; laurocapram (Azone), miscellaneous solvents – propylene glycol, glycerol, silicone fluids, isopropyl palmitate.
b) Surfactants
These compounds are proposed to enhance polar pathway transport, especially of hydrophilic drugs. The ability of a surfactant to alter penetration is a function of the polar head group and the hydrocarbon chain length.
Anionic Surfactants: e.g. Dioctyl sulphosuccinate, Sodium lauryl sulphate, Decodecylmethyl sulphoxide etc.
Nonionic Surfactants: e.g. PluronicF127, Pluronic F68, etc
Bile Salts:e.g. Sodium taurocholate, Sodium deoxycholate, Sodium tauroglycocholate.
Binary System:e.g. these systems apparently open up the heterogeneous multi-laminate pathway as well as the continuous pathways. E.g. Propylene glycol-oleic acid and 1, 4-butane diol-linoleic acid.
c) Miscellaneous chemicals
These include urea, a hydrating and keratolytic agent; N, N-dimetyl-m-touamide; calcium thioglycolate; anticholinergic agents.
Some potential permeation enhancers have recently been described but the available data on their effectiveness sparse. These include eucalyptol, di-o-methyl-ß-cyclodextrin and soyabean casein.
4. Other Excipients
a) Adhesives:
The fastening of all Transdermal devices to the skin has so far been done by using a pressure sensitive adhesive which can be positioned on the face of the device or in the back of the device and extending peripherally. Both adhesive systems should fulfill the following criteria:
- Should adhere to the skin aggressively, should be easily removed.
- Should not leave an unwashable residue on the skin.
- Should not irritate or sensitize the skin.
The face adhesive system should also fulfill the following criteria:
- Physical and chemical compatibility with the drug, excipients and enhancers of the device of which it is a part.
- Permeation of drug should not be affected.
- The delivery of simple or blended permeation enhancers should not be affected.
b) Backing membrane:
Backing membranes are flexible and they provide a good bond to the drug reservoir, prevent drug from leaving the dosage form through the top, and accept printing. It is impermeable substance that protects the product during use on the skin e.g. metallic plastic laminate, plastic backing with absorbent pad and occlusive base plate (aluminium foil), adhesive foam pad (flexible polyurethane) with occlusive base plate (aluminium foil disc) etc.
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1.4 TRANSDERMAL PATCHES(16)
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.
Transdermal Drug Delivery System has been a great field of interest in the recent time. Many drugs which can be injected directly into the blood stream via skin have been formulated. The main advantages of this system are that there is controlled release of the drug and the medication is painless. The drug is mainly delivered to the skin with the help of a Transdermal patch which adheres to the skin. A Transdermal Patch has several components like liners, adherents, drug reservoirs, drug release membrane etc. which play a vital role in the release of the drug via skin. Various types of patches along with various methods of applications have been discovered to delivery the drug from the transdermal patch. Because of its great advantages, it has become one of the highly research field among the various drug delivery system. Here, a general view over the transdermal patch has been discussed along with its advantages, disadvantages, methods of applying, care taken while applying, types and applications of transdermal patch and recent advances along with recent patents and market products.
1.4.4 DEFINITION
* A transdermal patch or skin 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.
The first commercially available prescription patch was approved by the U.S. Food and Drug Administration in December 1979, which administered scopolamine for motion sickness. (16, 17, 18)
1.4.5 DESIRABLE FEATURES FOR TRANSDERMAL PATCHES(19)
1. Composition relatively invariant in use.
2. System size reasonable.
3. Defined site for application.
4. Application technique highly reproducible.
5. Delivery is (typically) zero order.
6. Delivery is efficient.
1.4.6 THE MAIN COMPONENTS OF TRANSDERMAL PATCHES(13)
* 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
1.4.7 TYPES OF TRANSDERMAL PATCHES(15, 20, 21)
TYPES OF TRANSDERMAL PATCHES:
Classification of transdermal drug delivery systems:
Transdermal drug delivery systems generally fall into the following subcategories:
(1) Polymer membrane permeation-controlled
(2) Polymer matrix diffusion-controlled
(3) Drug reservoir gradient-controlled
(4) Micro reservoir dissolution-controlled
Liquid-filled laminate structure
Peripheral-adhesive laminate structure
Solid-state laminate structure
Sub-classes of the above
Single layer drug in adhesive
In this type the adhesive layer contains the drug. The adhesive layer not only serves to adhere the various layers together and also responsible for the releasing the drug to the skin. The adhesive layer is surrounded by a temporary liner and a backing.
