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(12) United States Patent (10) Patent No.: US 7,893,040 B2 Loftsson Et Al

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(12) United States Patent (10) Patent No.: US 7,893,040 B2 Loftsson Et Al US0078.93040B2 (12) United States Patent (10) Patent No.: US 7,893,040 B2 Loftsson et al. (45) Date of Patent: Feb. 22, 2011 (54) CYCLODEXTRINNANOTECHNOLOGY FOR Yasukawa et al., “Intraocular Sustained drug delivery using implant OPHTHALMC DRUG DELVERY able polymeric devices”. Advanced Drug Delivery Reviews, vol. 57. pp. 2033-2046, 2005, Elsevier B.V., Netherlands. (75) Inventors: Thorsteinn Loftsson, Reykjavik (IS); Jonas, “Intravitreal triamcinolone acetonide for treatment of Einar Stefánsson, Reykjavik (IS) intraocular oedematous and neovascular diseases'. Acta Ophthalmologica Scandinavia, vol. 83, pp. 645-663, 2005, (73) Assignee: Oculis ehf, Reykjavik (IS) Munksgaard, Denmark. Duan et al., “Cyclodextrin solubilization of the antibacterial agents (*) Notice: Subject to any disclaimer, the term of this triclosan and triclocarban: Formation of aggregates and higher-order patent is extended or adjusted under 35 complexes'. International Journal of Pharmaceutics, vol. 297, pp. U.S.C. 154(b) by 1134 days. 213-222, 2005, Elsevier B.V., Netherlands. Gonzalez-Gaitano et al., “The Aggregation of Cyclodextrins as Stud (21) Appl. No.: 11/489,466 ied by Photon Correlation Spectroscopy”. Journal of Inclusion Phe nomena and Macrocylclic Chemistry, vol. 44, pp. 101-105, 2002, (22) Filed: Jul. 20, 2006 Kluwer Academic Publishers, The Netherlands. Loftsson et al., “Cyclodextrins in drug delivery'. Expert Opinion, (65) Prior Publication Data vol. 2, Drug Delivery, pp. 335-351, 2005, Ashley Publications Ltd., London. US 2007/OO2O336A1 Jan. 25, 2007 Loftsson et al., “Cyclodextrins in ophthalmic drug delivery'. Advanced Drug Delivery Reviews, vol. 36, pp. 59-79, 1999, Elsevier Related U.S. Application Data B.V., Netherlands. (60) Provisional application No. 60/701,621, filed on Jul. Loftsson et al., “The effects of organic salts on the cyclodextrin 22, 2005, provisional application No. 60/795,563, solubilization of drugs'. International Journal of Pharmaceutics, vol. filed on Apr. 28, 2006. 262, pp. 101-107, 2003, Elsevier B.V., Netherlands. Loftsson et al., “The effects of water-soluble polymers on (51) Int. Cl. cyclodextrins and cyclodextrin solubilization of drugs'. J. Drug Del. A6 IK3I/724 (2006.01) Sci. Tech, vol. 14, pp. 35-43, 2004, Editions de Santé, France. A 6LX 3L/75 (2006.01) Loftsson et al., “Self-Association of Cyclodextrins and Cyclodextrin Complexes”,Journal of Pharmaceutical Sciences, vol. 93, No. 5, pp. (52) U.S. Cl. ........................... 514/58: 514/54: 514/914; 1091-1099, 2004, Wiley-Liss, Inc and the American Pharmacists 536/103 Association, USA. (58) Field of Classification Search ................... 