UV-CURABLE PRESSURE SENSITIVE ADHESIVE TRANSDERMAL DRUG DELIVERY PATCH BASED ON PVP-PEGDA-PEG COPOLYMERIZATION SARA FARAJI DANA NATIONAL UNIVERSITY OF SINGAPORE 2013 UV-curable Pressure Sensitive Adhesive Transdermal Drug Delivery Patch Based on PVP-PEGDA-PEG Copolymerization Sara Faraji Dana (M.Sc of Chemistry, Mount Allison University, Canada) (B.Sc of Chemistry, Sharif University of Technology, Iran) A Thesis Submitted For The Degree of Master of Science Department of Pharmacy National University of Singapore 2013 Declaration I hereby declare that the thesis is my original work and it has been written by me in its entirety I have duly acknowledged all the sources of information which have been used in the thesis This thesis has also not been submitted for any degree in any university previously _ Sara Faraji Dana 14 March 2013 i Acknowledgements I would not be able to fare well through this stage of my scientific journey without the help of many people I owe my gratitude to all who has contributed to this work one way or another First and foremost, I must acknowledge my supervisor, Dr Kang Lifeng, at Pharmacy Department of NUS, whose support has been wonderful Dr Kang is a pleasure to work with; he provides a good balance of direction and freedom to explore the possible avenues of research one may wish He clearly holds the best interests of his students at heart Thanks to his encouragement, positive attitude and guidance for my project which otherwise would not have been accomplished I would like to express my gratitude and appreciation to Prof Liu Xiang Yang for his trust and permission, working with the delicate instruments in his biophysical lab at Department of Physic I would like to thank his group members, Nguyen Duc Viet, Nguyen Anh Tuan, Toh Guoyang (William) and Xu Gangqin for their help teaching me how to use the instruments I would like to extend my sincere thanks to professors and lecturers in Department of Pharmacy who offered a peaceful and comfortable environment for studies and provided the required facilities for a good research It is an honour for me to thank all my lab mates, Jaspreet Singh Kochhar, Pan Jing, Li Hairui, and together with all other friends for their invaluable helps and creating such a pleasant working atmosphere for me in the lab I would like to take this opportunity to express my gratitude to Chan Wei Ling (Kelly), Lye Pey Pey, NG Sek Eng, and Sukaman Bin ii Seymo for their fervent support I would also like to thank the SBIC-Nikon Imaging Centre at Biopolis for providing the imaging facilities and special thanks to Ms Joleen Lim for the assistance provided in demonstration the proper usage of Confocal Laser Scanning Microscope I am also thankful to Ms Audrey Tay and Dr Teo Wei Boon from PerkinElmer, Singapore for their help in analysing ATR-FTIR samples At last, but not least, I thank the most important people of my life, those to whose unconditional love I am indebted, my family My deepest gratitude goes to my beloved parents, Maman Maryam and Ahmad Baba, for their influential role in my life and their sincere devoting of their lives to my progress, to Amir, my only brother for simply his presence in my life and to Maziar, the love of my life, who did whatever he could to help me concentrate on this work and for being a constant source of motivation and encouragement I humbly bow to my treasured mom and dad and dedicate this thesis to them as a little sign of sincere appreciation and love for all their sacrifices iii Table of Contents Declaration i Acknowledgements ii Table of Contents iv Summary vi List of Publications vii List of Tables viii List of Figures ix List of Abbreviations xi Introduction Materials and Methods 10 2.1 Materials 10 2.2 Fabrication of Pressure Sensitive Adhesive Films 10 2.3 Preparation of Pig Skin Samples for Peel Tests 17 2.4 Hydrogels Characterization 17 2.4.1 Morphologies of PEGDA-Based Hydrogels 17 2.4.2 Attenuated Total Reflection Fourier Transform Infrared (ATR-FTIR) Spectroscopy 18 2.4.3 Measurement of Film Thickness 19 2.4.4 Drug Distribution 20 2.4.5 Measurements of Rheological Properties 20 2.4.6 Measurement of Mechanical Properties 22 Results and Discussion 24 3.1 Microfabricated PSA hydrogels 24 3.2 Morphological Characterization by SEM 28 3.3 Spectral Characterization of PSA Hydrogels 29 3.4 Control of thickness and Drug Distribution 32 iv 3.5 Rheological Properties 35 3.5.1 Dynamic Strain Sweep Test 35 3.5.2 Dynamic Frequency Sweep Test 37 3.6 Viscoelastic Windows 40 3.7 Mechanical Properties 42 3.7.1 Tensile Testing 43 3.7.2 Peel Testing 46 Conclusions 50 Future Work 51 Reference 54 Appendices and Supporting