DRUG DELIVERY THROUGH HYDROGEL PLUGS

• US 20100209478A1
• Filed: 02/12/2010
• Published: 08/19/2010
• Est. Priority Date: 02/12/2009
• Status: Active Grant

• Current Assignee: Incept LLC
• Original Assignee: Incept LLC
• Inventors: Blizzard, Charles, Jarrett, Peter, Bassett, Michael, Sawhney, Amarpreet S.
• Granted Patent: US 8,409,606 B2
• Time in Patent Office: Days
• US Class Current: 424/427
• CPC Class Codes: A61B 17/12099 characterised by the location of the occluder
• CPC Class Codes: A61B 17/12159 Solid plugs; being solid before insertion
• CPC Class Codes: A61B 17/1219 expandable in contact with liquids
• CPC Class Codes: A61F 2250/0067 Means for introducing or releasing pharmaceutical products into the body
• CPC Class Codes: A61F 9/00772 Apparatus for restoration of tear ducts
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 9/0051 Ocular inserts, ocular implants
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 31/04 Antibacterial agents

Abstract

An embodiment is a medical prosthesis for blocking or reducing tear flow through a punctum or canaliculus of a human eye and delivering a drug to the eye that comprises a dehydrated covalently crosslinked synthetic hydrophilic polymer hydrogel with dimensions to pass through a puncta lacrimali, with the dehydrated hydrogel absorbing physiological water to swell to at least 1 mm in cross-sectional width and conformably fit a canaliculus, with the hydrogel comprising a therapeutic agent dispersed through the hydrogel for release to an eye, with the hydrogel having a water content of at least about 50% by weight or volume when allowed to fully hydrate in vitro in physiological saline.

Claims

1. A medical prosthesis for blocking or reducing tear flow through a punctum or canaliculus of a human eye and delivering a drug to the eye that comprises:

a dehydrated covalently crosslinked synthetic hydrophilic polymer hydrogel with dimensions to pass through a puncta lacrimali, with the dehydrated hydrogel absorbing physiological water to swell to at least 1 mm in cross-sectional width and conformably fit a canaliculus, with the hydrogel comprising a therapeutic agent dispersed through the hydrogel for release to an eye, with the hydrogel having a water content of at least about 50% by weight or volume when allowed to fully hydrate in vitro in physiological saline.

2. The prosthesis of claim 1 wherein the dehydrated hydrogel swells to at least the 1 mm width within 10 minutes of placement in a canaliculus.

3. The prosthesis of claim 2 wherein the hydrogel is stretched in length and dried.

4. The prosthesis of claim 3 wherein the amount of stretching increases the length of the hydrogel by a factor of at least about 1.5

5. The prosthesis of claim 1 further comprising a visualization agent that present in a concentration effective to provide visibility of the agent to a human without a machine-aid.

6. The prosthesis of claim 3 providing a substantially zero-order release kinetic for the drug, as measurable by the slope of a plot of release of the drug over time being a substantially straight line between the total cumulative release percentage at about day 2 and about 75% total cumulative release when the dehydrated hydrogel is placed into a physiological solution in vitro.

7. The prosthesis of claim 6 wherein the drug is encapsulated within a collection of microspheres dispersed throughout the hydrogel, with the collection being selected to have a range of particle diameters only from about 20 to about 300 microns and a size distribution that is necessary to provide the zero order release as a result of relatively smaller microspheres releasing drug more rapidly relative to larger particles within the range.

8. The prosthesis of claim 7 wherein the diameter range is from about 20 to about 150 microns.

9. The prosthesis of claim 7 further comprising an additional amount of the drug, with the additional amount being dispersed within the hydrogel without encapsulation in the microspheres, with the additional amount providing an initial burst of release of the additional amount of drug, as measurable by a plot of cumulative release of the drug over time, with the initial burst being between 0% and about 35% total drug cumulative release when the dehydrated hydrogel is placed into a physiological solution in vitro and wherein drug associated with the microspheres does not substantially contribute to the initial burst.

10. The prosthesis of claim 9, with the hydrogel spontaneously degrading by chemical hydrolysis in water.

11. The prosthesis of claim 10, consisting essentially of the hydrogel, the microspheres containing the drug, and the additional amount of the drug.

12. The prosthesis of claim 9 wherein the drug is substantially insoluble in aqueous solution.

13. The prosthesis of claim 9 wherein the drug is substantially soluble in aqueous solution.

14. The prosthesis of claim 1 wherein the hydrogel is a reaction product of a first synthetic polymer that comprises a plurality of polymerizable groups that are polymerized by free radical initiation.

15. The prosthesis of claim 1 wherein the hydrogel is a reaction product of a first synthetic water soluble polymer comprising at least three first functional groups and a second synthetic water soluble polymer that comprises at least three second functional groups, with the first and second functional groups reacting with each other to form covalent bonds and thereby form the hydrogel as a synthetic crosslinked hydrogel.

16. The prosthesis of claim 15 wherein the first polymer comprises polyethylene glycol and the first functional groups are succinimides, and wherein the second functional groups are selected from the group consisting of amine and thiol.

17. The prosthesis of claim 1 wherein the drug is latanoprost and the latanoprost is released in vivo from the hydrogel as placed in a canaliculus in an amount effective to reduce elevated intraocular pressure in patients suffering from open angle glaucoma or ocular hypertension over a time of at least about four weeks, with the hydrogel as swollen in place having a volume of no more than about 1 cubic millimeter.

