Formulation and evaluation of transdermal drug delivery system (TDDS)
- 1. FORMULATION AND EVALUATION OF TRANSDERMAL DRUG DELIVERY SYSTEM PRESENTED BY: PAWAR SANKET TULSHIDAS M PHARM PHARMACEUTICS D. Y. PATIL INSTITUTE OF PHARMACEUTICAL SCIENCES AND RESEARCH, PIMPRI PUNE .
- 2. CONTENT: INTRODUCTION TO TRANSDERMLA DRUG DELIVERY SYSTM (TDDS) GENERAL STRUCTURE OF TDDS BASIC COMPONENTS OF TDDS APPROCH USED IN DEVELOPMENT OF TDDS PRODUCTION OF TDDS EVALUATION 1 2 3 4 5 6
- 3. 1. INTRODUCTION TO TRANSDERMLA DRUG DELIVERY SYSTM (TDDS) . DEFINATION: Transdermal therapeutic systems are defined as self-contained, discrete dosage forms which, when applied to the intact skin, deliver the drug(s), through the skin, at a controlled rate to the systemic circulation.
- 4. Backing layer Drug reservoir Polymeric Membrane Adhesive layer liner 2. GENERAL STRUCTURE OF TDDS All such transdermal dosage forms have a basic structure comprising of many layers, each having specific function. Farthest from the skin, when the system is in place, is a backing layer, preventing wetting of the system during use. The second layer is a reservoir that supplies a continuous quantum of drug for the predetermined functional life-time of the system. Next to the reservoir is the rate control polymeric membrane which regulates the rate of drug during a predetermined time interval. The drug so delivered diffuses through the skin and enters the systemic circulation . Next is the adhesive layer it keeps the TDDS in contact with the skin and final layer is the liner which protect the drug during the storage
- 5. BASIC COMPONENTS OF TDDS The components of transdermal devices include : 1. The drug 2. Polymer matrix or matrices 3. Permiation enhancer 4. Other excipients 1 . The drug : Physicochemical properties: (i) The drug should have a molecular weight less than approximately 1000 daltons. (ii) The drug should have affinity for both- lipophilic and hydrophilic phases. Extreme partitioning characteristics are not conducive to successful drug delivery via the skin. (iii) The drug should have a low melting point. Biological properties: (i) The drug should be potent with a daily dose of the order of a few mg/day. (ii) The half life (t1/2 ) of the drug should be short. (iii) Drug which degrade in the GI tract o rare inactivated by hepatic first-pass effect suitable candidates for transdermal deliivery
- 6. 2. Polymer matrix or matrices: The polymer control the release of the drug from the device. The following criteria should be satisfied for a polymer to be used in a transdermal system The polymer membrane may be continuous or may be microporous membrane Stable Non reactive Non toxic Non- antagonistic to host Easy to manufacture
- 7. Natural polymers Synthetic elastomer Synthatic polymer Cellulose derivative Polybutadine Polyvinyl alcohol Zein Hydrin rubber Polyvinyl chloride Gelatine Polysiloxane Polyethylene Shellac Silicone rubber Polypropylene Waxes Nitrile Polyacrylate Gums Acrylonitrile Polyamide starch Butyl rubber Polyurea Natural rubber neoprene polyvinylpyrrolidone Different type and example of the polymers used in TDDS
- 8. Permeation enhancer: This are compounds which promote skin permiability by alterning the skin as a barrier to flux of a desired penetrent J = D dc dx where D is the diffusion coefficient and is a function of the size, shape and flexibility of the diffusing molecule as well as the membrane resistance; C is the concentration of the diffusing species; x is the spatial coordinate. Although the solution for J with various boundary conditions and membrane heterogeneities can be very complex, the basic concepts regarding flux enhancement can be found in equation. The concentration gradient is thermodynamic in origin, and the diffusion coefficient is related to the size and shape of permeant and the energy required to make a hole for diffusion. Thus enhancement of flux across membranes reduces to considerations of : 1) Thermodynamics (lattice energies, distibution coefficients). 2) Molecular size and shape. 3) Reducing the energy required to make a molecular hole in the membrane
- 9. Example of permeatin enhancer Solvent: alcohols – methanol and ethanol, alkyl methyl sulfoxides -dimethyl sulfoxide, alkyl homologs of methyl sulfoxide, dimethyl acetamide and dimethyl formamide; pyrrolidones 2-pyrrolidone, N-methyl, 2-pyrrolidone, (Azone), miscellaneous solvents - propylene glycol, glycerol, silicone fluids, isopropyl palmitate Surfactant: Anionic surfactants: dioctyl sulphosuccinate, sodium lauryl sulphate, decodecylmethyl sulphoxide. Non ionic surfactant: pluronic F127, pluronic F68, etc Bile salts: sodium taurocholate, sodium deoxycholate, sodium tauroglycocholate Binary systems: propylene glycol-oleic acid and 1,4-butane diol-linoleic acid Miscellaneous chemical: . urea, a hydrating and keratolytic agent: N,N-dimethyl-m- toluamide; calcium thioglycolate;
