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Intravenous infusion at a programmed rate has been recognized as a superior mode of drug delivery not only to bypass the hepatic first-pass elimination but also to maintain a constant, prolonged and therapeutically effective drug level in the body. A closely monitored intravenous infusion can provide both the advantages of direct entry of drug into the systemic circulation and control of circulating drug levels. However such a mode of drug delivery entails certain risks and therefore necessitates hospitalization of patients and close medical supervision of the medication. Recently there has been an increasing awareness that the benefits of intravenous drug infusion can be closely duplicated, without its potential hazards by continuous transdermal drug administration through intact skin (Chien YW, 1987)
For many decades, the skin has often been used as the site for topical administration of dermatological drugs to achieve a localized pharmacological action in the skin tissues, such as the use of hydrocortisone for dermatitis, benzoyl peroxide for acne and neomycin for superficial infection (Kastrip, 1983). The potential of using intact skin as the port for drug administration has been recognized for over several decades, as evidenced by the development and extensive use of medicated plasters for many decades. Historically, the medicated plasters
could be viewed as the first application of the idea of transdermal drug delivery: bringing medication into close contact with the skin, through which drug is delivered transdermally (Chein, 1988).
Medicated plasters have not only been used in oriental medicine, but also in Western medicine for several decades. In the united States alone three medicated plasters (belladonna plaster, mustard plaster and salicylic acid plaster) have been listed in the NF 1946 and USP, 1950. In contrast to the Oriental-type medicated plasters, these Western-type medicated plasters are often simple in formula and all contain only a single active ingredient. However, like the Oriental plasters, the Western medicated plasters were also developed mainly for local medication.
In response to this new idea several TDDS have recently been developed, aiming to achieve the objective of systemic medication through topical application to the intact skin surface (Barry, 2001). These examples were represented in table-
Deponit, Nitrodisc, Nitro-dur, Transderm-Nitro, Minitran
Estraderm, FemPatch, Climaderm, Climara
Nicoderm, nicotrol, Prostep
Hormone replacement therapy
Hormone replacement therapy
Advantages of TDDS
Avoid the risks and inconveniences of intravenous therapy
Bypass the variation in the absorption and metabolism associated with oral administration
Permit continuous drug administration and the use of drugs with a short biological half-life
Increase the bioavailability and efficacy of drugs through the bypass of hepatic first-pass elimination
Reduce the chance of over- or underdosing through the prolonged, preprogrammed delivery of drug at the required therapeutic rate
Provide a simplified therapeutic regime leading to better patient compliance
Permit a rapid termination of the medication, if needed, by simply removing the TDD system from the skin surface
Disadvantages of TDDS
The drug must have some desirable physicochemical properties like lipophilicity, low dose, low molecular weight etc., for penetration through stratum corneum.
A lag time associated with the delivery of the drug across the skin, resulting in a delay in onset of action.
Variation of absorption rate based on site of application skin type and patient age and variation in adhesive effectiveness across the skin.
Not suitable for drugs that produce irritation and contact dermatitis.
THE SKIN (Walters and Roberts, 2002)
The skin consists of four layers: the stratum corneum (nonviable epidermis), the remaining layers of the epidermis (viable epidermis), dermis, and subcutaneous tissues (Figure 1.1). There are also several associated appendages: hair follicles, sweat ducts, apocrine glands, and nails.
The outer (epidermal) layer of the skin is composed of stratified squamous epithelial cells. The epithelial cells are held together mainly by highly convoluted interlocking bridges, which are responsible for the unique integrity of the skin. The epidermis is thickest in the areas of the palms and soles and becomes thinner over the ventral surface of the trunk (Jacob and Francone, 1970)
The stratum corneum is the heterogeneous outermost layer of the epidermis and is approximately 10-20 Âµm thick. It is nonviable epidermis and consists, in a given crosssection, of 15-25 flattened, stacked, hexagonal, and cornified cells embedded in a mortar of intercellular lipid. Each cell is approximately 40 Âµm in diameter and 0.5 Âµm thick. The thickness varies, however, and may be a magnitude of order larger in areas such as the palms of the hand and soles of the feet, areas of the body associated with frequent direct and substantial physical interaction with the physical environment. The stratum corneum barrier properties may be partly related to its very high density (1.4 g/cm3 in the dry state),
Figure 1.1 Components of the epidermis and dermis of human skin.
its low hydration of 15-20%, compared with the usual 70% for the body, and its low surface area for solute transport (it is now recognized that most solutes enter the body through the less than 0.1-Âµm-wide intercellular regions of the stratum corneum). Each stratum corneum cell is composed mainly of insoluble bundled keratins (~70%) and lipid (~20%) encased in a cell envelope, accounting for about 5% of the stratum corneum weight. The intercellular region consists mainly of lipids and desmosomes for corneocyte cohesion.
