Stable liquid compositions of posaconazole
The present invention relates to stable, room-temperature storable, liquid compositions comprising posaconazole. The liquid compositions, when stored at room temperature conditions, exhibit no significant coloration and no significant loss in chemical stability. The liquid compositions also exhibit good dilution stability with no evidence of precipitation. The present invention also provides a process for the preparation of such liquid compositions.
1 . A posaconazole liquid composition, consisting essentially of:
(i) posaconazole at a concentration of about 15 mg/ml to about 30 mg/ml in the composition,
(ii) hydroxypropyl beta-cyclodextrin at a concentration of about 280 mg/ml to about 400 mg/ml in the composition, and
(iii) water as a vehicle,
wherein the composition is prepared by a process comprising:
(a) sparging water with nitrogen gas;
(b) dissolving hydroxypropyl beta-cyclodextrin in the sparged water to obtain a hydroxypropyl beta-cyclodextrin solution;
(c) acidifying the hydroxypropyl beta-cyclodextrin solution to a pH of about 1.5 to about 2.0;
(d) dissolving posaconazole in the acidified hydroxypropyl beta-cyclodextrin solution to obtain a posaconazole solution;
(e) adjusting the pH of the posaconazole solution to about 2.3 to about 2.8;
(f) adding water to obtain a final volume;
(g) filling the composition into a container, overlaying the container headspace with nitrogen, and sealing the container;
wherein, after storage at a temperature of about 20° C. to about 32° C. and a relative humidity of about 55% to about 80% for at least 6 months, the composition contains not more than 0.05% by HPLC of deshydroxy posaconazole, contains not more than 0.03% by HPLC of benzylated posaconazole when determined by HPLC method, has total impurities not more than 0.8%, and has coloration not more intense than BY5.
2 . The posaconazole liquid composition as claimed in claim 1 , wherein the concentration of hydroxypropyl beta-cyclodextrin in the composition ranges from about 280 mg/ml to about 380 mg/ml.
3 . The posaconazole liquid composition as claimed in claim 1 , wherein the composition further comprises at least one excipient selected from anti-oxidants, chelating agents, pH-adjusting agents, buffering agents or tonicity agents.
4 . The posaconazole liquid composition as claimed in claim 3 , wherein the chelating agent is sodium edetate.
5 . The posaconazole liquid composition as claimed in claim 1 , wherein the composition is in the form of a solution for parenteral administration.
6 . The posaconazole liquid composition as claimed in claim 2 , wherein the composition is stable to dilution when 1 part of the posaconazole liquid composition is diluted to about 30 parts by infusion fluids.
7 . The posaconazole liquid composition as claimed in claim 1 , wherein the osmolality of the composition ranges from about 200 mOsmol/kg to about 800 mOsmol/kg.
8 . The posaconazole liquid composition as claimed in claim 1 , wherein the composition, when stored in the container with the claimed amount of posaconazole at a temperature of about 20° C. to about 32° C., for at least 22 months, in an upright orientation or inverted orientation, contains posaconazole not less than about 90% by weight of the amount claimed on the container and contains not more than about 2% by weight of total impurities, at the end of the given storage period.
9 . The posaconazole liquid composition as claimed in claim 1 , wherein the pH of the posaconazole solution is adjusted from about 2.4 to about 2.7.
10 . The posaconazole liquid composition as claimed in claim 2 , wherein the concentration of hydroxypropyl beta-cyclodextrin in the composition is about 280 mg/ml.
11 . The posaconazole liquid composition as claimed in claim 2 , wherein the concentration of hydroxypropyl beta-cyclodextrin in the composition is about 380 mg/ml.
12 . A posaconazole liquid composition comprising
(i) posaconazole at a concentration of about 15 mg/ml to about 30 mg/ml in the composition,
(ii) hydroxypropyl beta-cyclodextrin at a concentration of about 200 mg/ml to about 400 mg/ml in the composition, and
(iii) water as a vehicle,
wherein the composition is prepared by dissolving posaconazole in an acidified hydroxypropyl beta-cyclodextrin solution and adjusting the pH of the composition to about 2 to about 4, and the composition is enclosed in a container,
wherein headspace of the container is overlayed with a non-oxygen containing gas,
wherein, after storage at a temperature of about 20° C. to about 32° C. and a relative humidity of about 55% to about 80% for at least 6 months, the composition contains not more than 0.05% by HPLC of deshydroxy posaconazole, contains not more than 0.03% by HPLC of benzylated posaconazole when determined by HPLC method, and has coloration not more intense than BY6.
13 . The composition as claimed in claim 12 , wherein the concentration of hydroxypropyl beta-cyclodextrin in the composition ranges from about 250 mg/ml to about 350 mg/ml.
14 . The composition as claimed in claim 12 , wherein the non-oxygen containing gas is nitrogen.
15 . The posaconazole liquid composition as claimed in claim 14 , wherein the posaconazole liquid composition after 22 months storage at a temperature of about 20° C. to about 32° C. and a relative humidity of about 55% to about 80% is stable and has coloration not more intense than BY5.