About Authors:Niroj Shrestha*, D. Nagasamy Venkatesh**, Jeevan Sharma
J. S. S. College of Pharmacy, Ooty, Tamilnadu, India
*Final Year B.Pharmacy Student.
**For correspondence:
Department of Pharmaceutics
J. S. S. College of Pharmacy,
(A constituent college of JSS University, Mysore)
Ooty – 643 001.
Tamil Nadu, India.
Reference ID: PHARMATUTOR-ART-1068
Abstract
Transdermal drug delivery system (TDDS) has emerged as a potential novel drug delivery system in the last 30 years to improve the therapeutic efficacy and safety, maintain steady state plasma level of drugs and overcome significant drawbacks of the conventional oral dosage forms and parenteral preparations. TDDS is ideally suited for diseases that demand chronic treatment with frequent dosing. This review deals with a brief insight on the formulation aspects, the physical and chemical enhancers being explored to enhance the transdermal delivery of drugs across the stratum corneum, the evaluation parameters (physicochemical, in vitro, in vivo studies) and therapeutic applications of TDDS.
Introduction
Transdermal drug delivery systems (TDDS) are topically applied “patches” designed to deliver a therapeutically effective amount of drug across a patient’s skin at controlled rate for systemic effect. [1,2] With the introduction of first transdermal patch of scopolamine in 1979, transdermal drug delivery has made an important contribution to medical practice in the past 3 decades but is yet to be recognized as a major alternative to oral delivery and hypodermic injections.[3,4]. The major obstacle for topical drug delivery is the low diffusion rate of drugs across the relatively impermeable, outermost skin layer, the stratum corneum.[5] Besides, the intercellular lipid region, the major pathway for lipophilic drugs, has a diffusion path length of about 500mm which is much longer than the thickness of stratum corneum (20 mm).[6,7]
Advantages
1. Unlike limited controlled release from i. v. and oral route, TDDS provides steady infusion of drug over extended period of time, suitable for drugs with short biological half life requiring frequent dosing, leading to increased patient compliance and decreased inter and intra patient variability.
2. Therapeutic failure or adverse effects frequently associated with intermittent dosing for chronic diseases can be avoided.
3. Self administration and removal when required.
4. Poor and variable absorption, low bioavailability and formation of fatal metabolites from first pass metabolism, and GI irritation associated with oral dosing are avoided.
5. Pain, inconvenience of injections can be overcomed by this non- invasive and safe parenteral route of drug delivery.[1, 2,8-10]
Composition of TDDS
1. Polymer matrix
2. Drug
3. Permeation enhancers
4. Pressure sensitive adhesives (PSA)
5. Backing membrane
6. Release liner
7. Other excipients
1. Polymer matrix / Drug reservoir
Polymer matrix, prepared by drug dispersion in suitable polymer, controls the release of the drug from the device. Polymers used in TDDS should be stable, compatible and non-reactive with the drug and other components of the system, should provide effective release of the drug throughout the device. They should be easily fabricated to desired product. Polymers and their degradation products must be non- toxic and non- antigenic to host. [1]
The polymers used for TDDS can be classified as:
Natural polymers: Cellulose derivatives(HPMC,[11-15] sodium CMC,[13,15-17] cellulose acetate,[10] methyl cellulose, [13,15] ethyl cellulose,[11,18,19] gelatin,[16] chitosan,[15,20] sodium carboxymethylguar, [16] sodium alginate,[10,13,15] polymerized rosin[21] etc.
Synthetic polymers: Polyvinyl alcohol,[16] polyethylene,[22] polyethylene glycol,[11] polyvinylpyrrolidone,[11,16,21] eudragits,[9,11,12,23-25] ethylene vinyl acetate copolymer,[26] ethyl vinyl acetate,[22] silicon rubber[27] etc.
2. Drug
Drugs having following properties are selected for TDDS:
a. Physicochemical properties
• Low molecular weight (less than 500 Daltons).
• Affinity for both hydrophilic and lipophilic phases(log P in the range of 1-3)
• Low melting point (less than 200°C).
b. Biological properties
• Extensive first pass metabolism.
• Narrow therapeutic window.
• Short biological half-life, requiring frequent dosing.