The cells of the stratum corneum originate in the viable epidermis and undergo many morphological changes before desquamation. Thus the epidermis consists of several cell strata at varying levels of differentiation (Figure 1.2). The origins of the cells of the epidermis lie in the basal lamina between the dermis and viable epidermis. In this layer there are melanocytes, Langerhans cells, Merkel cells, and two major keratinic cell types: the first functioning as stem cells having the capacity to divide and produce new cells; the second serving to anchor the epidermis to the basement membrane (Chien, 1987).
Figure 1.2 Epidermal differentiation: major events include extrusion of lamellar bodies, loss of nucleus, and increasing amount of keratin in the stratum corneum. The diagram is not to scale and only a few cells are shown for clarity.
The dermis, a critical component of the body, not only provides the nutrative, immune, and other support systems for the epidermis, through a thin papillary layer adjacent to the epidermis, but also plays a role in temperature, pressure, and pain regulation. The main structural component of the dermis is referred to as a coarse reticular layer. The dermis is about 0.1-0.5 cm thick and consists of collagenous fibers (70%), providing a scaffold of support and cushioning, and elastic connective tissue, providing elasticity, in a semigel matrix of mucopolysaccharides.
The upper portion of the dermis is formed into ridges (or papillae) projecting into the epidermis, which contains blood vessels, lymphatics, and nerve endings. Only the nerve fibers reach into the germinative zone of the epidermis.
The deepest layer of the skin is the subcutaneous tissue or hypodermis. The hypodermis acts as a heat insulator, a shock absorber, and an energy storage region. This layer is a network of fat cells arranged in lobules and linked to the dermis by interconnecting collagen and elastin fibers. As well as fat cells (possibly 50% of the body's fat), the other main cells in the hypodermis are fibroblasts and macrophages. One of the major roles of the hypodermis is to carry the vascular and neural systems for the skin (Szuba and Rockson, 1997).
DRUG DELIVERY ROUTES ACROSS HUMAN SKIN
Drug molecules in contact with the skin surface penetrate by three potential pathways (Figure 1.3):
through the sweat ducts
via the hair follicles and sebaceous glands (collectively called the shunt or appendageal route)
across the stratum corneum
The appendages comprise a fractional area for permeation of approximately 0.1% [Higuchi, 1962], 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.
The 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) [Scheuplein and Blank, 1971] (Figure 1.4). 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. Ideally, a drug must possess both lipoidal and aqueous solubilities. If a drug is too hydrophilic, the molecule will be unable to transfer into the stratum corneum, however if it is too lipophilic, the drug will tend to remain in the stratum corneum layers (Naik, Guy et al., 2000). The intercellular route is now considered to be the major pathway for permeation of most drugs across the stratum corneum.
Figure 1.3 Simplified diagram of skin showing routes of penetration: 1. through the sweat ducts; 2. directly across the stratum corneum; 3. via the hair follicles.
Figure 1.4 Simplified diagram of the stratum corneum and the intercellular and transcellular routes of penetration (adapted from [Barry, 2001]).
Factors affecting transdermal permeabilty
The principal factors influencing and causing differences in transdermal permeability of the stratum corneum can be classified as follows:
1. Physico-chemical properties of the penetrant molecule
Concentration of penetrant molecule
2. Physico-chemical properties of drug delivery system
Composition of drug delivery system
3. Physiological & Pathological conditions of the skin
Reservoir effect of the horny layer
Traumatic/pathologic injuries to the skin
Cutaneous drug metabolism
Drug metabolism by microorganisms
4. Physico-chemical properties of penetrant molecule
The salient approaches governing the physico-chemical properties of drug which influence the transdermal permeability include:
Drug transport within the delivery system to the device-skin surface interface.
