1. Matrix Dispersion Systems in Transdermal Drug Delivery Samantha Sarett, Kristina Vaci, Kyle Householder, and Si Young An

2. Transdermal Drug Delivery Systems (TDDS) Distributes a drug through the skin and directly into the bloodstream Avoids first pass effect

3. Types of TDDS Reservoir System Matrix System Microreservoir System

4. Matrix System Four Layers – Backing Layer – Drug Reservoir/Drug in Matrix – Adhesive Layer – Release Liner Rate of drug release is controlled by diffusion through and erosion of the matrix

5. Matrix Former Properties necessary – Release properties – Adhesion–cohesion balance – Physicochemical properties – Compatibility and stability with other components of the system as well as with the skin

6. Poly(ethylene glycol) PDI value of 1.01 High solubility in organic solvents Soluble in water Low intrinsic toxicity

7. Cross-linked poly(ethylene glycol) (PEG) networks PEGs cross-linked with tris(6-isocyanatohexyl) isocyanurate by means of a urethane– allophanate bond capable of swelling in phosphate-buffered saline or ethanol and forming gels. release the solutes (proteins) in a biphasic manner.

8. Disadvantages Non-biodegradability Oxidative degradation Molar mass matters Overcoming drawbacks of using PEG – Use of biodegradable polymers (e.g. PLA, PGA, PLGA)

9. HPMC Hydroxypropyl methylcellulose (HPMC) is a matrix former Pulp cellulose + caustic soda  Alkali-cellulose complex + Methyl chloride + Propylene oxide  HPMC

10. HPMC K grade, E grade, and F grade K: 19-24% methoxy substitution, 7-12% hydroxypropyl substitution, T g = 70 o C E: 28-30% methoxy substitution, 7-12% hydroxypropyl substitution, T g = 56 o C Degree of polymerization of 100 to 1,500 Molecular weight varies

11. HPMC Erosion occurs as the outer layer of the matrix is diluted by water to a disentanglement concentration Water diffuses into the matrix  glassy matrix to rubbery Drug is released from the swollen system; eventually it erodes

12. HPMC Used to deliver: – Enalapril maleate; hypertension – Propanolol; beta-blocker – Repaglinide; diabetes mellitus

13. Ethyl Cellulose Hydrophobic and Lipophilic

14. Ethyl Cellulose Addition of polyvinylpyrrolidone PVP Addition of dibutyl phthalate Tg= 129 °C Good Compatibility

15. Adhesive Layer Properties: Good Permeation Rate Biocombatible with the skin Tacky Chemically cohesive with drug Water Resistant Resistant to degradation

16. Acrylic Acid Chemical Structure Fabrication Synthesize in organic solvent at a boiling point temperature around 77˚C Add in monomers for 1 hour, then let reaction go for 7 hours Cast on to release liner with silicone Set to dry and laminate back for application

17. Acrylic Acid Mechanical Properties Low Tg and amorphous Resistant to oxidative and UV degradation Water Resistant Good gas permeation Compatible with several drugs including: – Nicotine – Estradiol – nitroglycerine

