Fluoroquinolone formulations and methods of making and using the same
A pharmaceutical composition comprising a fluoroquinolone such as ciprofloxacin, cyclodextrin, and a hydroxy acid is described. The composition may be an aqueous composition, with such aqueous compositions preferably having a pH between 5 and 7. In some preferred embodiments, the composition further comprises a soluble polymer.
1 . An aqueous pharmaceutical composition comprising:
from 1 to 100 mg/mL of a fluoroquinolone active agent;
from 0 to 100 mg/mL of a steroidal or non-steroidal anti-inflammatory agent;
from 1 to 50% by weight of cyclodextrin;
from 0.1 to 25 molar equivalents of a hydroxy acid;
from 0 to 20% by weight of a co-solibilizer; and
water to balance,
said formulation having a pH between 4 and 7.
2 . The composition according to claim 1 , wherein said cyclodextrin is selected from the group consisting of α cyclodextrins, β cyclodextrins, γ cyclodextrins, and δ cyclodextrins.
3 . The composition according to claim 1 , wherein said cyclodextrin is selected from the group consisting of sulfoalkylether cyclodextrins and hydroxyalkyl cyclodextrins.
4 . The composition according to claim 1 , wherein said hydroxy acid is selected from the group consisting of citric acid, ascorbic acid, malic acid, and tartaric acid.
5 . The composition according to claim 1 , further comprising from 0.001 to 2 percent by weight of a preservative.
6 . The composition according to claim 1 , further comprising a preservative selected from the group consisting of chlorobutanol, sorbic acid, and EDTA.
7 . The composition according to claim 1 , further comprising: from 0.05 to 5% by weight of a soluble polymer.
8 . The composition according to claim 7 , wherein said soluble polymer is selected from the group consisting of methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, and poloxamers.
9 . The composition according to clainm 1 , wherein said fluoroquinolone is selected from the group consisting of Gatifloxacin, Moxifloxacin, Sitafloxacin, Lomefloxacin, Grepafloxacin, Gemifloxacin, Norfloxacin, Ofloxacin, Levofloxacin, Trovafloxacin, Ciprofloxacin and combinations thereof.
10 . The composition according to claim 1 , wherein said steroidal or non-steroidal anti-inflammatory compound is a steroidal compound and is selected from the group consisting of cortisone, hydrocortisone, corticosterone, deoxycorticosterone, prednisolone, methylprednisolone, meprednisone, triamcinolone, paramethasone, fluprednisolone, betamethasone, dexamethazone, fludrocortisone, and combinations thereof.
11 . The composition according to claim 1 , wherein said steroidal or non-steroidal anti-inflammatory compound is a non-steroidal compound and is selected from the group consisting of aspirin, diclofenac, indomethacin, sulindac, ketoprofen, flurbiprofen, ibuprofen, naproxen, piroxicam, tenoxicam, tolmetin, ketorolac, oxaprosin, mefenamic acid, fenoprofen, nambumetone, acetaminophen, nimesulide, NS-398, flosulid, L-745337, celecoxib, rofecoxib, SC-57666, DuP-697, parecoxib sodium, JTE-522, valdecoxib, SC-58125, etoricoxib, RS-57067, L-748780, L-761066, APHS, etodolac, meloxicam, and S-2474, and combinations thereof.
12 . A method of treating a bacterial infection of an eye of a subject in need thereof, comprising topically administering a formulation according to claim 1 to the eye of said subject in an amount effective to treat said bacterial infection.
13 . A pharmaceutical formulation comprising:
from 1 to 100 mg/mL of a fluoroquinolone active agent;
from 0 to to 100 mg/mL of a steroidal or non-steroidal anti-inflammatory agent;
from 1 to 50% by weight of cyclodextrin;
from 0.1 to 25 molar equivalents of a hydroxy acid.
