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PHARMACEUTICS
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WELCOMEWELCOME
T.B.EKNATH BABU (T.B.E.K.B) STUDENT AT ARULMIGU KALASALINGAM COLLEGE OF
PHARMACY..
1
T.B.EKNATH BABU (T.B.E.K.B)2
IntroductionIntroduction
Transdermal drug delivery is hardly an old technology, since 1800’s and
the technology is no longer just adhesive patches. Due to recent advances
in technology and the ability to apply the drug to the site of action without
rupturing the skin membrane, transdermal route is becoming a widely
accepted route of drug administration.
Over the last two decades more than 35 Transdermal patch products have
been approved in US.
Definition: Transdermal drug delivery system can deliver the drugs
through the skin portal to systemic circulation at a predetermined rate and
maintain clinically the effective concentrations over a prolonged period of
time.
T.B.EKNATH BABU (T.B.E.K.B)3
Potential advantages of TDDS Avoids chemically hostile GI environment (drug degradation in acidic
and basic environments is prevented).
No GI distress and the factors like Gastric emptying, intestinal motility,
transit time, donot effect this route as in oral route.
Avoidance of significant presystemic metabolism (degradation in GIT
or by the liver) and therefore need lower doses.
Allows effective use of drugs with short biological half-life.
Allow administration of drugs with narrow therapeutic window because
drug levels are maintained within the therapeutic window for prolonged
periods of time.
Reduced inter and intra patient variability.
T.B.EKNATH BABU (T.B.E.K.B)4
Enhance therapeutic efficacy, reduced fluctuations (rapid blood level
spikes-low and high) due to optimization of blood concentration – time
profile.
Reduction of dosing frequency and enhancement of patient compliance.
Provides controlled plasma levels of very potent drugs.
Can provide adequate absorption of certain drugs.
Avoids the risk and inconveniences of parenteral therapy (Painless method
of drug administration).
Drug input can be promptly interrupted simply by removal of the patch
when toxicity occurs.
Provides suitability of self medication.
T.B.EKNATH BABU (T.B.E.K.B)5
Disadvantages of TDDS Drugs that require high blood levels cannot be administered – limited
only to potent molecules, those requiring a daily dose of 10mg or less.
Transdermal administration is not a means to achieve rapid bolus type drug
input, rather it is usually designed to offer slow, sustained drug delivery.
Adequate solubility of the drug in both lipophilic and aqueous
environments, to reach dermal microcirculation and gain access to the
systemic circulation.
The molecular size of the drug should be reasonable that it should be
absorbed percutaneously.
T.B.EKNATH BABU (T.B.E.K.B)6
Tolerance inducing compounds are not an intelligent choice for this mode
of administration unless an appropriate wash out period is programmed in
between the dosing regimen.
Difficulty of permeation of the drug through human skin –barrier function
of the skin.
Skin irritation or dermatitis due to excipients and enhancers of drug
delivery system used for increasing percutaneous absorption is another
major limitation.
Adhesive may not adhere well to all types of skin.
Uncomfortable to wear.
May not be economical.
Cross-section of human skin
T.B.EKNATH BABU (T.B.E.K.B)7
Stratum Corneum (topmost 15 μm layer) is the main barrier
T.B.EKNATH BABU (T.B.E.K.B)8
1.Through stratum corneum 2.Transfollicular
3.Through sweat glandT.B.EKNATH BABU (T.B.E.K.B)9
Pathways of drug penetration
Mechanisms of drug permeation
T.B.EKNATH BABU (T.B.E.K.B)10
Hydrophilic drugs permeates by Intercellular pathway and Lipophilic drugs permeates by Intracellular (Transcellular) mechanism.
Skin permeability kinetics
T.B.EKNATH BABU (T.B.E.K.B)11
Fick’s First Law of Diffusion
Percutaneous absorption of most drugs is a passive-diffusion process that
can be described by Fick’s first law of diffusion
dQ/dt = JT = PAΔC
JT is the total flux transported through a unit area of skin per unit time in
steady state (µg/hr)
A is area of the skin
P is the effective permeability coefficient
ΔC is the drug concentration gradient across the skin
Factors affecting percutaneous absorption
T.B.EKNATH BABU (T.B.E.K.B)12
Physicochemical factors
Biological factors
Formulation factors
T.B.EKNATH BABU (T.B.E.K.B)13
Physicochemical factors of penetrant/drug
Partition coefficient
Solubility
Ionization / pKa
Molecular size and weight
Stability or half-life
T.B.EKNATH BABU (T.B.E.K.B)14
Biological factors
PH of the environment
Area of application
Age, Sex, Race
Condition of the skin
• Integrity and Thickness of stratum corneum
• Pathological conditions of skin
• Hydration
• Metabolism
• Temperature
T.B.EKNATH BABU (T.B.E.K.B)15
Formulation factors
Vehicle-solubility of the drug
• Lipophilicity of the solvent
• PH of the vehicle
Composition of drug delivery system
• Surfactants
Drug properties
T.B.EKNATH BABU (T.B.E.K.B)16
Dose deliverable : ≤ 10mg/day
Aqueous solubility : >1mg/ml
Lipophilicity : log P (1-3)
Molecular size : < 500 Daltons
Melting point : < 200°C
Drug should not be an irritant to skin.