Information 58 Appendix I 58 Appendix II 60 v Summary We developed a new approach to fabricate pressure sensitive adhesive (PSA) hydrogels for dermatological applications These hydrogels were fabricated by using polyvinylpyrrolidone (PVP), poly (ethylene glycol) diacrylate (PEGDA) and polyethylene glycol (PEG) with/without propylene glycol (PG) via photo-polymerization Hydrogel films with the thickness of 130 to 1190 µm were obtained The surface morphology and drug distribution within the films were found to be uniform The influence of different factors (polymeric composition, i.e PEG/PG presence, and thickness) on the functional properties (i.e rheological and mechanical properties, adhesion performance and drug distribution) of the films was investigated The viscoelastic, mechanical and adhesion (against glass and skin substrates) behaviours of hydrogels were studied by rheological, tensile and adhesion strength tests Measurements were carried out on a porcine cadaver skin and glass surfaces as control, to investigate the potential dermatological applications of these hydrogel adhesives The addition of plasticizers, namely PEG and PG, resulted in a simultaneous increase in elasticity and tack of these hydrogels, due to formation of hydrogen bondings, which has a direct correlation with their adhesive properties The microfabricated hydrogel adhesives, modified with PG, are potentially useful for industrial applications, due to the simple procedure, precise control over film thickness, minimal usage of solvents and controllable mechanical, rheological and adhesive properties vi List of Publications  Sara Faraji Dana, Viet Nguyen Duc, Xiang-Yang Liu and Lifeng Kang, UV-curable Pressure Sensitive Adhesives: Effects of Biocompatible Plasticizers on Mechanical and Adhesion Properties, Soft Matter (Submitted, 2012)  Hairui Li, Yuan Yu, Sara Faraji Dana, Bo Li, Chi-Ying Li and Lifeng Kang, Novel engineered systems for oral, mucosal and transdermal drug delivery, Journal of Drug Targeting (Invited review, 2012) vii Figure 13 Average peel test run of (a) PVP-PEGDA-PEG and (b) PG incorporated PVP-PEGDA-PEG PSA films with the thickness of 910-1190 µm, from a rigid substrate, i.e glass, and a flexible substrate, i.e cadaver pig skin, at a speed of 50 mm/min, and nominal peel angel of 180 degree (C) Comparison of averaged 180 degree peel force for two different compositions from two different substrates 47 The low peel strength of the PVP-PEGDA-PEG hydrogel films with no PG incorporated is consistent with the morphology observed in SEM experiments The increased number of voids present in the PVP-PEGDA-PEG films, Fig 5(b), in other words the less packed structure of these films, lowered both the localized adhesive thickness and the contact area which leads to a reduction in the peel strength While the PVP-PEGDA-PEG adhesive films had a similar thickness to that of the other samples (i.e PG incorporated PVP-PEGDAPEG PSA films), due to the less dense structure, the amount of adhesive on the surface of substrate was reduced The reduced contact area also decreases the amount of mechanical interlocking The combination of these properties would lower the peel strength on any PSA as it does for the PVP-PEGDA-PEG PSA films It is also apparent that the peel strength of either of the compositions encounters a reduction when the substrates changed from glass to skin As for the PG incorporated films, maximum peel force reduced from 0.79 N to 0.59 N and for the films without PG incorporation, maximum peel force reduced from 0.42 N to 0.3 N by switching the substrate from glass to skin The peel strengths average of all the three measurements for each film type (PVPPEGDA-PEG with or without PG incorporation), against both surfaces were recorded in Newton and is shown in Fig 13(c) for a better comparison As noted, the PG incorporated films possess the highest peel strength against the rigid surfaces and the PSA films without PG possess the smallest peel strength against the flexible surface Removal of the PSA films from different substrates involves the work done in the extension of the adhesive, distortion of the backing during the stripping action and the separation of the adhesive/surface interface.5, As for our studies no backing layer was 48 involved and just the adhesive films, PVP-PEGDA-PEG and PG incorporated PVP-PEGDAPEG PSA, were used in the peeling test The debonding of our adhesive films was via “Adhesive failure Case I” mode which means when the PSA films were peeled away from either of substrates, i.e glass and pig skin cadaver, they were stripped cleanly, leaving no visible adhesive residue on the substrates.6 