Aqueous drug delivery system
Novel water stable pharmaceutical compositions, their liquid form oral pharmaceutical compositions and kits thereof, rehydration beverages containing these water stable pharmaceutical compositions methods of manufacture and methods of use thereof are disclosed. The novel aqueous delivery systems are useful, inter alia, as alternative pharmaceutical dosing agents to tablets, capsules and other forms of delivering medication to a mammalian host in need thereof.
1. A water stable pharmaceutical gel composition comprising:
a therapeutic agent selected from the group consisting of aspirin, naproxen sodium, acetaminophen, and ibuprofen; and
an off-flavor masking agent comprising a cyclodextrin;
in a water stable pharmaceutically acceptable gel matrix;
wherein:
the water stable pharmaceutically acceptable gel matrix comprises as non-ion-specific gel comprising gellan; and
wherein the water stable pharmaceutical gel composition is suitable for oral delivery of the therapeutic agent.
2. A water stable pharmaceutical composition of claim 1 , wherein the therapeutic agent is an anti-inflammatory agent.
3. A water stable pharmaceutical composition of claim 1 , wherein the therapeutic neat is water-sensitive.
4. A water stable pharmaceutical composition of claim 1 , wherein the cyclodextrin comprises alpha-, beta-, or gamma-cyclodextrin., or a derivative or mixture thereof.
5. A water stable pharmaceutical composition of claim 4 , wherein the cyclodextrin comprises beta-cyclodextrin, or a derivative thereof.
6. A water stable pharmaceutical composition of claim 4 , wherein the cyclodextrin comprises alpha-cyclodextrin, or a derivative thereof.
7. A water stable pharmaceutical composition of claim 4 , wherein at least a portion of the cyclodextrin and at least a portion of the therapeutic agent are present in the pharmaceutical composition as a therapeutic agent:cyclodextrin complex.
8. A water stable pharmaceutical composition of claim 2 , wherein:
the off-flavor masking agent is beta-cyclodextrin or hydroxypropyl beta-cyclodextrin.
9. A water stable pharmaceutical composition of claim 8 , wherein the therapeutic agent is aspirin.
10. A water stable pharmaceutical composition of claim 8 , wherein the therapeutic agent is naproxen sodium.
11. A water stable pharmaceutical composition of claim 8 , wherein the therapeutic agent is acetaminophen.
12. A water stable pharmaceutical composition of claim 8 , wherein the therapeutic agent is ibuprofen.
13. A water stable pharmaceutical composition of claim 8 , wherein the gellan matrix is provided in the form of beads.
14. A water stable pharmaceutical composition of claim 2 , wherein:
the off-flavor masking agent is alpha-cyclodextrin.
15. A water stable pharmaceutical composition of claim 14 , wherein the therapeutic agent is aspirin.
16. A water stable pharmaceutical composition of claim 14 , wherein the therapeutic agent is naproxen sodium.
17. A water stable pharmaceutical composition of claim 14 , wherein the therapeutic agent is acetaminophen.
18. A water stable pharmaceutical composition of claim 14 , wherein the therapeutic agent is ibuprofen.
19. A liquid form oral pharmaceutical composition; comprising:
a water stable pharmaceutical composition according to claim 1 ; and
a pharmaceutically acceptable aqueous liquid medium.
20. A liquid form oral pharmaceutical composition of claim 19 , wherein at least a portion of the cyclodextrin and at least a portion of the therapeutic agent are present as a therapeutic agent:cyclodextrin complex in the pharmaceutical composition.
21. A process for preparing a water stable pharmaceutical composition, said process comprising the steps of
contacting:
a therapeutic agent selected from the group consisting of aspirin, naproxen sodium, acetaminophen, and ibuprofen;
an off-flavor masking agent comprising a cyclodextrin;
a pharmaceutically acceptable gel matrix precursor comprising a non-ion-specific polysaccharide gelling agent comprising gellan; and
water:
for a time and under conditions effective to provide a hydrated mixture; and
gelling said mixture in an aqueous citric acid medium with for a time and under conditions effective to provide said water stable pharmaceutical composition.
22. A process for preparing a water stable pharmaceutical composition of claim 21 , wherein the cyclodextrin is first contacted with the therapeutic agent in an aqueous solution to form a cyclodextrin: therapeutic agent complex.
23. A kit, comprising:
a liquid form oral pharmaceutical composition of claim 19 in one or more containers; and
b. instructions for administering the liquid form oral pharmaceutical composition.
24. A kit of claim 23 , wherein the liquid form oral pharmaceutical composition in the kit container is provided as an individual dosage unit of therapeutic agent.
25. A rehydration beverage composition, comprising:
a water stable pharmaceutical composition according; to claim 1 :
a pharmaceutically acceptable aqueous liquid medium; and
optionally at least one mineral or non-mineral nutritional supplement;
wherein:
the aqueous medium comprises an isotonic solution.
26. A water stable pharmaceutical gel composition consisting essentially of:
a therapeutic agent selected from the group consisting of aspirin, naproxen sodium, acetaminophen, and ibuprofen; and
an off-flavor masking agent comprising a cyclodextrin,
in a water stable pharmaceutically acceptable gel matrix;
wherein the water stable pharmaceutically acceptable gel matrix comprises a non-ion-specific gel comprising gellan.