The drug should not stimulate an immune reaction in the skin.
Along with these properties the drug should be potent, having short half
life
Strategies for the enhancement of drug permeability
T.B.EKNATH BABU (T.B.E.K.B)17
T.B.EKNATH BABU (T.B.E.K.B)18
Drug vehicle interactions
1.Prodrugs The prodrug approach has been investigated to enhance
transdermal delivery of drugs with unfavourable partition coefficients.
The prodrug design strategy generally involves addition of a pro-moiety to increase partition coefficient and solubility to increase the transport of the drug in the stratum corneum.
Upon reaching the viable epidermis, esterases release the active drug by hydrolysis thereby optimizing concentration in the epidermis.
T.B.EKNATH BABU (T.B.E.K.B)19
2.Ion-pairs Charged drug molecules do not readily partition into or
permeate through human skin. Formation of lipophilic ionpairs has been investigated to increase stratum corneum penetration of charged species.
This strategy involves adding an oppositely charged species to the charged drug, forming an ion-pair in which the charges are neutralized so that the complex can partition into and permeate through the stratum corneum.
The ion-pair then dissociates in the aqueous viable epidermis releasing the parent charged drug that can diffuse within the epidermal and dermal tissues.
Needle-free Jet Injectors
T.B.EKNATH BABU (T.B.E.K.B)20
Advantages
T.B.EKNATH BABU (T.B.E.K.B)21
Pain-free delivery — particles are too small to trigger pain receptors on the skin. Improved efficacy and bioavailability. Targeting to a specific tissue, such as a vaccine delivered to
epidermal cells. Accurate dosing and Overcomes needle phobia. Safety — the device avoids skin damage or infection from needles or splash back of body fluids. The PowderJect system fires solid particles (20–100µm)
through stratum corneum into lower skin layers, using a supersonic shock wave of helium gas.
Intraject is a development of the vaccine gun designed to deliver liquids through skin without using needles.
2.Chemical permeation enhancers
T.B.EKNATH BABU (T.B.E.K.B)22
A substance that will increase the permeability of the epithelial barrier by modifying its structure also termed as accelerants or sorption promoters-can enhance drug flux.
Ideal Penetration EnhancerNon-toxic, non-irritating, non-allergenic.Immediate onset of increased permeability.Immediate recovery of normal barrier properties upon removal
(reversible).Physically and Chemically compatible with a wide range of drugs.
T.B.EKNATH BABU (T.B.E.K.B)23
• Solvents - Ethanol, acetone, polyethylene glycol, glycerol, propylene glycol, dimethyl sulfoxide
• Surfactants - Brij30, brij72, Pluronic, Sodium lauryl sulphate, Span 20, Tween 80.
• Azones - N- Acyl hexahydro-2-oxo-1H-azepines, N-Alkylmorpholine-2,3-diones.
• Terpenes - Limonene, Carvone
• Fatty alcohols - Lauryl alcohol, linolenyl alcohol, oleic and fatty acids acid and lauric acid.
• Miscellaneous - Lecithin, sodium deoxycholate, L-amino
acid, acid phosphatase,phospholipase & calonase
Electrically Assisted methods
T.B.EKNATH BABU (T.B.E.K.B)24
1.Ultrasound (Phonophoresis / Sonophoresis)
Used originally in physiotherapy and sports medicine, applies a preparation topically and massages the site with an ultrasound source.
The ultrasonic energy (at low frequency) disturbs the lipid packing in stratum corneum by cavitation.
Sonicators operating at frequencies in the range of 20kHz to 3MHz are available commercially and can be used for Sonophoresis.
Therapeutic ultrasound (1–3MHz) - for massage, Low-frequency ultrasound (23-40kHz) - in dentistry, High-frequency ultrasound (3–10 MHz) - diagnostic purposes.
Enhanced Transdermal Permeation by Cavitation of stratum corneum upon application of Ultrasound.
T.B.EKNATH BABU (T.B.E.K.B)25
Ultrasound to Enhance Skin Permeability
T.B.EKNATH BABU (T.B.E.K.B)26
2.Iontophoresis
T.B.EKNATH BABU (T.B.E.K.B)27
The electrical driving of charged molecules into tissue, passes a small direct current (approximately 0.5 mA/cm2) through a drug containing electrode in contact with the skin. The most popular electrodes are based on the silver/silver chloride redox couple.
Three main mechanisms enhance molecular transport:
Charged species are driven primarily by electrical repulsion from the driving electrode.
Flow of electric current may increase the permeability of skin and
Electroosmosis may affect uncharged molecules and large polar peptides.
Limitations: Hair follicle damage is possible.
T.B.EKNATH BABU (T.B.E.K.B)28
3.Electroporation
T.B.EKNATH BABU (T.B.E.K.B)29
Skin electroporation (electropermeabilization) creates transient aqueous pores in the lipid by application of high voltage of electrical pulses of approximately 100–1000 V/Cm for short time(milliseconds). These pores provide pathways for drug penetration that travel straight through the horny layer.
