dermal and transdermal drug delivery system
DESCRIPTION
This ppt gives an overview of dermal and transdermal DDS and also explains the different approaches in both.TRANSCRIPT
Presented by: Naraino Majie Nabiilah
Date: 5th November 2014
Table of content
• Introduction
• History
• Anatomy and physiology of the skin
• Dermal drug delivery system (DDDS)
• Recent approaches in DDDS
• Transdermal drug delivery system (TDDS)
• Recent approaches in TDDS
• Conclusion
• References
Introduction
• Drug products topically administered via the skin fall
into two general categories; those applied for local action
and those for systemic effects.
• Local actions include those at or on the surface of the
skin, those that exert their actions on the stratum
corneum, and those that modulate the function of the
epidermis and/or the dermis.
• Common products in the former category include
creams, gels, ointments, pastes, suspensions, lotions,
foams, sprays, aerosols, and solutions. Creams,
ointments, and gels generally are referred to as semisolid
dosage forms.
Introduction
• The most common drug products applied to the skin
for systemic effects are referred to as self-adhering
transdermal drug delivery systems (TDDS) or
transdermal patches.
• Transdermal drug delivery systems deliver drugs
through the skin as an alternative to oral,
intravascular, subcutaneous, and transmucosal routes.
• A transdermal patch or skin patch is a medicated
adhesive patch that is placed on the skin to deliver a
specific dose of medication through the skin and into
the bloodstream. Often, this promotes healing to an
injured area of the body.
History
• Topical and transdermal formulations have a long
history of use.
• Over 2000 years ago, Greek physicians used
formulations containing salt, vinegar, honey and resins
to treat skin lesions and ulcers.
• Chinese, Egyptian and Roman medical histories
describe numerous remedies applied topically as pastes
and poultices.
• Topical and transdermal products remain key
formulations for delivering drugs not only to the skin,
but also through it for systemic action.
History
• An estimated 40 million topical items are dispensed
annually, including 16 million emollient products and
13 million topical corticosteroid preparations.
• In addition, many other products are dispensed for
topical anaesthesia and antisepsis or for transdermal
delivery, such as fentanyl patches.
• Additionally, ‘over-the-counter’ products are widely
sought by patients and range from emollients to non-
steroidal anti-inflammatory creams and gels, to
treatments for warts, verrucae and fungal infections,
such as athletes’ foot.
History
• Thus, pharmacists often supply topical and transdermalformulations which contain a broad variety of activeingredients.
• It has been reported that up to 20% of all repeatprescriptions are for application to the skin.
• The efficacy of these products is critically dependenton biological factors, such as:
– the integrity of the skin,
– on the physicochemical properties of the activeingredient and
– on the formulation designed to release and deliverthe active into or across the skin.
Anatomy And Physiology of The Skin
• Human skin comprises of three distinct but mutually
dependent tissues:
– Epidermis
– Dermis
– Hypodermis.
• Epidermis
– The multilayered epidermis varies in thickness,
depending on cell size and number of cell layers of
epidermis, ranging from 0.8 mm on palms and
soles down to 0.06 mm on the eyelids.
Anatomy And Physiology of The Skin
• Stratum corneum
– This is the outermost layer of skin also called as hornylayer.
– It is approximately 10 mm thick when dry but swells toseveral times this thickness when fully hydrated.
– It contains 10 to 25 layers of dead, keratinized cells calledcorneocytes.
– It is flexible but relatively impermeable.
– The stratum corneum is the principal barrier forpenetration of drug.
– The lipids are arranged in multiple bilayers. There issufficient amphiphilic material in the lipid fraction, suchas polar free fatty acids and cholesterol, to maintain abilayer form.
Anatomy And Physiology of The Skin
• Viable epidermis
– This is situated beneath the stratum corneum.
– Going inwards, it consists of various layers as stratumlucidum, stratum granulosum, stratum spinosum andthe stratum basal.
– In the basal layer, mitosis of the cells constantlyrenews the epidermis and this proliferationcompensates the loss of dead horney cells from theskin surface.
– As the cells produced by the basal layer moveoutward, they alter morphologically andhistochemically, undergoing keratinisation to form theoutermost layer of stratum corneum.