Partitioning of drug across the stratum corneum
Diffusion of drug across the stratum corneum
Drug partitioning from the stratum corneum to the viable epidermis
Transport of drug through the viable tissue
Drug uptake by the cutaneous microscopically network and subsequent systemic distribution
Diffusion: The transport characteristics of the drug are determined by its size and its level of interaction with the media through which diffusion is taking place i.e. delivery system stratum corneum viable epidermis. Most drugs in current use have molecular weight less than 1000 daltons. Beyond this magnitude organic molecules tend to fall into categories such as polymers or peptides. The drugs having molecular weight less than 500 daltons have been widely accepted for transdermal patches for reasons of better diffusion characteristics. However drugs having molecular weight of more than 300 are also delivered through skin by other techniques like iontophoresis sonophoresis etc. For the small species (<1000 daltons) the effect of size on diffusion in liquids may be viewed in terms of the Stokes'-Einstein equation i.e. D=C.M-1/3, where M=molecular weight C=constant, D=diffusion.
Partition coefficient: Drug possessing both water and lipid solubilities are favourably absorbed through the skin. A lipid/water partition coefficient of 1 or greater is generally required for optimal transdermal permeability. In percutaneous absorption there are two key partitioning processes between the delivery system and stratum corneum and between the lipophilic stratum corneum and the aqueous epidermis with time. The molecules must favor the stratum corneum while striking a balance between stratum corneum and viable dermal tissue so as to have entry to systemic circulation.
The partition coefficient of a drug molecule may be altered by chemical modification of its functional groups. Membrane partition coefficient increases exponentially as the length of the lipophilic alkyl chain increases.
pH condition: Application of solutions whose pH values are very higher very low can be destructive to the skin. With moderate pH values the flux of the ionizable drugs can be affected by changes in pH that alter the ratio of charged and uncharged species and their transdermal permeability.
Concentration of penetrant molecule: The amount of drug percutaneously absorbed per unit surface area per unit time interval increase as the concentration of the rug in the vehicle is increased. Assuming membrane limited transport, increasing concentration of dissolved drug causes a proper increase in flux. At concentration higher than the solubility, excess solid drug functions as a reservoir and helps to maintain a constant drug concentration for a prolonged period of time.
Physico-chemical properties of drug delivery system: Generally in the drug delivery systems vehicles do not increase the rate of penetration of a drug into the body but serves as carriers for the drug.
Vehicle: Solubility of the drug in the vehicle determines the release rate. The mechanisms of drug release depend on the following factors:
a. Whether the drug molecules are dissolved or suspended in the delivery system. The interfacial partition coefficient of the drug from the system to the skin tissue. Lipophilic solvent vehicles facilitate penetration
b. pH of the vehicle: The pH of the vehicle can influence the rate of release of the drug from the delivery system since the thermodynamic activity of acidic and basic drugs is affected by the pH.
Composition of drug delivery system: It affects not only the rate of drug release but also the permeability of stratum corneum by means of hydration mixing with skin lipids or other sorption promoting effects.
Physiological & Pathological conditions of the skin: The various physiological & pathological parameters of the skin condition and related barrier functions include:
Pathophysiological nature of the skin: Reservoir effect of the horny layer
Lipid film on skin surface
Hydration of stratum corneum
General subject factors
general health of subject
disease and trauma
Factors associated with skin conditioning
Reservoir effect of the horny layer: The reservoir effect is due to the irreversible binding of a part of the applied drug with the skin. This binding can be reduced by the pretreatment of the skin surface with anionic surfactant.
Lipid film: This acts as a protective layer to prevent the removal of moisture from the skin and helps in maintaining the basic function of stratum corneum. Defatting of this film was found to decrease transdermal absorption.
Hydration of stratum corneum: Hydration results from water diffusion from underlying epidermal layers or from accumulating perspiration after application of an occlusive vehicle or covering on the surface under occlusive conditions. Occlusion also reduces the irreversible binding capacity of the stratum corneum. When the skin undergoes hydration its resistance and capacitance may change. As the time of hydration increases the low frequency impedance of the excised skin decreases with time. A much less activation energy is required to diffuse through hydrated skin
Temperature: Raising skin temperature results in an increase in the rate of skin permeation. This may be due to i) thermal energy required diffusivity ii) solubility of drug in the skin tissues iii) increased vasodilation of skin vessels.
