CONTENT

PRESENTED BY: GUIDED BY: SANI SINGH Prof. VIKAS ANAND M. Pharm (Pharmaceutics) 2nd Semester DEVELOPMENT APPROACHES FOR TRANSDERMAL DRUG DELIVERY SYSTEMSSARDAR BHAGWAN SINGH P.G. INSTITUTE OF BIO-MEDICAL SCIENCES & RESEARCH, BALAWALA, DEHRADUN, (UTTARAKHAND)FIRST SEMINAR (MPHR 120)

Introduction Advantages & Disadvantages Skin & Drug Permeation Percutaneous Absorption & Kinetics Factor Affecting Percutaneous Absorption Basic Components Of TDDS Types Of Transdermal Patch Formulation Approaches Used In Development Of TDDS Marketed Products Patents & Recent Research

ORGANISATION

INTRODUCTION TDDS facilitate the passage of therapeutic quantities of drug substance through the skin and into the general circulation for their systemic effects. In 1965 Stoughton first conceived of the percutaneous absorption of drug substance. The first transdermal system, Transderm Scop (Ciba, now Novartis) was approved by the FDA in 1979 for prevention of nausea and vomiting associated with travel, particularly by sea.

Allen LV, Popovich NG, Ansel HC. Ansels pharmaceutical dosage forms and drug delivery systems. 8th edition. Lippincott Williams and Wilkins. 2005, 298-315.

ADVANTAGESSubstitute for oral administrationAvoid the first-pass effectDelivers a steady infusion of a drug Self administration is possibleDrug therapy may be terminated rapidlyImproved patient complianceLack of peaks in plasma concentration (the risk of side effects) Used for drugs with narrow therapeutic window Allen LV, Popovich NG, Ansel HC. Ansels pharmaceutical dosage forms and drug delivery systems. 8th edition. Lippincott Williams and Wilkins. 2005, 298-315.

DISADVANTAGESCannot use for large molecule (>500 Dalton)Cannot be used for drugs requiring high blood levelsLong time adherence is difficultHigher costVariation in absorption efficiency a different sites of skinCannot deliver ionic drugsSkin irritation or contact dermatitis may occurNatural limits of drug entry imposed by the skins impermeability Upadhyay G, Verma S, Parvez N and Sharma PK. Recent trends in transdermal drug delivery system. Advances in Biological Research. 2014;8(3): 131-138. Allen LV, Popovich NG, Ansel HC. Ansels pharmaceutical dosage forms and drug delivery systems. 8th edition. Lippincott Williams and Wilkins. 2005, 298-315.

SKIN Stratum Corneum Stratum Lucidum Stratum Granulosum Stratum Spinosum Stratum Basale

Blood vessels Sweat glands Hair follicle Sebaceous glands

Adipose Tissue Artery VeinAnatomy & Physiology Of Skin

Skin

Saini Nitin, Bajaj Anshul. Recent trend on transdermal drug delivery system and advancements in drug delivery through skin. International Journal of Research in Pharmaceutical and Biosciences. 2014; 4(1): 5-14. Lembhe Swapnil, Dev Asish. Trasdermal drug delivery system: an overview . World Journal Of Pharmacy And Pharmaceutical Science. 2016;5(7): 584-610.

Routes Of Skin Permeation

Product/DeviceSolute VehicleStratum Corneum PenetrationEpidermis & Upper Dermis ConcentrationSystemic Blood ConcentrationHair Follicles, Sweat DuctsTherapeutic Activity TissuesUnderlying Subcutaneous & MusclesDevice, Solute, Vehicle Determination of Permeability DesquamationReleaseTarget DeliveryEffects on Skin Turnover LipidsDiffusion Local Blood FlowDermal Blood FlowEpidermal & Dermal MetabolismActionDistribution

Tanwar Himanshi, Sachdeva Ruchika. Transdermal drug delivery system: a review. International Journal Of Pharmaceutical Sciences And Research. 2016; 7(6): 2274-90.

MetabolitesUrine etc.ClearanceToxicitySchematic Representation Of Percutaneous Permeation

Skin permeation kinetics is vital to the successful development of transdermal therapeutic system. Transdermal permeation of drug involve following steps

1) Sorption by stratum corneum. 2) Penetration of drug through viable epidermis. 3) Uptake of drug by capillary network in dermal papillary layer.

