ransdermal drug deliver systems Presented by Akashara B. Jambhulkar M.Pharm 2 nd Sem. (Pharmaceutics) 1
Transcript
1. 1
2. 2Contents1. Introduction2.Structure of skin3.Absorption
mechanism4.History of patches5.Components of Transdermal
Devices6.Types of Transdermal Patches7.Evaluation of TDDS8.Recent
Advances9.Marketed preparations10.References
3. Transdermal Patch or Skin Patch is a medicatedadhesive patch
that is placed on the skin to deliver atime released dose of
medication through the skin andinto the bloodstream.The delivery
rate is controlled by the skin or membranein the delivery system.
3
4. Advantages of TDDS1. Avoidance of presystemic metabolism.2.
Reduced inter- & intra-patient variability.3. Maintained
systemic drug level.4. Peak & Valley effect of oral or
injectabletherapy is avoided.5. Extended duration of action.4
5. 6. Improved patient compliance.7. Drug input terminated by
simple removal ofpatch.8. Reduced dosage related
side-effects.5
6. Disadvantages of TDDSLimitations of TDDS are principally
associatedwith the barrier function of skin.1. Method is limited
only to potent drugmolecules.2. Physicochemical properties of drug
shouldallow to be absorbed percutaneously.3. Molecular wt should be
reasonable.6
7. 4. Solubility should be in both lipophilic andhydrophilic
environments. Absence in eitherphase will preclude permeation.5.
Drugs with short biological half-lives cannotbe delivered by
TDDS.6. Drugs must not be locally irritating orsensitizing.7
8. The most extensive and readily accessible organ Covers a
surface area of approximately 2 m2 Receives about one-third of the
blood circulation.Composed of three tissue layers: Epidermis
DermisSubcutaneous fat tissue or hypodermis.8
9. Fig: Structure of Skin9
10. Epidermis:Comprises of stratum corneum and stratum
germinativum.Stratum corneum (10-15 m thick) is dry.Consists of
blocks of cytoplasmic proteinmatrices(keratins) embedded in
extracellular lipid.Corneocytes are arranged in an interlocking
structure.Stratum corneum cells formed and continuouslyreplenished
by slow upward migration of cells produced bybasal cell layers of
Stratum germinativum.10
11. Stratum corneum lipids consists of ceramides and
neutrallipids like free sterols , free fatty acids and
triglycerides &phospholipids.Despite low phospholipid levels
Stratum corneum lipidsform bilayers.All above points contribute to
tightness and impermeabilitycharacteristics of intact
skin.Molecules with molecular mass greater than 200-350 Da
areinefficient to cross the intact skin.Removal of upper 3
epidermal layers results into water lossand an enhancement of the
transdermal permeability.11
12. Dermis: Composes of network of collagen and elastic
fibersembedded in mucopolysaccharide matrix.It provides
physiological support for epidermis.Blood vessels approach the
interface of 2 layers hence isnot considered significant barrier to
inward drug permeationin vivo.Beneath the dermis fibrous tissue
opens out and mergeswith the fat-containing subcutaneous
tissue.12
13. Percuteneous Absorption & its
MechanisticAspectsDesigning TDDS requires:1. Understanding
permeation behavior of drug through skin.2. The flux through the
skin into the systemic circulation.3. Mechanism of permeation.Route
Relative surfacearea (%)Diffusionalpathlength ( m)Relative
viscosityof ST (%)Transcellular 99.0 25 90-99Intercellular 0.7 350
1-10Transfollicular 0.1 200 0.113
14. 14Fig : Various routes of drug absorption
15. 15
16. 16 The stratum corneum limited skin permeation.For a
systematically active drug to reach a target tissue remotefrom the
site of drug administration on the skin surface, it mustposses
physicochemical properties that facilitate the sorption ofdrug by
the stratum corneum, the penetration of drug through theviable
epidermis, and also the uptake of drug by microcirculation inthe
dermal papillary layer.The rate of permeation dQ/dt across various
layers of skin tissuecan be expressed mathematically asMechanism of
Rate-Controlled Transdermal DrugDelivery
17. 17Where,Cd = conc. of drug in donor phase.Cr = conc. of
drug in the receptor phase.Ps = the overall permeability
coefficient of the skin tissues to the drug.Ks/d = the partition
coefficient for the interfacial partitioning of the drugmolecule
from a TDD system onto the stratum corneum .Dss = the apparent
diffusivity for the steady-state diffusion of the drugthrough the
skin tissues.hs = overall thickness of the skin tissues for
penetration.To achieve a constant rate of drug permeation one needs
to maintain acondition in which the drug concentration on the
surface of stratum corneumCd is consistently and substantially
greater the drug concentration in the bodyCr, i.e. Cd >>
Cr.So, if the magnitude of Cd value remains fairly constant
throughout the courseof skin permeation, the rate of skin
permeation should be constant.