Anatomy And Physiology of The Skin
• Dermis
– Dermis is 3 to 5 mm thick layer and is composed of amatrix of connective tissue, which contains bloodvessels, lymph vessels and nerves.
– The cutaneous blood supply has essential function inregulation of body temperature.
– It also provides nutrients and oxygen to the skin whileremoving toxins and waste products.
– Capillaries reach to within 0.2 mm of skin surface andprovide sink conditions for most molecules penetratingthe skin barrier.
– The blood supply thus keeps the dermal concentrationof a permeate very low and the resulting concentrationdifference across the epidermis provides essentialconcentration gradient for transdermal permeation
Anatomy And Physiology of The Skin
• Hypodermis
– The hypodermis or subcutaneous fat tissue supports
the dermis and epidermis.
– It serves as a fat storage area.
– This layer helps to regulate temperature, provides
nutritional support and mechanically protection.
– It carries principal blood vessels and nerves to skin
and may contain sensory pressure organs.
• For transdermal drug delivery, drug has to penetrate
through all these three layers and reach into systemic
circulation while in case of topical drug delivery only
penetration through stratum corneum is essential and
then retention of drug in skin layers is desired.
Dermal Drug Delivery Systems
• Semisolids constitute a significant proportion of
pharmaceutical dosage forms. They serve as carriers
for drugs that are topically delivered by way of the
skin.
• Because of their peculiar rheological behaviour,
semisolids can adhere to the application surface for
sufficiently long periods before they are washed off.
• This property helps prolong drug delivery at the
application site.
Dermal Drug Delivery Systems
• A semisolid dosage form is advantageous in terms of its
– easy application,
– rapid formulation, and
– ability to topically deliver a wide variety of drug
molecules.
• Semisolids are available as a wide range of dosage
forms, each having unique characteristics.
Dermal Drug Delivery Systems
• ADVANTAGES:
– Avoid of first pass metabolism.
– Site specific action of drug on affected area.
– Convenient for unconscious patient or patient havingdifficulty on oral administration.
– Suitable dosage form for bitter drugs.
– More stable than liquid dosage form.
• DISADVANTAGES:
– May cause staining.
– They are bulky to handle.
– Application with finger may cause contamination.
– Physico-chemically less stable than solid dosage form.
– May cause irritation.
– Allergic to some patients.
Dermal Drug Delivery Systems
• OINTMENTS
– Ointments are semisolid preparations for external
application to skin or mucous membranes.
– Their composition softens but does not melt upon
application to the skin.
– Therapeutically, ointments function as skin protectives
and emollients, but they are used primarily as vehicles
for the topical application of drug substances.
Dermal Drug Delivery Systems
• CREAMS
– Creams are semisolid dosage forms that contain oneor more drug substances dissolved or dispersed in asuitable base, usually an oil-in-water emulsion oraqueous microcrystalline dispersion of long-chainfatty acids or alcohols that are water-washable and arecosmetically and aesthetically acceptable.
• GELS
– Gels are semisolid systems that consist of eithersuspensions of small inorganic particles or largeorganic molecules interpenetrated by a liquid.
– Gels can be either water based (aqueous gels) ororganic solvent based (organogels).
Dermal Drug Delivery Systems
• PASTES
– Pastes are semisolid dosage forms that contain one or
more drug substances incorporated in a base with
large proportions of finely dispersed solids.
• LOTIONS
– Although the term lotion may be applied to a solution,
lotions usually are fluid, somewhat viscid emulsion
dosage forms for external application to the skin.
– Lotions share many characteristics with creams.
Recent Approaches in Dermal Drug Delivery
BIPHASIC VESICLES
• Scientists recently demonstrated that biphasicvesicles—a lipid-based, topical delivery system—can deliver large molecule or macromolecule drugsinto the skin.
• Biphasic vesicles may help revive drugs shelved inthe past due to problems with effective delivery.
• At the same time, biphasic vesicles enable thedesign of difficult-to-deliver molecules for a broadrange of new drugs, allowing non-invasive and safedelivery through the skin.