Humidity: Humidity has been directly related to skin permeability by way of its effect on insensible perspiration.
Race: Striking differences in skin coloration exist across races of the man which relates to nature numbers geometrics and distribution of melanin pigment granules deposited in the epidermis by melanocytes. The most striking evidence that there are racially derived permeability differences in the cutaneous barrier is provided by Weingand et al (1980). They found that Caucasians reacted more strongly to irritants than Negroes when the respective skin was intact. On stripped skin however the responses were equvivalent.
Age: Fetal & infant skin appears more permeable than adult skin. The stratum corneum of preterm infants is not well developed and as such provides little barrier to the ingress of substances. So this route of delivery is possible for neonatal therapy when difficulty is encountered in oral or intravenous administration. There appear good reasons to suspect that percutaneous absorption does change with age. It is known that the aged stratum corneum is considerably dryer than the young adult horny layer and that it contains lower lipid content (Evans et al. 1985). A reduced presence of water implies that aged skin provides a less attractive environment to less lipophilic moieties. The diminished lipid content provides a reduced dissolution medium for chemicals administered to skin surface. Thus probing the barrier function at both macroscopic & molecular levels as a function of age is now realistic.
Gender: Though there are striking differences in the general appearances of the skin and the distribution and prominence of hair between post adolescent males and females there is no convincing evidence to suggest that anatomical dissimilarities have much bearing on the barrier function of the tissue. The essential need for protection from water loss which does not differ between the sexes, seems to impart qualities to the skin, which determine its membrane function more than any other factor.
Anatomical site: Differences in the nature and thickness of the skin cause variation in permeability (Foremann, 1986)
BASIC COMPONENTS OF TRANSDERMAL DRUG DELIVERY SYSTEMS
The components of transdermal devices include
Polymer matrix or matrices
The polymer controls the release of drug from the device. The following criteria should be satisfied for a polymer to be used in a transdermal system (Kydoineus and Berner, 1987):
Molecular weight, glass transition temperature and chemical functionality of the polymer should be such that the specific drug diffuses properly and gets released through it.
The polymer should be stable, non-reactive with the drug, easily manufactured and fabricated into the desired product; and inexpensive.
The polymer and its degradation products must be non-toxic or non-antagonistic to the host.
The mechanical properties of the polymer should not deteriorate excessively when large amounts of active agent are incorporated into it.
Possible useful polymers for transdermal devices are:
Natural polymers: Cellulose derivatives, Zein, Gelatin, Shellac, Waxes, Proteins, Gums and their derivatives, Natural rubber, Starch etc.
Synthetic elastomers: Polybutadiene, Polysiloxane, Silicone rubber, Nitrile, Acrylonitrile, Butyl rubber, Styrenebutadiene rubber, Neoprene etc.
Synthetic polymers: Polyvinyl alcohol, Polyvinyl chloride, Polyethylene, Polypropylene, Polyacrylate, Polyamide, Polyurea, Polyvinylpyrrolidone, Polymethylmethacrylate etc.
For successfully developing a transdermal rug delivery system, the drug should be chosen with great care. The following are some of the desirable properties of a drug for transdermal delivery (Guy et al., 1987)
The drug should have a molecular weight less than approximately 1000 daltons.
The drug should have a affinity for both lipophilic and hydrophilic phases. Extreme partitioning characteristics are not conducive to successful drug delivery via the skin.
The drug should have a low melting point.
The drug should be potent with a daily dose of the order of a few mg/day.
The half life (t1/2) of the drug should be short.
The drug must not induce a cutaneous irritant or allergic response.
Drugs which degrade in the GI tract or are inactivated by hepatic first-pass effect are suitable candidates for transdermal delivery.
Tolerance to the drug must not develop under the near zero-order release profile of transdermal delivery.
Drugs which have to be administered for a long period of time or which cause adverse effects to non-target tissues can also be formulated for transdermal delivery.
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:
Sulfoxides: Dimethylsulfoxide (DMSO) is an effective penetration enhancer that promotes permeation by reducing skin resistance to drug molecules or by promotion of drug partitioning from the dosage form (Barry, 1987).