The rate of permeation across the skin (dq/dt) is given by dq/dt = Ps (Cd-Cr).. (1)

Where Cd and Cr are, the concentration of skin penetrant in the donor compartment and in the receptor compartment respectively Ps permeability coefficient

Kinetics Of Transdermal Permeation

Permeability coefficient is given by the relationship: -

Ps =Ks Dss / hs (2)

Where Ks is the partition coefficient for the interfacial partitioning of the penetrant molecule from a solution medium or a transdermal therapeutic system , Dss is the apparent diffusivity for the steady-state diffusion of the penetrant molecule through a thickness of skin tissues hs overall thickness of skin tissuesKs, Dss and hs are constant under given conditions, the Ps should be constant.

From equation (1) it is clear that a Cd>>Cr i.e., the drug concentration at the surface of the stratum corneum (Cd) is consistently and substantially greater than the drug concentration in the body (Cr). Then equation (1) becomes.

dq/dt = Ps Cd (3)

(dq/dt) is constant provided the magnitude of Cd remains fairly constant throughout the course of skin permeation. For keeping Cd constant, the drug should be released from the devices at a rate (Rr) that is either constant or greater than the rate of skin uptake (Ra) i.e., Rr>>Ra.

Since Rr>>Ra , the drug concentration on the skin surface (Cd) is maintained at a level equal to or greater than the equilibrium solubility of the drug in the stratum corneum (Cs) i.e., Cd>>Cs. Therefore, a maximum rate of skin permeation [(dq/dt) m] is obtained and is given by the equation: -

(dq/dt) m = Ps Cs (4) (dq/dt) m depends on (Ps) and its equilibrium solubility in the stratum corneum (Cs). Thus skin permeation appears to be stratum corneum-limited.

Jain NK. Controlled and novel drug delivery. 1st edition. CBS Publishers & Distributors. 1997, 107-110. Gupta Ravikant. Transdermal drug delivery system. World Journal of Pharmacy and Pharmaceutical Sciences. 2014; 3(8): 375-394

Factor Affecting Biological factors

Skin conditions Skin hydration Sunlight Skin age Temperature and pH Cold season Regional skin site Diffusion coefficient Air pollution Skin metabolism Drug concentration Effect of heat Partition coefficient Molecular size and shapePhysicochemical factorsEnvironmental factors Kumar D, Sharma N, Rana AC, Agarwal Gand Bhat ZA. A review: transdermal drug delivery system: a tools for novel drug delivery sestem. Int. J Drug Dev. Res. 2011;3(3): 70-84. Singh MC, Naik AS, Sawant SD. Transdermal drug delivery system with major emphasis on transdermal patches: a review. J Pharm Res. 2010;3(10): 2537-2543.

Components Of TDDSThe components of transdermal devices include. 1. Polymer matrix / Drug reservoir2. Drug 3. Permeation enhancers 4. Pressure sensitive adhesives 5. Backing laminate 6. Release liner 7. Other excipients

Polymer Matrix Ideal properties of a polymer to be used in a transdermal system - Molecular weight, chemical functionality of the polymer should be such that the specific drug diffuses properly and gets released through it. Stable, non-reactive with the drug. Non-toxic or non- antagonistic to the host.Easily of manufactured and fabricated into the desired product.Inexpensive.Large amounts of the active agent are incorporated into it. Jain NK. Controlled and novel drug delivery. 1st edition. CBS Publishers & Distributors. 1997, 107-110.

Commonly Used Polymers For Transdermal Devices Natural PolymersSynthetic ElastomersSynthetic Polymers Cellulose derivativesArabino GalactanZeinGelatinProteinsShellacStrarchPolybutadieneHydrin rubberPolysiloxaneAcrylonitrileNeopreneChloropreneSilicon rubberPolyvinyl alcoholPolyethylenePolyvinyl ChloridePolyacrylatesPolyamidePolyureaPolyvinlypyrrolidone

Drug SubstanceParameterPropertiesDoseLess than 20 mg/dayHalf life< 10 hrsMolecular weight0.510-3cm/hSkin ReactionNon irritating and non-sensitizingOral BioavailabilityLow

Ideal Properties Of Drug Candidate For Transdermal Drug Delivery Sharma RK, Keleb E, Mosa EB, Aljahwi AAZ. Transdermal drug delivery system- design and evaluation. Int. J Advances Pharm Sci. 2010;1: 201-211.