• Potent requiring few mg daily dose.
• Should not induce cutaneous irritation and allergic response. [1,2]
3. Permeation enhancers
a. Chemical permeation enhancers
They disrupt the highly ordered intercellular lipid bilayers of stratum corneum by inserting amphiphilic molecules or by extracting lipids, reversibly decreasing the barrier resistance and allowing better permeation of co-administered drugs.[4,7, 28] An ideal enhancer should be inert, non-toxic, non-allergenic, non-irritating, work unidirectionally and compatible with excipients and drugs. Their potency appear to be drug, skin and concentration dependent.[28]
Some examples of permeants are ethanol (the most common permeation enhancer),[29] essential oils or terpenes (Cineole, carveol, menthone, citral, menthol, d-limonene),[8,27,30,33-35] dimethyl sulfoxide,[17,25] propylene glycol,[9,27] N-methyl-2-pyrrolidine,[22,27] ethyl pyrrolidine[12] polyethylene glycol 400,[17] isopropyl myristate,[14, 24] myristic acid,[9] succinic acid,[9] laurocapram (azone),[7,27,31,32] methyl laureate,[24] lauric acid,[22,32] sodium lauryl sulfate,[14] non- ionic surfactant(spans, tweens),[14,17,26] pluronic,[17] oleic acid,[22,23,27,31,33] diethylene glycol monoethyl ether,[30] urea[28].
b. Physical permeation enhancers
Iontophoresis enhance and control drug penetration through the skin by applying low density electric current. Electroporation applies high voltage pulses across skin for fraction of second, creating new aqueous pathways in stratum corneum for drug diffusion.[37] Erbium: yttrium-aluminium-garnet (Er:YAG) laser applies single pulse of low energy to ablate stratum corneum layers.[38] Ultrasound or micro needle application breach stratum corneum and create micro channels for drug permeation.[39]
c. Other permeation enhancers
Ethanolic liposomes, niosomes, protransferosome gel and prodrug approach are reported to increase permeability by increasing drug solubilization and partitioning into skin.[29,40,41,42]
4. Pressure sensitive adhesives(PSA)
PSA affix TDDS firmly to the skin on applying light pressure. They should be skin-compatible, non- irritant, easily removable without leaving a residue or inflicting pain. They ensure intimate contact between drug releasing area of TDDS and skin surface which is critical for controlled release of drug. Commercially available PSAs include polyacrylate, polyisobutylene, and silicones. [14, 43, 44]
5. Backing membrane
Backing membrane is flexible with good tensile strength, having low water vapour transmission rates to promote increased skin hydration and thus greater skin permeability. Aluminized plastic laminate (Alupoly foil) [16, 17, 25] and polyvinyl alcohol[45, 21] are commonly used backing membranes.
6. Release Liner
Release liner is a protective liner for the TDDS patch that is removed prior to the application. Typically, it consists of a base layer which may be non-occlusive (e.g. paper fabric) or occlusive (e.g. polyethylene, polyvinylchloride) and a release coating layer of silicon.[25, 43]
7. Other excipients
Various solvents such as water,[22] ethanol,[15, 22] isopropylmyristate,[22] isopropyl alcohol,[25] and dichloromethane[25] are used alone or in combination to prepare drug reservoir. Propylene glycol, ethanol are used as co solvents along with permeation enhancer.[8,31] Plasticizers like diethyl phthalate,[26] dibutylpthalate,[9,11,19,21,45] glycerol,[11] triethylcitrate,[9] polyethylene glycol 400,[12,14,18,25] eudraflex[24] and propylene glycol[17] provide plasticity to the transdermal patch.