Alcohols: Alcohols may influence transdermal penetration by a number of mechanisms. The alkyl chain length of the alkanols is an important parameter in the promotion of permeation enhancement. Augmentation appears to increase as the number of carbon units increases, up to a limiting value (Chien et al, 1988). In addition, lower molecular weight alkanols are thought to act as solvents, enhancing the solubility of drugs in the matrix of the stratum corneum (Chien et al, 1988).
Polyols: Solubility of the drug in the delivery vehicle is markedly influenced by the number of ethylene oxide functional groups on the enhancer molecule; this solubility modification may either enhance or retard transdermal flux depending on the specific drug and delivery environment (Mollgaard and Hoelgaard, 1983). The activity of propylene glycol is thought to result from solvation of ï„ƒ-keratin within the stratum corneum; the occupation of proteinaceous hydrogen bonding sites reducing drug-tissue binding and thus promoting permeation (Barry, 1987).
Alkanes: Long chain alkanes (C7-C16) have been shown to enhance skin permeability by non-destructive alteration of the stratum corneum barrier.
Fatty acids: Selective perturbation of the intercellular lipid bilayers in the stratum corneum appears to be the major mode of enhancing activity of the fatty acids (Golden et al, 1987). Oleic acid has been found to decrease the phase transition temperatures of the skin lipids with a resultant increase in motional freedom or fluidity of these structures (Golden et al, 1987).
Esters: Esters such as ethyl acetate are relatively polar, hydrogen bonding compounds that may enhance permeation in a similar manner to the sulphoxides and formamides by penetrating into the stratum corneum and increasing the lipid fluidity by disruption of lipid packing (Friend et al, 1989).
Amines and amides
Urea: Urea promotes transdermal permeation by facilitating hydration of the stratum corneum and by the formation of hydrophilic diffusion channels within the barrier (Kim et al, 1993a).
Dimethylacetamide and dimethylformamide: These compounds are less potent penetration enhancing chemical alternatives to DMSO. At low concentrations their activity as enhancers is a result of partitioning into the keratin regions. At higher concentrations they increase lipid fluidity by disruption of lipid packing as a result of solvation shell formation around the polar head groups of the lipids (Barry, 1987a).
Pyrrolidones: Pyrrolidone and its derivatives are reported to interact with both keratin (Barry, 1987b) and with lipids (Kim et al, 1993b) in the skin. Azone is known to show significant accelerant effects at low concentrations for both hydrophilic and hydrophobic drugs (Stoughton, 1982) and is one of the few enhancers that have been developed commercially.
Terpenes: Both the mono- and sesquiterpenes are known to increase percutaneous absorption of compounds by increasing diffusivity of the drug in stratum corneum (Cornwell and Barry, 1993) and/or by disruption of the intercellular lipid barrier (Williams and Barry, 1991). A further mechanism of activity that has been postulated is that the terpenoids increase electrical conductivity of tissues thereby opening polar pathways within the stratum corneum (Cornwell and Barry, 1992).
Surface active agents: Surface active agents function primarily by adsorption at interfaces and thus interact with biological membranes contributing to the overall penetration enhancement of compounds. Cationic surfactants are more destructive to skin tissues causing a greater increase in flux than anionic surfactants (Kushla et al, 1993). The latter, in turn, produce greater increases in flux than nonionic surfactants (Stoughton, 1982). Sodium lauryl sulphate has been implicated in reversible lipid modification with resultant disorganization of the stratum corneum and enhanced per meation (Ribaud et al, 1994).
Cyclodextrins: Cyclodextrins are biocompatible substances that can form inclusion complexes with lipophilic drugs with a resultant increase in their solubility, particularly in aqueous solutions (Uekama et al, 1982).
The fastening of all transdermal devices to the skin has been done by using a pressure sensitive adhesive. The pressure sensitive adhesive 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 (Kydoineus and Berner, 1987):
They should be easily removed.
Should not irritate or sensitize the skin or cause an imbalance in the normal skin flora during its contact time with the skin.
Should adhere to the skin aggressively during the dosing interval without its position being disturbed by activities such as bathing, exercise etc.
Should not leave an unwashable residue on the skin.
