Recent advancements in transdermal drug delivery system

Technological advancements in transdermal drug delivery system: 

Technological advancements in transdermal drug delivery system Ratul Deb, M.Pharm (Pharmaceutics) 2 nd Semester, GIPS 22/02/2012

CONTENT: 

CONTENT Transdermal drug delivery systems are topically administered medicaments in the form of patches (or semisolids) that deliver drug for systemic effects at predetermined and controlled rate.

Skin Structure, Stratum Corneum & Permeation Mechanism: 

Skin Structure, Stratum Corneum & Permeation Mechanism

Factors affecting transdermal permeability: 

Physicochemical properties of the Penetrants Physicochemical properties of Drug Delivery Systems Physiologica l and pathological conditions of the skin Factors affecting transdermal permeability

Factors affecting transdermal permeability: 

Factors affecting transdermal permeability Physicochemical properties of the PENETRANTS Partition coefficient Penetrant concentration Diffusivity through SC Molecular size pH conditions Where, J= membrane flux, A= area of application D s = diffusivity in skin barrier ∆C s = concentration gradient h s = thickness of skin barrier K s = partition coefficient of vehicle & SC

Factors affecting transdermal permeability: 

Physicochemical properties of Drug Delivery Systems Release characteristics: This depends on whether the drug molecules are dissolved or suspended in the delivery system, interfacial partition coefficient of the drug from Drug Delivery Systems to skin. Composition of drug delivery systems It may affect not only the rate of drug release but also the permeability of stratum corneum by means of hydration, mixing with skin lipids or other sorption promoting effects. Enhancement of transdermal permeation By the addition of a sorption or permeation promoter. Factors affecting transdermal permeability

Factors affecting transdermal permeability: 

Factors affecting transdermal permeability Physiologica l and pathological conditions of the skin Reservoir effect of horny layer- The horny layer can act as a depot or reservoir and modify permeation characteristics of some drug. Lipid film - Formed on skin surface by the excretion of sebaceous gland and epidermal cell lipid maintains the barrier functions. Skin hydration- Hydration of SC can enhance the permeability of the skin by as much as eight fold. Skin temperature- A ten fold in the skin permeation was raised from 10 0 to 37 0 C of acetyl salicylic acid and glucosteroids .

Approaches Used In Development  of  TDDS: 

Membrane moderated, Matrix dispersion controlled, Drug Reservoir Gradient Controlled, and Micro reservoir type . Approaches Used In Development  of  TDDS

1. Membrane moderated TDDS: 

1. Membrane moderated TDDS The drug reservoir is totally encapsulated in a shallow compartment molded from a drug impermeable metallic/plastic lamination. The drug delivery side is covered by rate controlling polymeric membrane. The drug molecules are released through the rate controlling membrane. A thin layer of drug compatible adhesive polymer is applied on the external surface. where C R - the drug concentration in the reservoir compartment P a -the permeability coefficient of the adhesive layer P m -the permeability coefficient of rate controlling membrane

2. Matrix dispersion controlled TDDS: 

2. Matrix dispersion controlled TDDS Drug reservoir is prepared by homogeneously dispersing drug particles into hydrophilic or lipophilic polymer matrix. This drug reservoir containing polymer is then pasted on to an occlusive base plate in a compartment made of a drug impermeable plastic backing . The adhesive polymer is then spread along the circumference to form a strip of adhesive rim around the medicated disc.

3. Drug Reservoir Gradient Controlled TDDS.: 

3. Drug Reservoir Gradient Controlled TDDS. Here, drug is incorporated directly into the adhesive. They can be either single-layered or multi-layered. The multi-layer technique involves addition of a membrane between two distinct drug-in-adhesive layers. The concentration in uppermost layer is kept highest to maintain the concentration gradient.

4. Micro reservoir type TDDS: 

4. Micro reservoir type TDDS It is a combination of reservoir and matrix diffusion type drug delivery system. The drug reservoir is formed by first suspending the drug solids in an aqueous solution of a water soluble liquid polymer and then dispersing the drug suspension homogeneously in lipophilic polymer (viz. silicone elastomers ) by high energy dispersion technique to form several discrete, unleachable microscopic spheres of drug reservoirs. Adhesive pad Adhesive rim Polymer matrix

RECENT TECHNOLOGIES FOR IMPROVING TRANSDERMAL ABSORPTION: 

RECENT TECHNOLOGIES FOR IMPROVING TRANSDERMAL ABSORPTION

STUCTURE-BASED TECNIQUES: 

Microneedles Macroflux MDTS STUCTURE-BASED TECNIQUES

Microfabricated Microneedles: 

Microfabricated Microneedles consists of a drug reservoir and a some projections ( microneedles ), which helps in penetrating the stratum cornea and epidermis to deliver the drug. There are 4 approaches of using microneedles : Poke with patch approach - Involves piercing into the skin followed by application of the drug patch at the site of treatment. Coat and poke approach - Needles coated with the drug are inserted into the skin and release of medicament is then occurs by dissolution. Biodegradable microneedles - Involves encapsulation of the drug within the biodegradable, polymeric microneedles , which is then inserted into the skin. Hollow microneedles - Involves injecting the drug through the needle with a hollow bore.

