U.S. patent application number 11/356206 was filed with the patent office on 2007-08-23 for fluoroquinolone compositions.
Invention is credited to Yerramilli V. S. N. Murthy.
Application Number | 20070197548 11/356206 |
Document ID | / |
Family ID | 38429064 |
Filed Date | 2007-08-23 |
United States Patent
Application |
20070197548 |
Kind Code |
A1 |
Murthy; Yerramilli V. S.
N. |
August 23, 2007 |
Fluoroquinolone compositions
Abstract
The invention relates to pharmaceutical compositions comprising
(i) a fluoroquinolone, (ii) a salt formed between a carboxylate
anion and a divalent metal cation, (iii) a liquid comprising an
organic solvent selected from the group consisting of glycerol,
propylene glycol, glycerol formal, and (iv) optionally water. The
invention further relates to methods of treating or preventing a
condition in an animal comprising administering to the animal in
need thereof a pharmaceutical composition of the invention.
Inventors: |
Murthy; Yerramilli V. S. N.;
(Apex, NC) |
Correspondence
Address: |
KENYON & KENYON LLP
1500 K STREET N.W.
SUITE 700
WASHINGTON
DC
20005
US
|
Family ID: |
38429064 |
Appl. No.: |
11/356206 |
Filed: |
February 17, 2006 |
Current U.S.
Class: |
514/253.08 ;
514/312 |
Current CPC
Class: |
A61K 9/0095 20130101;
A61P 31/04 20180101; A61K 47/12 20130101; A61K 9/08 20130101; A61K
47/02 20130101; A61K 31/4709 20130101; A61K 31/496 20130101; A61K
47/40 20130101; A61K 47/10 20130101; A61K 9/0019 20130101 |
Class at
Publication: |
514/253.08 ;
514/312 |
International
Class: |
A61K 31/496 20060101
A61K031/496; A61K 31/4709 20060101 A61K031/4709 |
Claims
1. A pharmaceutical composition comprising: (i) a fluoroquinolone;
(ii) a salt formed between a carboxylate anion and a divalent metal
cation; and (iii) a liquid comprising (a) an organic solvent
selected from the group consisting of glycerol, propylene glycol,
glycerol formal, and mixtures thereof.
2. The pharmaceutical composition of claim 1, wherein the
fluoroquinolone is selected from the group consisting of
ciprofloxacin, enrofloxacin, enoxacin, gatifloxacin, gemifloxacin,
levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin,
sparfloxacin, trovafloxacin, difloxacin, cinofloxacin, pefloxacin,
tosufloxacin, temafloxacin, fleroxacin, amifloxacin, binfloxacin,
danofloxacin, marbofloxacin, ruflocaxin, and sarafloxacin.
3. The pharmaceutical composition of claim 1, wherein the divalent
metal cation is selected from the group consisting of Be.sup.+2,
Mg.sup.+2, Ca.sup.+2, Sr.sup.+2, Ba.sup.+2, Ra.sup.+2, Cu.sup.+2,
Fe.sup.+2, and Zn.sup.+2.
4. The pharmaceutical composition of claim 3, wherein the divalent
metal cation is Zn.sup.+2 or Mg.sup.+2.
5. The pharmaceutical composition of claim 1, wherein the
carboxylate anion is a C.sub.1 to C.sub.6 saturated or unsaturated,
straight chain or branched alkyl group optionally substituted with
--N(R.sub.1).sub.2, SR.sub.1, --COOR.sub.2, --Cl, --Br, --I, --F,
--OR.sub.1, wherein each R.sub.1 is independently a H or a C.sub.1
to C.sub.6 saturated or unsaturated, straight chain or branched
alkyl group and each R.sub.2 is a C.sub.1 to C.sub.6 saturated or
unsaturated, straight chain or branched alkyl group.
6. The pharmaceutical composition of claim 1, wherein the salt
formed between a carboxylate anion and a divalent metal cation is
zinc acetate.
7. The pharmaceutical composition of claim 1, wherein the salt
formed between a carboxylate anion and a divalent metal cation is
magnesium acetate.
8. The pharmaceutical composition of claim 1, wherein the liquid
comprises glycerol.
9. The pharmaceutical composition of claim 1, wherein the liquid
comprises propylene glycol.
10. The pharmaceutical composition of claim 1, wherein the liquid
comprises glycerol formal.
11. The pharmaceutical composition of claim 1, wherein the liquid
further comprises water.
12. The pharmaceutical composition of claim 1, wherein the water is
present in an amount of up to about 75 percent by volume of the
liquid.
13. The pharmaceutical composition of claim 1, wherein the liquid
comprises glycerol, propylene glycol, glycerol formal, or a mixture
thereof in an amount ranging from about 25 percent to 100 percent
by volume of the liquid and water in an amount ranging from about
75 percent to 0 percent by volume of the liquid.
14. The pharmaceutical composition of claim 1, wherein the liquid
comprises glycerol, propylene glycol, glycerol formal, or a mixture
thereof in an amount ranging from about 50 percent to 90 percent by
volume of the liquid and water in an amount ranging from about 50
percent to 10 percent by volume of the liquid.
15. The pharmaceutical composition of claim 1, wherein the
fluoroquinolone is present in an amount ranging from about 2
percent to 20 percent by weight of the pharmaceutical
composition.
16. The pharmaceutical composition of claim 15, wherein the
fluoroquinolone is present in an amount ranging from about 10
percent to 20 percent by weight of the pharmaceutical
composition.
17. The pharmaceutical composition of claim 1, wherein the ratio of
the fluoroquinolone to the salt formed between a carboxylate anion
and a divalent metal cation ranges from about 3 to 0.5.
18. The pharmaceutical composition of claim 1, wherein the ratio of
the fluoroquinolone to the salt formed between a carboxylate anion
and a divalent metal cation ranges from about 2.5 to 0.8.
19. The pharmaceutical composition of claim 11, wherein the salt
formed between a carboxylate anion and a divalent metal cation is
zinc acetate, the liquid comprises glycerol in an amount of about
75 percent by volume of the liquid and water in an amount of about
25 percent water by volume of the liquid, and the ratio of
fluoroquinolone to zinc acetate is about 2 to 1.
20. The pharmaceutical composition of claim 19, wherein the
fluoroquinolone is selected from the group consisting of
enrofloxacin, ciprofloxacin, and marbofloxacin.
21. The pharmaceutical composition of claim 11, wherein the salt
formed between a carboxylate anion and a divalent metal cation is
magnesium acetate, the liquid comprises glycerol in an amount of
about 75 percent by volume of the liquid and water in an amount of
about 25 percent water by volume of the liquid, and the ratio of
fluoroquinolone to magnesium acetate is about 2 to 1.
22. The pharmaceutical composition of claim 21, wherein the
fluoroquinolone is selected from the group consisting of
enrofloxacin, ciprofloxacin, and marbofloxacin.
23. The pharmaceutical composition of claim 1, wherein the
pharmaceutical composition is a solution.
24. The pharmaceutical composition of claim 1, wherein the
composition is injectable.
25. The pharmaceutical composition of claim 11, wherein the
pharmaceutical composition is a solution.
26. The pharmaceutical composition of claim 11, wherein the
composition is injectable.
27. The pharmaceutical composition of claim 1, wherein the
pharmaceutical composition is prepared by adding the
fluoroquinolone and the salt formed between a carboxylate anion and
a divalent metal cation to glycerol, propylene glycol, glycerol
formal, or a mixture thereof.
28. The pharmaceutical composition of claim 11, wherein the
pharmaceutical composition is prepared by adding the
fluoroquinolone and the salt formed between a carboxylate anion and
a divalent metal cation to glycerol, propylene glycol, glycerol
formal, water, or any combination thereof.
29. The pharmaceutical composition of claim 1, further comprising a
cyclodextrin.
30. A pharmaceutical composition comprising a complex of formula:
M.sup.+2(GLY)(FQ), M.sup.+2(PG)(FQ.sup.-), or M.sup.+2 (GF)(FQ),
wherein: FQ is a fluoroquinolone or an anion of a fluoroquinolone,
M.sup.+2 is a divalent metal cation, GLY is glycerol or an anion of
glycerol, PG is propylene glycol or an anion of propylene glycol;
and GF is glycerol formal or an anion of glycerol formal.
31. The pharmaceutical composition of claim 30, wherein the complex
can be detected by mass spectral analysis.
32. The pharmaceutical composition of claim 30, further comprising
a cyclodextrin.
33. A pharmaceutical composition comprising: (i) a fluoroquinolone;
(ii) a salt formed between a carboxylate anion and a divalent metal
cation; and (iii) a liquid comprising an organic solvent and water,
wherein the pharmaceutical composition is a solution of the
fluoroquinolone in the liquid and the concentration of the
fluoroquinolone in the solution is higher than can be obtained in
the absence of the organic solvent.
34. The pharmaceutical composition of claim 33, wherein the organic
solvent is selected from the group consisting of glycerol,
propylene glycol, glycerol formal, and mixtures thereof.
35. The pharmaceutical composition of claim 33, further comprising
a cyclodextrin.
36. A method of treating or preventing a condition in an animal
comprising orally administering to the animal in need thereof, the
pharmaceutical composition of claim 1.
37. The method of claim 36, wherein the condition is a bacterial
infection.
38. The method of claim 37, wherein the bacterial infection as a
bacterial infection caused by an organism selected from the group
consisting of Staphylococcus aureus, Streptococcus pneumoniae,
coagulese-negative staphylococci, Streptococcus pyogenes,
Staphylococcus epidermis, Pseudomonas aeruginosa, Escherichia coli,
Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis,
Proteus vulgaris, Providencia stuartii, Morganella morganii,
Citrobacter diversus, Citrobacter freundii, Haemophilus influenzae,
or Neisseria gonorrhea.
39. The method of claim 36, wherein the condition is a respiratory
tract infection, a urinary tract infection, a postoperative-wound
infection, a bone or joint infection, a skin infection, an ear
infection, or a sexually transmitted disease.
40. The method of claim 36, wherein the animal is selected from the
group consisting of a canine, a feline, an equine, a bovine, an
ovine, or a porcine.
41. The method of claim 40, wherein the animal is a cat.
42. The method of claim 40, wherein the animal is a dog.
43. The method of claim 36, wherein the composition is administered
in an amount to provide a dose of the fluoroquinolone that ranges
from about 0.1 mg/kg of body weight to 50 mg/kg of body weight.
44. The method of claim 43, wherein the pharmaceutical composition
is administered daily or twice daily until 2-3 days after cessation
of the condition.
45. The method of claim 43, wherein the pharmaceutical composition
is administered for about 7 days.
46. The method of claim 43, wherein the pharmaceutical composition
is administered for about 14 days.
47. The pharmaceutical composition of claim 1, wherein the
pharmaceutical composition show less than a 5 percent decrease in
the amount of the fluoroquinolone after being stored at 70.degree.
C., for 10 days.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] Not Applicable.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] Not Applicable.
INCORPORATION BY REFERENCE OF MATERIAL SUBMITTED ON A COMPACT
DISC
[0003] Not Applicable.
FIELD OF THE INVENTION
[0004] The present invention relates to pharmaceutical compositions
comprising (i) a fluoroquinolone, (ii) a salt formed between a
carboxylate anion and a divalent metal cation, and (iii) a liquid
comprising (a) an organic solvent selected from the group
consisting of glycerol, propylene glycol, glycerol formal, and
mixtures thereof and (b) optionally water. The invention further
relates to methods of treating or preventing a condition in an
animal comprising administering to the animal in need thereof a
pharmaceutical composition of the invention.
BACKGROUND OF THE INVENTION
[0005] The following discussion of the background of the invention
is merely provided to aid the reader in understanding the invention
and is not admitted to describe or constitute prior art to the
present invention.
[0006] Fluoroquinolones are antibiotics used to treat infections
caused by microorganisms. Fluoroquinolones have the basic structure
shown below: ##STR1## wherein R.sub.1, R.sub.2, R.sub.3, and
R.sub.4 can be a variety of functional groups and X can be carbon
or a variety of heteroatoms either of which may be substituted or
unsubstituted.
[0007] Fluoroquinolones were first developed in the early 1960s.
The first fluoroquinolone, nalidixic acid, was approved by the FDA
in 1963 for the treatment of urinary tract infections. Nalidixic
acid is rapidly absorbed after oral administration and is excreted
into the urine in bactericidal concentrations. Nalidixic acid,
however, has several limitations that prevents its use in other
types of infections. Specifically, nalidixic acid has a narrow
spectrum of activity and microorganisms easily developed resistance
to the drug. The development of other fluoroquinolones by
chemically altering the basic structure of nalidixic acid, however,
has led to improved fluoroquinolones that are more effective
against resistant bacteria and effective against a broader range of
bacteria.
[0008] Representative fluoroquinolones include but are not limited
to those described in BE 870,576, U.S. Pat. No. 4,448,962, DE
3,142,854, EP 047,005, EP 206,283, BE 887,574, EP 221,463, EP
140,116, EP 131,839, EP 154,780, EP 078,362, EP 310,849, EP
520,240, U.S. Pat. No. 4,499,091, U.S. Pat. No. 4,704,459, U.S.
Pat. No. 4,795,751, U.S. Pat. No. 4,668,784, and U.S. Pat. No.
5,532,239.
[0009] The fluoroquinolone class of antibiotics are a powerful tool
in combating bacterial infections. Fluoroquinolones have been used
extensively to treat respiratory tract infections (including for
example, bronchitis, pneumonia, tuberculosis), urinary tract
infections, diarrhea, postoperative-wound infections, bone and
joint infections, skin infections, inflammation of the prostate,
ear infections, various sexually transmitted diseases, various
infections that affect people with AIDS, and other conditions, in
animals and humans. Fluoroquinolones are active against a wide
spectrum of gram-positive and gram-negative bacteria. For example,
various fluoroquinolones have been found to be effective against
Staphylococcus aureus, Streptococcus pneumoniae, coagulese-negative
staphylococci, Streptococcus pyogenes, Staphylococcus epidermis,
Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae,
Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris,
Providencia stuartii, Morganella morganii, Citrobacter diversus,
Citrobacter freundii, Haemophilus influenzae, and Neisseria
gonorrhea, and other organisms. Indeed, the mounting resistance of
Staphylococcus aureus to both penicillin and erythromycin has made
the fluoroquinolone antibiotics a viable alternative for the
treatment of skin diseases.