18. 18To maintain Cd at a constant value, it is necessary to
deliver the drug at a rate Rdthat is either constant or always
greater than Ra the rate of skin absorption, i.e.Rd >>Ra. By
making Rd greater than Ra the drug concentration on the skin
surfaceCd is maintained at a level equal to or greater than the
equilibrium solubility ofthe drug in the stratum corneum Cse , i.e.
Cd > Cse.A maximum rate of skin permeation (dQ/dt)m can be
expressed asMembrane limited drug release.In such systems the drug
delivery is controlled by the use of rate-limitingmembrane. The
bioavailability of the drug does not depend only on this, but
alsoon its absorption through the stratum corneum, and its
subsequent uptake intothe systemic circulation.
19. 19Historically, the Chinese medicated plaster can beviewed
as the first development of transdermal drugdelivery; it is
designed to bring medication into closecontact with the skin, so
drug can be deliveredtransdermally.Medicated plasters were also
very common in Japan asOTC dosage forms called Cataplasms,
Salonpas.In Western countries Allocks porous plasters ofEngland and
the ABC plaster of Germany.In the US 3 medicated plasters have been
listed inthe official compendia since 40 yrs ago Belladonnaplaster,
Mustard plaster, and Salicylic acid plaster.History of patches
20. 20Components of transdermal devicesThere are 2 basic types
of transdermal dosing systems1. Those that control rate of drug
delivery to skin2. Those that allow the skin to control the rate of
drug absorption.The basic components of transdermal devices
include: Polymer matrix Drug Penetration Enhancers Other Excipients
Adhesive/Packaging
21. 21Polymer matrixPolymers used in TDDS should fulfill:1. Mol
wt, physical & chemical characteristics must allow diffusionof
drug.2. Should be chemically non-reactive (inert drug carrier).3.
Must not decompose on storage.4. Polymer & its decomposed
product should be nontoxic.5. Polymer must be easy to manufacture
and fabricate .6. Cost should not be excessively high.Polymers used
in TDDS are Poly-propylene Poly vinyl carbonate Cellulose acetate
nitrate Polyacrylonitrle Ethylene vinyl acetate copolymer
Polyethylene terephthalate Hydroxypropyl cellulose
polyestersEthylene vinylacetatecopolymer
22. 22DrugChoice of drug is critical in successful development
oftransdermal product.Important properties of drug that affect its
diffusion include1. Molecular weight2. Chemical functionality3.
Partition coefficient4. Skin metabolismSkin irritation &
clinical need should also be considered.The drug should be
non-irritating and non-allergic to humanskin.
23. 23Penetration enhancersSkin permeation enhancers are
considered as integral part ofmost TDDDS.Penetration enhancers are
classified into mainly 3 categories:1. Lipophilic solventse.g.
Dimethyl sulfoxide2. Surface-active agentse.g. Sodium lauryl
sulfate (SLS)3. Two component systemse.g. oleic acid and propylene
glycol
24. 24Other excipientsSolvents such
as:Chloroform,Methanol,Acetone,Isopropanol andDichloromethane are
used to prepare drug reservoir.Plasticizers such
as:Dibutylpthalate,Triethylcitrate,Polyethylene glycol andPropylene
glycol are added to provide plasticity to thetransdermal
patch.