Fabrication of TDDS
TDDS is mainly fabricated in the form of polymeric matrix film containing a specific amount of drug per unit area (sq. cm) by glass substrate casting-solvent evaporation technique. Here, the drug and permeation enhancer solution is dispersed in the polymer and plasticizer or adhesive solution. Then, the mixture is casted or poured into glass ring on mercury substrate or backing membrane foil cup and allowed to dry at room temperature for 24 hours or hot air oven at 400C for 6 hours. The evaporation rate can be controlled by inverting a funnel over the substrate. Adhesive solution is poured onto dried film and solvent is evaporated to form a thin uniform layer of adhesive on the film.[11, 14, 16, 45] Membrane controlled system can be obtained by casting rate controlling polymers onto the matrix film. [11] Adhesive diffusion controlled film can be obtained by directly incorporation the drug into adhesive.[23]
Characterization of TDDS
TDDS can be characterized in terms of following parameters:
a. Evaluation of adhesion
Adhesion of transdermal patch is evaluated for peel adhesion, tack properties (thumb tack test, rolling ball tack test, quick stick or peel tack test, probe tack test) and shear strength properties. [1]
b. Patch thickness
Thickness of patches is measured by using micrometer screw gauge and average thickness and standard deviation are calculated.[21]
c. Weight variation
Each patch is weighed individually and average weight and standard deviation are calculated. [10]
d. Folding endurance
The number of times a patch can be folded manually at the same place till it breaks gives the folding endurance.[45]
e. Mechanical properties
The mechanical property is determined using plastic tensile test with Instron Instrument.[21]
f. Moisture content
Accurately weighed patches of specific area are kept in a dessicator using activated silica and reweighed individually until a constant weight is obtained. Percentage of moisture content is calculated based on the change in the weight with respect to the initial weight.[21, 45]
g. Moisture uptake
Dry patches are exposed to higher relative humidity conditions and weight is taken periodically until a constant weight is obtained. The moisture uptake is calculated in terms of percentage increase in weight of patch over its initial weight.[21, 45]
h. Interaction study
Any interaction among drug, polymer, excipients and stratum corneum is analyzed by FTIR or DSC.[15, 39, 40]
i. Stability test
TDDS is analyzed for drug content and specific decomposition rate, color, consistency etc. [13, 18]
j. Drug content and uniformity
Patches of specific area are cut and weighed accurately. Drug is extracted in suitable solvent and analyzed by spectrophotometry or HPLC.[11, 21, 46]
k. In vitro drug release studies
The paddle over disc method (USP apparatus V) is used to assess the release of the drug from the prepared patches. Dry films of definite shape is weighed, and fixed over a glass plate with an adhesive. The glass plate is then placed in a 500-mL of phosphate buffer pH 7.4 as the dissolution medium and the apparatus is equilibrated to 37±2 °C. The paddle is operated at a speed of 50 rpm. Samples (5- ml aliquots) is withdrawn at appropriate time intervals and analyzed by spectrophotometry or spectrofluorimetry.[15, 21, 33]
l. In vitro skin permeation studies
Various diffusion cells such as Kehsary chain diffusion cell,[11,20,26] Franz diffusion cell ,[7,9,32,34,47] modified Franz diffusion cell (vertical type),[21,22,38] Cylindrical diffusion cell[10] are used for in vitro skin permeation studies. Skin of human cadaver,[9,14,33] rat,[12,32,36,45] mouse,[7,16] guinea pigs[16,23] or pig[22] can be excised from abdominal or dorsal region and whole, delipidised or stripped form of definite area and thickness is mounted between the compartments of the diffusion cell with the stratum corneum facing into the donor compartment. The receptor compartment is filled with definite volume of phosphate buffer pH 7.4 (PBS) and stirred by magnetic stirrer at constant speed. Samples of definite volume are withdrawn from the receptor compartment at regular intervals and an equal volume of fresh medium is replaced. Samples are filtered and analyzed by radioimmunoassay,[8, 23] spectrophotometry[12] or HPLC[29, 41, 46, 47].
m. In vivo evaluation
The in vivo studies explore the pharmacokinetic and pharmacodynamic parameters which cannot be taken into account during in vitro studies. In vivo evaluation of TDDS can be carried out using animal models or healthy human volunteers. The most common animal species used are mouse,[38] rat,[13, 19, 25, 32, 41] dog[10] and guinea pig[14]. However, animal models are not very good predictive models for human because the penetration in these animals is higher than in human. Rhesus monkey is one of the most reliable models for in vivo evaluation but ethical consideration limits its use.[1] Healthy human volunteers can be used for reliable results.[14,15,40] The parameters studied are plasma concentration by GLC,[32] in vivo absorption study,[35] in vivo delivery and deposition by confocal laser scanning microscopy,[38] in vivo permeation by GC-MS,[27] ultra structure of skin by TEM[38] and various pharmacodynamic studies[14,25,38,41].