18. The prosthesis of claim 1 wherein the drug is moxifloxacin and the moxifloxacin is releasable in vivo from the hydrogel into a tear film of an eye as placed in a canaliculus in an amount effective to substantially reduce S. aureus or S. epidermidis at the eye over a time of at least about six days, with the hydrogel as swollen in place having a volume of no more than about 1 cubic millimeter.

19. The prosthesis of claim 18 wherein the moxifloxacin is in a base form.

20. A process for making a prosthesis for blocking or reducing tear flow through a punctum or canaliculus of a human eye and delivering a drug to the eye comprising:

forming a plurality of microspheres from hydrolytically degradable materials, with the microspheres containing the drug,

washing the microspheres,

separating the microspheres to obtain a collection of microspheres with a diameter range of between about 20 and about 300 microns,

mixing the microspheres with a synthetic polymer hydrogel precursor and forming a hydrogel from the precursor inside a tube, with the microspheres being

dispersed throughout the hydrogel,

extruding the hydrogel from the tube,

stretching the hydrogel length by a factor of at least about 2, with the resultant maximum cross-sectional width of the hydrogel being less than about 1 mm,

dehydrating the hydrogel,

cutting or breaking the dried hydrogel into lengths of less than about 5 mm,

and selecting a distribution of microsphere diameters within the range for the collection to display substantially zero-order release kinetic for the drug, as measurable by the slope of a plot of release of the drug from the prosthesis over time being a substantially straight line between about the total cumulative percentage drug release at about day 2 and about 75% total cumulative release when the dehydrated hydrogel prosthesis is placed into a physiological solution in vitro;

with the dehydrated hydrogel absorbing physiological water to swell to at least 1 mm in cross-sectional width and conformably fit a cannaliculus, and

with the hydrogel having a water content of at least about 50% by weight or volume when allowed to fully hydrate in vitro in physiological saline.

21. The process of claim 20 wherein the dehydrated hydrogel swells to at least the 1 mm width within 10 minutes of placement in a canaliculus.

22. The process of claim 20 further comprising placing a visualization agent into the hydrogel at a concentration effective to provide visibility of the prosthesis to a human without a machine-aid.

23. The process of claim 20 further comprising mixing an additional amount of the drug within the hydrogel without encapsulation in the microspheres, with the additional amount providing an initial burst of release of the additional amount of drug, as measurable by a plot of cumulative release of the drug over time, with the initial burst being between 0% and about 35% total drug cumulative release when the dehydrated hydrogel is placed into a physiological solution in vitro and wherein drug associated with the microspheres during microsphere manufacture or loading does not substantially contribute to the initial burst.

24. The process of claim 20 wherein the hydrogel spontaneously degrades by chemical hydrolysis in water.

25. The process of claim 20 wherein the hydrogel is a reaction product of a first synthetic polymer that comprises a plurality of polymerizable groups that are polymerized by free radical initiation.

26. The process of claim 20 wherein the hydrogel is a reaction product of the synthetic polymer hydrogel precursor that further comprises at least three first functional groups and a second synthetic water soluble polymer that comprises at least three second functional groups, with the first and second functional groups reacting with each other to form covalent bonds and thereby form the hydrogel as a synthetic crosslinked hydrogel.

27. The process of claim 20 wherein the drug is latanoprost or moxifloxacin.

28. The process of claim 27 wherein the drug is the moxifloxacin and is in a base form.

29. A method of treating an eye condition of an eye with a drug comprising:

placing a dehydrated synthetic hydrogel in a canaliculus of the eye and thereby blocking or reducing tear flow through the canaliculus, with the dehydrated hydrogel absorbing physiological water to swell to at least 1 mm in cross-sectional width within about 10 minutes of placement and conformably fit the cannaliculus, with the hydrogel comprising a therapeutic agent dispersed through the hydrogel for release to the eye, and with the hydrogel having a water content of at least about 50% by weight or volume when allowed to fully hydrate in vitro in physiological saline,

wherein the hydrogel, when hydrated in the canaliculus, has a volume of less than about 1 cubic millimeters and releases an amount of the drug effective to treat the eye condition over a time of at least about six days as measurable by a concentration of the drug in a tear film of the eye.

30. The method of claim 29 further comprising providing a visualization agent in the hydrogel at a concentration effective to provide visibility of the agent to the patient without a machine-aid.

31. The method of claim 29, with the hydrogel spontaneously degrading by chemical hydrolysis in water.

32. The method of claim 29,

wherein the hydrogel is a reaction product of a first synthetic polymer that comprises a plurality of polymerizable groups that are polymerized by free radical initiation or

wherein the hydrogel is a reaction product of a first synthetic water soluble polymer comprising at least three first functional groups and a second synthetic water soluble polymer that comprises at least three second functional groups, with the first and second functional groups reacting with each other to form covalent bonds and thereby form the hydrogel as a synthetic crosslinked hydrogel or

wherein the hydrogel is a reaction product of a first synthetic polymer that comprises polyethylene glycol and the first functional groups are succinimides, and wherein the second functional groups are selected from the group consisting of amine and thiol.

33. The method of claim 29 wherein the drug is latanoprost and the latanoprost is released in vivo from the hydrogel as placed in a canaliculus in an amount effective to reduce elevated intraocular pressure in patients suffering from open angle glaucoma or ocular hypertension over a time of at least about four weeks.

34. The method of claim 29 wherein the drug is moxifloxacin and the moxifloxacin is released in vivo from the hydrogel into a tear film of an eye as placed in a canaliculus in an amount effective to substantially reduce S. aureus or S. epidermidis at the eye over a time of at least about six days.

35. The method of claim 34 wherein the moxifloxacin is in a base form.