Permeation EnhancersThese are compounds which promote skin permeability by altering the skin as a Barrier to the flux of desired penetrants.The flux, J, of drugs across the skin can be written as - Where D = diffusion coefficient C = concentration of the diffusing speciesx = spatial coordinate Enhancement of flux across membranes reduces to considerations them as follows - Molecular size and shape. Reducing the energy required to make a molecular hole in the membrane. 3. Thermodynamics (lattice energies, distribution coefficients). Tanwar Himanshi, Sachdeva Ruchika. Transdermal drug delivery system: a review. International Journal Of Pharmaceutical Sciences And Research. 2016;7(6): 2274-90. Walker BP, Smith EW. The role of percutaneous penetration enhancers. Advanced Drug Delivery Reviews. 1996;18: 295-301.

Types Of Absorption EnhancersClassExamplesMechanismSurfactantsAnionic : Sodium lauryl sulphateTranscellularNonionic : Pluronic F68 & F127Transcellular

Bile Salts : Sodium deoxycholate , Sodium taurocholate ParacellularSolventsMethanol, Ethanol, Propylene glycol, Glycerol etc.Transcellular

CyclodextrinsMethylated b cyclodextrins, a-, b- and g cyclodextrinsParacellularTranscelular

Chelating agentsEDTA,PolyacrylatesTranscellularParacellularPositively charged polymerChitosan salts,Trimethyl chitosanParacellular

Dhawan S, Aggarwal G. Development, fabrication and evaluation of transdermal drug delivery system: a review. Pharm info.net. 2009:1-25. Lende LK, Grampurohit ND, Gaikwad DD, Gadhave MV, Jadhav SL. Transdermal patches: a review. Int. J Pharm Res. Dev. 2011;4(3): 96-103.Pressure Sensitive Adhesive PSA helps in maintaining an intimate contact between transdermal system and the skin surface. It should be removable from the smooth surface without leaving a residue e.g.: polyacrylamates, polyacrylates, polyisobutylene, silicone based adhesive. The selection is based on numerous factors, including the patch design and drug formulation. PSA should be physicochemical and biologically compatible and should not alter drug release.

While designing a backing layer the consideration of chemical resistance and excipients may compatible because the prolonged contact between the backing layer and the excipients, drug or penetration enhancer through the layer. They should a low moisture vapour transmission rate. They must have optimal elasticity, flexibility and tensile strength. eg: aluminium vapour coated layer, a plastic film and heat real layer.

Release Linear

Prevents the loss of drug that has migrated into the adhesive layer and contamination. However, as the linear is inintimate contact with the delivery system, it should comply with specific requirements regarding chemical inertness and permeation to the drug, penetration enhancer and water. Tanwar Himanshi, Sachdeva Ruchika. Tansdermal drug delivery system: a review. International Journal Of Pharmaceutical Sciences And Research. 2016;7(6): 2274-90.

Backing Laminates

Other Excipients Various solvents such as chloroform, methanol, acetone, isopropanol and dichloromethane are used to prepare drug reservoir.

In addition plasticizers such as dibutylpthalate, triethylcitrate, polyethylene glycol and propylene glycol are added to provide plasticity to the transdermal patch. Lembhe Swapnil, Dev Asish. Trasdermal drug delivery system: an overview . World Journal Of Pharmacy And Pharmaceutical Science. 2016;5(7): 584-610.

Types Of Transdermal Patch 1. Single-layer Drug-in-Adhesive The adhesive layer of this system also contains the drug. 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. Example- Deponit

2. Multi-layer Drug-in-Adhesive Similar to the single-layer system in that both adhesive layers are also responsible for the releasing of the drug. 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. Example- Nicotrol

3. Reservoir 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. Example- Transderm-Nitro

4. Matrix The Matrix system has a drug layer of a semisolid matrix containing a drug solution or suspension. The adhesive layer in this patch surrounds the drug layer partially overlaying it. Example- Nitro-Dur

5. Vapour Patch Adhesive layer not only serves to adhere the various layers together but also to release vapour. The vapour patches are new on the market and they release essential oils for up to 6 hours & used in cases of decongestion mainly. Other vapour patches on the market are controller vapour patches that improve the quality of sleep. Vapour patches that reduce the quantity of cigarettes that one smokes in a month are also available on the market.

Patel D, Chaudhary SA, Parmar B, Bhura N. Transdermal drug delivery system: a review. The Pharm Innovation. 2012;1(4): 66-75. Dhiman S, Thakur GS, Rehni AK. Transdermal patches: a recent approach to new drug delivery system. Int. J Pharmacy Pharm Sci. 2011;3(5): 26-34.

Approaches Used In Development Of TDDS

Vyas SP, Khar RK. Controlled drug delivery: Concepts and advances. 2nd edition. Vallabh Prakashan. 2012, 420-426. Jain NK. Controlled and novel drug delivery. 1st edition. CBS Publishers & Distributors, 1997, 110-114.