[0010] The mode of action of fluoroquinolones is to target DNA
gyrase in the bacteria and interfere with bacterial
replication.
[0011] Fluoroquinolones can be administered orally, topically, or
parenterally.
[0012] U.S. Pat. No. 5,476,854 describes the oral, intravenous, and
transdermal use of lomefloxacin to treat urinary tract infections,
upper respiratory tract infections, sexually-transmitted
infections, opthalmological infections, and intestinal
infections.
[0013] U.S. Pat. No. 6,017,912 discloses a method of topically
treating bacterial infections of the skin caused by susceptible
organisms that comprises administering to an individual a
composition of a fluoroquinolone antibiotic in a vehicle containing
acetone and alcohol, applied directly to the affected areas of the
human skin.
[0014] U.S. Pat. No. 5,912,255 discloses a pharmaceutical
composition comprising a fluoroquinolone and benzoyl peroxide in a
vehicle. The compositions are useful for the topical treatment of a
variety of skin conditions.
[0015] U.S. Pat. No. 5,756,506 discloses a method of treating
animals with fluoroquinolones by administering to the animal a
single high dose of the fluoroquinolone to replace multiple lower
doses.
[0016] U.S. Pat. No. 5,532,239 discloses treating nephrotic
syndromes with fluoroquinolone derivatives.
[0017] Divalent cations are known to reduce the absorption and/or
bioavailability of fluoroquinolones. See, for example, S. Lecomte
et al., Effect of Magnesium Complexation by Fluoroquinolones on
Their Antibacterial Properties, Antimicrobial Agents and
Chemotherapy, 38:12, 2810-2816, December 1994; Hyoung-Ryun Park, et
al., Ionization and Divalent Cation Complexation of Quinolone
Antibiotics in Aqueous Solution, Bull. Korean Chem. Soc. 2000,
21:9, 849-854; B. Macias, et al., Complexes of Co (II) and Zn (II)
with Oflaxacin, Crystal Structure of
[Co(oflo).sub.2(MeOH).sub.2].4H.sub.2O, J. Pharm. Sci., 91:11,
2416-2423, November 2000; V. Loganathan et al., In-vitro and
In-vivo Drug-Drug Interaction Between Ciprofloxacin and Antacids,
The Eastern Pharmacist, June 1966, 119-121; A. Okhamafe et al.,
Pharmacokinetic Interactions of Norfloxacin with Some Metallic
Medicinal Agents, International Journal of Pharmaceutics, 68,
(1991), 11-18; B. Lomaestro et al., Quinolone-Antibiotic
Interactions: A Review, DICP, The Annals of Pharmacotherapy, 25,
November 1991, 1249-1258; S. Primozic et al., Transport Kinetics of
Zinc-Ciprofloxacin Complex Across the Model Lipid Membrane, Farm
Vestn, 1999, 50, 294-295; M. Zupancic et al., Synthesis and
Characterization of Two Novel Zinc (II) Complexes With
Ciprofloxacin. Crystal Structure of
[C.sub.17H.sub.19N.sub.3O.sub.3F].sub.2.ZnCl.sub.4.2H.sub.2O,
Croatia Chemica Acta, 74(1), 61-74, 2001; and F. Kozjec et al.,
Pharmacokinetics of Ciprofloxacin Metal Complexes, Acta. Pharm.,
46, 109-114, 1996).
[0018] Solid oral pharmaceutical compositions, such as tablets and
capsules, can be difficult for some individuals to swallow. For
example, pediatric patients often find it difficult to swallow
solid oral pharmaceutical compositions. Furthermore, solid oral
pharmaceutical compositions can be difficult to administer to
animals, such as cats. Thus, in many instances, liquid oral
pharmaceutical compositions, such as solutions and suspensions, are
desirable because they are easier to administer. Fluoroquinolones,
however, are difficult to dissolve in liquids. Accordingly, there
is a need in the art for new liquid fluoroquinolone compositions
that can be more easily administered to animals.
[0019] Citation of any reference in this section of this
application is not to be construed that such reference is prior art
to the present application.
SUMMARY OF THE INVENTION
[0020] The invention relates to pharmaceutical compositions
comprising (i) a fluoroquinolone, (ii) a salt formed between a
carboxylate anion and a divalent metal cation, and (iii) a liquid
comprising (a) an organic solvent selected from the group
consisting of glycerol, propylene glycol, glycerol formal, and
mixtures thereof and (b) optionally water.
[0021] The invention further relates to a pharmaceutical
composition comprising a complex of formula: M.sup.+2(GLY)(FQ),
M.sup.+2(PG)(FQ.sup.-), or M.sup.+2 (GF)(FQ.sup.-) wherein:
[0022] FQ is a fluoroquinolone or an anion of a
fluoroquinolone,
[0023] M.sup.+2 is a divalent metal cation,
[0024] GLY is glycerol or an anion of glycerol,
[0025] PG is propylene glycol or an anion of propylene glycol;
and
[0026] GF is glycerol formal or an anion of glycerol formal.
[0027] The invention further relates to a pharmaceutical
composition comprising:
[0028] (i) a fluoroquinolone;
[0029] (ii) a salt formed between a carboxylate anion and a
divalent metal cation; and
[0030] (iii) a liquid comprising an organic solvent and water,
wherein the pharmaceutical composition is a solution of the
fluoroquinolone in the liquid and the concentration of the
fluoroquinolone in the solution is higher than can be obtained in
the absence of the organic solvent.
[0031] The invention further relates to methods of treating or
preventing a condition in an animal comprising administering to the
animal in need thereof a pharmaceutical composition of the
invention. The pharmaceutical compositions of the invention, being
a liquid, are in many instances easier to administer than solid
oral dosage forms.
BRIEF DESCRIPTION OF THE DRAWINGS
[0032] FIG. 1 is a graphical representation of the concentration of
enrofloxacin in serum in .mu.g/mL as a function of time (hours)
when enrofloxacin is orally administered to a dog. The symbol
(.box-solid.) represents data points for administration of three
tablets (22.7 mg each, total 68 mg) of commercially available
enrofloxacin (Baytril.RTM., commercially available from Bayer
Health Care of Shawnee Mission, Kans.) and the symbol
(.diamond-solid.) represents data points for administration of
enrofloxacin as an oral liquid pharmaceutical formulation of the
invention at a dose of 68 mg (i.e., 3 mL of a liquid composition of
the invention having an enrofloxacin concentration of 23
mg/mL).
[0033] FIG. 2 is a graphical representation of the concentration of
enrofloxacin in serum in .mu.g/mL as a function of time (hours)
when enrofloxacin is orally administered to a cat. The symbol
(.box-solid.) represents data points for administration of a single
tablet (22.7 mg) of commercially available enrofloxacin (i.e.,
Baytril) at a dose of 22.7 mg/mL and the symbol (.diamond-solid.)
represents data points for administration of enrofloxacin as liquid
pharmaceutical formulation of the invention at a dose of 23 mg
(i.e., 1 mL of a liquid composition of the invention having an
enrofloxacin concentration of 23 mg/mL).
[0034] FIG. 3 is a graphical representation of the concentration of
enrofloxacin in serum in .mu.g/mL as a function of time (hours)
when enrofloxacin is orally administered to a cat. The symbol
(.diamond-solid.) represents data points for administration of a
single tablet (22.7 mg) of commercially available enrofloxacin
(i.e., Baytril) and the symbols (.sup..box-solid.),
(.tangle-solidup.), (.box-solid.) and represents data points for
administration of enrofloxacin as a liquid pharmaceutical
formulation of the invention at a dose of 23 mg (i.e., 1 mL of a
liquid composition of the invention having an enrofloxacin
concentration of 23 mg/mL).
[0035] FIG. 4 is the mass spectrum of the pharmaceutical
composition prepared in Example 7A.
[0036] FIG. 5 is the mass spectrum of the pharmaceutical
composition prepared in Example 7B.
[0037] FIG. 6 is the mass spectrum of the pharmaceutical
composition prepared in Example 8.
[0038] FIG. 7 is a graphical representation of the concentration of
enrofloxacin in serum in .mu.g/mL as a function of time (hours)
when enrofloxacin is orally administered to three cats. The symbol
(.diamond-solid.) represents data points for administration of a
single tablet (22.7 mg) of commercially available enrofloxacin
(i.e., Baytril) and the symbol (.sup..box-solid.), represents data
points for administration of enrofloxacin as a liquid
pharmaceutical formulation of the invention at a dose of 23 mg
(i.e., 1 mL of a liquid composition of the invention having an
enrofloxacin concentration of 23 mg/mL). Each data point is the
average for three cats.
[0039] FIG. 8 is a graphical representation of the concentration of
enrofloxacin in serum in .mu.g/mL as a function of time (hours)
when enrofloxacin is orally administered to three cats. The symbol
(.diamond-solid.) represents data points for administration of a
single tablet (22.7 mg) of commercially available enrofloxacin
(i.e., Baytril) and the symbol (.sup..box-solid.), represents data
points for administration of enrofloxacin as a liquid
pharmaceutical formulation of the invention at a dose of 23 mg
(i.e., 1 mL of a liquid composition of the invention having an
enrofloxacin concentration of 23 mg/mL). Each data point is the
average for three cats.
DETAILED DESCRIPTION OF THE INVENTION
[0040] The invention relates to pharmaceutical compositions
comprising (i) a fluoroquinolone, (ii) a salt formed between a
carboxylate anion and a divalent metal cation, and (iii) a liquid
comprising (a) an organic solvent selected from the group
consisting of glycerol, propylene glycol, glycerol formal, and
mixtures thereof and (b) optionally water. The invention further
relates to methods of treating or preventing a condition in an
animal comprising administering to the animal in need thereof a
pharmaceutical composition of the invention.
Definitions
[0041] The term "fluoroquinolone," as used herein, means any
compound having the basic structure: ##STR2## wherein R.sub.1,
R.sub.2, R.sub.3, and R.sub.4 can be a variety of functional groups
and X can be carbon, which may be substituted or unsubstituted, or
nitrogen. One skilled in the art would readily recognize
fluoroquinolones useful in the compositions and methods of the
invention. Typically, the fluoroquinolones are useful as
antibiotics but they may also be used to treat other conditions
(for example, nephrotic syndromes).
[0042] The term "salt," as used herein, means two compounds that
are not covalently bound but are chemically bound by ionic
interactions. Accordingly, in a salt formed between a carboxylate
anion and a divalent metal cation, the carboxylate anion and a
divalent metal cation are chemically bound by ionic
interactions.
[0043] The term "divalent metal cation," as used herein means a
metal ion in the +2 oxidation state. Representative divalent
cations include, but are not limited to, divalent cations of the
alkaline earth metals (i.e., Be.sup.+2, Mg.sup.+2, Ca.sup.+2,
Sr.sup.+2, Ba.sup.+2, and Ra.sup.+2), Cu.sup.+2, Fe.sup.+2, and
Zn.sup.+2.
[0044] The term "carboxylate anion," as that term is used herein,
means the anionic form of a carboxylic acid, i.e., R--COO.sup.-,
wherein R can be an optionally substituted phenyl or an optionally
substituted C.sub.1 to C.sub.6 saturated or unsaturated, straight
chain or branched alkyl group. Suitable substitutents include, but
are not limited to, --N(R.sub.1).sub.2, SR.sub.1, --COOR.sub.2,
--Cl, --Br, --I, --F, --OR.sub.1, wherein each R.sub.1 is
independently H or a C.sub.1 to C.sub.6 saturated or unsaturated,
straight chain or branched alkyl group and each R.sub.2 is a
C.sub.1 to C.sub.6 saturated or unsaturated, straight chain or
branched alkyl group.
[0045] Since the carboxylate anion is typically a mono anion, i.e.,
has a single carboxylate functional group, and the metal cation is
a divalent metal cation, the carboxylate salt of a divalent metal
cation includes two equivalents of carboxylate anion for each
equivalent of divalent metal cation. Accordingly, the carboxylate
salt of a divalent metal cation typically has the structure
(R--COO.sup.-).sub.2M.sup.+2, wherein M.sup.+2 is the divalent
metal cation.
[0046] The term "glycerol," as that term is used herein, means
CH.sub.2(OH)CH(OH)CH.sub.2(OH).
[0047] The term "propylene glycol," as that term is used herein,
means CH.sub.2(OH)CH.sub.2CH.sub.2(OH) or
CH.sub.2(OH)CH.sub.2(OH)CH.sub.3, i.e., 1,3-propylene glycol or
1,2-propylene glycol.
[0048] The term "glycerol formal," as used herein means an organic
solvent of formula C.sub.4H.sub.8O.sub.3 that exists as a mixture
of 5-hydroxy-1,3-dioxane and 4-hydroxymethyl-1,3-dioxolane in a
ratio of about 60:40. Although the solvent glycerol formal consists
of two chemical compounds, the two chemical compounds being in a
specific ratio of about 60:40, it is typically considered a
"solvent" rather than a mixture of compounds. This is because the
5-hydroxy-1,3-dioxane and 4-hydroxymethyl-1,3-dioxolane are in
equilibrium with each other. Accordingly, the term glycerol formal
(i.e., a mixture of 5-hydroxy-1,3-dioxane and
4-hydroxymethyl-1,3-dioxolane in a ratio of about 60:40), as used
herein, is an organic solvent.
[0049] The term "solution," as used herein, means a uniformly
dispersed mixture at the molecular or ionic level of one or more
solid or liquid substances (solute) in one or more other liquid
substances (solvent).
