Time-release and micro-dose formulations for topical application of estrogen and estrogen analogs or other estrogen receptor modulators in the treatment of dry eye syndrome, and methods of preparation and application

Abstract

A topical application formulation of estrogen and estrogen analogs or other estrogen receptor modulators is disclosed for the treatment of primary or secondary dry eye syndrome (also known as keratoconjunctivitis sicca (KCS)). Preferred formulations include 17-β-estradiol and its derivatives in lipid, liposomes, polymers, or aqueous or non-aqueous vehicles for the topical treatment of the ocular surface tissues particularly as time-release or micro-dose formulations. These formulations may also be useful in treating other conditions where KCS may occur, such as post-operative refractive surgery and corneal transplant patients.

1 - 33 . (canceled) 
     
     
         34 . A topical application pharmaceutical composition for timed release comprising estrogen or an estrogen analog or other estrogen receptor modulator wherein the timed release is sufficient for delivery of a therapeutically effective concentration for alleviation of kerato-conjunctivitis sicca (dry eye syndrome) when administered twice daily or less frequently. 
     
     
         35 . (canceled) 
     
     
         36 . The topical application pharmaceutical of  claim 34  or  claim 35  further comprising a bioadhesive viscoelastic compound. 
     
     
         37 - 38 . (canceled) 
     
     
         39 . The topical application pharmaceutical of  claim 34  wherein the bioadhesive viscoelastic compound is a polysaccharide and the polysaccharide is xanthan gum. 
     
     
         40 . The topical application pharmaceutical of  claim 39  wherein the xanthan gum is between about 0.1% to about 1% (w/w). 
     
     
         41 - 46 . (canceled) 
     
     
         47 . The topical application pharmaceutical of  claim 36  or claim  37  wherein the bioadhesive viscoelastic compound is a carbomer, optionally a carbopol. 
     
     
         48 - 49 . (canceled) 
     
     
         50 . The topical application pharmaceutical of  claim 34  further comprising cyclodextrin. 
     
     
         51 . The topical application pharmaceutical of  claim 50  wherein the cyclodextrin is from about 0.1% to about 7% (w/w). 
     
     
         52 - 55 . (canceled) 
     
     
         56 . The topical application pharmaceutical of  claim 34  wherein the timed release comprises a controlled, sustained drug release rate which does not vary by more than about 50% for a period of at least about 6-8 hours after application, at least about 8-12 hours after application, at least about 12-24 hours after application, at least about 24-48 hours after application, or at least about 48-72 hours after application. 
     
     
         57 - 58 . (canceled) 
     
     
         59 . The topical application pharmaceutical of  claim 34  wherein the estrogen analog is 17-β-estradiol. 
     
     
         60 - 61 . (canceled) 
     
     
         62 . The topical application pharmaceutical of  claim 34  wherein the increase in peak blood estradiol concentration after continuous use is less than that 30 pg/ml, less than 20 pg/ml, less than 15 pg/ml, less than 10 pg/ml or less than 6 pg/ml. 
     
     
         63 . (canceled) 
     
     
         64 . The topical application pharmaceutical of  claim 34  further comprising a therapeutically effective amount of an androgen. 
     
     
         65 - 66 . (canceled) 
     
     
         67 . A method of treatment comprising topical application to an eye of a topical application pharmaceutical according to  claim 34  for alleviation of kerato-conjunctivitis sicca (dry eye syndrome). 
     
     
         68 . The method of  claim 67  wherein the kerato-conjunctivitis sicca is associated with post-menopausal subjects, premature ovarian failure, post-operative refractive surgery patients, corneal transplant patients or patients with other conditions that cause dry eye symptoms. 
     
     
         69 - 70 . (canceled) 
     
     
         71 . A method of alleviation of kerato-conjunctivitis sicca (dry eye syndrome) comprising administering by topical application a therapeutically effective dose to an eye of a topical application pharmaceutical, wherein the therapeutically effective dose comprises a volume of less than a standard ophthalmic drop and wherein the therapeutically effective dose less than 35 micrograms of estrogen or an estrogen analog or other estrogen receptor modulator. 
     
     
         72 . The method of  claim 71  wherein the volume is less than 35 μl, less than 30 μl, less than 25 μl, less than 20 μl, less than 15 μl, or between 5 μl and 15 μl. 
     
     
         73 . The method of  claim 71  wherein the dose is less 30 micrograms, less 25 micrograms, less 20 micrograms, less 15 micrograms, or less 10 micrograms of estrogen or an estrogen analog or other estrogen receptor modulator. 
     
     
         74 . The method of  claim 71  wherein the topical application pharmaceutical is administered twice daily or less frequently. 
     
     
         75 - 78 . (canceled) 
     
     
         79 . The method of  claim 71  wherein the increase in peak blood estradiol concentration after continuous use is less that 30 pg/ml, less than 20 pg/ml, less than 15 pg/ml, less than 10 pg/ml or less than 6 pg/ml. 
     
     
         80 . (canceled) 
     
     
         81 . The method of  claim 71  further comprising a bioadhesive viscoelastic compound for timed release of the estrogen or estrogen analog or other estrogen receptor modulator. 
     
     
         82 . The method of  claim 81  wherein the bioadhesive viscoelastic compound is in a concentration sufficient to achieve the timed release. 
     
     
         83 - 131 . (canceled)