• Dermal delivery involves delivery of a drug intothe skin itself for dermatological treatments,vaccinations, or cosmetic applications
Recent Approaches in Dermal Drug Delivery
PERMEATION ENHANCERS
• Skin can act as a barrier to the deeperpenetration of drug molecules.
• Penetration enhancers incorporated in asuitable drug-carrying semisolid vehicle,enhance the amount of drug permeationthrough skin either by reversiblydisordering the lamellar packing of stratumcorneum or by increasing thethermodynamic activity of the drug.
• Another class of penetration enhancers actsby increasing the amount of drug insolubilised form at the skin surface,resulting in the enhanced permeability oflipophilic drug molecules.
Transdermal Drug Delivery System
• Transdermal drug delivery system (TDDS) provides a meansto sustain drug release as well as reduce the intensity ofaction and thus reduce the side effects associated with its oraltherapy.
• Transdermal drugs are self-contained, discrete dosage form.
• It delivers a drug through intact skin at a controlled rate intothe systemic circulation.
• Delivery rate is controlled by the skin or membrane in thedelivery system.
• A transdermal patch or skin patch is a medicated adhesivepatch that is placed on the skin to deliver a specific dose ofmedication through the skin and into the bloodstream.
• Often, this promotes healing to an injured area of the body.
Transdermal Drug Delivery System
• Advantages of transdermal drug delivery systems
– Avoidance of first pass metabolism
– Avoidance of gastro intestinal incompatibility
– Predictable and extended duration of activity
– Minimizing undesirable side effects
– Provides utilization of drugs with short biological half lives,narrow therapeutic window
– Improving physiological and pharmacological response
– Avoiding the fluctuation in drug levels
– Maintain plasma concentration of potent drugs
– Termination of therapy is easy at any point of time
– Greater patient compliance due to elimination of multiple dosingprofile
– Ability to deliver drug more selectively to a specific site
– Provide suitability for self administration
– Enhance therapeutic efficacy
Transdermal Drug Delivery System
• Disadvantages of transdermal drug delivery systems
– There is possibility of skin irritation due to the one ormany of the formulation components.
– Binding of drug to skin may result in dose dumping.
– It can be used only for chronic conditions where drugtherapy is desired for a long period of time
– Lag time is variable and can vary from several hours todays for different drug candidates.
– Cutaneous metabolism will affect therapeutic performanceof the system.
– Transdermal therapy is feasible for certain potent drugsonly.
– Transdermal therapy is not feasible for ionic drugs.
Transdermal Drug Delivery System
• TYPES OF PATCHES AVAILABLE
–Single-layer Drug-in-Adhesive
• The adhesive layer of this system also contains the
drug.
• In this type of patch the adhesive layer not only
serves to adhere the various layers together, along
with the entire system to the skin, but is also
responsible for the releasing of the drug.
• The adhesive layer is surrounded by a temporary
liner and a backing.
Transdermal Drug Delivery System
• Multi-layer Drug-in-Adhesive
– The multi-layer drug-in adhesive patch is similar to
the single-layer system in that both adhesive layers are
also responsible for the releasing of the drug.
– The multi-layer system is different however that it
adds another layer of drug-in-adhesive, usually
separated by a membrane (but not in all cases).
– This patch also has a temporary liner-layer and a
permanent backing.
Transdermal Drug Delivery System
• Reservoir
– Unlike the Single-layer and Multi-layer Drug-in-
adhesive systems the reservoir transdermal system has
a separate drug layer.
– The drug layer is a liquid compartment containing a
drug solution or suspension separated by the adhesive
layer.
– This patch is also backed by the backing layer.
– In this type of system the rate of release is zero order.
Transdermal Drug Delivery System
• Matrix
– The Matrix system has a drug layer of a semisolid matrixcontaining a drug solution or suspension.
– The adhesive layer in this patch surrounds the drug layerpartially overlaying it.
• Vapour Patch
– In this type of patch the adhesive layer not only serves toadhere the various layers together but also to releasevapour.
– The vapour patches are new on the market and theyrelease essential oils for up to 6 hours.
– The vapours patches release essential oils and are used incases of decongestion mainly.