[0050] The phrase "injectable" or "injectable composition," as used
herein, means a composition that can be drawn into a syringe and
injected subcutaneously, intraperitoneally, or intramuscularly into
an animal without causing adverse effects due to the presence of
solid material in the composition. Solid materials include, but are
not limited to, crystals, gummy masses, and gels. Typically, a
formulation or composition is considered to be injectable when no
more than about 15%, preferably no more than about 10%, more
preferably no more than about 5%, even more preferably no more than
about 2%, and most preferably no more than about 1% of the
formulation is retained on a 0.22 .mu.m filter when the formulation
is filtered through the filter at room temperature, i.e., about
22.degree. C.
[0051] The phrase "substantially free of," as used herein, means
less than about 2 percent by weight. For example, the phrase "a
liquid substantially free of water" means that the amount of water
in the liquid is less than about 2 percent by volume of the
liquid.
[0052] The phrase "treating," "treatment of," and the like includes
the amelioration or cessation of a specified condition.
[0053] The phrase "preventing," "prevention of," and the like
include the avoidance of the onset of a condition.
[0054] The term "animal," as used herein, includes, but is not
limited to, humans, canines, felines, equines, bovines, ovines,
porcines, amphibians, reptiles, and avians. Representative animals
include, but are not limited to a cow, a horse, a sheep, a pig, an
ungulate, a chimpanzee, a monkey, a baboon, a chicken, a turkey, a
mouse, a rabbit, a rat, a guinea pig, a dog, a cat, and a human. In
one embodiment, the animal is a canine, a feline, an equine, a
bovine, an ovine, or a porcine.
[0055] The term "condition," as used herein means an interruption,
cessation, or disorder of a bodily function, system, or organ.
Representative conditions include, but are not limited to,
bacterial infections and nephrotic syndromes (such as those
disclosed in U.S. Pat. No. 5,532,239, the contents of which are
expressly incorporated herein by reference thereto).
[0056] The term "effective amount," as used herein, means an amount
sufficient to treat or prevent a condition in an animal.
[0057] The term "about," as used herein to describe a range of
values, applies to both the upper limit and the lower limit of the
range. For example, the phrase "ranges from about 90:10 to 10:90"
has the same meaning as "ranges from about 90:10 to about
10:90."
The Pharmaceutical Compositions
[0058] The pharmaceutical compositions comprise (i) a
fluoroquinolone, (ii) a salt formed between a carboxylate anion and
a divalent metal cation, and (iii) a liquid comprising (a) an
organic solvent selected from the group consisting of glycerol,
propylene glycol, glycerol formal, and mixtures thereof and (b)
optionally water.
[0059] In one embodiment, the pharmaceutical composition is a
solution.
[0060] In one embodiment, the pharmaceutical composition is
injectable.
[0061] The fluoroquinolone can be any fluoroquinolone known to
those skilled in the art. Representative fluoroquinolones useful in
the compositions and methods of the invention include, but are not
limited to, those described in BE 870,576, U.S. Pat. No. 4,448,962,
DE 3,142,854, EP 047,005, EP 206,283, BE 887,574, EP 221,463, EP
140,116, EP 131,839, EP 154,780, EP 078,362, EP 310,849, EP
520,240, U.S. Pat. No. 4,499,091, U.S. Pat. No. 4,704,459, U.S.
Pat. No. 4,795,751, U.S. Pat. No. 4,668,784, and U.S. Pat. No.
5,532,239, the contents of which are expressly incorporated herein
by reference thereto.
[0062] Representative fluoroquinolones useful in the compositions
and methods of the invention include, but are not limited to,
ciprofloxacin (commercially available as Cipro.RTM.), enrofloxacin
(commercially available as Baytril.RTM.), enoxacin (commercially
available as Penetrex.RTM.), gatifloxacin (commercially available
as Tequin.RTM.), gemifloxacin (commercially available as
Factive.RTM.), levofloxacin (commercially available as
Levaquin.RTM.), lomefloxacin (commercially available as
Maxaquin.RTM.), moxifloxacin (commercially available as
Avelox.RTM.), norfloxacin (commercially available as Noroxin.RTM.),
ofloxacin (commercially available as Floxin.RTM.), sparfloxacin
(commercially available as Zagam.RTM.), trovafloxacin (commercially
available as Trovan.RTM.), difloxacin, cinofloxacin, pefloxacin,
tosufloxacin, temafloxacin, fleroxacin, amifloxacin, binfloxacin,
danofloxacin, marbofloxacin, ruflocaxin, and sarafloxacin.
[0063] In one embodiment, the fluoroquinolone is ciprofloxacin.
[0064] In one embodiment, the fluoroquinolone is enrofloxacin.
[0065] In one embodiment, the fluoroquinolone is gatifloxacin.
[0066] In one embodiment, the fluoroquinolone is gemifloxacin.
[0067] In one embodiment, the fluoroquinolone is levofloxacin.
[0068] In one embodiment, the fluoroquinolone is lomefloxacin.
[0069] In one embodiment, the fluoroquinolone is moxifloxacin.
[0070] In one embodiment, the fluoroquinolone is ofloxacin.
[0071] In one embodiment, the fluoroquinolone is sparfloxacin.
[0072] In one embodiment, the fluoroquinolone is trovafloxacin.
[0073] In one embodiment, the fluoroquinolone is difloxacin.
[0074] In one embodiment, the fluoroquinolone is cinofloxacin.
[0075] In one embodiment, the fluoroquinolone is pefloxacin.
[0076] In one embodiment, the fluoroquinolone is tosufloxacin.
[0077] In one embodiment, the fluoroquinolone is temafloxacin.
[0078] In one embodiment, the fluoroquinolone is fleroxacin.
[0079] In one embodiment, the fluoroquinolone is amifloxacin.
[0080] In one embodiment, the fluoroquinolone is binfloxacin.
[0081] In one embodiment, the fluoroquinolone is danofloxacin.
[0082] In one embodiment, the fluoroquinolone is marbofloxacin.
[0083] In one embodiment, the fluoroquinolone is ruflocaxin.
[0084] In one embodiment, the fluoroquinolone is sarafloxacin.
[0085] In one embodiment, the divalent metal cation is a divalent
metal cation of an alkaline earth metal.
[0086] In one embodiment, the divalent metal cation is Mg.sup.+2.
Mg.sup.+2 is a preferred divalent metal cation.
[0087] In one embodiment, the divalent metal cation is Zn.sup.+2.
Zn.sup.+2 is a preferred divalent metal cation.
[0088] In one embodiment, the divalent metal cation is
Ca.sup.+2.
[0089] In one embodiment, the divalent metal cation is
Cu.sup.+2.
[0090] In one embodiment, the divalent metal cation is
Fe.sup.+2.
[0091] In one embodiment, the carboxylate anion is a substituted
benzoate anion.
[0092] In one embodiment, the carboxylate anion is a benzoate
anion.
[0093] In one embodiment, the carboxylate anion is an optionally
substituted C.sub.1 to C.sub.6 saturated or unsaturated, straight
chain or branched alkyl group.
[0094] In one embodiment, the carboxylate anion is an unsubstituted
C.sub.1 to C.sub.6 saturated or unsaturated, straight chain or
branched alkyl group.
[0095] In one embodiment, the carboxylate anion is an unsubstituted
C.sub.1 to C.sub.6 saturated straight chain or branched alkyl
group.
[0096] In one embodiment, the carboxylate anion is an unsubstituted
C.sub.1 to C.sub.6 saturated straight chain alkyl group.
[0097] In one embodiment, the carboxylate anion is acetate
anion.
[0098] In one embodiment, the salt formed between a carboxylate
anion and a divalent metal cation is zinc acetate.
[0099] In one embodiment, the salt formed between a carboxylate
anion and a divalent metal cation is magnesium acetate.
[0100] When the liquid includes water, the water is typically
present in an amount up to about 90 percent (v/v) of the liquid. In
one embodiment, the water is present in an amount up to about 75
percent (v/v) of the liquid. In one embodiment, the water is
present in an amount up to about 50 percent (v/v) of the liquid. In
one embodiment, the water is present in an amount up to about 25
percent (v/v) of the liquid. In one embodiment, the water is
present in an amount up to about 20 percent (v/v) of the liquid. In
one embodiment, the water is present in an amount up to about 10
percent (v/v) of the liquid.
[0101] In one embodiment, the liquid is substantially free of
water. In one embodiment, the liquid contains less than about 1
percent by volume of water. In one embodiment, the liquid contains
less about 0.5 percent by volume of water. In one embodiment, the
liquid contains less about 0.2 percent by volume of water.
Pharmaceutically compositions that are substantially free of water
are advantageous since they are not conducive to bacterial growth.
Accordingly, it is typically not necessary to include a
preservative in pharmaceutical compositions that are substantially
free of water.
[0102] In one embodiment, the organic solvent comprises
glycerol.
[0103] In one embodiment, the organic solvent comprises propylene
glycol. In one embodiment, the propylene glycol is 1,3-propylene
glycol. In one embodiment, the propylene glycol is 1,2-propylene
glycol.
[0104] In one embodiment, the solvent comprises glycerol
formal.
[0105] In one embodiment, the solvent comprises a mixture of
glycerol and propylene glycol.
[0106] In one embodiment, the solvent comprises a mixture of
glycerol and glycerol formal.
[0107] In one embodiment, the solvent comprises a mixture of
propylene glycol and glycerol formal.
[0108] In one embodiment, the solvent comprises a mixture of
propylene glycol, glycerol, and glycerol formal.
[0109] In one embodiment, the organic solvent comprises a mixture
of glycerol and water.
[0110] In one embodiment, the organic solvent comprises a mixture
of propylene glycol and water. In one embodiment, the propylene
glycol is 1,3-propylene glycol. In one embodiment, the propylene
glycol is 1,2-propylene glycol.
[0111] In one embodiment, the solvent comprises a mixture of
glycerol formal and water.
[0112] In one embodiment, the solvent comprises a mixture of
glycerol, propylene glycol, and water.
[0113] In one embodiment, the solvent comprises a mixture of
glycerol, glycerol formal, and water.
[0114] In one embodiment, the solvent comprises a mixture of
propylene glycol, glycerol formal, and water.
[0115] In one embodiment, the solvent comprises a mixture of
propylene glycol, glycerol, glycerol formal, and water.
[0116] In one embodiment, the organic solvent is glycerol.
[0117] In one embodiment, the organic solvent is propylene glycol.
In one embodiment, the propylene glycol is 1,3-propylene glycol. In
one embodiment, the propylene glycol is 1,2-propylene glycol.
[0118] In one embodiment, the solvent is glycerol formal.
[0119] In one embodiment, the solvent is a mixture of glycerol and
propylene glycol.
[0120] In one embodiment, the solvent is a mixture of glycerol and
glycerol formal.
[0121] In one embodiment, the solvent is a mixture of propylene
glycol and glycerol formal.
[0122] In one embodiment, the solvent is a mixture of propylene
glycol, glycerol, and glycerol formal.
[0123] In one embodiment, the organic solvent is a mixture of
glycerol and water.
[0124] In one embodiment, the organic solvent is a mixture of
propylene glycol and water. In one embodiment, the propylene glycol
is 1,3-propylene glycol. In one embodiment, the propylene glycol is
1,2-propylene glycol.
[0125] In one embodiment, the solvent is a mixture of glycerol
formal and water.
[0126] In one embodiment, the solvent is a mixture of glycerol,
propylene glycol, and water.
[0127] In one embodiment, the solvent is a mixture of glycerol and
glycerol formal, and water.
[0128] In one embodiment, the solvent is a mixture of propylene
glycol, glycerol formal, and water.
[0129] In one embodiment, the solvent is a mixture of propylene
glycol, glycerol, glycerol formal, and water.
[0130] In one embodiment, the liquid comprises glycerol in an
amount ranging from about 25 percent to 100 percent by volume of
the liquid.
[0131] In one embodiment, the liquid comprises glycerol in an
amount ranging from about 50 percent to 90 percent by volume of the
liquid.
[0132] In one embodiment, the liquid comprises glycerol in an
amount ranging from about 60 percent to 80 percent by volume of the
liquid.
[0133] In one embodiment, the liquid comprises glycerol in an
amount ranging from about 75 percent to 80 percent by volume of the
liquid.
[0134] In one embodiment, the liquid comprises propylene glycol in
an amount ranging from about 25 percent to 100 percent by volume of
the liquid.
[0135] In one embodiment, the liquid comprises propylene glycol in
an amount ranging from about 50 percent to 90 percent by volume of
the liquid.
[0136] In one embodiment, the liquid comprises propylene glycol in
an amount ranging from about 60 percent to 80 percent by volume of
the liquid.
[0137] In one embodiment, the liquid comprises propylene glycol in
an amount ranging from about 75 percent to 80 percent by volume of
the liquid.
[0138] In one embodiment, the liquid comprises glycerol formal in
an amount ranging from about 25 percent to 100 percent by volume of
the liquid.
[0139] In one embodiment, the liquid comprises glycerol formal in
an amount ranging from about 50 percent to 90 percent by volume of
the liquid.
[0140] In one embodiment, the liquid comprises glycerol formal in
an amount ranging from about 60 percent to 80 percent by volume of
the liquid.
[0141] In one embodiment, the liquid comprises glycerol formal in
an amount ranging from about 75 percent to 80 percent by volume of
the liquid.
[0142] In one embodiment, the liquid comprises a mixture of
glycerol and propylene glycol; glycerol and glycerol formal;
propylene glycol and glycerol formal; or glycerol, propylene
glycol, and glycerol formal in an amount ranging from about 25
percent to 100 percent by volume of the liquid.
[0143] In one embodiment, the liquid comprises a mixture of
glycerol and propylene glycol; glycerol and glycerol formal;
propylene glycol and glycerol formal; or glycerol, propylene
glycol, and glycerol formal in an amount ranging from about 50
percent to 90 percent by volume of the liquid.
[0144] In one embodiment, the liquid comprises a mixture of
glycerol and propylene glycol; glycerol and glycerol formal;
propylene glycol and glycerol formal; or glycerol, propylene
glycol, and glycerol formal in an amount ranging from about 60
percent to 80 percent by volume of the liquid.
