approaches of Transdermal drug delivery system

approaches of Transdermal drug delivery system

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  Formulation approaches usedin the development of TDDS their Evaluation & Permeation enhancers Presented by…. NIVEDITHA G M. Pharm 1st Year Dept. of Pharmaceutics NARGUND COLLEGE OF PHARMACY Seminar on…..
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  Dept. of Pharmaceutics2 Table of Contents…..  Formulation approaches used in the development of TDDS  Evaluation of TDDS  Permeation Enhancers  Advances in TDDS  References.
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  Dept. of Pharmaceutics3 Schematic Skin absorption of drug
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  Dept. of Pharmaceutics4 Formulation Approaches used in the development of TDDS 1. Membrane permeation – controlled systems. 2. Adhesive dispersion – type systems. 3. Matrix diffusion – controlled systems. 4. Microreservoir type or Microsealed dissolution – controlled systems. 5. Poroplastic – type systems. 6. Transdermal delivery of Macromolecules.
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  Dept. of Pharmaceutics5 1. Membrane permeation – controlled systems  The drug reservoir is totally encapsulated in a shallow compartment moulded from a drug – impermeable metallic plastic laminate & a rate controlling polymeric membrane which may be microporous or non-porous.  The rate of drug release from this type of TDDS can be tailored by varying the composition of polymer, permeability coefficient, thickness of the rate limiting membrane & adhesive.  Example:- i) Nitroglycerine-releasing Transdermal system (Transderm-nitro) for once a day medication in angina pectoris. ii) Scopolamine-releasing Transdermal system (Transderm- scop) for 72 hrs. prophylaxis of motion sickness.
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  Dept. of Pharmaceutics6 Fig. Membrane moderated Transdermal drug delivery system
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  Dept. of Pharmaceutics7 Continued…  The intrinsic rate of drug release from this type is… Where, CR = Drug conc. In the reservoir compartment. Pa & Pm = permeability coefficients of Adhesive & the rate controlling membrane respectively. dQ dt CR 1 1 Pa ……………………(1)
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  Dept. of Pharmaceutics8 Continued…  For microporous membrane, Pm is the sum of permeability coefficients for simultaneous penetration across the pores & polymeric material, hence… Pm Km/r Dm hm & Pa Ka/m Da ha …….(2) …….(3)
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  Dept. of Pharmaceutics9 Continued…  In case of microporous membrane, the porosity of the membrane should be taken in to the calculation of Dm & hm values, Substituting eq. (2) & (3) in eq. (1)… dQ dt Km/r Ka/m Dm Da Km/r Dm ha Ka/m Da ha CR …………...(4)
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  Dept. of Pharmaceutics10 2. 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.
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  Dept. of Pharmaceutics11 Fig. Adhesive dispersion type Transdermal drug delivery system
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  Dept. of Pharmaceutics12 Continued…  The rate of drug release in this system is defined by… Where, Ka/r = Partition coefficient for the interfacial partitioning of the drug from the reservoir layer to adhesive layer. dQ dt Ka/r Da ha CR
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  Dept. of Pharmaceutics13 3. Matrix diffusion – controlled systems i) 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 temp. ii) It can also be prepared by dissolving the drug & polymer in a common solvent followed by solvent evaporation in a mould at an elevated temp. or in a vaccum. It is then pasted on to an occlusive base plate in a compartment fabricated from 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.
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  Dept. of Pharmaceutics14 Fig. Matrix diffusion controlled Transdermal drug delivery system
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  Dept. of Pharmaceutics15 Continued…  Example: Nitroglycerine-releasing Transdermal system (Nitro- Dur & Nitro- Dur II ) at a daily dose of 0.5 g/cm2 for therapy of angina pectoris.  The rate of drug release from this type is given by… Where, A = Initial drug loading dose dispersed in the polymer matrix. Cp & Dp = Solubility & diffusivity of the drug in the polymer respectively. dQ dt ACp Dp 2t 1/2
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  Dept. of Pharmaceutics16 4. Microreservoir type or Microsealed dissolution – controlled systems  This is the combination of reservoir & matrix diffusion type drug delivery systems.  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 dispersion technique.  Example: Nitroglycerine-releasing Transdermal system (Nitro disc) for once a day therapy of angina pectoris.
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  Dept. of Pharmaceutics17 rim Fig. Micro reservoir dissolution-controlled transdermal drug delivery system
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  Dept. of Pharmaceutics18 5. Poroplastic– type systems  It is made utilizing the concept of the water coagulation of cellulose triacetate solution in organic acids at low temp.  The coagulation is performed under controlled condition.  The water may be exchanged subsequently for another vehicle by a diffusional exchange process, & hence it is also known as “solid composed mostly of liquid.”