This technology has been successfully used to enhance the skin permeability of molecules with differing lipophilicity and size including biopharmaceuticals with molecular weights
greater that 7kDA..
T.B.EKNATH BABU (T.B.E.K.B)30
T.B.EKNATH BABU (T.B.E.K.B)31
T.B.EKNATH BABU (T.B.E.K.B)32
Basic components of TDDS
T.B.EKNATH BABU (T.B.E.K.B)33
Drug
Polymer matrix
Penetration enhancers
Other Excipients
• Rate controlling membrane
• Adhesive
• Release liner
• Backing membrane
Types of Transdermal delivery devices
T.B.EKNATH BABU (T.B.E.K.B)34
Transdermal matrix system
35
Rate controlling factors Drug concentration in polymer matrix
Chemical nature of polymer matrix Geometry of device
Polymers: PVC, PVP, Ethylene vinylacetate, microporous polypropylene.
Initially the drug is released rapidly, then rate declines as matrix is depleted.
Advantages: Sleeker and thinner, daily or multiple-day Applications. Appropriate for drugs that penetrate readily and/or have low
dosage requirements.
Transdermal reservoir system
36
Rate controlling factorsMembrane thickness
Membrane permeability
Polymers: Cellulosic esters, polyamides or PVC.
Advantages: Used when matrix systems cannot penetrate skin and drugs require significant penetration enhancement and/or high dosage levels.
T.B.EKNATH BABU (T.B.E.K.B)37
Release liners Protects the skin-contacting adhesive during storage. Substrate carries a very thin release coating. Provides low energy surface for ease of removal.e.g.: polyester or polystyrene based films.
Backing material Contains formulation throughout shelf life and during wear period. They have laminate structure. They must be compatible with the formulation (nonadsorptive). They are occlusive and completely water impermeable in nature. e.g.: Poly urethane films, Ethyl vinyl acetate, Poly olefins.
Adhesive layer Acrylic copolymers, polyisobutylene and polysiloxane.
Evaluation of TDDSEvaluation of TDDS
T.B.EKNATH BABU (T.B.E.K.B)38
Content, Content uniformity. In vitro release Vs Ex vivo permeation of active and
penetration enhancer – difussion cells. Residual solvent, residual monomer Release liner peel, adhesion. Mechanical properties Moisture absorption & Moisture loss Microbiology Pouch integrity
Franz Diffusion CellFranz Diffusion Cell
T.B.EKNATH BABU (T.B.E.K.B)39 Skin: Rat abdominal, Rabbit, Porcine, Human cadaver
Mechanical properties evaluation by Mechanical properties evaluation by
ultra testerultra tester
T.B.EKNATH BABU (T.B.E.K.B)40
Moisture absorption & Moisture loss Moisture absorption & Moisture loss
studiesstudies
T.B.EKNATH BABU (T.B.E.K.B)41
Moisture absorption study: Saturated solution of Alcl3 (79.50% RH)/ 3 days.
• Moisture loss study: Patches were placed in a desiccator containing Cacl2 at 40oC/24 hr.
Transdermal patches available in the market
T.B.EKNATH BABU (T.B.E.K.B)42
Marketed Products of Modified Transdermal Drug Delivery Technologies
T.B.EKNATH BABU (T.B.E.K.B)43
Conclusion
T.B.EKNATH BABU (T.B.E.K.B)44
Transdermal drug delivery technologies are becoming one of
the fastest growing sectors within the pharmaceutical industry.
Advances in drug delivery systems have increasingly brought
about rate controlled delivery with fewer side effects as well
as increased efficacy and constant drug delivery.
The market value for transdermal delivery was $12.7 billion in
2005, and is expected to increase to $21.5 billion in the year
2010 and $31.5 billion in the year 2015 – suggesting a
significant growth potential over the next 10 years.
References
T.B.EKNATH BABU (T.B.E.K.B)45
Controlled drug delivery –concepts and advances – by S.P.Vyas R.K.Khar.
Encyclopedia of pharmaceutical technology -third edition edited by James Swarbrick volume-4 Microsphere Technology and Applications by Diane J. Burgess and Anthony J. Hickey.
Controlled and Novel drug delivery edited by N.K.Jain reprint 2007
Encyclopedia of controlled drug delivery volume 2 encyclopedia of controlled drug delivery
Asian Journal of Pharmaceutical and Clinical Research transdermal drug delivery system: a review p. k.gaur,s. mishra, s. purohit, k. dave..
T.B.EKNATH BABU (T.B.E.K.B)46
European Journal of Pharmaceutical Sciences Review -Novel
mechanisms and devices to enable successful transdermal drug
delivery by B.W. Barry.
Transdermal drug delivery- penetration enhancement
techniques- Heather A.E. Benson.
Microneedles : The option for painless delivery by Geeta M
Patel.
T.B.EKNATH BABU (T.B.E.K.B)47