[0145] In one embodiment, the liquid comprises a mixture of
glycerol and propylene glycol; glycerol and glycerol formal;
propylene glycol and glycerol formal; or glycerol, propylene
glycol, and glycerol formal in an amount ranging from about 75
percent to 80 percent by volume of the liquid.
[0146] In one embodiment, the liquid comprises glycerol in an
amount ranging from about 25 percent to 100 percent by volume of
the liquid and water in an amount ranging from about 75 percent to
0 percent by volume of the liquid.
[0147] In one embodiment, the liquid comprises glycerol in an
amount ranging from about 50 percent to 90 percent by volume of the
liquid and water in an amount ranging from about 50 percent to 10
percent by volume of the liquid.
[0148] In one embodiment, the liquid comprises glycerol in an
amount ranging from about 60 percent to 80 percent by volume of the
liquid and water in an amount ranging from about 40 percent to 20
percent by volume of the liquid.
[0149] In one embodiment, the liquid comprises glycerol in an
amount ranging from about 75 percent to 80 percent by volume of the
liquid and water in an amount ranging from about 25 percent to 20
percent by volume of the liquid. In one embodiment, the liquid
comprises propylene glycol in an amount ranging from about 25
percent to 100 percent by volume of the liquid and water in an
amount ranging from about 75 percent to 0 percent by volume of the
liquid.
[0150] In one embodiment, the liquid comprises propylene glycol in
an amount ranging from about 50 percent to 90 percent by volume of
the liquid and water in an amount ranging from about 50 percent to
10 percent by volume of the liquid.
[0151] In one embodiment, the liquid comprises propylene glycol in
an amount ranging from about 60 percent to 80 percent by volume of
the liquid and water in an amount ranging from about 40 percent to
20 percent by volume of the liquid.
[0152] In one embodiment, the liquid comprises propylene glycol in
an amount ranging from about 75 percent to 80 percent by volume of
the liquid and water in an amount ranging from about 25 percent to
20 percent by volume of the liquid.
[0153] In one embodiment, the liquid comprises glycerol formal in
an amount ranging from about 25 percent to 100 percent by volume of
the liquid and water in an amount ranging from about 75 percent to
0 percent by volume of the liquid.
[0154] In one embodiment, the liquid comprises glycerol formal in
an amount ranging from about 50 percent to 90 percent by volume of
the liquid and water in an amount ranging from about 50 percent to
10 percent by volume of the liquid.
[0155] In one embodiment, the liquid comprises glycerol formal in
an amount ranging from about 60 percent to 80 percent by volume of
the liquid and water in an amount ranging from about 40 percent to
20 percent by volume of the liquid.
[0156] In one embodiment, the liquid comprises glycerol formal in
an amount ranging from about 75 percent to 80 percent by volume of
the liquid and water in an amount ranging from about 25 percent to
20 percent by volume of the liquid.
[0157] In one embodiment, the liquid comprises glycerol in an
amount ranging from about 25 percent to 100 percent by volume of
the liquid and propylene glycol in an amount ranging from about 75
percent to 0 percent by volume of the liquid.
[0158] In one embodiment, the liquid comprises glycerol in an
amount ranging from about 50 percent to 90 percent by volume of the
liquid and propylene glycol in an amount ranging from about 50
percent to 10 percent by volume of the liquid.
[0159] In one embodiment, the liquid comprises glycerol in an
amount ranging from about 60 percent to 80 percent by volume of the
liquid and propylene glycol in an amount ranging from about 40
percent to 20 percent by volume of the liquid.
[0160] In one embodiment, the liquid comprises glycerol in an
amount ranging from about 75 percent to 80 percent by volume of the
liquid and propylene glycol in an amount ranging from about 25
percent to 20 percent by volume of the liquid.
[0161] In one embodiment, the liquid comprises glycerol in an
amount ranging from about 25 percent to 100 percent by volume of
the liquid and glycerol formal in an amount ranging from about 75
percent to 0 percent by volume of the liquid.
[0162] In one embodiment, the liquid comprises glycerol in an
amount ranging from about 50 percent to 90 percent by volume of the
liquid and glycerol formal in an amount ranging from about 50
percent to 10 percent by volume of the liquid.
[0163] In one embodiment, the liquid comprises glycerol in an
amount ranging from about 60 percent to 80 percent by volume of the
liquid and glycerol formal in an amount ranging from about 40
percent to 20 percent by volume of the liquid.
[0164] In one embodiment, the liquid comprises glycerol in an
amount ranging from about 75 percent to 80 percent by volume of the
liquid and glycerol formal in an amount ranging from about 25
percent to 20 percent by volume of the liquid.
[0165] In one embodiment, the liquid comprises propylene glycol in
an amount ranging from about 25 percent to 100 percent by volume of
the liquid and glycerol in an amount ranging from about 75 percent
to 0 percent by volume of the liquid.
[0166] In one embodiment, the liquid comprises propylene glycol in
an amount ranging from about 50 percent to 90 percent by volume of
the liquid and glycerol in an amount ranging from about 50 percent
to 10 percent by volume of the liquid.
[0167] In one embodiment, the liquid comprises propylene glycol in
an amount ranging from about 60 percent to 80 percent by volume of
the liquid and glycerol in an amount ranging from about 40 percent
to 20 percent by volume of the liquid.
[0168] In one embodiment, the liquid comprises propylene glycol in
an amount ranging from about 75 percent to 80 percent by volume of
the liquid and glycerol in an amount ranging from about 25 percent
to 20 percent by volume of the liquid.
[0169] In one embodiment, the liquid comprises propylene glycol in
an amount ranging from about 25 percent to 100 percent by volume of
the liquid and glycerol formal in an amount ranging from about 75
percent to 0 percent by volume of the liquid.
[0170] In one embodiment, the liquid comprises propylene glycol in
an amount ranging from about 50 percent to 90 percent by volume of
the liquid and glycerol formal in an amount ranging from about 50
percent to 10 percent by volume of the liquid.
[0171] In one embodiment, the liquid comprises propylene glycol in
an amount ranging from about 60 percent to 80 percent by volume of
the liquid and glycerol formal in an amount ranging from about 40
percent to 20 percent by volume of the liquid.
[0172] In one embodiment, the liquid comprises propylene glycol in
an amount ranging from about 75 percent to 80 percent by volume of
the liquid and glycerol formal in an amount ranging from about 25
percent to 20 percent by volume of the liquid.
[0173] In one embodiment, the liquid comprises glycerol formal in
an amount ranging from about 25 percent to 100 percent by volume of
the liquid and propylene glycol in an amount ranging from about 75
percent to 0 percent by volume of the liquid.
[0174] In one embodiment, the liquid comprises glycerol formal in
an amount ranging from about 50 percent to 90 percent by volume of
the liquid and propylene glycol in an amount ranging from about 50
percent to 10 percent by volume of the liquid.
[0175] In one embodiment, the liquid comprises glycerol formal in
an amount ranging from about 60 percent to 80 percent by volume of
the liquid and propylene glycol in an amount ranging from about 40
percent to 20 percent by volume of the liquid.
[0176] In one embodiment, the liquid comprises glycerol formal in
an amount ranging from about 75 percent to 80 percent by volume of
the liquid and propylene glycol in an amount ranging from about 25
percent to 20 percent by volume of the liquid.
[0177] In one embodiment, the liquid comprises glycerol formal in
an amount ranging from about 25 percent to 100 percent by volume of
the liquid and glycerol in an amount ranging from about 75 percent
to 0 percent by volume of the liquid.
[0178] In one embodiment, the liquid comprises glycerol formal in
an amount ranging from about 50 percent to 90 percent by volume of
the liquid and glycerol in an amount ranging from about 50 percent
to 10 percent by volume of the liquid.
[0179] In one embodiment, the liquid comprises glycerol formal in
an amount ranging from about 60 percent to 80 percent by volume of
the liquid and glycerol in an amount ranging from about 40 percent
to 20 percent by volume of the liquid.
[0180] In one embodiment, the liquid comprises glycerol formal in
an amount ranging from about 75 percent to 80 percent by volume of
the liquid and glycerol in an amount ranging from about 25 percent
to 20 percent by volume of the liquid.
[0181] Organic solvents other than glycerol, propylene glycol, and
glycerol formal that can be used in the pharmaceutical compositions
of the invention include C.sub.3-C.sub.6 alcohols. In one
embodiment, the C.sub.3-C.sub.6 alcohols have at least two hydroxyl
groups. In one embodiment, the C.sub.3-C.sub.6 alcohol is a
dihydroxy alcohol. In one embodiment, the C.sub.3-C.sub.6 alcohol
is a trihydroxy alcohol.
[0182] Typically, the fluoroquinolone is present in the
pharmaceutical composition in an amount ranging from about 2
percent to 20 percent by weight of the pharmaceutical composition.
In one embodiment, the fluoroquinolone is present in the
pharmaceutical composition in an amount ranging from about 3
percent to 20 percent by weight of the pharmaceutical composition.
In one embodiment, the fluoroquinolone is present in the
pharmaceutical composition in an amount ranging from about 5
percent to 20 percent by weight of the pharmaceutical composition.
In one embodiment, the fluoroquinolone is present in the
pharmaceutical composition in an amount ranging from about 10
percent to 20 percent by weight of the pharmaceutical composition.
In one embodiment, the fluoroquinolone is present in the
pharmaceutical composition in an amount ranging from about 15
percent to 20 percent by weight of the pharmaceutical composition.
Preferably, the fluoroquinolone is present in the pharmaceutical
composition without using excipients to improve the solubility. In
one embodiment, the fluoroquinolone is present in the
pharmaceutical composition in an amount ranging from about 2
percent to 15 percent by weight of the pharmaceutical composition.
In one embodiment, the fluoroquinolone is present in the
pharmaceutical composition in an amount ranging from about 2
percent to 10 percent by weight of the pharmaceutical composition.
In one embodiment, the fluoroquinolone is present in the
pharmaceutical composition in an amount ranging from about 2
percent to 5 percent by weight of the pharmaceutical composition.
In one embodiment, the fluoroquinolone is present in the
pharmaceutical composition in an amount ranging from about 5
percent to 15 percent by weight of the pharmaceutical composition.
In one embodiment, the fluoroquinolone is present in the
pharmaceutical composition in an amount ranging from about 5
percent to 10 percent by weight of the pharmaceutical
composition.
[0183] In some embodiments, it is even possible that the
fluoroquinolone is present in the pharmaceutical composition in an
amount greater than about 20 percent by weight of the
pharmaceutical composition. In one embodiment, the fluoroquinolone
is present in the pharmaceutical composition in an amount greater
than about 30 percent by weight of the pharmaceutical composition.
In one embodiment, the fluoroquinolone is present in the
pharmaceutical composition in an amount greater than about 35
percent by weight of the pharmaceutical composition. In one
embodiment, the fluoroquinolone is present in the pharmaceutical
composition in an amount of about 40 percent by weight of the
pharmaceutical composition.
[0184] The ratio of the fluoroquinolone to the salt formed between
a carboxylate anion and a divalent metal cation ranges from about 3
to 0.5. In one embodiment, the ratio of the fluoroquinolone to the
salt formed between a carboxylate anion and a divalent metal cation
ranges from about 2.5 to 0.8. In one embodiment, the ratio of the
fluoroquinolone to the salt formed between a carboxylate anion and
a divalent metal cation ranges from about 2.3 to 0.9. In one
embodiment, the ratio of the fluoroquinolone to the salt formed
between a carboxylate anion and a divalent metal cation ranges from
about 2.1 to 1.
[0185] In one embodiment, the pharmaceutical composition is a
solution.
[0186] In one embodiment, the pharmaceutical composition is
injectable.
[0187] The pharmaceutical compositions of the invention can be a
solution of the fluoroquinolone in the liquid, wherein the
fluoroquinolone is present in a sufficiently high concentration to
provide a pharmaceutical composition that is therapeutically
useful. Typically, fluoroquinolones are not sufficiently soluble in
water to provide pharmaceutical compositions that are solutions,
wherein the fluoroquinolone is present in a sufficiently high
concentration to be therapeutically useful. For example,
enrofloxacin will not dissolve in water at a sufficient
concentration to provide a therapeutically useful pharmaceutical
composition. Similarly, salts formed between two fluoroquinolone
molecules and a divalent metal ion, i.e.
(fluoroquinolone).sub.2M.sup.+2, such as those known in the art,
are not sufficiently soluble in water to provide pharmaceutical
compositions that are solutions. Salts formed between two
fluoroquinolone molecules and a divalent metal ion, i.e.
(FQ).sub.2M.sup.+2, can be prepared according to the reaction shown
below: FQ+MO+HCl.fwdarw.M[FQ].sub.2 wherein FQ is a fluoroquinolone
or anion of fluoroquinolone. For examples of salts formed between
two fluoroquinolone molecules and a divalent metal ion see, B.
Macias, et al., Complexes of Co(II) and Zn(II) with Oflaxacin,
Crystal Structure of [Co(oflo).sub.2(MeOH).sub.2].4H.sub.2O, J.
Pharm. Sci., 91:11, 2416-2423, November 2000; M. Zupancic et al.,
Synthesis and Characterization of Two Novel Zinc (II) Complexes
With Ciprofloxacin. Crystal Structure of
[C.sub.17H.sub.19N.sub.3O.sub.3F].sub.2.ZnCl.sub.4.2H.sub.2O,
Croatia Chemica Acta, 74(1), 61-74, 2001; and F. Kozjec et al.,
Pharmacokinetics of Ciprofloxacin Metal Complexes, Acta. Pharm.,
46, 109-114, 1996)).
[0188] Fluoroquinolones, however, are significantly more soluble in
the pharmaceutical compositions of the invention. Accordingly, the
invention further relates to a pharmaceutical composition
comprising (i) a fluoroquinolone, (ii) a salt formed between a
carboxylate anion and a divalent metal cation, and (iii) a liquid
comprising (a) an organic solvent selected from the group
consisting of glycerol, propylene glycol, glycerol formal, and
mixtures thereof and (b) optionally water, wherein the
pharmaceutical composition is a solution of the fluoroquinolone in
the liquid and the concentration of the fluoroquinolone in the
solution is higher than the concentration that can be obtained in
the absence of the organic solvent, i.e., wherein the organic
solvent is replaced with water.