Multi -layer drug in adhesive:
This type is also similar to the single layer but it contains a immediate drug release layer and other layer will be a controlled release along with the adhesive layer. The adhesive layer is responsible for the releasing of the drug. This patch also has a temporary liner-layer and a permanent backing.
Vapour patch:
In this type of patch the role of adhesive layer not only serves to adhere the various layers together but also serves as release vapour. The vapour patches are new to the market, commonly used for releasing of essential oils in decongestion. Various other types of vapor patches are also available in the market which are used to improve the quality of sleep and reduces the cigarette smoking conditions.
Reservoir system:
In this system the drug reservoir is embedded between an impervious backing layer and a rate controlling membrane. The drug releases only through the ratecontrolling membrane, which can be micro porous or non porous. In the drug reservoir compartment, the drug can be in the form of a solution, suspension, gel or dispersed in a solid polymer matrix. Hypoallergenic adhesive polymer can be applied as outer surface polymeric membrane which is compatible with drug.
Matrix system:
i. Drug-in-adhesive system:
In this type the drug reservoir is formed by dispersing the drug in an adhesive polymer and then spreading the medicated adhesive polymer by solvent casting or melting (in the case of hot-melt adhesives) on an impervious backing layer. On top of the reservoir, unmediated adhesive polymer layers are applied for protection purpose.
ii. Matrix-dispersion system:
In this type the drug is dispersed homogenously in a hydrophilic or lipophilic polymer matrix. This drug containing polymer disk is fixed on to an occlusive base plate in a compartment fabricated from a drug impermeable backing layer. Instead of applying the adhesive on the face of the drug reservoir, it is spread along with the circumference to form a strip of adhesive rim.
Micro reservoir system:
In this type the drug delivery system is a combination of reservoir and matrix-dispersion system. The drug reservoir is formed by first suspending the drug in an aqueous solution of water soluble polymer and then dispersing the solution homogeneously in a lipophilic polymer to form thousands of unreachable, microscopic spheres of drug reservoirs. This thermodynamically unstable dispersion is stabilized quickly by immediately cross-linking the polymer in situ by using cross linking agents.
1.4.8 EVALUATION OF TRANSDERMAL PATCHES (22)
Evaluation of Pressure-Sensitive Adhesives Properties
The pressure-sensitive adhesives are evaluated for general adhesive properties as well as for dermal toxicity and human wear.
Adhesive Properties:
Pressure-sensitive adhesive can be evaluated on the basis of their three basic properties:
1. Peel Adhesion Properties
2. Tack Adhesion Properties
3. Shear-Strength properties
1. Peel Adhesion Properties:
The force required to remove an adhesive coating from a test substrate is referred to as peel adhesion. Molecular weight of adhesive polymer, the type and amount of additives, i.e. tackifiers and polymer composition are the variables that determine the peel adhesion properties.
A single tape is applied to a stainless steel plate or a backing membrane of choice and then tape is pulled from the substrate at a 180 degree angle, and the force required for tape removed is measured. The force is expressed in ounces (or grams) per inch width of tape, with higher values indicating greater bond strength. If the pulled tape dose not leaves any residue on the plate, it indicates “adhesive failure,” If some residue is left behind, it suggests “cohesive failure”, which often signifies a lack of cohesive strength.
2. Tack Adhesion Properties:
Tack is the ability of a polymer to adhere to a substrate with little contact pressure. Molecular weight, composition of polymer and tackifying resins affect the tack properties of TDD systems.
There are four generally used tests for tack determination namely:
- Thumb Tack Test
- Rolling Ball Tack Test
- Quick-stick(peel-tack) Test
- Probe Tack Test
Thumb Tack Test:
In a qualities test applied for tack property determination of adhesive. In this test, the thumb is simply pressed on the adhesive and the relative tack property is detected.