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  Dept. of Pharmaceutics19 6. Transdermal delivery of Macromolecules  Macromolecules such as Hormones, interferon's, bioactive peptides can be deliver by Transdermal delivery system.  The devices used for this purpose are divided in to two categories…. a. Devices based on ethylene vinyl acetate copolymers (EVAc). b. Devices based on silicone elastomers.  This both the systems utilize one common concept i.e. matrix must have channels to facilitate the release of macromolecules.  These devices are used as implants.
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  Dept. of Pharmaceutics20 Evaluation of TDDS 1. Evaluation of Adhesive : A. Peel adhesion properties:- i) It is the force required to remove an adhesive coating from a test substrate. ii) It is affected by molecular wt. of the adhesive polymer, the type & amount of additives & polymer composition. iii) It is tested by measuring the force required to pull a single coated tape, applied to a substrate, at an angle of 1800, no residue on the substrate indicates ‘Adhesive failure’ signifying a deficit of cohesive strength in the coating. Fig. Peel adhesion test for adhesive evaluation
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  Dept. of Pharmaceutics21 B. Tack properties:- i) It is the ability of polymer to adhere to a substrate with little contact pressure. ii) It is dependent on the molecular wt. & composition of the polymer as well as the use of tackifying resins in the polymer. iii) It includes…. a. Thumb tack test b. Rolling ball tack test : It involves the measurement of the distance that a stainless steel ball travels along an upward- facing adhesive, less tacky the adhesive, the further the ball will travel. Fig. Rolling ball tack test for adhesive evaluation
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  Dept. of Pharmaceutics22 c. Quick- stick (peel tack) test : The peel force required to break the bond between an adhesive & substrate at 900 at a speed of 12 inch/min. The force recorded as the tack value & is expressed in ounces (or grams) per inch width with higher values indicating increasing tack. Fig. Quick stick test for adhesive evaluation
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  Dept. of Pharmaceutics23 d. Probe tack test : The force required to pull a probe away from an adhesive at a fixed rate is recorded as tack. (expressed in grams) Fig. Probe tack test for adhesive evaluation Probe Force gauge
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  Dept. of Pharmaceutics24 C. Shear strength properties i) It is affected by molecular wt. as well as the type & amount of tackifier added. ii) Shear strength is determined by measuring the time it takes to pull an adhesive coated tape of stainless steel plate when a specified wt. is hung from the tape which pulls the tape in a direction parallel to the plate. Fig. Shear strength test for adhesive evaluation
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  Dept. of Pharmaceutics25 2. In-vitro drug release evaluation : i) In these studies, excised skin is mounted on skin permeation cells. ii) Skin of hairless mouse is used rather than human cadaver skin. iii) In-vitro system should be designed in such a way that the intrinsic rate of release or permeation which is theoretically independent of the in-vitro design can be accurately determined. iv) Several designs of the in-vitro membrane permeation apparatus are in existence. E.g. Valia-Chien (V-C) cell, Ghannam-Chien (G-C) membrane permeation cell, Jhawer-Lord (J-L) rotating disc cell, Franz diffusion cell & Keshary-Chien (K-C) cell.
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  Dept. of Pharmaceutics26  Keshary-Chien (K-C) cell : It has an effective receptor volume 12 ml & a skin surface area of 3.14 cm2. The receptor solution is stirred by a star-head magnet rotating at a constant speed of 600 rpm driven by 3 W Synchronous motor. Fig. K-C cell for permeation study
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  Dept. of Pharmaceutics27 A. Animal models:-  The species used for this are mouse, rat, guinea pig, rabbit, hairless mouse, hairless cat, hairless dog, cat, dog, pig, goat, squirrel, monkey, rhesus monkey, chimpanzee.  The rhesus monkey is the most reliable model for in-vivo evaluation of TDDS.  Standard radio tracer methodology is used .  The application site is generally the forearm or abdomen which are less hairy sites on the animals body.  The compound is applied after light clipper shaving of the site. 3. In-vivo evaluation :
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  Dept. of Pharmaceutics28 B. Human volunteers:-  Procedures for in-vivo evaluation in humans were first described by Feldmann & Mailbach in 1974.  They involve the determination of cutaneous absorption by an indirect method of measuring radioactivity in excreta following topical application of the labelled drug.  This method is used since plasma level following Transdermal administration of a drug are too low to use chemical assay procedure.  The % of dose absorbed transdermally is calculated by… % of dose absorbed = Total radioactivity excreted after topical administration Total radioactivity excreted after I. V. administration x 100
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  Dept. of Pharmaceutics29  Various modifications have been made for above method… A. “Reservoir” technique:- It involves a simple, short exposure of the skin to the compound (radio labelled) under study followed by removal of the striatum corneum by tape striping & analysis of the content of the compound in the striatum corneum. From this it is possible to predict amount of drug that will penetrate over a long period of time.  Limitations: i) Invasive nature of the technique due to the tape striping required. ii) The single measurement obtained which does not allow detailed kinetic analysis & the administration of large dose of radioactive material is required. B. “Mass balance” technique.
