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Transdermal Drug Delivery Systems

Transdermal Drug Delivery Systems

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Published by Kim Manlangit

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Published by: Kim Manlangit on Sep 12, 2010
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01/30/2013

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1
 Name:Pharmaceutical DosageChapter 11: Transdermal Drug Delivery SystemsTopical Dermatological Products
y
 
Drugs delivered into the skin for treatment of dermaldisorders
y
 
F
or local effects
y
 
Skin as the target organTransdermal Products
y
 
Drugs delivered through the skin (percutaneous absorption)to the general circulation
y
 
F
or systemic effects
y
 
Skin: not the target organTransdermal Drug Delivery System (TDDS)
y
 
F
acilitate the passage of therapeutic quantities of drugsubstances through the skin and into the general circulationfor their systemic effects
y
 
Transderm scop
 
F
irst transdermal (Ciba, now Novartis) approved by the
F
DA in 1979
 
Prevents motion sickness, nausea, and vomitingresulting from the use of certain anestheticsEvidences of Percutaneous Drug Absorption
y
 
Evidences of percutaneous drug absorption
 
M
easurable blood levels of the drug
 
Detectable excretion of the drug and/or itsmetabolites in the urine
 
Clinical response of the patient to the therapy
y
 
B
lood concentration needed to achieve (with TDDS)therapeutic efficacy determined by:
 
Comparative analysis of the patient¶s response tothe drug blood levels
y
 
I
deal for the drug
 
To migrate through the skin: blood supplywithout build up in the dermal layersStratum Corneum
y
 
Skin is composed of:
 
Stratum corneum (the outer layer)
 
L
iving epidermis
 
Dermis: provide the skin barrier (blockade) layersto penetration by external agents
y
 
Stratum corneum (keratinized tissue: major rate limiting barrier of TDDS)
 
B
ehaves as a semipermeable artificial membranedrug molecules penetrate by passive diffusionDrug Penetration in the
B
arrier 
y
 
Drug molecules through the stratum corneum: deeper epidermal tissues: dermis: vascularized dermal layer,
 
B
ecomes available for absorption into the generalcirculation
y
 
G
ood candidates for diffusion through the stratumcorneum, epidermis, and dermis: aqueous and lipid solublesubstances
F
actors Affecting Percutaneous Absorption
y
 
Physical and chemical properties of drugs including itsmolecular weight, solubility, partition coefficient, anddissociation constant, the nature of the carrier vehicle, andthe conditioning of the skin
y
 
Drug concentration
y
 
Area of application: the larger, the more drug is absorbed
y
 
G
reater physiochemical attraction to the skin than to thevehicle
y
 
Can permeate skin: with molecular weights ranging from100 to 800 (ideal molecular weight for TDDS: 400 or less)and adequate lipid and aqueous solubility
y
 
H
ydration of the skin favors percutaneous absorption
y
 
Site with a thin horny layer than with a thick one
y
 
The longer the medicated application is permitted to remainin contact with the skin and the greater is the total drugabsorptionCadaver Skin Permeation Testing
y
 
H
elps determine the feasibility of a compound to beincorporated into a TDDSChemical Enhancers
y
 
Chemical skin permeation enhancer: increases skin permeability by damaging or altering the physiochemicalnature of the stratum corneum to reduce its diffusionsubstance
y
 
Among the alterations of the stratum corneum are:
 
I
ncreased hydration of the stratum corneum
 
Change in the structure of lipids and lipoproteinsin the intercellular channels through solventaction or denaturation or both
y
 
Some drugs inherent capacity to permeate the skin withoutchemical enhancer.
y
 
Chemical permeation enhancer: render impenetrablesubstance useful in TDDS
y
 
M
ore than 275 chemical compounds have cited as skin penetration enhancers that include: acetone, azone,dimethyl acetamide, dimethly formamide, dimethylsulfoxide, ethanol, oleic acid, PE
G
, P
G
, and sodium laurylsulfatePhysical
M
ethods to Enhance TDDS
y
 
I
ontophoresis
 
Delivery of charged chemical compounds acrossthe skin membrane using an applied electricalfield
 
Drugs examined: lidocaine, dexamethasone,amino acids, peptides, insulin, verapamil, propanolol,
 
Delivered by rapid injection because of rapid metabolism and poor absorptionin oral delivery and from TDDS (largemolecular size, ionic character)
 