25. 25Adhesive and packaging:Adhesion of all transdermal
devices to skin is an essentialrequirement.Pressure-sensitive
polymeric adhesives are generally used.The adhesive system should
posses following characteristics:1. Should not cause irritation,
sensitization & imbalance to skin.2. Should adhere to skin
strongly.3. Should resist to normal routine disturbances
likebathing, abrasion and exercise.4. Should be easily removable.5.
Should have intimate contact with the skin.
26. 26Pressure-sensitive adhesive:It is defined as a material
that adheres to a substance when a lightpressure is applied and
leaves no residue when removed.There are 3 different categories of
adhesives:1. Butyl Rubberse.g. It is a copolymer of isobutylene
& isoprene.2. Polyisobutylenesdiffer from butyl rubber in
terminal unsaturation.used in polyolefin plaster surface.3. Butyl
rubber and PolyisobutylenesCombination of above two.
28. 281. Polymer Membrane Permeation ControlledTransdermal
PatchDrug reservoir - sandwiched between a drug impermeablebacking
laminate and a rate-limiting polymeric membrane.The drug molecules
are permitted to release only throughthe rate-controlling polymeric
membrane.
29. 29 In the drug reservoir compartment the drug solids are
:-dispersed homogeneously in a solid polymer matrix
polyisobutylenesuspended in a unleachable, viscous liquid medium
silicone fluiddissolved in a releasable solvent alkyl alcoholThe
rate-controlling membrane can be either a microporous or anonporous
membrane ethylene-vinyl acetate copolymer.On the external surface
of the polymeric membrane a thin layer ofdrug-compatible,
hypoallergenic pressure-sensitive adhesive polymermay be applied to
provide intimate contact of the TDD system with theskin surface.
These adhesives are usually based on silicones, acrylatesor
polyisobutylene.Examples Scopolamine releasing TDD system
Transderm-Scop system,Clonidine releasing TDD system Catapress-TSS
system
30. 30
31. 312. Polymer Matrix Diffusion ControlledTransdermal Patch2
types of systems1. Drug-in-adhesive system2. Matrix-dispersion
system1. Drug-in-adhesive system:Drug reservoir drug dispersed in
hydrophilic or lipophilicpolymer matrixDrug reservoir is then
mounted on a baseplate over which isthe drug-impermeable plastic
backing with an absorbent pad.Adhesive rim surrounds the reservoir
disc.
32. 32
33. 332. Matrix-dispersion systemDrug reservoir drug is
directly dispersed in a pressure-sensitive adhesive polymer, e.g.
polyacrylateThis is then coated onto a flat sheet of a
drug-impermeablebacking laminate. Additionally Release liner is
present.Examples Nitroglycerin releasing TDD system the Minitran
systemIsosorbide dinitrate releasing TDD system Frandol tape.
34. 343. Drug Reservoir Gradient ControlledTransdermal
PatchZero order releaseDrug reservoir drug loading level is varied
in an incrementalmanner, forming a gradient of drug reservoir along
theDiffusional path across the multilaminate adhesive
layers.Example Nitroglycerinreleasing TDD systemthe Deposit
system
35. 354. Micro reservoir Dissolution ControlledTransdermal
PatchIt is a hybrid of the reservoir and matrix dispersion-
typedrug delivery systems.Drug reservoir - formed by first
suspending the drugsolids in an aq. solution of drug solubilizer,
e.g.polyethylene glycol, and then homogeneously dispersingthe drug
suspension, in a lipophilic polymer to formthousands of unleachable
microscopic drug reservoirs.This thermodynamically unstable
dispersion is quicklystabilized by immediately cross-linking the
polymer chainsin situ. A TDD system is then produced by mounting
themedicated disc at the centre of adhesive pad.