[0189] The pharmaceutical compositions of the invention can be
prepared by adding the fluoroquinolone, typically with stirring, to
the organic solvent, optionally mixed with water, followed by
adding the salt formed between a carboxylate anion and a divalent
metal cation, typically with stirring.
[0190] In one embodiment, the pharmaceutical compositions of the
invention are prepared by adding the salt formed between a
carboxylate anion and a divalent metal cation to water followed by
adding the fluoroquinolone, typically with stirring. To the
resulting mixture is then added the organic solvent to provide the
pharmaceutical composition. Preferably, the organic solvent is
added soon (i.e., less than 24 h, preferably less than 12 h, more
preferably less than 6 h, and most preferably less than 2 h) after
the salt formed between a carboxylate anion and a divalent metal
cation and the fluoroquinolone are added to the water. The pH of
the water preferably ranges from about 5.5 to 8, more preferably
about 6 to 7.5, even more preferably about 6 to 7, and most
preferably about 6 to 6.5.
[0191] Accordingly, the invention further relates to a
pharmaceutical composition comprising (i) a fluoroquinolone, (ii) a
salt formed between a carboxylate anion and a divalent metal
cation, and (iii) a liquid comprising (a) an organic solvent
selected from the group consisting of glycerol, propylene glycol,
glycerol formal, and mixtures thereof and (b) optionally water,
wherein the pharmaceutical composition is prepared by adding the
fluoroquinolone and the salt formed between a carboxylate anion and
a divalent metal cation to glycerol, propylene glycol, glycerol
formal, water, or any combination thereof.
[0192] Without wishing to be bound by theory, it is believed that
the improved solubility of the fluoroquinolone is due to the
formation in the pharmaceutical composition of a complex of formula
M.sup.+2(GLY)(FQ), M.sup.+2(PG)(FQ), and or M.sup.+2(GF)(FQ),
wherein FQ is the fluoroquinolone or an anion of fluoroquinolone,
M.sup.+2 is a divalent metal cation, GLY is glycerol or an anion of
glycerol, PG is propylene glycol or an anion of propylene glycol,
and GF is glycerol formal or an anion of glycerol formal. Indeed,
analysis of the pharmaceutical compositions of the invention using
mass spectral analysis indicates the presence of a complex
containing: (i) 1 equivalent of fluoroquinolone; (ii) 1 equivalent
of the divalent metal cation, and (iii) 1 equivalent of the organic
solvent. Without wishing to be bound by theory, it is believed that
the formation of this complex is what leads to the improved
solubility of the fluoroquinolone in the liquid.
[0193] Accordingly, the invention further relates to a
pharmaceutical composition comprising a complex of formula
M.sup.+2(GLY)(FQ), M.sup.+2(PG)(FQ), and or M.sup.+2 (GF)(FQ),
wherein FQ is the fluoroquinolone or an anion of fluoroquinolone,
M.sup.+2 is a divalent metal cation, GLY is glycerol or an anion of
glycerol, PG is propylene glycol or an anion of propylene glycol,
and GF is glycerol formal or an anion of glycerol formal. As
discussed above, the complex can be detected by mass spectral
analysis of the pharmaceutical composition. In one embodiment, the
pharmaceutical composition is a solution. In one embodiment, the
pharmaceutical composition is injectable.
[0194] Without wishing to be bound by theory, it is believed that
the following reactions take place when a fluoroquinolone and a
salt formed between a carboxylate anion and a divalent metal cation
are combined in a liquid comprising an organic solvent selected
from glycerol, propylene glycol, glycerol formal, and mixtures
thereof. ##STR3## wherein FQ is the fluoroquinolone or an anion of
the fluoroquinolone, M(RCOO.sup.-).sub.2 is the salt formed between
a carboxylate anion and a divalent metal cation, and OS is the
organic solvent, i.e., glycerol, propylene glycol, or glycerol
formal. Without wishing to be bound by theory it is believed that
the complex M(FQ)(OS) is soluble in the liquid and leads to the
increased solubility of the fluoroquinolone.
[0195] In contrast, in the absence of the organic solvent, the
complex M(FQ)(OS) cannot form. Rather, what is believed to occur is
the following reaction to form M(FQ).sub.2: ##STR4## wherein FQ is
the fluoroquinolone or an anion of the fluoroquinolone and
M(RCOO.sup.-).sub.2 is the salt formed between a carboxylate anion
and a divalent metal cation. The complex M(FQ).sub.2, however, is
much less soluble than the complex M(FQ)(OS).
[0196] In one embodiment, the pharmaceutical composition further
comprises a cyclodextrin. The cyclodextrin can be any cyclodextrin
known to those skilled in the art. For example, the cyclodextrin
can be a .alpha.-cyclodextrin, .beta.-cyclodextrin, or
.gamma.-cyclodextrin. The cyclodextrin can also be a chemically
modified cyclodextrin, for example, a cyclodextrin wherein some or
all of the hydroxyl groups of the cyclodextrin are chemically
modified to replace some or all of the hydroxylprotons with methyl,
hydroxypropyl, carboxymethyl, or acetyl groups (for example, the
hydroxypropyl .beta.-cyclodextrin TrappsolHPB.RTM., the randomly
methylated .beta.-cyclodextrin TrappsolRMB.RTM., or the 2,6
di-O-methyl .beta.-cyclodextrin TrappsolDMB.RTM., each commercially
available from CTD, Inc. of High Springs, Fla.).
[0197] Typically, the cyclodextrin is present in an amount ranging
from about 0.05 to 5 molar equivalents per equivalent of the
fluoroquinolone. In one embodiment, the cyclodextrin is present in
an amount ranging from about 0.1 equivalent to 5 equivalents per
equivalent of the fluoroquinolone. In one embodiment, the
cyclodextrin is present in an amount ranging from about 0.1
equivalent to 2.5 equivalents per equivalent of the
fluoroquinolone. In one embodiment, the cyclodextrin is present in
an amount ranging from about 0.1 equivalent to 2 equivalents per
equivalent of the fluoroquinolone. In one embodiment, the
cyclodextrin is present in an amount ranging from about 0.1
equivalent to 1 equivalents per equivalent of the
fluoroquinolone.
[0198] Without wishing to be bound by theory, it is believed that
the presence of the cyclodextrin in the pharmaceutical composition
further stabilizes the M(FQ)(OS) complex, possibly by forming an
inclusion complex, and/or by shifting the equilibrium to the
described M(FQ)(OS) complex. Indeed, when the mass spectrum of a
pharmaceutical composition of the invention containing a
cyclodextrin is compared to the mass spectrum of a similar
pharmaceutical composition, but without the cyclodextrin, the mass
spectrum shows a significantly larger amount of the M(FQ)(OS)
complex relative to the M(FQ).sub.2 complex in the composition
containing the cyclodextrin.
[0199] The pharmaceutical compositions of the invention have
similar or improved bioavailability compared to commercially
available fluoroquinolone compositions, as illustrated in the
Examples. The pharmaceutical composition of the invention show
similar or improved bioavailability even though salts of
fluoroquinolones, particularly salts of fluoroquinolone with a
divalent metal cation, are typically significantly less
bioavailable compared to fluoroquinolone in the acid form, i.e.,
fluoroquinolone that is not a salt. (See, for example, S. Lecomte
et al., Effect of Magnesium Complexation by Fluoroquinolones on
Their Antibacterial Properties, Antimicrobial Agents and
Chemotherapy, 38:12, 2810-2816, December 1994; Hyoung-Ryun Park, et
al., Ionization and Divalent Cation Complexation of Quinolone
Antibiotics in Aqueous Solution, Bull. Korean Chem. Soc. 2000,
21:9, 849-854; B. Macias, et al., Complexes of Co(II) and Zn(II)
with Oflaxacin, Crystal Structure of
[Co(oflo).sub.2(MeOH).sub.2].4H.sub.2O, J. Pharm. Sci., 91:11,
2416-2423, November 2000; V. Loganathan et al., In-vitro and
In-vivo Drug-Drug Interaction Between Ciprofloxacin and Antacids,
The Eastern Pharmacist, June 1966, 119-121; A. Okhamafe et al.,
Pharmacokinetic Interactions of Norfloxacin with Some Metallic
Medicinal Agents, International Journal of Pharmaceutics, 68,
(1991), 11-18; B. Lomaestro et al., Quinolone-Antibiotic
Interactions: A Review, DICP, The Annals of Pharmacotherapy, 25,
November 1991, 1249-1258; S. Primozic et al., Transport Kinetics of
Zinc-Ciprofloxacin Complex Across the Model Lipid Membrane, Farm
Vestn, 1999, 50, 294-295; M. Zupancic et al., Synthesis and
Characterization of Two Novel Zinc (II) Complexes With
Ciprofloxacin. Crystal Structure of
[C.sub.17H.sub.19N.sub.3O.sub.3F].sub.2.ZnCl.sub.4.2H.sub.2O,
Croatia Chemica Acta, 74(1), 61-74, 2001; and F. Kozjec et al.,
Pharmacokinetics of Ciprofloxacin Metal Complexes, Acta. Pharm.,
46, 109-114, 1996).
[0200] In one embodiment, the divalent metal cation is Zn.sup.+2,
and the carboxylate anion is an optionally substituted C.sub.1 to
C.sub.6 saturated or unsaturated, straight chain or branched alkyl
group. In another embodiment, the carboxylate anion is an
unsubstituted C.sub.1 to C.sub.6 saturated or unsaturated, straight
chain or branched alkyl group. In another embodiment, the
carboxylate anion is an unsubstituted C.sub.1 to C.sub.6 saturated
straight chain or branched alkyl group. In another embodiment, the
carboxylate anion is an unsubstituted C.sub.1 to C.sub.6 saturated
straight chain alkyl group. In another embodiment, the carboxylate
anion is acetate anion.
[0201] In one embodiment, the divalent metal cation is Mg.sup.+2,
and the carboxylate anion acid is an optionally substituted C.sub.1
to C.sub.6 saturated or unsaturated, straight chain or branched
alkyl group. In another embodiment, the carboxylate anion is an
unsubstituted C.sub.1 to C.sub.6 saturated or unsaturated, straight
chain or branched alkyl group. In another embodiment, the
carboxylate anion is an unsubstituted C.sub.1 to C.sub.6 saturated
straight chain or branched alkyl group. In another embodiment, the
carboxylate anion is an unsubstituted C.sub.1 to C.sub.6 saturated
straight chain alkyl group. In another embodiment, the carboxylate
anion is acetate anion.
[0202] In one embodiment, the divalent metal cation is Zn.sup.+2,
the fluoroquinolone anion is ciprofloxacin anion, and the
carboxylate anion is acetate.
[0203] In one embodiment, the divalent metal cation is Zn.sup.+2,
the fluoroquinolone anion is enrofloxacin anion, and the
carboxylate anion is acetate.
[0204] In one embodiment, the divalent metal cation is Zn.sup.+2,
the fluoroquinolone anion is gatifloxacin anion, and the
carboxylate anion is acetate.
[0205] In one embodiment, the divalent metal cation is Zn.sup.+2,
the fluoroquinolone anion is gemifloxacin anion, and the
carboxylate anion is acetate.
[0206] In one embodiment, the divalent metal cation is Zn.sup.+2,
the fluoroquinolone anion is levofloxacin anion, and the
carboxylate anion is acetate.
[0207] In one embodiment, the divalent metal cation is Zn.sup.+2,
the fluoroquinolone anion is lomefloxacin anion, and the
carboxylate anion is acetate.
[0208] In one embodiment, the divalent metal cation is Zn.sup.+2,
the fluoroquinolone anion is moxifloxacin anion, and the
carboxylate anion is acetate.
[0209] In one embodiment, the divalent metal cation is Zn.sup.+2,
the fluoroquinolone anion is sparfloxacin anion, and the
carboxylate anion is acetate.
[0210] In one embodiment, the divalent metal cation is Zn.sup.+2,
the fluoroquinolone anion is trovafloxacin anion, and the
carboxylate anion is acetate.
[0211] In one embodiment, the divalent metal cation is Zn.sup.+2,
the fluoroquinolone anion is cinofloxacin anion, and the
carboxylate anion is acetate.
[0212] In one embodiment, the divalent metal cation is Zn.sup.+2,
the fluoroquinolone anion is pefloxacin anion, and the carboxylate
anion is acetate.
[0213] In one embodiment, the divalent metal cation is Zn.sup.+2,
the fluoroquinolone anion is tosufloxacin anion, and the
carboxylate anion is acetate.
[0214] In one embodiment, the divalent metal cation is Zn.sup.+2,
the fluoroquinolone anion is temafloxacin anion, and the
carboxylate anion is acetate.
[0215] In one embodiment, the divalent metal cation is Zn.sup.+2,
the fluoroquinolone anion is fleroxacin anion, and the carboxylate
anion is acetate.
[0216] In one embodiment, the divalent metal cation is Zn.sup.+2,
the fluoroquinolone anion is amifloxacin anion, and the carboxylate
anion is acetate.
[0217] In one embodiment, the divalent metal cation is Zn.sup.+2,
the fluoroquinolone anion is binfloxacin anion, and the carboxylate
anion is acetate.
[0218] In one embodiment, the divalent metal cation is Zn.sup.+2,
the fluoroquinolone anion is danofloxacin anion, and the
carboxylate anion is acetate.
[0219] In one embodiment, the divalent metal cation is Zn.sup.+2,
the fluoroquinolone anion is marbofloxacin anion, and the
carboxylate anion is acetate.
[0220] In one embodiment, the divalent metal cation is Zn.sup.+2,
the fluoroquinolone anion is sarafloxacin anion, and the
carboxylate anion is acetate.
[0221] In one embodiment, the divalent metal cation is Mg.sup.+2,
the fluoroquinolone anion is ciprofloxacin anion, and the
carboxylate anion is acetate.