Should have excellent (intimate) contact with 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.
The peripheral adhesive system is less elegant, contains several more layers, is substantially larger and is more difficult to manufacture than the face adhesive system. However, there is no need to further package the reservoir layer, containing the drug, when peripheral adhesive systems are used. The reservoir of the face adhesive system cannot be hermetically contained and therefore has to be packaged in an aluminium foil pouch. Some widely used pressure sensitive adhesives include polyisobutylenes, acrylics and silicones.
These are flexible and they provide a good bond to the drug reservoir, accept printing and prevent drug from leaving the dosage form through the top. 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.
TECHNOLOGIES FOR DEVELOPING TRANSDERMAL DRUG DELIVERY SYSTEMS
These technologies are classified into four basic approaches (Chien, 1992).
Polymer Membrane Permeation-Controlled TDD Systems
In this type of device, the drug reservoir is sandwiched between a drug-impermeable backing laminate and a rate-controlling polymeric membrane (figure 1.5). The drug molecules are permitted to release only through the rate-controlling polymeric membrane. In the drug reservoir compartment the drug solids are dispersed homogeneously in a solid polymer matrix (e.g., polyisobutylene), suspended in a unleachable, viscous liquid medium (e.g., silicone fluid) to form a pastelike suspension, or dissolved in a releasable solvent (e.g., alkyl alcohol) to form a clear drug solution. The rate-controlling membrane can be either a microporous or a nonporous polymeric membrane, e.g., ethylene-vinyl acetate copolymer, with a specific drug permeability. On the external surface of the polymeric membrane a thin layer of drug-compatible, hypoallergenic pressure-sensitive adhesive polymer, e.g., silicone adhesive, may be applied to provide intimate contact of the TDD system with the skin surface.
e.g., Transderm-Nitro, Transderm-Scop, Catapres-TTS, Estraderm, Duragesic.
Fig. 1.5 Cross-sectional view of a polymer membrane permeation-controlled TDD system showing various major structural components, with a liquid drug reservoir (top) or a solid drug reservoir (bottom).
Polymer Matrix Diffusion-Controlled TDD Systems
The drug reservoir is formed by homogeneously dispersing the drug solids in a hydrophilic or lipophilic polymer matrix, and the medicated polymer formed is then molded into medicated disks with a defined surface area and controlled thickness. This drug reservoir-containing polymer disk is then mounted onto an occlusive baseplate in a compartment fabricated from a drug-impermeable plastic backing (figure 1.6)
e.g., Nitro-Dur, NTS
Figure 1.6 Cross-sectional view of a polymer matrix diffusion-controlled TDD systems showing various major structural components. (Reproduced from Y.W.Chien, 1985.)
Alternatively, the polymer matrix drug dispersion-type TDD system can be fabricated by directly dispersing the drug in a pressure-sensitive adhesive polymer, e.g., polyacrylate, and then coating the drug-dispersed adhesive polymer by solvent casting or hot melt onto a flat sheet of a drug-impermeable backing laminate to form a single layer of drug reservoir(figure 1.7). This yields a thinner and/or smaller TDD patch.
e.g., Minitran, Nitro-Dur II, Frandol tape
Figure 1.7. Cross-sectional view of an adhesive polymer drug dispersion-type TDD system showing various major structural components.
C. Drug Reservoir Gradient-Controlled TDD Systems
Polymer matrix drug dispersion-type TDD system can be modified to have the drug loading level varied in an incremental manner, forming a gradient of drug reservoir along the diffusional path across the multilaminate adhesive layers (figure 1.8)
Figure 1.8 Cross-sectional view of a drug reservoir gradient-controlled TDD system showing various major structural components.
D. Microreservoir Dissolution-Controlled TDD Systems
This type of drug delivery system can be considered a hybrid of the reservoir- and matrix dispersion-type drug delivery systems. In this approach the drug reservoir is formed by first suspending the drug solids in an aqueous solution of a water-miscible drug solubilizer, e.g., polyethylene glcol, and then homogeneously dispersing the drug suspension, with controlled aqueous solubility, in a lipophilic polymer, by highshear mechanical force, to form thousands of unleachable microscopic drug reservoirs (figure 1.9). This thermodynamically unstable dispersion is quickly stabilized by immediately cross-linking the polymer chains in situ, which produces a medicated polymer disk with a constant surface area and a fixed thickness. A TDD system is then produced by mounting the medicated disk at the center of an adhesive pad.