- 10. OTHER EXCIPIENTS: ADHESIVE: The fastening of all transdermal devices to the skin has so far been done by using a pressure sensitive adhesive. (i) Should not irritate or sensitize the skin or cause an imbalance in the normal skin flora during its contact time with the skin. (II) Should adhere to the skin aggressively during the dosing interval without its position being disturbed by activities such as bathing, exercise etc. (iii) Should be easily removed. (iv) Should not leave an unwashable residue on the skin. Eg. Polyisobutylenes , acrylics and silicones. Backing membranes e.g. metallic plastic laminate, plastic backing with absorbent pad and occlusive base plate (aluminium foil), adhesive foam pad (flexible polyurethane) with occlusive base plate (aluminium foil disc) etc.
- 11. APPROCH USED IN DEVELOPMENT OF TDDS 1. membrane permeation – controlled system Membrane permeation Controlled systems In this type of system, the drug reservoir is totally encapsulated in a shallow compartment moulded from a drug-impermeable metallic plastic laminate and a rate controlling polymeric membrane which may be microporous or non-porous.
- 12. The intrinsic rate of drug release from this type of drug delivery system is defined as : dQ = CR Dt 1/Pm +1/Pa where, CR = concentration in reservior Pa and Pm = permiability coefficient of adhisive layer and membrane Pm = Km/r . Dm hm Pa = ka/m . Da ha Where, Km/r and ka/m = partion coefficient
- 13. ADHESIVE DISPERSION-TYPE SYSTEM This is a simplified form of the membrane permeation-controlled system. As represented in Fig. , the drug reservoir is formulated by directly dispersing the drug in an adhesive polymer e.g. poly (isobutylene) or poly (acrylate) adhesive and then spreading the medicated adhesive, by solvent casting or hot melt, on to a flat sheet of drug impermeable metallic plastic backing to form a thin drug reservoir layer. On top of the drug reservoir layer, thin layers of non-medicated, rate-controlling adhesive polymer of a specific permeability and constant thickness are applied to produce an adhesive diffusion-controlled
- 14. The rate of drug release in this system is defined by: dQ = Ka/r . Da . CR dt hA Alternatively, this type of transdermal therapeutic system can be modified to have the drug loading level varied at increments to form a gradient of drug reservoir along the multilaminate adhesive layers dQ = Ka/r . Da dt ha
- 15. Maxtrix diffusion- controll system: In this approach, the drug reservoir is prepared by homogeneously dispersing drug particles in a hydrophilic or lipophilic polymer matrix. The resultant medicated polymer is then moulded into a medicated disc with a defined surface area and controlled thickness. The dispersion of drug particles in the polymer matrix can be accomplished by either homogeneously mixing the finely ground drug particles with a liquid polymer or a highly viscous base polymer followed by cross-linking of the polymer chains or homogeneously blending drug solids with a rubbery polymer at an elevated temperature. The drug reservoir can also be formed by dissolving the drug and polymer in a common solvent followed by solvent evaporation in a mould at an elevated temperature and/or under vaccum. This drug reservoir containing polymer disc 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 the medicated disc
- 16. The rate of drug release from this type of system is defined as dQ = ACp Dp 1/2 Dt 2t Where, A = initial drug loading Cp and dp = are solubility and diffusivity
- 17. Microreservoir type or microsealed dissolution controlled systems: This can be considered a combination of the reservoir and matrix diffusion type drug delivery systems. Here 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 a lipophilic polymer viz. silicone elastomers by high energy dispersion technique
- 18. The rate of release of drug: dQ = Dp.Dd.m.Kp n.Sp D1.S1.1(1-n) 1 + 1 dt Dp.hd+Dd.hp.m.kp h1 K1 Km Where, m= a/b a is the ratio of the drug concentration in the bulk of the elution medium over drug solubility in the same medium and b is ratio of drug concentration at outer edge of the polymer coatingover the drug solubility in the same polymer composition Other type: Development of other types of potential drug delivery systems has been completed and products have started reaching market. These systems are poroplastic membrane and a hydrophilic polymeric reservoir. The poroplastic membrane is an open cell ultramicroporous form of cellulose triacetate. It holds saturated drug solution (water or mineral oil) by capillary action, it can also be described as a "molecular sponge"However, the pores are perhaps a million times smaller than those of an ordinary sponge.