Enhance TDDS for peptide or proteinadministration
y
 
Sonophoresis
 
Studied as a means to enhance TDDS
 
2
 
 
I
nfluence integrity of stratum corneum and thusaffect penetrability
 
Agents examined: hydrocortisone, lidocaine, andsalicylic acid in such formulations as gels, creamsand lotionsDifferent Purposes for 
I
n-Vivo Skin Penetration Studies
y
 
To verify and quantify:
 
Cutaneous bioavailability of a topically applieddrug
 
Systemic bioavailability of a transdermal drug
y
 
To establish bioequivalence of different topicalformulations of the same drug substance
y
 
To determine the incidence and degree of systemictoxicological risk following topical application of a specificdrug or drug product
y
 
To relate resultant blood levels of drug in human tosystemic therapeutic effects
I
n-Vivo Skin Penetration Studies
y
 
M
ost relevant studies performed in humans and animalmodels (predictors of human response)
M
aterials Used
I
n-Vitro Skin Penetration Studies
y
 
Skin penetration may be tested in vitro using:
 
Various skin tissues (human or animal) in adiffusion cell
 
Using human skin: limited because of difficultiesof procurement, storage, expense, and variationin permeation
 
Animal skin: shown to be effective like shedsnakeskin (Elaphe obsolete, black rat snake)which is nonliving, pure stratum corneum,hairless and similar to human skin but slightlyless permeable
y
 
L
iving Skin Equivalent (
L
SE) Test Skin (Organogenesis
I
nc.)
 
Product developed as an alternative for dermalabsorption studies
 
An organotypic culture of human dermalfibroblasts in a collagen-containing matrix andstratified epidermis composed of humanepidermal keratinocytesDiffusion Systems and Principle Utilized
y
 
Diffusion cell systems
 
Employed in vitro to quantify the release rates of drugs from topical preparations
 
Skin membranes or synthetic membranesemployed as barriers to the flow of drug andvehicle to stimulate the biologic systemTwo Categories of the TDDS
y
 
M
onolithic system
 
I
ncorporate a drug matrix layer between backingand frontal layers
 
Drug matrix layer 
 
Composed of polymeric material (drugis dispersed)
 
Controls the rate at which the drug isreleased for percutaneous absorption
 
2 types either with or without an excessof drug with regard to its equilibriumsolubility and steady: stateconcentration gradient at the stratumcorneum
 
As the concentration of the drug in the devicediminishes below the skin¶s saturation limit
 
Transport of drug from device to skindeclines
 
M
ost TDDs designed to contain an excess of drug
 
Drug-releasing capacity beyond thetime frame recommended for replacement
y
 
M
embrane-controlled transdermal system
 
Designed to contain drug reservoir or pouch (inliquid or in gel form, a rate controllingmembrane)
 
B
acking, adhesive, and protecting layers
 
Examples of this technology: TransdermNitro(Novartis) and Transderm-Scop (Novartis)
 
Advantage over monolithic systems: release rateof drug remains constant when the drug solutionin the reservoir remains saturated
 
Prepared by preconstruction of the delivery unitfilling the drug reservoir: sealing or lamination
 
Continuous process
 
Serves as a rate-controlling mechanism or factor:
 
Drug delivery device
o
 
I
f the drug is delivered to thestratum corneum at a rate lessthan the absorption capacity
 
Skin
o
 
I
f the drug is delivered to theskin area toThe Transderm-Nitro System Comprises of 
F
our 
L
ayers
y
 
A tan-colored backing layer (aluminized plastic) that isimpermeable to nitroglycerin
y
 
A drug reservoir or matrix system containing nitroglycerinadsorbed on lactose, colloidal silicon dioxide, and siliconmedical fluid
y
 
An ethylene-vinyl acetate copolymer membrane that is permeable to nitroglycerin
y
 
A layer of hypoallergenic silicon adhesive: a protective peel strip that is removed from the adhesive surface prior touseDifferent
L
ayers of the Transdermal Drug Delivery System
y
 
Occlusive or blockade backing membrane
 
Protects the system from environmental entry andfrom loss of drug from the system or moisturefrom skin
y
 
Drug reservoir or matrix system
 
Stores and releases the drug at the skin site
y
 
elease liner 
 
emoved before application and enables drugrelease
y
 
Adhesive layer 
 
M
aintains contact with the skin after application
B
acking
L
ayer 
y
 
M
ust be occlusive
 
3
 
 
To retain the skin moisture and hydrate the site of application for increase drug penetration
y
 
Used as backing liners
 
Transparent or pigmented films of propylene, polyethylene, and polyofelinAdhesive
L
ayer 
y
 
M
ust be pressure sensitive
 
Adheres to the skin with minimal pressure andremains in place for intended period of wear 
y
 