Figure 1.9. Cross-sectional view of a microreservoir dissolution-controlled TDD system showing various major structural components. (Reproduced from Y.W.Chien, 1985.)
EVALUATION(n k. jain)
Transdermal drug delivery system requires systematic evaluation at various stages of its development. These evaluation tests are described below:
Evaluation of Adhesive
In vitro drug release evaluation
Effect of skin uptake and metabolism
Cutaneous toxicological evaluations
Evaluation of adhesive
Pressure sensitive adhesives are evaluated for the following properties:
Peel adhesion properties
Shear Strength Properties
The detailed description of these properties is as follows:
Peel Adhesion Properties
Peel adhesion is the force required to remove an adhesive coating from a test substrate. It is important in transdermal devices because the adhesive should provide adequate contact of the device with the skin and should not damage the skin on removal. Peel adhesion properties are affected by the molecular weight of the adhesive polymer, the type and amount of additives, and polymer composition. It is tested by measuring the force required to pull a single coated tape, applied to a substrate, at a 180Â° angle. No residue on the substrate indicates "adhesive failure" which is desirable for transdermal devices. Remnants on the substrate indicate "cohesive failure" signifying a deficit of cohesive strength in the coating.
Tack is the ability of a polymer to adhere to a substrate with little contact pressure. Tack is dependent on the molecular weight and composition of polymer as well as the use of tackifying resins in the polymer. Tests for tack include:
Thumb tack test
Rolling ball tack test
Quick-stick (or peel-tack) test and
Probe tack test
Thumb tack test: This is a subjective test in which evaluation is done by pressing the thumb briefly into the adhesive.
Rolling ball tack test: This test involves measurement of the distance that a stainless steel ball travels along an upward-facing adhesive. The less tacky the adhesive, the farther the ball will travel.
Quick-stick (or peel-tack test): The peel force required to break the bond between an adhesive and substrate is measured by pulling the tape away from the substrate at 90Â° at a speed of 12 inch/min.
The force is recorded as the tack value and is expressed in ounces (or grams) per inch width with higher values indicating increasing tack.
Probe tack test: In this test, the force required to pull a probe away from an adhesive at a fixed rate is recorded as tack (expressed in grams).
C. Shear Strength Properties
Shear strength is the measurement of the cohesive strength of an adhesive polymer. Adequate cohesive strength of a device will mean that the device will not slip on application and will leave no residue on removal. It is affected by molecular weight as well as the type and amount of tackifier added. Shear strength or creep resistance is determined by measuring the time it takes to pull an adhesive coated tape off a stainless steel plate when a specified weight is hung from the tape which pulls the tape in a direction parallel to the plate.
In-vitro drug release evaluation
In vitro Skin Diffusion Cells: Most common methods for evaluation of in vitro skin penetration use diffusion cells. The major advantage of in vitro investigations is that the experimental conditions can be controlled precisely, such that the only variables are the skin and the test material.
The most commonly used solutions to diffusion equations that are applied to the in vitro situation make the following assumptions:
1. The receptor phase is a perfect sink.
2. Depletion of the donor phase is negligible.
3. The membrane is a homogeneous slab.
None of these assumptions is wholly true in practice, and the potential significance of these imperfections must not be overlooked. Careful experimental design can be used to achieve a close approximation to reality.
Diffusion Cell Design: In vitro systems range in complexity from a simple two-compartment ''static'' diffusion cell (Franz, 1975) (figure 1.10) to multijacketed ''flow-through'' cells (Bronaugh and Stewart, 1985). Construction materials must be inert, and glass is most common, although Teflon and stainless steel are also used. Excised skin is always mounted as a barrier between a donor chamber and a receptor chamber, and the amount of compound permeating from the donor to the receptor side is determined as a function of time. Efficient mixing of the receptor phase (and sometimes the donor phase) is essential, and sample removal should be simple. Neither of these processes should interfere with diffusion of the permeant. Continuous agitation of the receptor medium, sampling from the bulk liquid rather than the side arm, and accurate replenishment after sampling, are important practical considerations. It is essential that air bubbles are not introduced below the membrane during sampling.