Membrane permeation controlled systemsExample:Nitroglycerine-releasing Transdermal system (Transderm-nitro) for once a day medication in angina pectoris.Scopolamine-releasing Transdermal system (Transderm-scop) for 72 hrs. Prophylaxis of motion sickness.

Adhesive dispersion type systems

The drug reservoir is formulated by directly dispersing the drug in an adhesive polymer & then spreading the medicated adhesive by hot melt, on to a flat sheet of drug impermeable metallic plastic backing to form a thin drug reservoir layer.

Example: Isosorbide dinitrate-releasing transdermal therapeutic system (Frandol tape) for once a day medication of angina pectoris.

Matrix diffusion controlled systems

It is prepared by homogeneously dispersing the drug particles with a liquid polymer or a highly viscous base polymer followed by cross linking of the polymer chains or homogeneously blending the drug solids with a rubbery polymer at an elevated temperature.

Example: Nitrogiycerine-releasing transdermal system (Nitro- Dur and Nitro- Dur II) a daily dose of 0.5 mg/cm2 for therapy of angina pectoris.

Microreservoir type or Microsealed dissolution controlled systems

It is combination of reservoir & matrix diffusion type drug delivery system. Drug reservoir is formed by first suspending the drug solids in an aqueous solution of a water soluble liquid polymer & then dispersing the drug suspension homogeneously in a lipophilic polymer such as silicone elastomers by high energy dispersion technique.

Example: Nitroglycerine-releasing transdermal system (Nitro disc) for once a day of angina pectoris.

Marketed ProductsTherapeutic Agent Brand Name Manufacturer Name Indication Clonidine Catapres-TTSBoehringer IngelheimHypertension Estradiol EstradermNovartisPostmenstr ual syndromVivelle NovartisFentanyl E-Trans Alza CorporationModerate/severe painDuragesic Alza/Janssen PharmaceuticaNicotine Habitrol Novartis Smoking cessationNicotrol McNeil Consumer

Nicoderm CQ GlaxoSmithKlineNitroglycerineDeponit Schwarz Pharma Angina pectoris Nitro-DurKey pharmaceutical Transderm-NitroNovartisTestosterone Testoderm Alza corporationHypogonadism in maleAndroderm GlaxoSmithKlineScopolamine Transderm-ScopNovartis Motion sickness Lidocaine Sona PrepEcho Therapeutics Local anesthetic

Allen LV, Popovich NG, Ansel HC. Ansels pharmaceutical dosage forms and drug delivery systems. 8th edition. Lippincott Williams and Wilkins. 2005, 298-315. Upadhyay G, Verma S, Parvez N and Sharma PK. Recent trends in transdermal drug delivery system. Advances in Biological Research. 2014;8(3): 131-138.

InsulinSono DermImarx DiabetesPowderjectPowderject PharmaceuticalsEstrogenNuvelle-TSEthical Holding/ScheringPostmenstr ual syndrom

Some Patents On Transdermal Drug Delivery SystemPatent No. InventoNovelty 20060135911Mittur et al Prepared a device which is known as a trans-body-surface drug delivery device including a reservoir having at least one drug and a thermo effector having a first surface. 20050186262Osborne et al Prepared a transdermal delivery device for treatment of hypertension with the drug delivery of dihydropyridine-type calcium antagonist through the skin . 20120277695Cottrell et al Prepared a transdermal patch for administration of an opioid the composition comprising a phosphate compound of tocopherol and a polymer carrier . 8252319Yum et alThe invention relates to the transdermal delivery of Sufentanil which provides sufficient amount of sufentanil to induce and maintain analgesia for extended periods when applied to a subject .

4956171Chang, YunikDescribes transdermal drug delivery system with dual permeation enhancers and has a basal surface that contacts an area of skin and transmits the drug . The dual permeation enhancers used are sucrose cocoate& methyl laurate .

Recent Research Reports From PubmedDrugPolymer or Major ExcipientsType of Patch and Preparation MethodRemarks ReferenceDomperidone HPMC & Eudragit RL 100 (polymer), d-limonene (permeation enhancer)Bilayered matrix type patchs & Film casting methodPatchs prepared with the required fiux (86.02 ug/hr/cm2)& permeation coefficient (0.86x10-2 cm/hr)Madishetti et al , 2010Lercanidipine hydrochlorideHPMC & Eudragit RL 100 (polymer), d-limonene (permeation enhancer)Matrix type & Solvent evaporation techniqueTo determine the effect of penetration enhancer, limonene on drug permeation Mamatha et al , 2010

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