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TRANSDERMAL DRUG DELIVERY:
FORMULATION & EVALUATION
SUBMITTED BY :
Pandya Sanket M.Roll no. 50/09MS (PHARMACEUTICS)NIPER, Raebareli GUIDED BY :
Mr. Md. Sajid AliLecturerNIPER, Raebareli
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Introduction Potential benefits Factors affecting TD route Mechanism of skin permeation Basic components Different types of transdermal patches
Evaluation (physicochemical, invitro, invivo) Recent advancements Conclusion
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Potential benefits oftransdermal routes
The system avoids the chemically hostile GI environment
No GI distress or other physiological contraindications ofthe oral route
Avoids first-pass effect
Allows effective use of drugs with short biological half-life Allow administration of drugs with narrow therapeutic
windows
Provides controlled plasma levels of very potent drugs
Increased patient compliance Painless
Simple application and removal
Flexibility of terminating drug administration by
simply removing the patch
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Controlled drug delivery
Maintain efficacious plasma drug levels for over 1-7 days
Drug input can be promptly interrupted when toxicity
occurs
Disadvantages
Drug that require high blood levels cannot be administered
Drug or drug formulation may cause skin irritation orsensitization
Adhesive may not adhere well to all types of skin
Expensive
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Factors influencing TD route
Physicochemical properties of penetrant (pKa, molecularsize, stability, binding affinity, solubility, partitioncoefficient)
Integrity and thickness of stratum corneum
Density of sweat glands and folicles
Skin hydration
Metabolism
Vehicle effects Time scale of permeation (steady-state vs. transient
diffusion)
Microenvironment of skin surface
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Basic Components Of TDDS
Polymer matrix / Drug reservoir
Drug
Permeation enhancers
Pressure sensitive adhesive (PSA) Backing laminates
Release liner
Other excipients like plasticizers and solvents
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Polymer matrix / Drug reservoir:
Backbone of TDDS
Control the release of the drug from the device.
Prepared by dispersion of drug in liquid or solid state
synthetic polymer base. Natural Polymers: e.g. cellulose derivatives, zein, gelatin,
shellac, waxes, gums, natural rubber and chitosan etc.
Synthetic Elastomers: e.g. polybutadiene, hydrin rubber,polyisobutylene, silicon rubber, nitrile, acrylonitrile, neoprene,
butylrubber etc.
Synthetic Polymers: e.g. polyvinyl alcohol, polyvinylchloride,polyethylene, polypropylene, polyacrylate, polyamide,polyurea, polyvinylpyrrolidone, polymethylmethacrylate etc
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Drug Properties Potency of the drug
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Penetration Enhancers
Activity of penetration enhancers Interaction with the polar head groups of lipid viahydrogen and ionic bonding
Increase volume of the aqueous layer : swelling andhydration
Alter the packing of the lipid tailsdisorder andtraverse by a lipid-like penetrant
Solvents DMSO, propylene glycol, ethanol
Cosolvent Azone (1-dodecylazacycloheptane-2-one) Cis-unsaturated oleic acid Additive : PGincrease solubilizing ability for lipid-like
materials Flip over to insert between the hydrophobic groups of the
membrane lipids
increasing fluidity of lipid
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Pressure-sensitive adhesive ASTM (American Society for Testing and Materials) definition :
viscoelastic material which remains permanently tacky
Remove from a surface without leaving a residue
Natural or synthetic rubbers, polyacrylates, silicone
Release liner (release paper, peel-away strip)
Sheet that serve as a protectant or carrier for an adhesive film(easily removed)
Paper, polystyrene or polyester films with coating of silicone, long-chain branched polymers, chromium complex, fluorochemicals or
various hard polymers
Rate controlling membranes Ethyl vinyl (EVA) copolymers
Microporous polyethylene or polypropylene
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Backing Laminate: High flexibility
Good oxygen transmission
High moisture vapor transmission rate
EG. vinyl, polyethylene and polyester films
Other excipients: Various solvents such as chloroform, methanol, acetone,
isopropanol and dichloromethane are used to prepare drug
reservoir. In addition plasticizers such as dibutylpthalate,
triethylcitrate, polyethylene glycol and propylene glycol areadded to provide plasticity to the transdermal patch
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Figure 1: Design of matrix type
transdermal patch
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Figure 2: Design of reservoir type
transdermal patch
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Figure 3: Design of micro reservoir
type transdermal patch
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Figure 4: Design of drug in adhesive
type transdermal patch
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Evaluation
Physicochemical evaluation.