514/58, 514/54,914: 536/103 (Continued) See application file for complete search history. Primary Examiner Shaojia Anna Jiang (56) References Cited Assistant Examiner Michael C Henry (74) Attorney, Agent, or Firm—Buchanan Ingersoll & U.S. PATENT DOCUMENTS Rooney PC 5,472,954 A 12/1995 Loftsson 2005/OO31697 A1 2/2005 Vehige et al. (57) ABSTRACT 2005/0234018 A1 10/2005 Lyons et al. FOREIGN PATENT DOCUMENTS The invention provides an ophthalmic composition which is EP O 579 435 B1 1, 1994 an aqueous Suspension comprising drug, cyclodextrin and EP O 709 O99 A2 5, 1996 water, the composition having an aqueous phase of from WO 2004/087100 A2 10, 2004 about 0.1% (w/v) to about 90% (w/v) of the drug in solution, WO WO 2005,105067 A2 11/2005 as dissolved free drug and as dissolved drug/cyclodextrin WO WO 2005,105067 A3 11/2005 complex(es), and a solid phase of from about 10% (w/v) to OTHER PUBLICATIONS about 99.9% (w/v) of the drug as solid drug/cyclodextrin particles, Suspended in the aqueous phase; the size of the Solid Sugrue, “The Pharmacology of Antiglaucoma Drugs'. Pharmac. particles being from about 10 nm to about 1 mm, the drug/ Ther. vol.43, pp. 91-138, 1989, Maxwell Pergamon Macmillian plc, cyclodextrin particles being capable of dissolving in aqueous Great Britain. Salminen et al., “Disposition of Ophthalmic Timolol in Treated and tear fluid within 24 hours of application to the eye surface. Untreated Rabbit Eyes. A Multiple and Single Dose Study”. Exp. Eye The aqueous eye suspension can be in the form of eye drops, Res., vol. 38, pp. 203-206, 1984, Academic Press Inc, London. eye gel or eye mist. Further, the invention provides a method Beeley et al., “Fabrication, implantation, elution, and retrieval of a for treating a condition of the posterior segment and/or ante Steroid-loaded polycaprolactone Subretinal implant'. Journal of bio rior segment of the eye comprising applying to the eye Sur medical materials research, vol. 73, pp. 437-444, 2005, Wiley Peri face, in an amount which delivers to said segment or segments odicals, Inc., USA. a therapeutically effective amount of a drug suitable for treat Myles et al., “Recent progress in ocular drug delivery for posterior ing said condition, an ophthalmic composition which is as segment disease: Emphasis on transscleral iontophoresis'. Advanced defined above. Nasal compositions and methods and oph Drug Delivery Reviews, vol. 57, pp. 2063-2079, 2005, Elsevier B. thalmic and nasal compositions in powder form are also pro V., Netherlands. vided. Raghava et al., “Periocular routes for retinal drug delivery'. Expert Opinion, Drug Delivery, vol. 1, pp. 99-114, 2004, Ashley Publica tions Ltd., England. 20 Claims, 7 Drawing Sheets US 7,893,040 B2 Page 2 OTHER PUBLICATIONS Loftsson et al., “Evaluation of cyclodextrin solubilization of drugs'. International Journal of Pharmaceutics, vol. 302, pp. 18-28, 2005, Loftsson et al., “Cyclodextrins in eye drop formulations: enhanced topical delivery of corticosteroids to the eye'. Acta Ophthalmologica Elsevier B.V., Netherlands. Scandinavia 2002, vol. 80, pp. 144-150, Munksgaard, Denmark. Ammar et al., “Cyclodextrins in acetazolamide eye drop formula Loftsson et al., “Cyclodextrin Solubilization of the Antibacterial tions'. Pharmazie, vol. 53, pp. 559-562, 1998, Govi-Verlag Agents Triclosan and Triclocarban: Effect of Ionization and Poly Pharmazeutischer Verlag GmbH Eschborn, Germany. mers', Journal of Inclusion Phenomena and Macrocyclic Chemistry, Loftsson et al., “Topically effective ocular hypotensive vol. 52, pp. 109-117, 2005, Springer, Netherlands. acetazolamide and ethoxyzolamide formulations in rabbits”. J. Magnusdottir et al., “Self Association and Cyclodextrin Solubiliza Pharm. Pharmacol., vol. 46, pp. 503-504, 1994, Pharmaceutical tion of NSAIDs”, Journal of Inclusion Phenomena and Macrocyclic Press, England. Chemistry, vol. 