14 . A pharmaceutical formulation according to claim 13 in lyophilized form which when reconstituted with water produces an aqueous pharmaceutical composition having a pH between 4.5 and 7 and comprising:
from 1 to 100 mg/mL of a fluoroquinolone active agent;
from 1 to 50% by weight of cyclodextrin;
from 0.1 to 25 molar equivalents of a hydroxy acid; and water to balance.
15 . The composition according to claim 13 , wherein said cyclodextrin is selected from the group consisting of α cyclodextrins, β cyclodextrins, γ cyclodextrins, and δ cyclodextrins.
16 . The composition according to claim 13 , wherein said cyclodextrin is selected from the group consisting of sulfoalkylether cyclodextrins and hydroxyalkyl cyclodextrins.
17 . The composition according to claim 13 , wherein said hydroxy acid is selected from the group consisting of citric acid, ascorbic acid, malic acid, and tartaric acid.
18 . The composition according to claim 13 , further comprising from 0.001 to 2 percent by weight of a preservative.
19 . The composition according to claim 18 , said preservative selected from the group consisting of chlorobutanol, sorbic acid, and EDTA.
20 . The composition according to claim 14 , further comprising: from 0.05 to 5% by weight of a soluble polymer.
21 . The composition according to claim 21 , wherein said soluble polymer is selected from the group consisting of methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, and poloxamers.
22 . The composition according to clainm 13 , wherein said fluoroquinolone is selected from the group consisting of Gatifloxacin, Moxifloxacin, Sitafloxacin, Lomefloxacin, Grepafloxacin, Gemifloxacin, Norfloxacin, Ofloxacin, Levofloxacin, Trovafloxacin, Ciprofloxacin and combinations thereof.
23 . The composition according to claim 13 , wherein said steroidal or non-steroidal anti-inflammatory compound is a steroidal compound and is selected from the group consisting of cortisone, hydrocortisone, corticosterone, deoxycorticosterone, prednisolone, methylprednisolone, meprednisone, triamcinolone, paramethasone, fluprednisolone, betamethasone, dexamethazone, fludrocortisone, and combinations thereof.
24 . The composition according to claim 13 , wherein said steroidal or non-steroidal anti-inflammatory compound is a non-steroidal compound and is selected from the group consisting of aspirin, diclofenac, indomethacin, sulindac, ketoprofen, flurbiprofen, ibuprofen, naproxen, piroxicam, tenoxicam, tolmetin, ketorolac, oxaprosin, mefenamic acid, fenoprofen, nambumetone, acetaminophen, nimesulide, NS-398, flosulid, L-745337, celecoxib, rofecoxib, SC-57666, DuP-697, parecoxib sodium, JTE-522, valdecoxib, SC-58125, etoricoxib, RS-57067, L-748780, L-761066, APHS, etodolac, meloxicam, and S-2474, and combinations thereof. thereof.
25 . In a method of topically applying a pharmaceutical composition containing an active compound to the eye of a subject in need thereof, which active compound precipitates from said composition on the cornea of said subject, the improvement comprising: including a soluble polymer in said composition in an amount effective to reduce the precipitation of said active compound on the cornea of said subject.
26 . The method according to claim 25 , wherein said soluble polymer is selected from the group consisting of methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, and polyvinyl alcohol, and poloxamers.
27 . The method according to claim 25 , wherein said active compound is a fluoroquinolone.
28 . The method according to claim 25 , said pharmaceutical composition further comprising a steroidal or non-steroidal anti-inflammatory compound.
29 . In a topical pharmaceutical composition containing an active compound used to topically apply said active compound to the eye of a subject in need thereof, which active compound precipitates from said composition on the cornea of said subject, the improvement comprising: including from 0.05 to 5% by weight of a soluble polymer in said composition in an amount effective to reduce the precipitation of said active compound on the cornea of said subject.
30 . The composition according to claim 29 , wherein said soluble polymer is selected from the group consisting of methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, and polyvinyl alcohol, and poloxamers.
31 . The composition according to claim 29 , wherein said active compound is a fluoroquinolone.
32 . The composition according to claim 29 , said composition further comprising a steroidal or non-steroidal anti-inflammatory compound.