27. A water stable pharmaceutical gel composition according, to claim 1 , wherein the water stable pharmaceutical gel composition is further:
substantially stable in the presence of an aqueous liquid medium for at least about 20 days at 55° C.;
substantially stable for at least about 60 minutes at about 121‘C.’ under retort processing conditions;
substantially stable to hot fill, pasteurization conditions;
substantially stable in the presence of an aqueous liquid medium for at least about 300 days at 20° C.:
substantially stable to HTST processing conditions; or
substantially stable to UHT processing conditions.
28. A water stable pharmaceutical gel composition according to claim 27 , wherein the gel composition is substantially stable in the presence of an aqueous liquid medium for at least about 20 days at 55° C.
29. A water stable pharmaceutical gel composition according to claim 27 , wherein the gel composition is substantially stable for at least about 60 minutes at about 121° C. under retort processing conditions.
30. A water stable pharmaceutical gel composition according to claim 27 , wherein the gel composition substantially stable in the presence of an aqueous liquid medium for at least about 300 days at 20° C.
31. A water stable pharmaceutical gel composition according to claim 27 , wherein the gel composition is substantially stable to hot fill pasteurization conditions.
32. A water stable pharmaceutical gel composition according, to claim 28 , wherein the gel composition is substantially stable to HTST processing conditions.
33. A water stable pharmaceutical gel composition according to claim 27 , wherein the gel composition is substantially stable to UHT processing conditions.
34. A water stable pharmaceutical gel composition according to claim 28 , wherein the gel composition is substantially stable to at. least two conditions selected from the group consisting of:
at least about 20 days at 55° C. in the presence of an aqueous liquid medium;
at least about 60 minutes at about 121° C. under retort processing conditions;
at least about 300 days at 20° C. in the presence of an aqueous liquid medium;
hot fill pasteurization conditions;
HTST processing conditions; and
UHT processing conditions.
35. A liquid form oral pharmaceutical composition according to claim 19 , wherein the liquid form oral pharmaceutical composition is:
substantially stable in the presence of an aqueous liquid medium for at least about 20 days at 55° C.;
substantially stable for at least about 60 minutes at about 121° C. under retort processing; conditions;
substantially stable to hot fill pasteurization conditions;
substantially stable in the presence of an aqueous liquid medium for at least about 300 days at 20° C.;
substantially stable to HTST processing conditions; or
substantially stable to UHT processing conditions.
36. A kit according to claim 23 , wherein the kit is:
substantially stable in the presence of an aqueous liquid medium for at least about 20 days at 55° C.;
substantially stable for at least about 60 minutes at about 121° C. under retort processing conditions:
substantially stable to hot fill pasteurization conditions;
substantially stable in the presence of an aqueous liquid medium for at least about 300 days at 20° C.;
substantially stable to HTST processing conditions; or
substantially stable to UHT processing conditions.
37. A rehydration beverage composition according to claim 25 , wherein the rehydration beverage composition is:
substantially stable in the presence of an aqueous liquid medium for at least about 20 days at 55° C.:
substantially stable for at least about 60 minutes at about 121° C. under retort processing conditions;
substantially stable to hot fill pasteurization conditions;
substantially stable in the presence of an aqueous liquid medium for at least about 300 days at 20° C.:
substantially stable to HTST processing conditions; or
substantially stable to UHT processing conditions.
38. A liquid form oral pharmaceutical composition according to claim 19 , wherein the liquid form oral pharmaceutical composition is suitable for oral delivery of the therapeutic agent.
39. A liquid form oral pharmaceutical composition comprising:
a water stable pharmaceutical composition according to claim 26 ;
a pharmaceutically acceptable aqueous liquid medium;
wherein the liquid form oral pharmaceutical composition is:
substantially stable in the presence of an aqueous liquid medium for at least about 20 days at 55° C.;
substantially stable for at least about 60 minutes at about 121° C. under retort processing conditions;
substantially stable to hot till pasteurization conditions;
substantially stable in the presence of an aqueous liquid medium for at least about 300 days at 20° C.;
substantially stable to HTST processing conditions; or
substantially stable to UHT processing conditions.
40. A rehydration beverage composition, comprising:
a water stable pharmaceutical composition according to claim 26 ;
a pharmaceutically acceptable aqueous liquid medium; and
optionally at least one mineral or non-mineral nutritional supplement;
wherein the aqueous medium comprises an isotonic solution; and
wherein the rehydration beverage composition is:
substantially stable in the presence of an aqueous liquid medium for at least about 20 days at 55° C.;
substantially stable for at least about 60 minutes at about 121° C. under retort processing conditions;
substantially stable to hot fill pasteurization conditions;
substantially stable in the presence of an aqueous liquid medium for at least about 300 days at 20° C.;
substantially stable to HTST processing conditions; or
substantially stable to UHT processing conditions.
41. A water stable pharmaceutical composition of claim 7 , wherein more than about 50% by weight of the therapeutic agent is present in the pharmaceutical composition as a therapeutic agent:cyclodextrin complex.
42. A water stable pharmaceutical composition of claim 2 , wherein the molar ratio of anti-inflammatory agent to cyclodextrin is from about 1:2 to about 2:1.
43. A water stable pharmaceutical composition of claim 2 , wherein the molar ratio of anti-inflammatory agent to cyclodextrin is from about 1:1.5 to about 1.5:1.