Should be non-irritating, permit unimpeded drug flux to theskin, compatible with all other systems, allow easy peel-off after use
y
 
Commonly used as adhesive: polybutyl acrylateDifferent Design Objectives of TDDS
y
 
Deliver the drug to the skin for percutaneous absorption attherapeutic levels at an optimal rate
y
 
Contain medicinal agents having necessary physiochemical characteristics to release from the system,and partition to the stratum corneum
y
 
Occlude the skin to ensure one way flux of drug into thestratum corneum
y
 
H
ave a therapeutic advantage over other dosage forms anddrug delivery systems
y
 
 No irritation or sensitize the skin
y
 
Adhere well to the patient¶s skin and have size,appearance, and site placement that encourage acceptanceAdvantages of TDDS
y
 
Avoid:
 
G
astrointestinal absorption difficulties
 
F
irst-pass effect
 
I
nconvenience of parenteral therapy
y
 
Substitute for oral administration of medication
y
 
Provide extended:
 
Therapy with a single application
 
Activity of drugs having a short half- life through thereservoir of drug in the therapeutic delivery systemand its controlled release
y
 
Drug therapy may be terminated rapidly by removal of theapplication from the surface of the skin
y
 
I
dentified easily and rapidly in emergenciesDisadvantages of TDDS
y
 
Only relatively potent drugs are suitable candidates for transdermal delivery
y
 
Some patients develop contact dermatitis at the site of applicationExamples of Transdermal Drug Delivery Systems
y
 
Transdermal Scopolamine (transderm scop system)
 
Patch is worn (at least 4 hours before the anti-nausea effect is required) in a hairless area behindthe ear 
 
Prevents motion sickness, nausea and vomitingresulting from the use of certain anesthetics andanalgesics used in surgery
y
 
Transdermal Nitroglycerin
 
F
or prophylactic treatment of angina
 
W
hen taken sublingually: relatively low dose,short plasma half-life, high peak plasma levels,and inherent side effects
 
Examples: Deponit (Schawarz),
M
initram (3
M
 Pharmaceuticals), Nitro-Dur (Key), andTransderm-Nitro (Novartis)
y
 
Transdermal Clonidine (Catapres TTS)
 
F
irst trandermal system for hypertension
y
 
Transdermal Nicotine (Nicotrol)
 
As adjunct in smoking cessation programs
 
Effective aid in quitting smoking
 
Provides sustain blood levels of nicotinereplacement therapy
y
 
Transdermal Estradiol
 
Treatment of moderate to severe vasomotor symptoms associated with menopause, femalehypogonadism, female castration, primaryovarian failure, and atrophic conditions caused bydeficient endogenous estrogen production(atrophic vaginitis and kraurosis vulvae)
 
Examples: Vivelle (Novartis)
y
 
Transdermal Testosterone
 
F
or optimal absorption, applied to clean, dryscrotal skin that has been dry-shaved
 
Placed on the scrotum (stretching the scrotal skinwith one hand and pressing the adhesive side of the TDDS against the skin with the other hand,holding it in place for about 10 seconds)
 
Androderm TDDS: applied nightly to a clean, dryunbraded area of the skin of the back, abdomen,upper arms, or thighsOther Transdermal Therapeutic Systems
y
 
I
nclude:
 
Diltiazem, isosorbide dinitrade, propranolol,nifedipine, mepindolol, and verapamil, cardiovascular agents
 
L
evonorgestrel with estradiol for hormonalcontraception
 
Physostigmine and xanomeline for Alzheimer¶sdisease therapy
 
 Naltrexone and methadone for substance addiction
 
B
uspirone for anxiety
 
B
upropion for smoking cessation
 
Papaverine for male impotence
G
eneral Clinical Considerations in the Use of TDDSs
y
 
Percutaneous absorption varies with the site of application
y
 
Applied to clean, dry skin: relatively free of hair and notoily, irritated, inflamed, broken, or callused
y
 
Use of skin lotion: avoided at the application site: affectskin hydration and can alter the partition coefficient between the drug and the skin
y
 
Should not be physically altered by cutting since it destroysthe integrity of the system
y
 
Should be removed from its protective package or backing
y
 
Placed at a site not subjected to being rubbed off byclothing or movement
y
 
W
orn for full period stated in the products instructions
y
 
The patient or caregiver should clean the hands thoroughly before and after applying TDDS.
y
 
I
n case of sensitivity or intolerance, the patient should seek revaluation
y
 
TDDS should be folded in half: cannot be reused

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