Macroflux ®: 

Macroflux ® First developed by ALZA Corporation. Consists of a titanium microprojection array of area up to 8 cm 2 containing 300 microprojections per cm 2 . Individual micro projection length < 200 μ m. A coating process is applied drug to the tip of each microprojection . Three types of Macroflux ® have been designed till now. They are: Dry-Coated Macroflux D-TRANS ® Macroflux E-TRANS ® Macroflux

Metered-Dose Transdermal Spray (MDTS): 

Metered-Dose Transdermal Spray (MDTS) Developed at the Victorian College of Pharmacy [ Monash University,Victoria , Australia] and commercialized by Acrux Limited [Melbourne, Australia]. It is a topical solution made up of a volatile-cum-nonvolatile vehicle containing the drug dissolved as a single-phase solution . The non-volatile material is generally a penetration enhancer. A finite ( metered )- dose application of the formulation to intact skin  subsequent evaporation of the volatile component of the vehicle  remaining nonvolatile penetration enhancer and drug rapidly partitions into SC (within the first min after application), resulting in a stratum corneum reservoir of drug and enhancer.

ELECTRICALLY-BASED TECHNIQUES: 

Iontophoresis Sonophoresis Electroporation ELECTRICALLY-BASED TECHNIQUES

Iontophoresis: 

Iontophoresis Iontophoresis is a process of transportation of ionic molecules into the tissues by application of electric potential using a suitable electrode polarity. Drug is placed on the skin under the active electrode, and a current (< 0.5 mA ) passed between the two electrodes effectively repelling drug away from the active electrode and into the skin.

Sonophoresis (phonophoresis, Ultrasound): 

Sonophoresis ( phonophoresis , Ultrasound) This is a technique for increasing the skin permeation of drugs using ultrasound (20 KHZ to 16 MHZ) as a physical force. The drug is mixed with a coupling agent (may be a gel, cream or ointment) which transfers the ultrasonic energy from device to skin. Drug is placed on the skin beneath the ultrasonic probe. Ultrasound pulses are passed through the probe and drug molecules are hypothesized to move into the skin through a combination of physical wave pressure and permeabilisation of intercellular bilayers .

Electroporation: 

Electroporation High voltages in the form of direct current [DC (100 volts)] are applied on skin for a very short period of time ( miliseconds ) which induce formations of transient pores. This pores allow the passage of macromolecules from the outside of the cell to the intracellular space via a combination of possible processes such as diffusion and local elctrophoresis .

VELOCITY-BASED TECHNIQUES: 

VELOCITY-BASED TECHNIQUES

Intraject and Powderject: 

Intraject and Powderject This technology uses high velocities to force particles across the stratum corneum. This transdermal devices push drug molecules into the skin by creation of a high-velocity jet (> 100 m/s) of compressed gas (usually helium) that accelerates through the nozzle of the injector device, carrying drug particles with it. There are two types of devices: Intraject (Weston Medical), and Powderject ( PowderJect Pharmaceuticals Plc).

OTHER MISCELENIOUS METHODS: 

Transfersome Medicated tattoo Skin abrasion Heat Laser radiation OTHER MISCELENIOUS METHODS

Transfersomes : 

Transfersomes These devices penetrates skin along the skin moisture gradient . This leads the compounds through the “virtual” pores between the cells in the organ, without affecting their biological barrier properties. Transfersomes are vesicles with ultradeformability , so that they can sqeez through channels in stratum corneum. Liposomes and Niosomes are best suited for this purpose (for the carrier of drug). Transfersomes contain a component (bile salts, polysorbates ) that destabilizes the lipid bilayers and thus leading to the deformable vesicles. Therefore they can be easily transported through skin. Transfersome carriers can create a drug depot in the systemic circulation that is having a high concentration of drug.

Medicated Tattoos: 

Medicated Tattoos Med-Tats is a modification of temporary tattoo which contains an active drug substance for trandermal delivery. This technique is useful in the administration of drug in those children who are not able to take traditional dosage forms.

Skin Abrasion: 

Skin Abrasion This involves direct removal or disruption of the upper layers of the skin to provide better permeation of topically applied drug substance. This technique is used in treatment of acne, scars, hyperpigmentation and other skin blemishes. There are several approaches; one of them involve creating micro channels in the skin by eroding the impermeable outer layers with sharp microscopic metal granules.

Controlled Heat Aided Drug Delivery (CHADD) System: 

Controlled Heat Aided Drug Delivery (CHADD) System It facilitates the transfer of drug substance to the blood circulation by applying heat to the skin. Heat increases the microcirculation and ultimately the permeability of blood vessel is increased. Drug solubility , both in the patch formulation and within the skin, may increase with a rise in temperature. This technique has been utilized for the transport of DNA vaccines and conventional drugs to animal.

