PARTIALLY MICROCELLULAR, SELECTIVELY HYDROPHILIC COMPOSITE CONSTRUCT FOR OCULAR DRUG DELIVERY

• US 20110268783A1
• Filed: 04/28/2011
• Published: 11/03/2011
• Est. Priority Date: 04/28/2010
• Status: Active Grant

• Current Assignee: Poly-Med, Inc.
• Original Assignee: Poly-Med, Inc.
• Inventors: CORBETT, JOEL T., OLBRICH, JASON M., SHALABY, SHALABY W.
• Granted Patent: US 9,028,860 B2
• Time in Patent Office: Days
• US Class Current: 424/427
• CPC Class Codes: A61K 31/085 having an ether linkage to aromatic ring nuclear carbon
• CPC Class Codes: A61K 31/4164 1,3-Diazoles
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 9/0009 involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis microelectromechanical systems A61K9/0097
• CPC Class Codes: A61K 9/0051 Ocular inserts, ocular implants
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: A61P 27/02 Ophthalmic agents

Abstract

A partially microcellular, selectively hydrophilic composite as a self-standing construct or a component of a device for ocular delivery of at least one bioactive agent, the composite comprising a highly hydrophilic microcellular foam adjoined with a flexible hydrophobic barrier polymeric film.

Claims

1. A partially microcellular, selectively hydrophilic composite as a self-standing construct or a component of a device for ocular delivery of at least one bioactive agent, the composite comprising a highly hydrophilic microcellular foam adjoined with a flexible hydrophobic barrier polymeric film.

2. A partially microcellular, selectively hydrophilic composite as in claim 1 wherein the highly hydrophilic microcellular foam comprises an open cell structure of at least one freeze-dried polymer selected from the group consisting of polyvinyl alcohol or poly(vinyl alcohol-co-vinyl acetate), an hydroxyalkyl cellulose, polyethylene oxide, polyvinyl pyrrolidone, poly(vinyl acetate-co-vinyl pyrrolidone), a polyether-ester, a polyether-ester-urethane, poly(methyl methacrylate-co-vinyl pyrrolidone), poly(ethylene-co-vinyl alcohol), and poly(hydroxy-ethyl methacrylate-co-alkyl methacrylate).

3. A partially microcellular, selectively hydrophilic composite as in claim 1 wherein the flexible hydrophobic barrier polymeric film comprises at least one polymer selected from the group consisting of polydimethylsiloxane, poly--caprolactone, polyethylene adipate, polytetramethylene adipate, low density polyethylene, poly(ethylene-vinyl acetate), and a polyalkylene succinate.

4. A partially microcellular, selectively hydrophilic composite as in claim 2 wherein the freeze-dried foam has a thickness of from about 1 to about 3 mm, a pore fraction of at least 0.5 to 0.9 and an average pore diameter of from about 1 to about 400 microns.

5. A partially microcellular, selectively hydrophilic composite as in claim 4 further comprising soluble or dispersed solid nanoparticles or microparticles of at least one bioactive agent selected from the group consisting of steroidal or non-steroidal anti-inflammatory drugs, vasoconstricting drugs, antimicrobial agents, antiviral agents, antiretroviral agents, antineoplastic agents, and drugs used for treating glaucoma and other eye disorders.

6. A partially microcellular, selectively hydrophilic composite as in claim 3 wherein the flexible hydrophobic barrier film is made by compression molding or solution casting and adjoined with the microcellular foam by thermoforming at 50 to 150°

C., solvent or ultrasonic welding or crosslinkable prepolymeric intermediates.

7. A partially microcellular, selectively hydrophilic composite as in claim 6 wherein the flexible hydrophobic barrier film itself exhibits a flexural modulus of less than 30 MPa, a tensile strength of more than 50 Kpsi, an ultimate elongation of at least 200%, and melts or softens below 150°

, the assembled composite construct, presoaked for less than 10 minutes with water using about 100 μ

L per 120 mm³, displaying a flexural modulus of less than 1 MPa.

8. A partially microcellular, selectively hydrophilic composite as in claim 5 wherein the steroidal anti-inflammatory drug comprises a dexamethasone disodium phosphate, the vasoconstricting drug comprises oxymetazoline, and the antimicrobial drug comprises triclosan or triclosan sodium.

9. A partially microcellular, selectively hydrophilic composite as in claim 4 further comprising an aqueous solution of at least one bioactive agent selected from the group consisting of steroidal and non-steroidal drugs, vasoconstricting drugs, antimicrobial drugs, antineoplastic drugs, antiviral and antiretroviral agents, and drugs used for treating glaucoma and other eye disorders.

10. A partially microcellular, selectively hydrophilic composite as in claim 9 wherein the steroidal agent comprises dexamethasone disodium phosphate, the vasoconstricting drug comprises oxymetazoline and the antimicrobial drug is selected from triclosan and triclosan sodium.

11. A partially microcellular, selectively hydrophilic composite as in claim 1 as a self-standing construct, crescent-shaped ocular drug delivery device with rounded free ends at a distance exceeding the radius of a typical mammalian eye cornea by at least 10%.

12. A partially microcellular, selectively hydrophilic composite as in claim 11 wherein the crescent-shaped device is designed for initial deployment at the rim of the conjunctiva for subsequent upward movement to partially cover the sclera forming a POLTF-like film without interfacing with the cornea through vertical or horizontal movement.

13. A partially microcellular, selectively hydrophilic composite as in claim 12 with two lateral flaps extending toward the sides of a mammalian eye to further stabilize the position of the device at the application site.

14. A partially microcellular, selectively hydrophilic composite as in claim 1 in the form of a ring-shaped disc affixed to an applicator wherein the disc is designed to have a lumen diameter which exceeds that of the cornea by at least 10%, and a difference between the outside and inside diameter of at least 3 mm, and capable of covering at least 30% of the accessible scleral surface.

15. A partially microcellular, selectively hydrophilic composite as in claim 4 suitable for loading with a solution of the drug(s) in less than 10 minutes and delivering of at least 30% of it drug payload at the ocular site in less than 10 minutes.

16. A partially microcellular, selectively hydrophilic composite as in claim 1 as a component of an iontophoretic ocular delivery device of at least one bioactive agent wherein a flexible conductive film or mesh is sandwiched securely between the hydrophilic microcellular foam and the hydrophobic barrier film and the conductive film or mesh is further connected to one pole of a direct current mini-battery to function as an iontophoretic system with the mammalian ear or adjacent facial tissue being the counter pole of the circuit to allow the iontophoretic transport of the drug from the microcellular foam to the sclera and underlying eye tissues.

17. A partially microcellular, selectively hydrophilic composite as in claim 16 wherein the flexible film or mesh of the iontophoretic delivery system is made of a highly conductive metal or surface- or bulk-conducting polymer having a maximum thickness of less than 500 micron.

18. A partially microcellular, selectively hydrophilic composite as in claim 17 wherein the metal film or mesh comprises at least one metal selected from the group consisting of silver, gold, platinum, titanium, copper and different iron or chrome alloys, the surface conducting polymer comprises a sulfonated polyalkylene with doped covalently bonded polypyrrole and the bulk-conducting polymer comprises carbon fibers.