Invitro studies
Invivo studies
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Physicochemical evaluation
THICKNESS
TACK PROPERTIES
UNIFORMITYOF WEIGHT
CONTENTUNIFORMITY
FOLDINGENDURANCE
MOISTURECONTENT
TENSILESTRENGTH
WATER VAPOURTRANSMISSION
STUDIES
PEELADHESION
PROPERTIES
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Invitro Release studies
The Paddle over Disc: (USP apparatus 5 )
The Cylinder modified USP Basket: (USPapparatus 6 )
The reciprocating disc: (USP apparatus 7)Diffusion Cells e.g. Franz Diffusion Cell and its
modification Keshary- Chien Cell
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pH of the dissolution medium= 1-5
Temp = 320C ( physiological skin temp. )
100 rpm
Concn
of drug determined
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Invivo studies :Animal models
mouse, hairless rat, hairless dog, hairless rhesus
monkey, rabbit, guinea pig etc
Human volunteerscollection of pharmacokinetic and pharmacodynamic
data following application of the patch to human
volunteers.Phase I,II.III.IV clinical trials
Skin irritation studiesWhite albino rats, mice or white rabbits are used
to study any hypersensitivity reaction on the skin. Stability studies
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RECENT ADVANCES
Rolf Amphoteric enhancers : SLS, lauryl amine oxide, Azone
decylmethylsulfoxide, lauryl ethoxylate, octanol
PSA (pressure sensitive adhesives) Adhesive matrix, multilaminated PSA matrix
Adverse interaction between the drug, exicipents, cosolvents
and permeation enhancers in reservoir and matrix-typesystem
Silicone PSA : tack, adhesion, cohesive strength
Polydimethylsioxane PSA : biocompatibility and high
permeability
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Actiderm (Bristol Myers Squibb) Path with no drug as occlusive dressing
Placed over topically applied corticosterids to enhance
efficacy by promoting hydration of the stratum corneum Laminated reservoir system by
Hercon Steady-state blood levels for extended periods
Two or four layers, including a backing membrane, thedrug reservoir, a rate-controlling membrane, and anadhesive
Ketobemidone and carbonate esterprodrug Prodrug with isopropyl myristate, ethanol and ethanol-
water readily penetrate the skin
Enzymatic conversion, high solubility of prodrug in polarand apolar solvents
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EXAMPLES OF TRANSDERMALAPPLICATIONS
Drug Trade Name Type of
Devices
Indication
Scopolamine Transderm-Scop
Reservoir Motionsickness
Nitroglycerine Transderm-Nitro
Reservoir Angina
Nitro-Dur Monolithic
Nitrodisc Monolithic
Estradiol Estraderm Reservoir andethanolenhancer
Hormonetreatment
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TABLE 2 TRANSDERMAL PRODUCTS UNDER
DEVELOPMENT
Drug Trade name Producer-Marketer
Minocycline Sunstar American Cyanamide,Takeda
Estradiol+Norethisterone
EstracombiTIS
Ciba-Geigy, Alza
DHEA Pharmedic
Fentanyl Duragesic Alza pharmaceuticals
Triamcinolone acetonide
Whitby Pharm.
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Conclusion
Critical parameter in designing a TDS Drug stability, physical stability of the formulation,irritation and sensitization properties, preservation andesthetic acceptability
Vehicle affect drug bioavailability
Maximizing drug penetration into skin
Two mechanism that manipulate thediffusion of a drug across the skin Change the degree of interaction between drug and
vehicle(drugs thermodynamic activity)
Changes in the stratum corneum that will affect itsdiffusional resistance (vehicle-barrier interaction)
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Transdermal therapy
70% or more of all drugs : potentially delive.redby TDS
Limitation : drug potency, skin permeability,topical reaction, cutaneous metabolism, delivery
by small volume of skin Further TTS : use of prodrug, penetration
enhancer and specific nontoxic enzymeinhibitors, Iontophoresis
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