Static diffusion cells are usually of the upright (''Franz'') or side-by-side type, with receptor chamber volumes of about 2-10 mL and surface areas of exposed membranes of near 0.2-2 cm2. Cell dimensions should be accurately measured, and precise values should be used in subsequent calculations, with due attention to analyte dilution resulting from sampling and replenishment. The main difference in the application of these two static cell types is that side-by-side cells can be used for
the measurement of permeation from one stirred solution, through a membrane, and into another stirred solution. This is of particular advantage when examining flux from saturated solutions in the presence of excess solid if accumulation of solid on the membrane surface must be prevented. This type of cell can also be modified to allow the absorption of permeants in the vapor phase. For example, volatile material may be retained in a small depression in the donor chamber so that the membrane is exposed to only the permeant in the gaseous state. Upright cells are particularly useful for studying absorption from semisolid formulations spread on the membrane surface and are optimal for simulating in vivo performance. The donor compartments can be capped to provide occlusive conditions, or left open, according to the objectives of the particular study.
Flow-through cells can be useful when the permeant has a very low solubility in the receptor medium, and designs are continuously improving (Tanojo, 1997). Sink conditions are maximized as the fluid is continually replaced using a suitable pump (at a rate of about 1.5 mL/h) (Bronaugh, 1996). However, the dilution produced by the continuous flow can raise problems with analytical sensitivity, particularly if the permeation is low.
To summarize, a well-designed skin diffusion cell should
1. Be inert
2. Be robust and easy to handle
3. Allow the use of membranes of different thicknesses
4. Provide thorough mixing of the receptor chamber contents
5. Ensure intimate contact between membrane and receptor phase
6. Be maintainable at constant temperature
7. Have precisely calibrated volumes and diffusional areas
8. Maintain membrane integrity
9. Provide easy sampling and replenishment of receptor phase
10. Be available at reasonable cost
2. Receptor Chamber and Medium
Receptor chamber dimensions are constrained by the conflicting requirements of guaranteeing that the receptor phase can act as a sink, while ensuring that sample dilution does not preclude analysis. A large receptor volume may ensure sink conditions, but will reduce analytical sensitivity unless large samples can be taken and subsequently concentrated. Concentration of permeant in an aqueous receptor phase
may be possible by lyophilization, or by techniques such as solid-phase extraction.
The ideal receptor phase provides an accurate simulation of the conditions pertaining to in vivo permeation of the test compound. As a general rule the concentration of the permeant in the receptor fluid should not be allowed to exceed approximately 10% of saturation solubility. Excessive receptor-phase concentration can lead to a decrease in the rate of absorption, which may result in an underestimate of bioavailability. The most commonly used receptor fluid is pH 7.4 phosphate-buffered saline (PBS), although this is not always the most appropriate material. It has been postulated that if a compound has a water solubility of less than about 10 Âµg/mL, then a wholly aqueous receptor phase is unsuitable, and the addition of solubilizers becomes necessary (Bronaugh, 1985).
Figure 1.10 Static diffusion cell
Effect of skin uptake and metabolism
It has been shown that skin possesses some ability to metabolize drugs. The contribution of skin metabolism to the elimination of a drug from the body may be relatively small as compared to that in the liver when a drug is administered systemically. Nevertheless, skin could become an important organ for the metabolism when a drug is applied directly to the skin surface, since by this route, every molecule that becomes systemically available must penetrate through the metabolic-activity-rich region in the epidermis.
In vivo evaluation
In vivo transdermal studies in animals have been conducted since the 1960s and are used on a routine basis during the development of a transdermal product. The animal models provide important permeability parameters when little is known about clinical toxicity in human patients. The selection of an animal model or tissue culture model is a very difficult decision to make because there is no model available that approaches the human skin in terms of permeability, histology and lipid composition (Chein, 1987).
Cutaneous toxicological evaluations
An important part of the evaluation of transdermal drug delivery systems pertains to the deleterious effects they may have on the skin. While there have been significant advances in the evaluation of transdermal systems for cutaneous toxicology, the enormous range of structural and functional capacity of skin from one individual to another compounds the difficulty in assessing the potential adverse effects a transdermal system may have on the skin.
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