44, pp. 213-218, 2002, Kluwer Academic Publishers, Loftsson et al., “Cyclodextrin solubilization of benzodiazepines: for The Netherlands. mulation of midazolam nasal spray'. International Journal of Mele et al., “Non-covalent associations of cyclomaltooligosac Pharmaceutics, vol. 212: pp. 29-40, 2001, published by Elsevier, The charides (cyclodextrins) with trans-f- carotene in water: evidence for Netherlands. the formation of large aggregates by light scattering and NNR spec Frióriksdóttir, Hafra, “Polymer Enhancement of Cyclodextrin troscopy”. Carbohydrate Research, vol. 310, pp. 261-267, 1998, Complexation. In vivo and in vitro observations.” A Doctoral Thesis, Elsevier B.V. Netherlands. 1997, pp. 6-114, University of Iceland, IS. Zimmer et al., “Microspheres and nanoparticles used in ocular deliv ery systems”. Advanced Drug Delivery Reviews, vol. 16, pp. 61-73, Rowe, Raymond C. et al., eds., “Cyclodextrins'. Handbook of Phar 1995, Elsevier B.V. Netherlands. maceutical Excipients, 4th Edition, 2003, pp. 186-190,The Pharma Kirstinsson et al., “Dexamethasone-Cyclodextrin-Polymer Co-com ceutical Press, London, England. plexes in Aqueous Eye Drops'. Investigative Ophthalmology & Written Opinion of the International Searching Authority for corre Visual Science, vol. 37, No. 6, pp. 1199-1203, 1996, Lippincott sponding PCT/IB2006/002769. Raven Publication, USA. International Search Report for corresponding PCT/IB2006/002769. U.S. Patent Feb. 22, 2011 Sheet 1 of 7 US 7,893,040 B2 60 HNaSa -(-ntravenous -A-Topical (eye) O 30 60 90 120 Time after treatment (min) FIG. 1 U.S. Patent Feb. 22, 2011 Sheet 2 of 7 US 7,893,040 B2 Topical absorption Systemic absorption N N N N N N NI-I-T- S? N N ,) -T-T-I- suæT Bu???}} eeuJOO euÐ10S"?uV/ JounHºbvy Áue]]|O-SIJI SnO3I}IA ?Auðuo?do FIG. 2 U.S. Patent Feb. 22, 2011 Sheet 3 of 7 US 7,893,040 B2 40 3 O 2 O 1. O FIG. 3 U.S. Patent Feb. 22, 2011 Sheet 4 of 7 US 7,893,040 B2 100 468 OOO 2 O Comea Sclera Aq humor Iris-Ciliary Lens Witreous Retina Optic nerve 1.5% (w/v) Dexamethasone in RM3CD solution. O 1.5% (w/v) Dexamethasone in YCD suspension. FIG. 4 U.S. Patent Feb. 22, 2011 Sheet 5 Of 7 US 7,893,040 B2 16 14 12 5 10 15 20 25 30 35 40 45 50 55 60 Particle size (um) FIG. 5 U.S. Patent Feb. 22, 2011 Sheet 6 of 7 US 7,893,040 B2 14 12 10 8 6 4 2 O 5 10 15 20 25 30 35 40 45 Particle size (um) FIG. 6 U.S. Patent Feb. 22, 2011 Sheet 7 Of 7 US 7,893,040 B2 3 O O 2 4. 6 8 10 B-Cyclodextrin (% w/v) FIG. 7 US 7,893,040 B2 1. 2 CYCLODEXTRINNANOTECHNOLOGY FOR gate formation is about 5.4% (w/v) (Duan, Zhao et al. 2005; OPHTHALMC DRUG DELVERY Loftsson, Ossurardóttiretal. 2005). Lysine, polyvinylpyrroli done and magnesium ions formed non-inclusion complexes CROSS-REFERENCE TO RELATED resulting in formation of ternary, quaternary and even pente APPLICATIONS nary complexes in aqueous solutions (Duan, Zhao et al. 2005). The diameter of these self-assembling aggregates has This application claims the benefit of earlier copending been estimated to be about 6 nm (aggregates of two or three U.S. provisional applications No. 60/701,621, filed Jul. 22. drug/cyclodextrin complexes). 2005, and No. 60/795,563, filed Apr. 28, 2006, both hereby The usage of cyclodextrins in ophthalmic formulation has incorporated by reference in their entireties and relied upon.
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