Rolling Ball Tack Test:
This test measures the softness of a polymer that relates to tack. In this test, a stainless steel ball of 7/16 inches in diameter is released on an inclined track so that it rolls down and comes into contact with horizontal, upward-facing adhesive. The distance the ball travels along the adhesive provides the measurement of tack, which is usually expressed in inch. The less tacky the adhesive, farther the ball will travel.
Quick- stick (peel- tack) Test:
In this test, the tape is pulled away from the substrate at 90 degree Celsius at a speed of 12 inches/min. The forced required breaking the bond between adhesive and substrate is measured and recorded as tack value, which is expressed in ounces (or grams) per inch width. The higher value of force required indicates the higher degree of tack.
Probe Tack Test:
In this test probe tack tester is used. The tip of a clean probe with a defined surface roughness is brought into contact with adhesive, and when a bond is formed between probe and adhesive. The subsequent removal of the probe mechanically breaks it. The force required to pull the probe away from the adhesive at fixed rate is recorded as tack (expressed in grams).
3. Shear Strength Properties:
Shear strength is the measurement of the cohesive strength of an adhesive polymer. If transdermal device has adequate cohesive strength, it will not slip after application and will leave no residue upon removal. In this particular, adhesive-coated tape is applied onto a stainless steel plate. A specified weight is hung from the tape, to affect its pulling in a direction parallel to the plate. The longer the time taken for removal, greater is the shear- strength.
1.4.9 MECANISM OF ACTION OF TRANSDERMAL PATCH
The application of the transdermal patch and the flow of the active drug constituent from the patch to the circulatory system via skin occur through various methods.
1. Iontophoresis(23)
Iontophoresis passes a few milliamperes of current to a few square centimeters of skin through the electrode placed in contact with the formulation, which facilitates drug delivery across the barrier. Mainly used of pilocarpine delivery to induce sweating as part of cystic fibrosis diagnostic test. Iontophoretic delivery of lidocaine appears to be a promising approach for rapid onset of anesthesia.
2. Electroporation(23, 24, 25, 26, 27)
Electroporation is a method of application of short, high-voltage electrical pulses to the skin. After electroporation, the permeability of the skin for diffusion of drugs is increased by 4 orders of magnitude. The electrical pulses are believed to form transient aqueous pores in the stratum corneum, through which drug transport occurs. It is safe and the electrical pulses can be administered painlessly using closely spaced electrodes to constrain the electric field within the nerve-free stratum corneum.
3. Application by ultrasound(23, 28)
Application of ultrasound, particularly low frequency ultrasound, has been shown to enhance transdermal transport of various drugs including macromolecules. It is also known as sonophoresis. Katz et al. reported on the use of low-frequency sonophoresis for topical delivery of EMLA cream.
4. Use of microscopic projection(23)
Transdermal patches with microscopic projections called microneedles were used to facilitate transdermal drug transport. Needles ranging from approximately 10-100 µm in length are arranged in arrays. When pressed into the skin, the arrays make microscopic punctures that are large enough to deliver macromolecules, but small enough that the patient does not feel the penetration or pain. The drug is surface coated on the microneedles to aid in rapid absorption. They are used in development of cutaneous vaccines for tetanus and influenza.
Various other methods are also used for the application of the transdermal patches like thermal portion, magnetophoresis, and photomechanical waves. However, these methods are in their early stage of development and required further detail studying.
CONCLUSION
Transdermal drug delivery is hardly an old technology, and the technology no longer is just adhesive patches. Due to the recent advances in technology and the incorporation of the drug to the site of action without rupturing the skin membrane .Transdermal route is becoming the most widely accepted route of drug administration. It promises to eliminate needles for administration of a wide variety of drugs in the future.
Transdermal ultrasound-mediated drug delivery has been studied as a method for needle-less, non-invasive drug administration. Potential obstacles include the stratum corneum, which is not sufficiently passively permeable to allow effective transfer of many medications into the bloodstream without active methods. A general review of the transdermal ultrasound drug delivery literature has shown that this technology offers promising potential for non-invasive drug administration. Included in this review are the reported acoustic parameters used for achieving delivery, along with the known intensities and exposure times. Ultrasound mechanisms are discussed as well as spatial field characteristics. Accurate and precise quantification of the acoustic field used in drug delivery experiments is essential to ensure safety versus efficacy and to avoid potentially harmful bioeffects.
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