[0222] In one embodiment, the divalent metal cation is Mg.sup.+2,
the fluoroquinolone anion is enrofloxacin anion, and the
carboxylate anion is acetate.
[0223] In one embodiment, the divalent metal cation is Mg.sup.+2,
the fluoroquinolone anion is gatifloxacin anion, and the
carboxylate anion is acetate.
[0224] In one embodiment, the divalent metal cation is Mg.sup.+2,
the fluoroquinolone anion is gemifloxacin anion, and the
carboxylate anion is acetate.
[0225] In one embodiment, the divalent metal cation is Mg.sup.+2,
the fluoroquinolone anion is levofloxacin anion, and the
carboxylate anion is acetate.
[0226] In one embodiment, the divalent metal cation is Mg.sup.+2,
the fluoroquinolone anion is lomefloxacin anion, and the
carboxylate anion is acetate.
[0227] In one embodiment, the divalent metal cation is Mg.sup.+2,
the fluoroquinolone anion is moxifloxacin anion, and the
carboxylate anion is acetate.
[0228] In one embodiment, the divalent metal cation is Mg.sup.+2,
the fluoroquinolone anion is sparfloxacin anion, and the
carboxylate anion is acetate.
[0229] In one embodiment, the divalent metal cation is Mg.sup.+2,
the fluoroquinolone anion is trovafloxacin anion, and the
carboxylate anion is acetate.
[0230] In one embodiment, the divalent metal cation is Mg.sup.+2,
the fluoroquinolone anion is cinofloxacin anion, and the
carboxylate anion is acetate.
[0231] In one embodiment, the divalent metal cation is Mg.sup.+2,
the fluoroquinolone anion is pefloxacin anion, and the carboxylate
anion is acetate.
[0232] In one embodiment, the divalent metal cation is Mg.sup.+2,
the fluoroquinolone anion is tosufloxacin anion, and the
carboxylate anion is acetate.
[0233] In one embodiment, the divalent metal cation is Mg.sup.+2,
the fluoroquinolone anion is temafloxacin anion, and the
carboxylate anion is acetate.
[0234] In one embodiment, the divalent metal cation is Mg.sup.+2,
the fluoroquinolone anion is fleroxacin anion, and the carboxylate
anion is acetate.
[0235] In one embodiment, the divalent metal cation is Mg.sup.+2,
the fluoroquinolone anion is amifloxacin anion, and the carboxylate
anion is acetate.
[0236] In one embodiment, the divalent metal cation is Mg.sup.+2,
the fluoroquinolone anion is binfloxacin anion, and the carboxylate
anion is acetate.
[0237] In one embodiment, the divalent metal cation is Mg.sup.+2,
the fluoroquinolone anion is danofloxacin anion, and the
carboxylate anion is acetate.
[0238] In one embodiment, the divalent metal cation is Mg.sup.+2,
the fluoroquinolone anion is marbofloxacin anion, and the
carboxylate anion is acetate.
[0239] In one embodiment, the divalent metal cation is Mg.sup.+2,
the fluoroquinolone anion is sarafloxacin anion, and the
carboxylate anion is acetate.
[0240] In one embodiment, the pharmaceutical composition comprises
a fluoroquinolone; zinc acetate; and a liquid comprising about 75
percent glycerol, propylene glycol, glycerol formal, or a mixture
thereof by volume of the liquid and about 25 percent water by
volume of the liquid, and the ratio of fluoroquinolone to zinc
acetate is about 2 to 1.
[0241] In one embodiment, the pharmaceutical composition comprises
a fluoroquinolone; zinc acetate; and a liquid comprising about 80
percent glycerol, propylene glycol, glycerol formal, or a mixture
thereof by volume of the liquid and about 20 percent water by
volume of the liquid, and the ratio of fluoroquinolone to zinc
acetate is about 2 to 1.
[0242] In one embodiment, the pharmaceutical composition comprises
a fluoroquinolone; magnesium acetate; and a liquid comprising about
75 percent glycerol, propylene glycol, glycerol formal, or a
mixture thereof by volume of the liquid and about 25 percent water
by volume of the liquid, and the ratio of fluoroquinolone to
magnesium acetate is about 2 to 1.
[0243] In one embodiment, the pharmaceutical composition comprises
a fluoroquinolone; magnesium acetate; and a liquid comprising about
80 percent glycerol, propylene glycol, glycerol formal, or a
mixture thereof by volume of the liquid and about percent volume by
weight of the liquid, and the ratio of fluoroquinolone to magnesium
acetate is about 2 to 1.
[0244] In one embodiment, the pharmaceutical composition comprises
a fluoroquinolone; zinc acetate; and a liquid comprising about 75
percent glycerol, propylene glycol, glycerol formal, or a mixture
thereof by volume of the liquid and about percent water by volume
of the liquid, and the ratio of fluoroquinolone to zinc acetate is
about 1 to 1.
[0245] In one embodiment, the pharmaceutical composition comprises
a fluoroquinolone; zinc acetate; and a liquid comprising about 80
percent glycerol, propylene glycol, glycerol formal, or a mixture
thereof by volume of the liquid and about percent water by volume
of the liquid, and the ratio of fluoroquinolone to zinc acetate is
about 1 to 1.
[0246] In one embodiment, the pharmaceutical composition comprises
a fluoroquinolone; magnesium acetate; and a liquid comprising about
75 percent glycerol, propylene glycol, glycerol formal, or a
mixture thereof by volume of the liquid and about percent water by
volume of the liquid, and the ratio of fluoroquinolone to magnesium
acetate is about 1 to 1.
[0247] In one embodiment, the pharmaceutical composition comprises
a fluoroquinolone, zinc acetate, and a liquid comprising about 75
percent glycerol by volume of the liquid and about 25 percent water
by volume of the liquid, and the ratio of fluoroquinolone to zinc
acetate is about 2 to 1.
[0248] In one embodiment, the pharmaceutical composition comprises
a fluoroquinolone, zinc acetate, and a liquid comprising about 80
percent glycerol by volume of the liquid and about 20 percent water
by volume of the liquid, and the ratio of fluoroquinolone to zinc
acetate is about 2 to 1.
[0249] In one embodiment, the pharmaceutical composition comprises
a fluoroquinolone, magnesium acetate, and a liquid comprising about
75 percent glycerol by volume of the liquid and about 25 percent
water by volume of the liquid, and the ratio of fluoroquinolone to
magnesium acetate is about 2 to 1.
[0250] In one embodiment, the pharmaceutical composition comprises
a fluoroquinolone, magnesium acetate, and a liquid comprising about
80 percent glycerol by volume of the liquid and about 20 percent
volume by weight of the liquid, and the ratio of fluoroquinolone to
magnesium acetate is about 2 to 1.
[0251] In one embodiment, the pharmaceutical composition comprises
a fluoroquinolone, zinc acetate, and a liquid comprising about 75
percent glycerol by volume of the liquid and about 25 percent water
by volume of the liquid, and the ratio of fluoroquinolone to zinc
acetate is about 1 to 1.
[0252] In one embodiment, the pharmaceutical composition comprises
a fluoroquinolone, zinc acetate, and a liquid comprising about 80
percent glycerol by volume of the liquid and about 20 percent water
by volume of the liquid, and the ratio of fluoroquinolone to zinc
acetate is about 1 to 1.
[0253] In one embodiment, the pharmaceutical composition comprises
a fluoroquinolone, magnesium acetate, and a liquid comprising about
75 percent glycerol by volume of the liquid and about 25 percent
water by volume of the liquid, and the ratio of fluoroquinolone to
magnesium acetate is about 1 to 1.
[0254] In one embodiment, the pharmaceutical composition comprises
a fluoroquinolone, magnesium acetate, and a liquid comprising about
80 percent glycerol by volume of the liquid and about 20 percent
volume by weight of the liquid, and the ratio of fluoroquinolone to
magnesium acetate is about 1 to 1.
Methods of Treatment
[0255] Due to their activity, the pharmaceutical compositions
comprising (i) a fluoroquinolone, (ii) a salt formed between a
carboxylate anion and a divalent metal cation, and (iii) a liquid
comprising (a) an organic solvent selected from the group
consisting of glycerol, propylene glycol, glycerol formal, and
mixtures thereof and (b) optionally water are advantageously useful
in veterinary and human medicine. The pharmaceutical compositions
are particularly useful for treating or preventing a bacterial
infection or a nephrotic syndrome in an animal in need thereof.
[0256] Accordingly, the invention further relates to methods of
treating or preventing a condition in an animal comprising
administering to an animal in need thereof an effective amount of a
pharmaceutical composition of the invention.
[0257] In one embodiment, the invention relates to methods of
treating a condition in an animal comprising administering to an
animal in need thereof an effective amount of a pharmaceutical
composition of the invention.
[0258] In one embodiment, the invention relates to methods of
preventing a condition in an animal comprising administering to an
animal in need thereof an effective amount of a pharmaceutical
composition of the invention.
[0259] In one embodiment, the animal is a mammal.
[0260] In one embodiment, the animal is a canine, a feline, an
equine, a bovine, an ovine, or a porcine.
[0261] In one embodiment the animal is a human.
[0262] In one embodiment, the animal is a non-human animal.
[0263] In one embodiment, the animal is a dog.
[0264] In one embodiment, the animal is a cat.
[0265] In one embodiment, the animal is a cow.
[0266] In one embodiment, the animal is a pig.
[0267] In one embodiment, the animal is a horse.
[0268] In one embodiment, the animal is a sheep.
[0269] In one embodiment, the animal is a monkey.
[0270] In one embodiment, the animal is a baboon.
[0271] In one embodiment, the animal is a rat.
[0272] In one embodiment, the animal is a mouse.
[0273] In one embodiment, the animal is a guinea pig.
[0274] In one embodiment, the condition is a bacterial
infection.
[0275] In one embodiment, the condition is a bacterial infection
caused by Staphylococcus aureus, Streptococcus pneumoniae,
coagulese-negative staphylococci, Streptococcus pyogenes,
Staphylococcus epidermis, Pseudomonas aeruginosa, Escherichia coli,
Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis,
Proteus vulgaris, Providencia stuartii, Morganella morganii,
Citrobacter diversus, Citrobacter freundii, Haemophilus influenzae,
or Neisseria gonorrhea.
[0276] In one embodiment, the condition is a respiratory tract
infection, a urinary tract infection, a postoperative-wound
infection, a bone or joint infection, a skin infection, an ear
infection, or a sexually transmitted disease.
[0277] In one embodiment, the condition is a nephrotic
syndrome.
[0278] The effective amount administered to the animal depends on a
variety of factors including, but not limited to the type of animal
being treated, the condition being treated, the severity of the
condition, the specific fluoroquinolone being administered and the
susceptibility of the infecting organism to the fluoroquinolone
being administered. The amount of the pharmaceutical composition
that is effective in the treatment or prevention of a condition,
such as a bacterial infection, can be determined by standard
clinical techniques. In addition, in vitro or in vivo assays can
optionally be employed to help identify optimal dosage ranges. One
of ordinary skill in the art will readily be able determine the
precise dose to be employed. Suitable effective dosage amounts,
however, typically range from about 0.1 mg/kg of body weight to
about 50 mg/kg of body weight, preferably about 0.5 mg/kg of body
weight to about 25 mg/kg of body weight, more preferably 0.75 mg/kg
of body weight to about 20 mg/kg of body weight, and most
preferably 1 mg/kg of body weight to about 15 mg/kg of body weight.
The effective dosage amounts described herein refer to total
amounts administered, that is, if more than one fluoroquinolone is
administered, the effective dosage amounts correspond to the total
amount administered.
[0279] For example when the fluoroquinolone is ciprofloxacin the
divalent metal cation is Zn.sup.+2, and the carboxylate anion is
acetate, the condition is a bacterial infection, and the animal is
a dog, an effective amount is typically between about 2.5 and 10 mg
of ciprofloxacinab (between about 5 and 30 mg of ciprofloxacin/kg)
administered orally once a day or two times per day until 2-3 days
after cessation of the condition. When the fluoroquinolone is
ciprofloxacin the divalent metal cation is Zn.sup.+2, and the
carboxylate anion is acetate, the condition is a bacterial
infection, and the animal is a cat, an effective amount is
typically not more than 5 mg of fluoroquinolone/kg administered
orally once a day until 2-3 days after cessation of the
condition.
[0280] In one embodiment, the pharmaceutical compositions are
administered parenterally.
[0281] In one embodiment, the pharmaceutical compositions are
administered subcutaneously.
[0282] In one embodiment, the pharmaceutical compositions are
administered intravenously.
[0283] In one embodiment, the pharmaceutical compositions are
administered orally.
[0284] In one embodiment, the effective amount of the
pharmaceutical composition is administered once per day until 2-3
days after cessation of the condition.
[0285] In one embodiment, the effective amount of the
pharmaceutical composition is administered as two doses per day
until 2-3 days after cessation of the condition.
[0286] In one embodiment, effective amount of the pharmaceutical
composition is administered once per day for 7 days.
[0287] In one embodiment, the effective amount of the
pharmaceutical composition is administered as two doses per day for
7 days.
[0288] In one embodiment, the effective amount of the
pharmaceutical composition is administered once per day for 14
days.
[0289] In one embodiment, the effective amount of the
pharmaceutical composition is administered as two doses per day for
14 days.
[0290] In one embodiment, the effective amount of the
pharmaceutical composition is administered once per day for 21
days.
[0291] In one embodiment, the effective amount of the
pharmaceutical composition is administered as two doses per day for
21 days.
[0292] To treat some conditions, the pharmaceutical compositions of
the invention can be administered for even longer periods of time,
for example several months.
[0293] The following examples are set forth to assist in
understanding the invention and should not be construed as
specifically limiting the invention described and claimed herein.
Such variations of the invention, including the substitution of all
equivalents now known or later developed, which would be within the
purview of those skilled in the art, and changes in formulation or
minor changes in experimental design, are to be considered to fall
within the scope of the invention incorporated herein.
