USOO8361492B2 (12) United States Patent (10) Patent No.: US 8,361,492 B2 Tauber et al. (45) Date of Patent: *Jan. 29, 2013 (54) DRUG DELIVERY SYSTEMAND METHODS (56) References Cited OF USE U.S. PATENT DOCUMENTS (75) Inventors: Shachar Tauber, Ozark, MO (US); 2003/0017208 A1* 1/2003 Ignatious et al. ............. 424/486 Randall Fuerst, Orangevale, CA (US); 2003/01931 18 A1 10/2003 Bango et al. 2003/0215624 A1 1 1/2003 Layman et al. Keela Davis, Springfield, MO (US); Lyle 2003/0232287 A1 12/2003 Bango Bowman, Pleasanton, CA (US); Gary 2004/0018226 A1 1/2004 Winek et al. Wnek, Cleveland, OH (US); Joseph J. 2005, OO67287 A1 3/2005 Fuerst et al. Bango, Jr., New Haven, CT (US) 2006/0085063 A1* 4/2006 Shastri et al. ................ 623, 141 2006/0171991 A1 8/2006 Bango 2006/0246113 A1 11/2006 Griffith et al. (73) Assignee: Ocugenics, LLC, Orangevale, CA (US) 2008.0002149 A1 1/2008 Fritsch et al. 2009/0217849 A1 9, 2009 Eastin et al. (*) Notice: Subject to any disclaimer, the term of this 2009, 0238858 A1 9, 2009 Kohnet al. patent is extended or adjusted under 35 OTHER PUBLICATIONS U.S.C. 154(b) by 493 days. Office Action issued in related U.S. Appl. No. 12/416,802, dated Sep. This patent is Subject to a terminal dis 17, 2010, 11 pages. claimer. International Search Report and Written Opinion issued in PCT/ US2010/029126, dated Jan. 14, 2011, 11 pages. Kenawy, E.R. et al. “Controlled Release of Ketoprofen from (21) Appl. No.: 12/490,972 electrospun poly(vinyl alcohol) nanofibers' Materials Science & Engineering A 459, pp. 390-396, 2007. (22) Filed: Jun. 24, 2009 Huang, Z.M., et al. A review on polymer nanofibers by electrospin ning and their applications in nanocomposites. Composites Science (65) Prior Publication Data & Terchnology 63, pp. 2223-2253, 2003. US 2009/O269392 A1 Oct. 29, 2009 * cited by examiner Related U.S. Application Data Primary Examiner — Frederick Krass Assistant Examiner — Dennis J Parad (63) Continuation-in-part of application No. 12/416,802, (74) Attorney, Agent, or Firm — Lathrop & Gage LLP filed on Apr. 1, 2009, now Pat. No. 8,083,347. (57) ABSTRACT (60) Provisional application No. 61/125,985, filed on Apr. Electrospun fibers are utilized to improve the mechanical 29, 2008. characteristics of a contact lens reducing the weight and mechanical strength of the polymers from which the lenses (51) Int. C. are typically formed. Electrospun fibers are also utilized as a A6DF 3/00 (2006.01) drug delivery system, both through direct use in the eye and A6 IK9/00 (2006.01) by inclusion of the fibers in a contact lens. The fibers are U.S. Cl. ........................................ 424/443; 424/429 loaded with therapeutic drugs by a variety of methods and (52) processed by coating and cross-linking the fibers. (58) Field of Classification Search ................... 424/429 See application file for complete search history. 25 Claims, 8 Drawing Sheets U.S. Patent Jan. 29, 2013 Sheet 1 of 8 US 8,361,492 B2 FIGURE 1 U.S. Patent Jan. 29, 2013 Sheet 2 of 8 US 8,361,492 B2 FIGURE 2 U.S. Patent Jan. 29, 2013 Sheet 3 of 8 US 8,361,492 B2 FIGURE 3 U.S. Patent Jan. 29, 2013 Sheet 4 of 8 US 8,361,492 B2 "F'———— TO-BOOZ’T ?0-3000°T Z0-3000°C (u/8) uoeulue2uoo U.S. Patent Jan. 29, 2013 Sheet 5 of 8 US 8,361,492 B2 0-Z-º- OOOT00800900700Z0009T0017TOOZT (u/8) uo eulue ouo) U.S. Patent Jan. 29, 2013 Sheet 6 of 8 US 8,361,492 B2 09 09 VSEIRIO!!OIH OT (u/8) uo euque,0uOO U.S. Patent Jan. 29, 2013 Sheet 8 of 8 US 8,361,492 B2 an V O O d 600’0 O ZOO’O(= u/8) uoheulueouOO US 8,361,492 B2 1. 2 DRUG DELIVERY SYSTEMAND METHODS fiber materials. The thinner cross-section lens provides OF USE increased oxygen permeability while maintaining mechani cal strength. CROSS-REFERENCE TO RELATED APPLICATIONS BRIEF DESCRIPTION OF THE DRAWINGS This is a continuation-in-part application which claims FIG. 1 is a scanning electron micrograph of a mat of fibers priority of U.S. Non-provisional patent application Ser. No. formed by electrospinning poly(vinyl) alcohol. 12/416,802 filed on Apr. 1, 2009, now issued as Pat. No. FIG. 2 is a scanning electron micrograph of a mat of fibers 8,083,347, which claims priority of U.S. Provisional Patent 10 formed by electrospinning poly(vinyl) alcohol and crosslinked by Submersion in methanol. Application No. 61/125,985 filed on Apr. 29, 2008, which FIG. 3 is a scanning electron micrograph of a mat of fibers applications are incorporated herein by reference. formed by electrospinning poly(vinyl) alcohol, crosslinked BACKGROUND by Submersion in methanol, coated with an aqueous solution 15 of poly(vinyl) alcohol, and then crosslinked a second time. FIG. 4 is a graph of the concentration of a therapeutic drug Field of the Invention released by a fiber mat soak-loaded with the