Generally, a PSA should be able to flow into the cavities of the substrate (so called viscosity), in order to interact tightly with the surface of the substrate.5 When it makes a close contact with the surface of substrate because of its viscoelastic properties then it will be able to make molecular interactions such as Van der Waals forces with the skin or substrate The PSA-skin bonds can be built by stronger interactions (i.e hydrogen bonding), following the initial adhesion.5, So, enhancements of adhesion by incorporation of PG may be attributed to the improvement of viscoelastic properties of films and hence a better wetting effect And also it may be due to enhancement of the number of hydrogen bonding in the polymer network, as PG has two hydroxyl groups in its structure Besides peel strength measurements for two different compositions of films (without and with PG incorporation) against both soft and hard surfaces, the effect of varying the thickness of adhesive while keeping other factors constant was also studied The effect of adhesive thickness, either 650-850 µm or 900-1190 µm thick, on peel strength was almost negligible Thus, according to these results, it was noted that the peel force would increase with the incorporation of PG, and/or utilizing a hard substrate instead of a flexible one, but not with the change of the film thickness from 650-850 µm (5 spacers) to 900-1190 µm (7 spacers) 49 Conclusions To develop a suitable pressure sensitive adhesive film for dermatological applications, we devised photo-crosslinked PVP-PEGDA-PEG hydrogels The PSA films were successfully fabricated by photo-polymerization of PVP, PEGDA and PEG polymers with/without PG The resulted PSA hydrogel films thickness is controllable, with a densely phase-separated and uniform surface morphology These hydrogels were capable of undergoing UV irradiation and formation of the films within a few seconds with minimal usage of solvents compared with those prepared with conventional methods Both the lack of solvents and the quick cure speed are key features of this green approach to chemical processing Furthermore, there was a precise control over the thickness of the films The simple fabrication process enabled us to control the adhesive properties, such as gel strength and adhesiveness, by manipulating the preparative composition and conditions Employing simultaneous optimizations (various thicknesses, PG incorporation), the optimal formulation of photo-crosslinked hydrogels, i.e PVP-PEGDA-PEG-PG, for potential use as dermatological adhesives was successfully established The PVP-PEGDA-PEG-PG films are shown to be more flexible and adhesive than the correspondent PVP-PEGDA-PEG films Increasing the thickness of the films decreased the flexibility and elongation at break percentage of the films, but has no effect on the adhesiveness of the films Incorporation of PG, as a plasticizer, into the PVP-PEGA-PEG hydrogel provided the best film properties The optimized film has shown suitable mechanical and rheological properties, i.e flexibility, resistance and bioadhesion, which make it a promising adhesive hydrogel film for dermatological applications 50 Future Work As a future work, the development of these microfabricated, photo-crosslinked PVPPEGDA-PEG hydrogel films modified with PG, will be further investigated with the incorporation of different drugs and by determination of the drug release profiles and drug permeation studies through the skin in order to assess the viability of using these films as adjustable dermatological drug delivery systems Encapsulation of drugs in microfabricated PSA hydrogels: Different model drugs, such as Rhd B, lidocaine, will be encapsulated in the hydrogel matrix of PVP-PEGDA-PEGPG PSA films The amount of drug encapsulated in the hydrogel films can be calculated from the percent weight of the drugs in the precursor solution and the weight of microfabricated films In vitro release profile of drugs from PSA hydrogel films: Following the encapsulation of drugs, e.g model drug Rhd B, in the PSA hydrogel films, the in vitro release from hydrogel matrix can be tested The PSA films will be immersed in PBS and the release solutions should be periodically sampled Once done with the sampling, each sample should be pipetted into the wells of Corning 96 well plate and analyzed by absorbance measurements in a microplate reader The cumulative percentage release is then will be calculated In vitro drug permeation studies from PSA hydrogel films through the skin: Complementing the in vitro release profile of model drugs, e.g Rhd B, from PSA hydrogels, the next step is to study the drug permeability