EXAMPLES
Example 1
Oral Liquid Enrofloxacin Composition--Zinc Cation and Strawberry
Flavored
[0294] 2.3 gr of enrofloxacin and 0.7024 gr of zinc acetate were
mixed well with 15 mL of de-ionized water in a 100 ml volumetric
flask. To the resulting composition was added 60 mL of glycerol
with mixing to provide a homogeneous solution. To this solution was
added 5 mL of strawberry flavor and the resulting solution mixed
well. The volume of the solution was made up to 100 mL with
glycerol and mixed well to provide a liquid oral enrofloxacin
formulation. The concentration of enrofloxacin in the formulation
is 23 mg/mL.
[0295] A pharmaceutical composition similar to that described above
can be prepared except that the flavoring is not included in the
composition and the pharmaceutical composition is sterile filtered
to provide an injectable pharmaceutical composition.
Example 2
Oral Liquid Enrofloxacin Composition--Magnesium Cation and
Strawberry Flavored
[0296] 575 mg of enrofloxacin and 114 mg of magnesium acetate (0.8
mL of 1 M aqueous solution, commercially available from
Sigma-Aldrich of Milwaukee, Wis.) were mixed well with 3.75 mL of
de-ionized water in a 25 mL volumetric flask. To the resulting
composition was added 15 mL of glycerol with mixing to provide a
homogeneous solution. To the resulting solution was added 1.25 mL
of strawberry flavor with mixing. The volume of the solution was
made up to 25 mL with glycerol and mixed well to provide a liquid
oral enrofloxacin formulation. The concentration of enrofloxacin in
the formulation is 23 mg/mL.
[0297] A pharmaceutical composition similar to that described above
can be prepared except that the flavoring is not included in the
composition and the pharmaceutical composition is sterile filtered
to provide an injectable pharmaceutical composition.
Example 3
Oral Liquid Enrofloxacin Composition--Magnesium Cation and Mint
Flavored
[0298] 575 mg of enrofloxacin and 114 mg of magnesium acetate (0.8
mL of 1 M aqueous solution, commercially available from
Sigma-Aldrich of Milwaukee, Wis.) were mixed well with 3.75 mL of
de-ionized water in a 25 ml volumetric flask. To the resulting
composition was added 15 mL of glycerol with mixing to provide a
homogeneous solution. To the resulting solution was added 1.25 mL
of mint oil with mixing. The volume of the solution was made up to
25 mL with glycerol and mixed well to provide a liquid oral
enrofloxacin formulation. The concentration of enrofloxacin in the
formulation is 23 mg/mL.
[0299] A pharmaceutical composition similar to that described above
can be prepared except that the flavoring is not included in the
composition and the pharmaceutical composition is sterile filtered
to provide an injectable pharmaceutical composition.
Example 4
Administration of Oral Liquid Enrofloxacin to Dogs
[0300] Three tablets (22.7 mg per tablet, total 68 mg) of
commercially available enrofloxacin (Baytril.RTM., commercially
available from Bayer Health Care of Shawnee Mission, Kans.) was
orally administered to each of two dogs. To each of another two
dogs was orally administered 3 mL of the liquid enrofloxacin
composition of Example 2. For each dog, the concentration of
enrofloxacin in serum was determined as a function of time over a
period of about 24 hours. Blood samples were obtained as a function
of time and frozen.
[0301] For analysis of the blood samples the following procedure
was followed:
[0302] 1) Thaw sample completely and mix well;
[0303] 2) Transfer 200 .mu.l of the sample into a microfuge
tube;
[0304] 3) Add 400 .mu.l of methanol and mix well;
[0305] 4) Centrifuge at 13,000 rpm, -9.degree. C. for 15
minutes;
[0306] 5) Transfer the supernatant to a 20 mL scintillation vial
and add 3,400 .mu.l of mobile phase A (described below);
[0307] 6) Mix well, filter using a Acrodisc 13 mm syringe filter
with 0.2 .mu.m membrane and analyze by HPLC using the following
conditions: [0308] Column: Waters X Bridge C-18 4.6 mm.times.50 mm
column equipped with a Gemini 4 mm.times.3 mm guard cartridge.
[0309] Injection Volume: 20 .mu.L [0310] Flow Rate: 2 mL/min.,
isochratic 85% mobile phase A 15% mobile phase B [0311] Mobile
Phase: [0312] Composition: [0313] A: 100 mM phosphate buffer--pH
2.1 [0314] B: Methanol [0315] Acquisition Wavelength: 274 nm [0316]
Fluorescence: [0317] Excitation: 297 nm [0318] Emission: 440 nm
[0319] Gain 1000 [0320] Attenuation: 4 [0321] Run time: 10 min.
[0322] At the end of each analysis, the column is washed with 90
percent aqueous methanol.
[0323] Mobile phase A can be prepared by the following
procedure:
[0324] 1. Weigh 13.8 g of sodium phosphate monobasic monohydrate
into a 1 liter beaker.
[0325] 2. Add 500 mL of de-ionized water with stirring.
[0326] 3. Adjust the pH to 2.11 with phosphoric acid.
[0327] 4. Transfer the resulting solution into a 1 liter volumetric
flask and fill with water to the mark and mix well.
[0328] The concentration of enrofloxacin was determined by
comparing the enrofloxacin peak area obtained from HPLC analysis of
the sample to a standard curve of peak area versus concentration of
enrofloxacin obtained by HPLC analysis of several samples of known
enrofloxacin concentration.
[0329] The standard curve was obtained by weighing 100 mg of
commercially available enrofloxacin into a 100 mL volumetric flask
and filling the flask to 100 mL with methanol to provide a 1 mg/mL
enrofloxacin stock solution. The 1 mg/mL enrofloxacin stock
solution was then diluted with methanol to provide various
standards by adding 5 mL of the 1 mg/mL enrofloxacin stock solution
to 500 mL of methanol to provide a 10 .mu.g/mL standard, adding
0.25 mL of the 1 mg/mL enrofloxacin stock solution to 100 mL of
methanol to provide a 0.025 .mu.g/mL standard, adding 0.5 mL of the
1 mg/mL enrofloxacin stock solution to 100 mL of methanol to
provide a 0.05 .mu.g/mL standard, adding 1 mL of the 1 mg/mL
enrofloxacin stock solution to 100 mL of methanol to provide a 0.1
.mu.g/mL standard, adding 3 mL of the 1 mg/mL enrofloxacin stock
solution to 100 mL of methanol to provide a 0.3 .mu.g/mL standard,
adding 7 mL of the 1 mg/mL enrofloxacin stock solution to 100 mL of
methanol to provide a 0.70 .mu.g/mL standard, adding 15 mL of the 1
mg/mL enrofloxacin stock solution to 100 mL of methanol to provide
a 1.5 .mu.g/mL standard.
[0330] 200 .mu.L of blank serum was then placed in each of four
microfuge tubes labeled standard for points 1, 2, 3, and 4. To the
tubes labeled standard for points 1, 2, 3, and 4 was then added 200
.mu.L of the 0.025 .mu.g/mL standard, 0.05 .mu.g/mL standard, 0.1
.mu.g/mL standard, 0.3 .mu.g/mL standard, respectively. 200 .mu.L
of methanol was then added to each of the tubes; the resulting
mixtures mixed with a vortex mixture for about 20 seconds; and then
centrifuged at 13,000 rpm at -9.degree. C. for 15 minutes. The
resulting supernatant of each sample was then transferred to
individual 20 mL scintillation vial and 1400 mL of mobile phase A
was added to each supernatant. Each resulting solution was then
mixed filtered using a Acrodisc 13 mm syringe filter with 0.2 .mu.m
membrane and analyze by HPLC using the HPLC method described above
to provide the standard curve.
[0331] FIG. 1 is a graphical representation of the concentration of
enrofloxacin in serum in .mu.g/mL as a function of time for each
dog. The symbol (.box-solid.) represents data points for
administration of the solid dosage form of commercially available
enrofloxacin (i.e., Baytril.RTM.) and the symbol (.diamond-solid.)
represents data points for administration of enrofloxacin as the
liquid pharmaceutical formulation of the invention. The data
demonstrates that the oral liquid formulation is bioavailable. FIG.
1 shows that each dosage form has a similar C.sub.max but that the
pharmaceutical composition of the invention was 10 percent more
bioavailable, as measured by area under the curve.
Example 5
Administration of Oral Liquid Enrofloxacin to Cats
[0332] A single tablet (22.7 mg) of commercially available
enrofloxacin (Baytril.RTM., commercially available from Bayer
Health Care of Shawnee Mission, Kans.) was orally administered to
each of two cats. 1 mL of the liquid enrofloxacin composition of
Example 1 was orally administered to each of two cats. For each
cat, the concentration of enrofloxacin in serum was determined as a
function of time over a period of about 24 hours using the method
described above in Example 4.
[0333] FIG. 2 is a graphical representation of the concentration of
enrofloxacin in serum as a function of time. Each data point
represents the serum concentration of enrofloxacin in .mu.g/mL.
(Each data point represents the average of the serum concentration
for two cats. The symbol (.box-solid.) represents data points for
administration of the solid dosage form of commercially available
enrofloxacin (i.e., Baytril.RTM.) and the symbol (.tangle-solidup.)
represents data points for administration of enrofloxacin as liquid
pharmaceutical formulation of Example 1. The data demonstrates that
the oral liquid formulation is bioavailable.
Example 6
Administration of Oral Liquid Enrofloxacin to Cats
[0334] A single tablet (22.7 mg) of commercially available
enrofloxacin (Baytril, commercially available from Bayer Health
Care of Shawnee Mission, Kans.) was orally administered to each of
three cats. To each of three cats was orally administered 1 mL of
the liquid enrofloxacin composition of Example 1. To each of three
cats was orally administered 1 mL of the liquid enrofloxacin
composition of Example 2 and to another three cats was orally
administered 1 mL of the liquid enrofloxacin composition of Example
3. For each group of cats, the concentration of enrofloxacin in
serum was determined as a function of time over a period of about
24 hours using the method described above in Example 4.
[0335] FIG. 3 is a graphical representation of the concentration of
enrofloxacin in serum as a function of time. Each data point
represents the serum concentration of enrofloxacin in .mu.g/mL.
Each data point represents the average of the serum concentration
for the three cats. The symbol (.diamond-solid.) represents data
points for administration of the solid dosage form of commercially
available enrofloxacin (i.e., Baytril). The symbol
(.sup..box-solid.) represents data points for administration of
enrofloxacin as liquid pharmaceutical formulation of Example 1. The
symbol (.tangle-solidup.) represents data points for administration
of enrofloxacin as liquid pharmaceutical formulation of Example 2.
The symbol (.box-solid.) represents data points for administration
of enrofloxacin as liquid pharmaceutical formulation of Example 3.
The data demonstrates that the oral liquid formulation is
bioavailable.
Example 7
Mass Spectral Analysis of the Pharmaceutical Composition
[0336] A: A pharmaceutical composition was prepared by suspending
1.15 g of enrofloxacin and 702.4 mg of zinc acetate in 10 mL of
water and mixing the suspension well. The resulting mixture was
then filled to a volume of 50 mL with glycerol and mixed to provide
a homogeneous solution. The pharmaceutical composition can be
sterile filtered to provide an injectable formulation.
[0337] B: A second pharmaceutical composition was prepare by
suspending 575 mg of enrofloxacin and 354.7 mg of zinc acetate in 5
mL of water and mixing the suspension well. To the resulting
composition was added 238 mg of .beta.-cyclodextrin (commercially
available from Sigma-Aldrich of Milwaukee, Wis.) and the resulting
mixture mixed well with a vortex mixer. The flask was then filled
to a volume of 25 mL with glycerol and mixed to provide a
homogeneous solution. The pharmaceutical composition can be sterile
filtered to provide an injectable formulation.
[0338] Pharmaceutical compositions A and B are identical except
that pharmaceutical composition B also includes
.beta.-cyclodextrin.
[0339] Each of the above solutions was analyzed by mass
spectroscopy using an Applied Biosystem QTRAP LC/MS/MS system,
serial number m2170311. The following procedure was followed to
obtain the mass spectrum:
[0340] 1 drop of the pharmaceutical composition is added to a clean
scintillation vial;
[0341] 20 mL of methanol is added to the scintillation vial and the
contents of the vial are mixed using a vortex mixer;
[0342] a portion of the contents of the vial are drawn into a 1 mL
Hamilton gas tight syringe and the contents of syringe are infused
into the mass spectrometer using a Harvard syringe pump at a flow
rate of 10 .mu.L/min.; and
[0343] the mass spectrum is obtained.
[0344] The mass spectral data was analyzed using Analyst version
1.4 software and the mass spectrometer was operated using the
following parameters:
[0345] Ion source: Turbo spray
[0346] Curtain gas (CUR): 40
[0347] Ion spray voltage (IS): 5500
[0348] Temperature (TEM): 0.0
[0349] Ion source gas 1 (GS1): 20
[0350] Ion source gas 2 (GS2) 0
[0351] Declustering potential (DP): 45
[0352] Entrance potential (EP): 10
[0353] Quad 1 Ion energy 1 (IE1): 0.8
[0354] Q1 resolution is sent to unit
[0355] Deflector (DF): -150.0
[0356] CEM: 2800
[0357] The mass spectrum of pharmaceutical composition A and B are
shown in FIG. 4 and FIG. 5, respectively. A comparison of the mass
spectrum of pharmaceutical composition A (FIG. 4) and
pharmaceutical composition B (FIG. 5) shows that the ratio of the
Zn(enrofloxacin)(glycerol) complex to the Zn(enrofloxacin).sub.2
complex is significantly larger in pharmaceutical composition B,
which contains .beta.-cyclodextrin.
Example 8
Mass Spectral Analysis of the Pharmaceutical Composition
[0358] A pharmaceutical composition was prepared by combining 575
mg of enrofloxacin and 230 mg of magnesium acetate (1.62 mL of a 1M
solution in water, commercially available from Sigma-Aldrich of
Milwaukee, Wis.) in 8.38 ml of water to provide a suspension and
mixing the suspension well to provide a clear solution. To the
resulting solution was added 238 mg of .beta.-cyclodextrin
(commercially available from Sigma-Aldrich of Milwaukee, Wis.) and
the resulting mixture mixed well with a vortex mixer to provide a
clear solution. The clear solution was filled to a volume of 25 mL
with glycerol to provide a homogeneous solution. The pharmaceutical
composition can be sterile filtered to provide an injectable
formulation.