therapeutic drug after deposition. Electrospun polymer fibers provide a material with a vari FIG. 5 is a graph of the concentration of a therapeutic drug ety of favorable characteristics that may be tailored to fit released by a fiber mat fabricated from a precursor solution various applications. The fibers in the electrospun materials containing the therapeutic drug and coated with poly(vinyl) provide Superior mechanical strength with reduced weight alcohol. and Volume. They also have high Surface area and porosity FIG. 5A is a graph of the first 60 minutes of the time period which may be altered as desired during fabrication. shown in FIG. 5. It is therefore desirable to provide a drug delivery system 25 FIG. 6 is a graph of the concentration of a therapeutic drug utilizing electrospun polymer fibers. The drug delivery sys released by a fiber mat fabricated from a precursor solution tem may utilize the fibers for insertion directly into the eye containing the therapeutic drug coated with poly(vinyl) alco maintaining the concentration of the drug in the eye at an hol, and crosslinked with methanol. efficacious level throughout the period of drug delivery. FIG. 6A is a graph of the first 60 minutes of the time period The system may also utilize an improved contact lens 30 shown in FIG. 6. incorporating electrospun fibers with desired characteristics, and a system and method for delivering ophthalmic drugs DETAILED DESCRIPTION from the improved contact lens to an eye over an extended period of time while maintaining the concentration of the Electrospun Fiber Mat Fabrication 35 The electrospun fiber mat used in the present invention is drug in the eye at an efficacious level throughout the period of fabricated by polymerizing electrospun fibers and loading a drug delivery. therapeutic drug in the fibermat using a variety of techniques, It is also desirable to provide a system and method for which are described below with examples. preloading drugs in the delivery system in a manner that The electrospinning process typically comprises an appa allows the delivery system to be stored for an extended period 40 ratus including one or more electrically-conducting liquid of time. dispenser, such as a stainless Steel needle, disposed adjacent to a collector. The liquid dispenser is held at a high electric SUMMARY OF THE INVENTION potential, or voltage, with respect to the collector. The electric potential may be either alternating current (AC) or direct The drug delivery system described herein utilizes both 45 current (DC), or a DC biased AC voltage. Alternatively, a “raw' electrospun fibers and an improved contact lens as the substrate for receiving the electrospun fibers may be inserted means of drug delivery. The fibers and the improved contact between the conducting dispenser and the collector Such that lens provide a drug delivery system comprising a drug-releas the fibers will be deposited on the substrate as they are pro ing scaffold formed from a mat of electrospun fibers and pelled from the liquid dispenser by the electric field toward methods for incorporating various therapeutic drugs into the 50 the collector. mat. The fiber mat may be utilized directly in the eye for A Solution Source, or well, containing a solution of the delivery of drugs, or incorporated into an improved contact polymer and various other components which may include a lens. polymer precursor (monomer) is attached to the electrically The therapeutic drugs may be loaded into the drug delivery conducting liquid dispenser by a fluid conducting element system by soaking the electrospun mats in a solution contain 55 such as a short tube. The polymer solution is propelled ing the drug, or by providing the drugs in the Solution feeding through the dispenser at a predetermined rate, either by grav the electrospinning process thus incorporating the drug into ity or by mechanical means such as a pump. As the Solution is the fibers in the electrospun mat. Various processes for treat dispensed through the electrically-conducting dispenser, the ing the electrospun mats after loading with therapeutic drugs high electric potential between the dispenser and the collector are also described for improving the drug delivery character 60 leads to the formation of uniform fibers which are deposited istics, such as coating the mats in a polymer and cross-linking on the collector. The fibers may be micro-fibers or nano-fibers the electrospun fibers. depending on the parameters of the electrospinning process. The improved contact lens described herein also comprises As the fibers are deposited on the collector they overlap to a contact lens that incorporates electrospun fibers to provide form a mat, as further described below.