from microfabricated hydrogels across cadaver pig skin in an in vitro setting using horizontal diffusion cell (Fig 14) 51 Figure 14 A horizontal diffusion cell assembly Investigation of drug stability upon UV exposure: Although, fabrication of the PSA hydrogels at small polymerization time of 1-7 seconds is expected not to compromise the stability of incorporated drug (e.g model drug Rhd B) as the exposure to UV is minimized As a part of our future work, we plan to investigate the UV stability of different drugs incorporated into the PSA films Since the model drug Rhd B was incorporated into the PEGDA-based PSA films by dissolving it in the polymer precursor solution before UV irradiation, we intend to check the drug composition before and after UV radiation to trace any possible degradation We expect that our method of fabrication ensures higher drug stability than previously used methods in 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Supporting Information Appendix I Furthermore, the fabrication process was also optimized by performing trials of different variable settings, i.e adjustment of UV light strength (0.6-12.4 W/cm2), UV exposure time (differing from 1-30 seconds) and UV light distance (2-10 cm) It was observed that as the UV light distance from the setting stage was increased (from to cm), due to increase of UV irradiation area, larger portion of the fabrication set up was being photo-polymerized On the other hand, increase of the distance between the UV light and the fabrication setup, above cm, resulted in the formation of non uniform films With the intensity lower than W/cm2, no PSA hydrogel films were formed and between the intensities of 4–8 W/cm2, hydrogels formed were observed to be uneven and the uniformity of thickness was poor The uniform PSA film structures were obtained at all intensities above W/cm2 The microfabricated PSAs at 12.4 W/cm2 were found to possess the optimum mechanical properties Moreover, fabrication of PSA hydrogel films were attempted at different polymerization durations ranging from second to 30 seconds, keeping the UV light intensity constant (12.4 W/cm2) and with two fixed distances from UV light source, i.e we tried both cm and cm It was noticed that the photo-polymerization of the precursor solution required minimum UV exposure duration of seconds At polymerization durations longer than 15 seconds, the microfabricated films were slightly difficult to detach from the setup Eventually, cm distance from UV light source and 1-7 seconds of polymerization time (the time was increased from second to seconds, upon increasing the spacer 58 thickness We manipulated the spacer thickness by increasing the number of coverslips, i.e 1-9 coverslips) at the UV intensity of 12.4 W/cm2 were set as optimum conditions for the fabrication process of the PSA films 59 Appendix II As mentioned before for model drug experiments, 4500 µg of Rhd B was added to the PVP-PEGDA-PEG precursor solution before UV irradiation The yielded PVP-PEGDAPEG-Rhd B films were then analyzed by CLSM to assess the quality of drug distribution and the intensity of fluorescence in each film at different depth intervals (2 µm increments) and three different spots to reconfirm the uniformity of drug distribution within PSA films As shown in Fig 15 (a) and (b), the Rhd B incorporated PSA films, with different thicknesses (130-5170 to 910-1190 µm), showed a similar trend at different spots on different films and the maximum fluorescence intensity for all of them is about 4095 AU 60 Figure 15 Fluorescence intensity of each film as measured by CLSM at different depth intervals (2 µm), in three different parts of each film (two corners and one center), a) L1 and L3 refer to number of spacers used for the fabrication (1 for films with a thicknesses of 130-170 µm and for films with a thickness of 390-510 µm, respectively), b) L5 and L7 refer to number of spacers used for the fabrication (5 for films with a thicknesses of 650-850 µm and for films with a thickness of 910-1190 µm, respectively) 61 ... Spectroscopy Pure PEGDA macromer, and PVP, PEG and PG macromers and hydrogels of PEGDA, PVP- PEG, PVP- PEGDA, PVP- PEGDA- PEG and PVP- PEGDA- PEG- PG were analyzed by ATR-FTIR to investigate the interactions between.. .UV- curable Pressure Sensitive Adhesive Transdermal Drug Delivery Patch Based on PVP- PEGDA- PEG Copolymerization Sara Faraji Dana (M.Sc of Chemistry, Mount Allison University, Canada)... comparing the ATR-FTIR spectra of pure PEGDA macromer and PG, PEG and PVP 29 monomers, PEGDA hydrogels and PVP- PEGDA, PVP- PEGDA- PEG and PG incorporated PVP- PEGDA- PEG hydrogels, shown in Fig 6, an