Recent Approaches in Transdermal Drug Delivery
• A) CHEMICAL APPROACH:
– Solvents: Water, alcohols, alkyl methyl sulfoxides
(dimethyl sulfoxide), dimethyl acetamide etc
– Azones
– Terpenes, terpenoids and essential oils
– Fatty acids and esters
– Surfactants
– Bile salts
– Prodrug approach
CHEMICAL APPROACH
Water
Water is the most natural penetration enhancer. Usually,hydration of the stratum corneum is one of the primary measuresto increase the penetration of both hydrophilic and lipophilicpermeants. Free water within the tissue could alter the solubilityof a permeant in the stratum corneum. Also increased skinhydration may swell and open up the compact structure of thestratum corneum, leading to an increase in penetration.
Alcohols
These include alkanols, alkenols, glycols, polyglycols andglycerols. Alcohols can enhance skin permeation by a varietyof mechanisms such as extraction of lipids and proteins,swelling of the stratum corneum or improving drugpartitioning into the skin or solubility of the drug in theformulation. Ethanol increases the permeation of ketoprofenfrom a gel spray formulation and triethanolamine salicylatefrom a hydrophilic emulsion base.
• SOLVENTS:
CHEMICAL APPROACH
Azone
Azone was the first molecule specifically designed as a skinpenetration enhancer. Azone is regarded as an effective and non-toxic chemical enhancer. It is most effective at low concentrations,being employed typically between 0.1- 5%. Azone partitions into abilayer lipid to disrupt their packing arrangement. Azone enhancespermeation of wide variety of drugs like indomethacin, urea,methadone, 5-fluorouracil, propranolol hydrochloride.
Terpenes, terpenoids and essential oils
Terpenes and terpenoids are usually the constituents of volatileoil. In general smaller terpenes with non-polar groups are betterskin permeation enhancers. L-menthol has been shown toincrease the skin absorption of testosterone, ceramides andcholesteryl oleate. Menthol affects skin permeation by formingeutectic mixture with the penetrating compound, therebyincreasing its solubility and by altering the barrier properties ofthe stratum corneum.
CHEMICAL APPROACH
Fatty acids and esters
A large number of fatty acids and their esters have beenused as permeation enhancers. Variety of mechanismsof action suggested for these chemicals such aspartitioning into the lipid bilayers and disrupting theirordered domains, improving drug partitioning into thestratum corneum and forming lipophilic complexes withdrugs.
Surfactants
Usually, surfactants are added to formulations in order tosolubilise lipophilic active ingredients, and so they havepotential to solubilise lipids within the stratum corneum.These include Anionic surfactants like sodium laurylsulphate (SLS), cationic surfactants include cetyltrimethylammonium bromide, the nonoxynol surfactants are non-ionic surfactants and zwitter ionic surfactants includedodecyl betaine.
CHEMICAL APPROACH
Bile salts
The potential of sodium choleate, an ox bile extract containing thesodium salts of taurocholic, glycoeolic, desoxycholic and cholicacids, and of the free choleic acids (HCOL) to enhance thetranscutaneous penetration of progesterone and prednisolone, wasevaluated by using excised hairless mouse skin.
Prodrug approach
Drug candidates for topical delivery may lack the requisitephysicochemical properties that would allow them to permeatethe skin to a clinically useful extent. One way to overcome thisobstacle is to make prodrug of the drug with the correctphysicochemical properties. Prodrugs are therapeutically inactivederivatives of drugs that undergoes in vivo metabolism to producethe therapeutically active drug. E.g. The release rate of estradiolfrom Transdermal Bioactive Hormone Delivery is dependent onthe chain length of the ester group at the 17th position.
Recent Approaches in Transdermal Drug Delivery
• B) PHYSICAL APPROACH:
– Abrasion
– Microscissuining
– Electroporation
– Iontophoresis
– Laser Radiation
– Pressure waves
– Sonophoresis/phonophoresis
– Microneedle-based Devices
– Needle-less Injection
– Magnetophoresis
– Aquasomes
– Ethosomes
– Solid lipid nanoparticles
PHYSICAL APPROACH
Abrasion
The abrasion technique involves the direct removal or disruptionof the upper layers of the skin to facilitate the permeation oftopically applied medicaments. The observed enhancement ofpermeability is a result of disruption of the cells of the stratumcorneum, causing a reduction of the barrier function of the skin.Upper layers of skin can be simply removed by using chemicalpeels. Adhesive tape and rotating brush can remove stratumcorneum prior to drug application.
