Formulations of 4-(7-Hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile
The present invention provides formulations of 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) and methods for treating ocular surface pain by administering such formulations. The present invention also provides methods for treating dry eye disease and ocular hyperemia by administering formulations of 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile.
1. A formulation, comprising:
a suspension of 4-(7-Hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) or a salt, co-crystal, or polymorph thereof, in an amount of about 0.5% w/v to about 3.5% w/v,
tyloxapol in an amount of about 0.04% w/v to about 0.06% w/v;
carbomer homopolymer Type B in an amount from about 0.05% w/v to about 0.4% w/v;
a tonicity agent;
a buffer;
sodium chloride in an amount of from 0.01% w/v to about 1% w/v;
optionally, a preservative; and
water in quantity sufficient (qs) to 100%.
2. The formulation according to claim 1 , wherein the tonicity agent is a polyol selected from the group selected from mannitol, glycerin, xylitol, sorbitol, propylene glycol, and combinations thereof.
3. The formulation according to claim 1 , wherein the buffer is selected from the group consisting of acetate, ascorbate, borate, hydrogen carbonate, carbonate, citrate, edetate (EDTA) gluconate, lactate, phosphate, propionate and TRIS (tromethamine).
4. The formulation according to claim 1 , wherein the pH of the formulation is about 5.0 to about 8.0, about 5.5 to about 8.0, about 5.5 to about 7.5, about 5.0 to about 7.4, about 5.5 to about 7.4, about 6.0 to about 8.0, about 6.5 to about 8.0, about 6.0 to about 7.4, or about 6.5 to about 7.4.
5. The formulation according to claim 1 , further comprising an additional agent selected from the group consisting of polyvinylprrolidone, hydroxypropylβcyclodextrin, and sulfoalkylether β-cyclodextrin in an amount of at least about 1.5 w/v %, at least about 3.0 w/v %, at least about 3.5 w/v % or at least about 4.5 w/v, but no greater than about 10.0 w/v %, no greater than about 8.0% w/v, no greater than about 6.5 w/v %, or no greater than about 5.5 w/v.
6. The formulation according to claim 1 , further comprising an additional agent selected from the group consisting of cyclodextrins in an amount of at least about 1.5 w/v %, at least about 3.0 w/v %, at least about 3.5 w/v % or at least about 4.5 w/v, but no greater than about 10.0 w/v %, no greater than about 8.0% w/v, no greater than about 6.5 w/v %, or no greater than about 5.5 w/v.
7. A formulation according to claim 1 , wherein compound I is in polymorphic form B.
8. The formulation according to claim 7 , wherein the polymorphic form B is characterized by an X-ray diffraction pattern having three or more peaks at 2θ values selected from 9.3, 10.6 and 14.4.+−.0.2° 2θ.
9. The formulations according to claim 1 , having a osmolality of about 200 to about 450 milliosmoles per kilogram (mOsm/kg).
10. The formulation according to claim 1 , wherein the formulation comprises no more than about 10% of a degradation product after 6 months under refrigeration, wherein the degradation product has a relative retention time of 1.23, compared to compound I, when analyzed by HPMC using a gradient 0.1% trifluoroacetic acid (TFA) water/acetonitrile mobile phase.
11. A method of making a formulation, comprising mixing an amount of 4-(7-Hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile
(compound I) or a salt, co-crystal, or polymorph thereof,
a non-ionic surfactant;
a suspending agent;
a tonicity agent;
a buffer;
optionally, a salt;
optionally, a preservative; and
water qs to 100%, and
adjusting the pH to a range of from about 5.0 to about 8.0.