n. Skin Irritation study
Skin irritation and sensitization testing is performed on hairless dorsal skin of healthy rats or rabbits. The patch is applied over the skin for 24 hours and removed and the skin is observed and classified into 4 grades (none, mild, moderate and severe) on the basis of the severity of erythema/edema and compared with the standard irritant, 0.8% formalin. [16, 18, 23, 24]
o. Histological examination
It is carried out to access the anatomical changes by enhancers.[40, 48]
p. Localized superficial infection
Bacteria, fungi may proliferate under occlusive dressing due to favorable conditions like increased temperature, hydration etc. It can be tested by quantitative bacteriological cultures of skin site before and after application of transdermal patches.[1]
Therapeutic applications
• Hisetal, used in treatment of multiple sclerosis can be formulated in TDDS using oleic acid as permeation enhancer to achieve sufficient drug delivery.[31]
• Diclofenac sodium, celecoxib used as NSAIDs, formulated in TDDS can overcome gastric lesions associated with oral dose.[12,33]
• Drugs used for long term dosing in chronic diseases like captopril, verapamil, terbutaline sulphate, pinacidil, propranolol which have short biological half life, considerable first pass metabolism can be formulated as TDDS to achieve prolonged steady state plasma concentration.[10,16,20,25,45]
• Hydrophilic polymers like polyvinylpyrrolidone can provide faster drug release whereas hydrophobic polymers like ethyl cellulose can provide prolonged drug delivery.[45]
• Gel formulation with lipid disperse system of betahistine has potential for development of an efficient controlled release transdermal system.[32]
• Enhancer and co-solvent can synergistically enhance the delivery of peptides like thyrotropin releasing hormone across human skin.[8]
• Prazosin HCl in membrane controlled TDDS can deliver drug enough to maintain minimum effective concentration and can avoid hypotension associated with high initial oral dosing.[26]
• TDDS of indomethacin in polyvinylpyrrolidone polymer(acting as antinucleating agent) can provide better anti-inflammatory activity and lower ulcer indices compared to oral administration.[19]
• Diclofenac sodium, existing in anionic form at skin pH can be formulated as ion-pairs with oppositely charged enhancers to enhance transdermal delivery compared to non-ion paired forms.[12]
• Iontophoresis can increase permeation rate of hydrophilic atenolol to a greater extent than permeation enhancer and overcome incomplete absorption in GIT.[17]
• Nimesulide in sodium alginate transdermal gel can provide better analgesic and anti-inflammatory activity and avoid adverse effects associated with long term treatment with high oral dose.[13]
• Terbutaline sulphate, being diamagnetic, can be incorporated in magnetic TDDS to experience driving force to escape from applied magnetic field and enhance diffusion across the skin. [14]
• Bupropion HCl, an antidepressant drug can be converted to free base to increase lipophilicity and transdermal delivery and avoid release of fatal metabolites associated with oral dosing.[9]
• Zidovudine, an anti-HIV drug, formulated in TDDS and overcome toxic effects associated with frequent higher oral dose.[22]
• Levonorgestrel, a potent contraceptive agent, formulated as transdermal protransferosome gel can provide enhanced, prolonged and controlled delivery and overcome GI disturbances, weight gain, irregular bleeding, headache etc. associated with oral dosing.[41]
• Polymerized rosin can be used to design matrix type TDDS of Diltiazem HCl to prolong drug release and avoid variable and extensive first pass metabolism on oral dose.[21]
• Ester prodrug of ketorolac can provide enhanced permeation whereas nanostructured lipid carrier can act as controlled release system and avoid gastric ulceration and renal failure associated with frequent long term oral dosing.[42]
Conclusion
TDDS has gained realistic potential as the next generation drug delivery system for prolonged, controlled release of both hydrophobic and hydrophilic drugs, efficiently addressing the low oral bioavailability and inconvenience of injections. Future research will be aimed at better transdermal device design with greater understanding of the different mechanisms of biological interactions with permeation enhancers and improving the fluxes for a wide variety of molecules especially macromolecules and vaccines using cost effective, novel physical enhancement techniques along with existing chemical enhancers.
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