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  Dept. of Pharmaceutics30 4.Cutaneous toxicological evaluations:- a. Contact dermatitis:- 1) Contact irritant dermatitis:-  Two types of protocols are used… i) Ten-day primary irritation test ii) Twenty-one day irritation test 2) Laser Doppler 3) Evaporative water loss measurements 4) Contact allergic dermatitis b. Growth of microorganisms 1) Localized superficial infections 2) Miliaria (prickly heat)
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  Dept. of Pharmaceutics31 Permeation Enhancers  These are the compounds which promotes skin permeability by altering the skin as a barrier to the flux of desired penetrant.  The flux ‘J’ of drugs across the skin can be written as…. Where, D = Diffusion coefficient, c = conc. of diffusing species x = spatial coordinate J = D dc dx
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  Dept. of Pharmaceutics32  Ideal properties of Permeation enhancers:- i) They should be non-toxic, non-irritating & non-allergenic. ii) They would ideally work rapidly & the activity & duration of effect should be both predictable & reproducible. iii) They should have no pharmacological activity within the body. iv) When removed from skin, barrier properties should return both rapidly & fully. v) They should be compatible with both excipients & drugs. vi) They should be cosmetically acceptable with an appropriate skin feel.
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  Dept. of Pharmaceutics33  The flux ‘J’ of a drug through skin can be approximated by Fick’s second law of diffusion. Where, m = cumulative mass of permeant that passes per unit area through the membrane in time ‘t’. C0 = conc. of diffusant in the first layer of the membrane at the skin surface contacting the source of the penetrant. h = membrane thickness. δC δ t D δ2C δ x2 …………..(1) dm dt = = DC0 h ………….(2)
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  Dept. of Pharmaceutics34  It is difficult to measure C0 but C0’ which is the conc. of diffusant in the donor phase, C0 & C0’ is related by…  Substituting eq. (3) into eq. (2) gives… C0 = PC0’ ……………(3) dm DC0’ P dt = h …………...(4)
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  Dept. of Pharmaceutics35  Classification of Permeation enhancers:- a. Solvents b. Surfactants i) Anionic surfactants: Dioctyl sulphosuccinate, Sodium lauryl sulphate. ii) Non-ionic surfactants: Pluronic F127, Pluronic F68 iii) Bile salts : Sodium taurocholate,Sodium deoxycholate. c. Binary systems : Propylene glycol-oleic acid d. Miscellaneous chemicals : Urea, Calcium thioglycholate.
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  Dept. of Pharmaceutics36 Advances in TDDS  Active Transdermal Systems:-  Microstructured Transdermal System (MTS) is a state-of-the-art microneedle system for transcutaneous drug delivery that has potential for providing a drug delivery solution for a wide variety of molecules, including vaccines, proteins and peptides. MTS provides targeted delivery to the dermal/epidermal layers of the skin.  Further, MTS has the potential to enhance the efficacy of vaccines while improving the overall delivery efficiency for vaccines, proteins, or peptides.  Finally, MTS is an easy-to-use system with the potential to improve health care providers vaccine regimen.
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  Dept. of Pharmaceutics37 References  Y. W. Chien, Novel drug delivery systems, 2nd edition, Revised & expanded, Marcel Dekker, Inc., New York, 1992.  N. K. Jain, Controlled & Novel drug delivery, CBS Publishers & Distributors, New Delhi, First edition, 1997.  Controlled drug delivery devices by Pravin Tyle, Marcel Dekker, Inc., New York, 1992, pg. no. 406 – 408.  Mechanisms of Transdermal drug delivery system by Y. W. Chien, Marcel Dekker, Inc., New York.  www.google.com
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  Dept. of Pharmaceutics38 THANK YOU