Microscissuining:
It is a process which creates micro channels in the skin byeroding the impermeable outer layers with sharpmicroscopic metal granules. Carlisle Scientific is currentlyin the process of developing a pen-like handheld devicecalled the microscissioner. A recently developed noveldermal abrasion device (D3S) has shown to increase thepenetration of angiotensin into the skin 100-fold comparedto untreated human skin.
PHYSICAL APPROACH
Electroporation
Electroporation or electro permeabilization is asignificant increase in the electricalconductivity and permeability of the cellplasma membrane caused by an externallyapplied electrical field. It involves theapplication of short (microsecond ormillisecond), high voltage (50-1000 volts)pulses to the skin. The mechanism ofpenetration is the formation of transient poresdue to electric pulses that subsequently allowthe passage of macromolecules from theoutside of the cell to the intracellular space viaa combination of processes such as diffusionand electrophoresis. Voltage, pulse length,number of pulses, electrode area andphysicochemical properties of drugs are amongthe factors affecting drug permeation inelectroporation.
PHYSICAL APPROACH
Iontophoresis
Iontophoresis is a process of transportation of ionic moleculesinto the tissues by passage of electric current through theelectrolyte solution containing the ionic molecules using suitableelectrodes. Electrical energy assists the movement of ions acrossthe stratum corneum according to the basic electrical principle oflike charges repel each other and opposite charges attracts. Thedrug is applied under an electrode of the same charge as thedrug, and a return electrode opposite in charge to the drug isplaced at a neutral site on the body surface.
Laser Radiation
This method involves direct and controlled exposure of a laser tothe skin which results in the ablation of the stratum corneumwithout significantly damaging the underlying epidermis.Removal of the stratum corneum using this method has beenshown to enhance the delivery of lipophilic and hydrophilicdrugs.
PHYSICAL APPROACHPressure waves
Pressure waves are generated by the intense laserradiation and can permeabilize the stratumcorneum and cell membrane; it allowsmacromolecules to diffuse stratum corneum andfacilitate the transdermal drug transport throughthe skin. The pressure wave is applied for a veryshort time (100 ns-1μs). It is thought that thepressure waves form a continuous or hydrophilicpathway across the skin due to expansion oflacunae domains in the stratum corneum. Thedelivery of the drug takes place by diffusion underthe concentration gradients. A single pressurewave is sufficient to permeabilize the stratumcorneum and allow the transport ofmacromolecules into the epidermis and dermis.Pressure wave can be generated by opticalbreakdown, ablation, or rapid heating of anabsorbing medium (thermoelastic generation).
PHYSICAL APPROACH
Sonophoresis/Phonophoresis
Sonophoresis is the movement of drug molecules throughthe skin under the influence of ultrasound. Ultrasound is apressure wave having a frequency of more than 18 kHz.The mechanism involved in the Sonophoresis may befollowing
1. Cavitation: Open up the intracellular pathways, allowingsubstances with high molecular weights a higher degree ofpenetration.
2. Thermal effects: Reduced the density of lipid in theintercellular domain of the bi-layers.
3. Induction of convective transport
4. Mechanical effects: Occurrence of stresses due topressure variation induced by ultrasound.
Low-frequency ultrasound has been found to enhancetransdermal transport of several permeants, includingestradiol, salicylic acid, corticosterone, sucrose,aldosterone, water, and butanol.
PHYSICAL APPROACH
Microneedles
It consists of an array of micro-structured projectionsthat are applied to the skin so that they pierce only thestratum corneum to create micropores without causingbleeding and increase skin permeability. They aregenerally one micron in diameter and range from 1-100 microns in length. Microneedles have beenfabricated with various materials such as: metals,silicon, silicon dioxide, polymers, glass and othermaterials. Microneedles used in transdermal deliverycan be classified into two categories – solid andhollow microneedles. Solid microneedles have beensuccessfully used in the delivery of proteins, peptides,oligonucleotides and nanoparticles in vitro and invivo. Hollow microneedles contain a hollow boreoffering the possibility of rapid bolus dose drugdelivery by pressure driven flow. Factors affectingmicroneedle based transdermal drug delivery mayinclude insertion force, shape of the needle tip andskin insertion time.