Laser Radiation : 

Laser Radiation 2 Approaches: This involves the exposure of the skin to the laser beam that results in the ablation of the stratum cornea without damaging the epidermis. Removal of the stratum cornea by this technique is considered to improve the delivery of lipophilic and hydrophilic drugs. In another approach, laser beam is applied on a target material (polystyrene) which is the backing material for drug reservoir. As a result, pressure-pulses are generated which helps in increasing the permeability.

‘CURRENT TRENDS’ IN TDDS: 

DOT Matrix technology Skin-Contact-Actuated Pump Pain-free Diabetic Monitoring ‘CURRENT TRENDS’ IN TDDS

DOT MatrixTM Technology : 

DOT Matrix TM Technology New class of highly-efficient passive systems. Drug is solubilized in acrylic in very high concentrations  this is further mixed with Silicon adhesive  formation of concentrated drug cells in silicon adhesive. The concentration gradient between drug & skin is very high, so highly efficient diffusion takes place. The circular image is the surface of the drug/adhesive layer of a DOT matrix patch (photographed with Scanning Electron Microscope).

Skin-Contact-Actuated Pump for TDDS: 

Skin-Contact-Actuated Pump for TDDS It consists of a micropump and some fluorocarbon compound as propellants . Liquid-to-vapor phase change of these propellants are responsible for actuation. As a result, a gradient is generated which drives the liquid through microneedle array.

Pain-free Diabetic Monitoring Using Transdermal Patches: 

Pain-free Diabetic Monitoring Using Transdermal Patches This is an electronic device, which can sensor the glucose level in interstitial fluid . The patch contains a micro-heating element, through which a high temperature can be applied locally ( 130 0 C for 30ms ). Ablation of stratum corneum occurs, without affecting living tissue/nerve. The interstitial fluid thus comes into contact with the electrodes, and level of glucose is measured.

Most recent patents in TDDS: 

Most recent patents in TDDS Patent No. Date Title US7415306 33 Aug. 19, 2008 Transdermal Delivery System for Anti-Emetic Medication US7413748 34 Aug. 19, 2008 Transdermal Buprenorphine to treat Pain in Sickle Cell Crisis US7387789 35 Jul. 17, 2008 Transdermal Delivery of Non-Steroidal Anti Inflammatory Drugs US7398121 36 Jul. 8, 2008 Iontophoresis Device US7395111 37 Jul. 1, 2008 Transdermal Delivery System for Water Insoluble Drug

Some marketed Brands: 

Some marketed Brands Brand Name Drug Manufacturer Indications Nicotinell R Nicotine Novartis Pharmacological smoking cessation NuPatch 100 Diclofenac & diethylamine Zydus Cadila Anti Inflammatory Nicoderm R Nicotine Alza/GlaxoSmithKline Smoking cessation Androderm Testosterone TheraTech/GlaxoSmithKline Hypogonadism in males Transderm - Scop R Scopolamine Alza/Norvatis Motion sickness FemPatch Estradiol Parke-Davis Postmenstrual syndrome Estraderm Estradiol Alza/Norvatis Postmenstrual syndrome

CONCLUSION: 

Transdermal drug delivery is hardly an old technology, and the technology is no longer just adhesive patches. Transdermal drug delivery technologies are becoming one of the fastest growing sectors within the pharmaceutical industry. CONCLUSION

References : 

References Vyas SP, Khar RK; Controlled Drug Delivery: concepts and advances ; Vallabh Prashan ; page-411-447. Bharadwaj S, Sharma RK; RECENT ADVANCEMENT IN TRANSDERMAL DRUG DELIVERY SYSTEM ; International Journal Of Pharma Professional's Research; ISSN 0976-6723; Volume 2, Issue 1, January 2011 A. Ahad et al, Transdermal Drug Delivery: The Inherent Challenges And Technological Advancements, Transdermal Drug Delivery/Asian Journal Of Pharmaceutical Sciences 2010, 5 (6): 276-288 Ritesh Kumar and Anil Philip; Modified Transdermal Technologies: Breaking theBarriers of Drug Permeation via the Skin; Tropical Journal of Pharmaceutical Research, March 2007; 6 (1): 633-644

PowerPoint Presentation: 

Innovations In Passive Transdermal Drug Delivery,noven Pharmaceuticals, Inc, A Releasing Technology Workshop Crs 2006 Annual Meeting July 23, 2006 C. Mousoulis , M. Ochoa, B. Ziaie ; Skin-Contact-Actuated Dispense/Pump for Transdermal Drug Delivery [ C. Mousoulis , et al., IEEE Trans. on Biomed. Eng., vol. 58, no. 5, pp. 1492-8, May. 2011. ] Pain-free diabetic monitoring using transdermal patches; Paranjape , Makarand ; Biomedical Optics & Medical Imaging, Pain-free diabetic monitoring using transdermal patches Available: http://spie.org/x27077.xml

Thank you !: 

Thank you !