- 19. A new variation on existing polymeric transdermal delivery systems employs hydrophilic gel matrix membrane The matrix is an "open cell molecular sponge", is a plasticizer which contains a drug in a soluble and/or suspended state in a microspace suspended by the polymeric meshwork of linkages. It contains one or a mixture of hydrogen bonding liquids such as water, glycerine, propylene glycol polyethylene glycol etc. comprising from 40-70 % patch weight. Gelation agents such as Karaya, algin, xanthan, guar, locust bean gum and/or synthetic hydrophilie polymers- polyacrylamide, polyvinyl sulphonates, polyvinyl alcohol, polyacrylic acid, polyvinyl pyrrolidone and others are also used. hydrophilic gel matrix membrane
- 20. 5. Production of TDDS 1. Membrane permeation-controlled
- 22. Matrix diffusion – controlled systems
- 23. Microsealed dissoloution- controlled systems
- 24. 6. Evaluations: 1. Evaluation of adhesive A. Peel adhesion properties : It is tested by measuring the force required to pull a single coated tape applied to a substrate at a 1800 angle
- 25. B. Track properties: • Thumb tack test: This is a subjective test in which evaluation is done by pressing the thumb briefly into the adhesive. Experience is required for using this test. • Rolling ball tack test: This test involves measurement of the distance that a stainlesS steel ball travels along an upward-facing adhesive . The less tacky the adhesive, the farther the ball will travel.
- 26. • Quick-stick (or pee-tack) test: The peel force required to break the bond between an adhesive and substrate is measured by pulling the tape away from the substrate at 90° at a speed of 12 inch/min • Probe tack test: Here, the force required to pull a probe away from an adhesive at a fixed rate is recorded as tack (expressed in grams)
- 27. C. Shear Strength Properties: Shear strength is the measurement of the cohesive strength of an adhesive polymer. Adequate cohesive Strength of a device will mean that the device will not slip on application and will leave no residue on removal. it is affected by molecular weight as well as the type and amount of tackifier added. Shear strength or creep resistance is determined by measuring the time it takes to pull an adhesive coated tape off a stainless steel plate when a specified weight is hung from the tape which pulls the tape in a direction parallel to the plate
- 28. 2. In-vitro drug release evaluation The design and development of transdermal drug delivery systems is greatly aided by in vitro studies. In vitro studies can help in investigating the mechanisms of skin permeation of the drug before it can be developed into a transdermal therapeutic system. Information such as the time needed to attain steady- state permeation and the permeation flux at steady state can be obtained from in vitro studies of the developed transdermal drug delivery system and used to optimize the formulation before more expensive in vivo studies are performed. Studies on skin metabolism can also be performed. The advantages of in vitro studies include ease of methodology, ease of analytical assay since there are no complications arising From the disposition of the drug in the body and better control over experimental conditions than is possible in vivo.
- 29. 3. Effect of skin uptake and metabolism For studying in vitro skin uptake and metabolism of drug, a piece (3 cm x 3 cm) of full thickness skin (human cadaver skin) or stripped skin freshly excised from a hairless mouse, 5-7 week old, was mounted between the two compartments of each V-C permeation cell. It was mounted in such a way that either the stratum comeum or the dermis faced the drug solution and the other side of the skin was protected with impermeable aluminium foil. The compartment with the skin surface uncovered was filled with a saturated solution of drug in normal saline and the compartment with the skin surface covered with aluminium foil remained empty. Both compartments were maintained isothermally at 370C. Samples were withdrawn from solution compartment at predetermined times and assayed for drug and any possible metabolites 4. In vivo evaluation A. Animal model B. Human model C. Bio physical model
- 30. 5. Cutaneous toxicological evaluation A. Contact dermatitis • Contact irritant dermatitis • Ten days primary irritation test • Twenty one day irritation test • Laser doppler • Evaporative water loss measurement • Contact allergic dermatitis B. Growth of microorganism • Localized superficial infection • Miliaria