PHYSICAL APPROACH
Needleless injection
Needle-free injectors are devices that do notuse a needle to administer. The mechanisminvolves high pressure to push themedication into the skin to the desiredpenetration site thus allowing non-invasiveand painfree drug delivery. Pressure isproduced by using either a gas (carbondioxide, helium or nitrogen) or a springdevice. The pressure forces medicationthrough a small opening in the device whileit is held against the skin. This creates a finestream of the medication that penetrates theskin. The penetration depth of the drug isdependent upon the amount of drug used.
PHYSICAL APPROACH
Magnetophoresis
It enhances skin permeability by applying a magnetic field. Theresearch on animal models suggests that skin penetration can beenhanced by application of a magnetic field to therapeuticmolecules that are diamagnetic in nature. Magnetoliposomesconsist of magnetic nanoparticles wrapped by a phospholipidbilayer which can be successfully subjected for magneticresonance imaging markers, for cancer diagnosis, and thermalcancer therapy.
Aquasomes
Aquasomes are spherical 60–300 nm particles used fordrug and antigen targeting. It is a successful carrier systemas they provide protection of fragile biological molecules,and surface exposure for bioactive compounds likepeptide, protein, hormones, antigens and genes.
PHYSICAL APPROACH
Ethosomes:
A form of Liposomes with high alcoholic content which havecapability of penetration to deep tissues and the systemic circulationcalled ethosomes. It is due to the presence of alcohol, fluidized theethosomal lipids and the stratum corneum bilayer lipids.
Liposomes: Liposomes are colloidal particles drug delivery systeminvolve concentric biomolecular layers that are capable ofencapsulating drugs. The skin delivery of tri-amcinolone acetonidewas four to five times for lotion than an ointment containing thesoybean or egg. Recent studies have tried to deliver macromoleculessuch as interferon, gene, and cutaneous vaccination as liposomes.
Microemulsions: These systems are transparent mixtures of water,oil, surfactants. They are thermodynamically stable and opticallyisotropic. Microemulsion are spontaneously produced in a narrowrange of o/w composition, they are dynamic system withcontinuously fluctuating. Their good dermal and transdermaldelivery properties may be attributed to their excellent solublizingproperties.
PHYSICAL APPROACH
Nanoemulsions: These are oil in water emulsions with an averagedroplet ranging from 100 to 500 nm. They have a very goodstability and they do not undergo phase separation during storage.Many studies showed trans-epidermal water loss, which meanssupport to the barrier of the skin. Nanoemulsion viscosity is verylow, which is because they can be produced as sprays. Thepreparation requires high-pressure homogenization.
Micro or nanocapsules: Nanocapsules are submicroscopiccolloidal drug systems composed of an oily or an aqueous coresurrounded by the polymer membrane. It consists of a shell and aspace, in which desired drug may be placed. Dispersed polymernanocapsules can serve drug to achieve controlled release as wellas efficient drug targeting. Their release and degradation propertieslargely depend on the composition. The nanocapsules can beprepared by four principally different approaches:polymerization, interfacial precipitation, interfacial deposition, andself assembly procedures.
Conclusion
• Delivering medicine to the general circulation throughthe skin is seen as a desirable alternative to the oralroute.
• Intact skin is not sufficiently permeable to the majorityof drugs, hence permeation enhancement is needed.
• Though chemical enhancers have achieved limitedsuccess in increasing the transdermal transport, theycan be employed together with physical methods togive synergistic action which would improve theefficacy, safety and convenience of use, and open upthe benefits of the transdermal drug deliverytechnology to a much broader range of therapeuticareas.
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2012, Transdermal Drug Delivery System: A Review, THEPHARMA INNOVATION, Vol. 1 No. 4 2012
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