18. Other Adhesive Polymers PolyIsobutylene Good Low Temperature Properties Silicones Very easily modified

19. References Cho, Y.J, Choi, H.K. “Enhancement of percutaneous absorption of ketoprofen: effect of vehicles and adhesive matrix.” International Journal of Pharmaceutics. Vol. 169 (1998): 95-104. Kandavilli, S., Nair, V., Panchagnula, R. “Polymers in Transdermal Drug Delivery Systems.” Pharmaceutical Technology. Pharmtech, (2002): 62-80. Czech, Zbigniew, Kurzawa, Rafal. “Acrylic Pressure-Sensitive Adhesive Drug Delivery Systems.” Journal of Applied Polymer Science. Vol. 106 (2007): 2398-2404. T. Pongjanyakul, S. Prakongpan, and A. Priprem, “Permeation Studies Comparing Cobra Skin with Human Skin Using Nicotine Transdermal Patches,” Drug Dev. Ind. Pharm. Vol. 26 (2000): 635–642. Kim, J, Cho, Y.J., Choi, H.K. “Effect of vehicles and pressure sensitive adhesives on the permeation of tacrine across hairless mouse skin.” International Journal of Pharmaceutics. Vol. 196 (2000): 105-113. Gavali, P. G. (2010). Design and development of hydroxypropyl methylcellulose (HPMC) based polymeric film of enalapril maleate. Journal of PharmTech Research, 2, 274-282. Kandavilli, S. V. (2002). Polymers in transdermal drug delivery systems. Pharmaceutical Technology. Dow Chemical Company. (2000). Using METHOCEL cellulose ethers for controlled release of drugs in hydrophilic matrix systems. United States. Chi, L. L. (2005). The use of hypermellose in oral drug delivery. Journal of Pharmacy and Pharmacology(57), 533-546. Lamberti. (2012). Carboxymethyl cellulose. Retrieved from The valueof custom-made chemistry: http://www.lamberti.com/technologies/carboxymethilcellulose.cfm http://www.lamberti.com/technologies/carboxymethilcellulose.cfm Heydarzadeh, H. D.-M. (2009). Catalyst-free conversion of alkali cellulose to fine carboxymethyl cellulose at mild conditions. World Applied Sciences Journal, 6(4), 564-569. Kavanagh, N. C. (2004). Swelling and erosion properties of hydroxypropylmethylcellulose (Hypromellose) matrices-influence of agitation rate and dissolution medium composition. International Journal of Pharmaceutics, 279, 141-152.

20. References H.M. Wolff, “Optimal Process Design for the Manufacturing of Transdermal Drug Delivery Systems”. PSTT 3 (5), 173–181 (2000). K. Knop, R. Hoogenboom, D. Fischer, Schubert. “U.S. Poly(ethylene glycol) in Drug Delivery: Pros and Cons as Well as Potential Alternatives”. Angew Chem Int Ed. 49, 6288-6308 (2010). L. Bromberg, “Cross-Linked Poly(ethylene glycol) Networks as Reservoirs for Protein Delivery”. J Appl Poly Sci. 59, 459–466 (1996). G. Pasut, F.M. Veronese. “Polymer-drug Conjugation, Recent Achievements and General Strategies”. Prog Polym Sci. 32, 933-961 (2007). F.M. Veronese, G. Pasut. “PEGylation, Successful Approach to Drug Delivery”. Drug Discov Today. 10, 1451-1458 (2005). 12. D.A. Herold, K. Keil, D.E. Bruns. “Oxidation of polyethylene glycols by alcohol dehydrogenase”. Biochem Pharmacol. 38, 73-76 (1989). R.L Kronenthal. Biodegradable polymers in medicine and surgery. In: Kronenthal RL, Oser Z, Martin E, Eds., Polymers in Medicine and Surgery, Plenum Press, New York, 1975, pp. 119. Prajapati, S. T. (2011). Formulation and evaluation of transdermal patch of repaglinide. International Scholarly Research Network Pharmaceutics. Guyot, M. F. (2000). Design and in vitro evaluation of adhesive matrix for transdermal delivery of propanolol. International Journal of Pharmaceutics, 204, 171-182. Kandavilli S. Nair V. and Panchagnula R. “Polymers in Transdermal Drug Delivery Systems.” Pharmaceutical Technology. March 2002. 62-80. "ETHOCELL: Ethyl Cellulose Technical Handbook." Dow Chemical Company. Web..http://msdssearch.dow.com/PublishedLiteratureDOWCOM/dh_004f/0901b8038004fb7c.pdf?filepath=eth ocel/pdfs/noreg/192-00818.pdf&fromPage=GetDoc Arora, P. and Mukherjee, B. “Design, development, physicochemical, and in vitro and in vivoevaluation of transdermal patches containing diclofenac diethylammonium salt.” J. Pharm. Sci., 91: 2076–2089. doi: 10.1002/jps.10200

21. Questions?