36. 36Example Nitroglycerin releasing TDD system Nitrodisc
systemProgestin-estrogen releasing TDD system Transdermal
contraceptive system
37. 37Evaluation of Transdermal Drug DeliverySystemsEvaluation
of Adhesives1. Peel adhesion properties : Tested by measuring
theforce required to pull single coated tape.2. Tack propertiesa)
Thumb tack testb) Rolling ball tack testc) Quick-stick (or
peel-tack) testd) Probe tack test3. Shear Strength Properties:
Measurement of cohesivestrength of adhesive polymer.
38. 38Evaluation of Patches1. Interaction study2. Thickness of
patch3. Weight uniformity4. Folding Endurance of patch5. % Moisture
content6. % Moisture uptake7. Drug content8. Uniformity of unit
dosage form test9. Skin irritation studies10. Stability
studies
39. 39In-vitro drug release studies:Paddle over disc method is
used.(USP apparatus V)In-vitro skin permeation studies:1.
Keshery-Chien Diffusion Cell
40. 402. Franz diffusion cell
41. 41
42. 423. Valia Chien Diffusion Cell
43. 43Recent Advancements in TDD SystemsIontophoresis :- It can
be defined as the facilitation of ionizable drugpermeation across
the skin by an applied electrical potential, thedriving force of
which may be simply visualized as electrostaticrepulsion. Technique
involves application of small electric current(0.5mA/cm2)Example :-
Piroxicam
44. 44
45. 45Sonophoresis :- It is the enhancement of migration of
drug molecules through the skin byultrasonic energy. Mechanism of
drug permeation involves disruption of stratum corneumlipids. The
acoustic waves that reduce the resistance offered by stratumcorneum
lie in the frequency range of 20 KHz to 20 MHz.Example :- Salicylic
acid
46. 46
47. 47ElectroporationIt involves application of high voltage
pulses to the skin whichinduces formation of transparent pores.High
voltages of Direct Current 100 volts for few milliseconds
areemployed.The technology has been successfully used to enhance
skinpermeation of molecules differing in lipophilicity &
size.Example :- metoprolol, lidocaine, tetracaine, etc
48. 48Marketed Preparations :- Scopolamine-releasing TDD system
for 72 hrs prophylaxis ortreatment of motion-induced nausea
(Transderm-Scop) Nitroglycerine-releasing TDD system (Deponit,
Nitrodisc,Transderm-Nitro) and other isosorbide
dinitrate-releasingTDD system for once-a-day medication of angina
pectoris Clonidine-releasing TDD system for the weekly therapy
ofhypertension (Catapres-TTS) Estradiol-releasing TDD system for
the twice-a-weektreatment of postmenopausal syndromes (Estraderm)
Fentanyl-releasing TDD system for the twice-a-weekanalgesic in
cancer patients (Duragesic).
49. 491. Chien Y.W; Novel Drug Delivery System ; 2nd
edition;volume 50; Informa healthcare; pg no 301-380.2. Jain N.K;
Controlled and Novel Drug Delivery ; 1st edition;CBS Publishers; pg
no 100-129.3. Wokovich Anna M. Transdermal drug delivery
system(TDDS) adhesion as a critical safety, efficacy and
qualityattribute European Journal of Pharmaceutics
andBiopharmaceutics 64 (2006) 1-84. Mark Gibson; PHARMACEUTICAL
PREFORMULATION ANDFORMULATION- A practical guide for candidate
drugselection to commercial dosage form CRC press LLC 331-353.
50. 505. Keleb E, et al; Transdermal Drug Delivery
System-Design and Evaluation; International Journal of Advancesin
Pharmaceutical Sciences1 (2010) 201-211.6. Prabhakar V et al;
Transdermal drug delivery system:Review; International Resarch
Journal of Pharmacy 2012 3(5).7. Arunachalam. A. et al; Transdermal
Drug DeliverySystem: A Review; Current Pharma Research vol 1, issue
1,Oct-Dec 2010.8. J. Ashok Kumar et al; Transdermal Drug
DeliverySystem: A Overview; International Journal ofPharmaceutical
Sciences Review and Research; Volume 3,Issue 2, July August 2010;
Article 009