[0359] The pharmaceutical composition was analyzed by mass
spectroscopy using the analysis conditions described in Example 7.
The mass spectrum is provided in FIG. 6. The mass spectrum shows
the presence of the Mg(enrofloxacin)(glycerol) complex.
Example 9
Liquid Pharmaceutical Composition with Enrofloxacin and Zinc
Acetate
[0360] A pharmaceutical composition was prepared by suspending 575
mg of enrofloxacin and 354.7 mg of zinc acetate in 5 mL of
de-ionized water in a 25 mL volumetric flask and the resulting
suspension mixed well. 10 mL of propylene glycol was then added to
the resulting suspension with mixing to provide a homogeneous clear
solution. To the resulting solution was then added 1.818 g of
.beta.-cyclodextrin (commercially available from Sigma-Aldrich of
Milwaukee, Wis.) and the volume of the solution made up to 25 mL
with glycerol. The resulting composition was then mixed and
intermittently placed in a sonic bath until the cyclodextrin
dissolved to provide a clear solution. The concentration of
enrofloxacin in the resulting pharmaceutical composition is 23
mg/mL.
Example 10
Liquid Pharmaceutical Composition with Ciprofloxacin and Zinc
Acetate
[0361] A pharmaceutical composition was prepared by suspending 526
mg of ciprofloxacin and 3.551 mg of zinc acetate in 10 mL of
de-ionized water in a 50 mL volumetric flask. The resulting
suspension was mixed well, the volume of the flask filled to 50 mL
with glycerol, and the resulting composition mixed well to provide
a clear solution. The resulting pharmaceutical composition has a
ciprofloxacin concentration of 10.5 mg/mL (10.5 percent by
weight).
Example 11
Liquid Pharmaceutical Composition with Ofloxacin and Zinc
Acetate
[0362] A pharmaceutical composition was prepared by suspending
1.156 g of ofloxacin and 710.2 mg of zinc acetate in 10 mL of
de-ionized water in a 50 mL volumetric flask. The resulting
suspension was mixed well, the volume of the flask filled to 50 mL
with glycerol, and the resulting composition mixed well to provide
a clear solution. The resulting pharmaceutical composition has an
ofloxacin concentration of greater than 2 percent by weight. In
contrast, it was not possible to obtain a solution having an
ofloxacin concentration of even 1 percent by weight when ofloxacin
was added to water, ethanol, methanol, glycerol formal, propylene
glycol, or N-methylpyrrolidone.
Example 12
Liquid Pharmaceutical Composition with Ofloxacin and Magnesium
Acetate and Cyclodextrin
[0363] A pharmaceutical composition was prepared by combining 1.156
g of ofloxacin, 1.765 mL of de-ionized water, 3.235 mL of 1M
aqueous magnesium acetate solution (commercially available from
Sigma-Aldrich of Milwaukee, Wis.) in a 50 mL volumetric flask and
adding 20 mL of propylene glycol to the resulting mixture. The
resulting mixture was then mixed well using a vortex mixer, 3.6 g
of .beta.-cyclodextrin (commercially available from Sigma-Aldrich
of Milwaukee, Wis.) added, and the resulting mixture mixed well
using a vortex mixer. The volumetric flask was then filled to a
volume of about 40 mL with glycerol and sonicated to provide a
clear solution. The volume of the volumetric flask was then filled
to a volume of 50 mL and the resulting solution mixed well to
provide the pharmaceutical composition. The concentration of
ofloxacin in the pharmaceutical composition is 23 mg/mL.
Example 13
Liquid Pharmaceutical Composition with Enrofloxacin and Magnesium
Acetate
[0364] 2.3 gr of enrofloxacin, 6.47 mL of 1M aqueous magnesium
acetate solution (commercially available from Sigma-Aldrich of
Milwaukee, Wis.), and 8.53 mL of de-ionized water were combined in
a 100 mL volumetric flask and the resulting composition mixed well
using a vortex mixer. The volumetric flask was then filled to a
volume of about 75 mL with glycerol and the resulting mixture
sonicated to provide a clear solution. To the resulting solution
was added 5 mL of aqueous strawberry flavor, the solution mixed
well, the volumetric flask filled to a volume of 100 mL with
glycerol, and the resulting solution mixed well to provide the
pharmaceutical composition. The concentration of enrofloxacin in
the pharmaceutical composition is 23 mg/mL.
Example 14
Administration of Oral Liquid Enrofloxacin to Cats
[0365] A single tablet (22.7 mg) of commercially available
enrofloxacin (Baytril.RTM., commercially available from Bayer
Health Care of Shawnee Mission, Kans.) was orally administered to
each of three cats. 1 mL of the liquid enrofloxacin composition of
Example 13 was orally administered to each of three cats. For each
cat, the concentration of enrofloxacin in serum was determined as a
function of time over a period of about 24 hours using the method
described above in Example 4.
[0366] FIG. 7 is a graphical representation of the concentration of
enrofloxacin in serum as a function of time. Each data point
represents the serum concentration of enrofloxacin in .mu.g/mL.
Each data point represents the average of the serum concentration
for the three cats. The symbol (.diamond-solid.) represents data
points for administration of the solid dosage form of commercially
available enrofloxacin (i.e., Baytril.RTM.) and the symbol
(.box-solid.) represents data points for administration of
enrofloxacin as liquid pharmaceutical formulation of Example 13.
The data demonstrates that the oral liquid formulation is
bioavailable and that the bioavailability, as measured by area
under the curve, is similar to, and in fact slightly better than,
the bioavailability of Baytril.RTM.. The results demonstrate that
the enrofloxacin when administered as the oral liquid
pharmaceutical compositions of the invention have similar or
improved bioavailability compared to Baytril.RTM. (i.e.
fluoroquinolone in the acid form) even though salts of
fluoroquinolones, particularly salts of fluoroquinolone with a
divalent metal cation, are typically significantly less
bioavailable compared to fluoroquinolone in the acid form. Without
wishing to be bound by theory, it is believed that the improved
bioavailability is due the formation of the complex
Mg.sup.+2(enrofloxacin)(GLY).
Example 15
Liquid Pharmaceutical Composition with Enrofloxacin, Magnesium
Acetate, and Cyclodextrin
[0367] 1.15 gr of enrofloxacin, 1.765 mL of de-ionized water, and
3.235 mL of 1 M aqueous magnesium acetate solution (commercially
available from Sigma-Aldrich of Milwaukee, Wis.) were combined in a
50 mL amber volumetric flask and the resulting composition mixed
well using a vortex mixer. 20 mL of propylene glycol was then added
to the volumetric flask and the resulting composition mixed well
using a vortex mixer, with occasional sonication, to provide a
clear solution. To the resulting clear solution was then added 3.6
g of .beta.-cyclodextrin (commercially available from Sigma-Aldrich
of Milwaukee, Wis.) and the solution mixed well using a vortex
mixer. About 15 mL of glycerol was added to the volumetric flask
and the resulting solution mixed well using a vortex mixer. The
volumetric flask was then filled to a volume of 50 mL with glycerol
and the solution mixed to provide the pharmaceutical composition.
The concentration of enrofloxacin in the pharmaceutical composition
is 23 mg/mL.
Example 16
Administration of Oral Liquid Enrofloxacin to Cats
[0368] A single tablet (22.7 mg) of commercially available
enrofloxacin (Baytril.RTM., commercially available from Bayer
Health Care of Shawnee Mission, Kans.) was orally administered to
each of three cats. 1 mL of the liquid enrofloxacin composition of
Example 15 was orally administered to each of three cats. For each
cat, the concentration of enrofloxacin in serum was determined as a
function of time over a period of about 24 hours using the method
described above in Example 4.
[0369] FIG. 8 is a graphical representation of the concentration of
enrofloxacin in serum as a function of time. Each data point
represents the serum concentration of enrofloxacin in .mu.g/mL.
Each data point represents the average of the serum concentration
for the three cats. The symbol (.diamond-solid.) represents data
points for administration of the solid dosage form of commercially
available enrofloxacin (i.e., Baytril.RTM.) and the symbol
(.box-solid.) represents data points for administration of
enrofloxacin as liquid pharmaceutical formulation of Example 15.
The data demonstrates that the oral liquid formulation is
bioavailable and that the bioavailability, as measured by area
under the curve, is better than the bioavailability of
Baytril.RTM.. The results demonstrate that the enrofloxacin in the
oral liquid pharmaceutical compositions of the invention can have
improved bioavailability compared to commercially available
Baytril.RTM. (i.e. fluoroquinolone in the acid form) even though
salts of fluoroquinolones, particularly salts of fluoroquinolone
with a divalent metal cation, are typically significantly less
bioavailable compared to fluoroquinolone in the acid form. Without
wishing to be bound by theory, it is believed that the improved
bioavailability is due the formation of the complex
Mg.sup.+2(enrofloxacin)(GLY) and/or Mg.sup.+2 (enrofloxacin)(PG).
Without wishing to be bound by theory, it is also believed that the
presence of the .beta.-cyclodextrin in the pharmaceutical
composition further stabilizes the Mg.sup.+2 (enrofloxacin)(GLY)
and/or Mg.sup.+2(enrofloxacin)(PG) complex, possibly by forming an
inclusion complex, and/or by shifting the equilibrium to the
complex.
Example 17
Stability of the Pharmaceutical Compositions
[0370] The pharmaceutical compositions of Examples 13 and 15 were
stored at 70.degree. C. (humidity not controlled) and analyzed
daily by the following procedure:
[0371] A standard containing 100 mg of enrofloxacin is prepared
by:
[0372] 1. Weigh 100 mg of enrofloxacin into a 100 mL volumetric
flask;
[0373] 2. Add 5 mL methanol and about 50 mL 100 mM phosphate buffer
pH 2.11 (prepared as described above for mobile phase A), mix well,
and sonicate for about 1 minute to dissolve solids;
[0374] 3. Fill the flask to 100 mL with 100 mM phosphate buffer pH
2.11 to provide Dilution 1;
[0375] 4. Transfer 25 mL of Dilution 1 into a 50 mL volumetric
flask, add 100 mM phosphate buffer pH 2.11 to a volume of 50 mL,
and mix well to provide Dilution 2;
[0376] 5. Filter a portion of Dilution 2 into an HPLC vial using an
Acrodisc 13 mm syringe filter with 0.2 .mu.m membrane;
[0377] 6. Repeat steps 1-5 two more times to obtain three
standards;
[0378] 7. Analyze each standard by HPLC using the following
conditions: [0379] Column: Waters X Bridge C-18 4.6 mm.times.50 mm
column equipped with a Gemini 4 mm.times.3 mm guard cartridge.
[0380] Injection Volume: 10 .mu.L [0381] Flow Rate: 2 mL/min.,
isochratic 85% mobile phase A 15% mobile phase B [0382] Mobile
Phase: [0383] Composition: [0384] A: 100 mM phosphate buffer--pH
2.1 [0385] B: Methanol [0386] Acquisition Wavelength: 274 nm [0387]
Run time: 10 min.
[0388] At the end of each analysis, the column is washed with 90
percent aqueous methanol.
[0389] 8. Average the peak area obtained for each standard to
provide an averaged peak area for the standard.
[0390] The pharmaceutical compositions of Example 13 and 15 were
then analyzed by the following procedure to provide the amount of
enrofloxacin at time 0 in each pharmaceutical composition:
[0391] 1. Weigh 40-120 mg of the pharmaceutical composition into a
20 mL scintillation vial;
[0392] 2. Add 5 mL of 100 mM phosphate buffer pH 2.11 (prepared as
described above for mobile phase A) and shake well
[0393] 3. Filter a portion of this solution using an Acrodisc 13 mm
syringe filter with 0.2 .mu.m membrane into an HPLC vial to provide
a time 0 sample;
[0394] 4. Repeat steps 1-3 twice to obtain a total of three time 0
samples;
[0395] 5. Analyze each time 0 sample by HPLC using the conditions
described above;
[0396] 6. Average the peak areas for each of the time zero samples
to provide an averaged peak area for the time 0 sample;
[0397] 7. Compare the averaged peak area for the time 0 sample to
the averaged peak area for the standard averaged standards to
obtain the actual amount of enrofloxacin in the pharmaceutical
composition.
[0398] At various time points, t, a sample of the pharmaceutical
composition of Example 13 or 15 stored at 70.degree. C. was removed
and analyzed following the procedure used to determine the amount
of enrofloxacin as time 0 except that a single sample, rather than
3 samples, is analyzed. The peak area obtained by HPLC analysis for
the time t sample is then compared to the averaged peak area for
the time 0 sample to determine the percent of enrofloxacin in the
time t sample relative to the time 0 sample.
[0399] The table provided below provides the percent enrofloxacin
compared to time 0 as a function of time for the pharmaceutical
compositions of Example 13 and Example 15 after storage at
70.degree. C. TABLE-US-00001 Percent enrofloxacin Time (days)
Example 13 Example 15 1 99.3 98.6 2 99.4 99.3 3 99.9 100.0 4 99.8
99.8 5 100.0 99.8 6 98.6 100.1 7 99.5 99.7 8 101.1 98.6 9 99.3 99.5
10 99.9 99.8
[0400] The results show that the pharmaceutical compositions of the
invention have excellent stability even though they include a
divalent metal cation. Typically, the pharmaceutical compositions
of the invention show less than a 5 percent decrease in the amount
of the fluoroquinolone after being stored at 70.degree. C. for 10
days. In one embodiment, the pharmaceutical compositions of the
invention show less than a 4 percent decrease in the amount of the
fluoroquinolone after being stored at 70.degree. C. for 10 days. In
one embodiment, the pharmaceutical compositions of the invention
show less than a 3 percent decrease in the amount of the
fluoroquinolone after being stored at 70.degree. C. for 10
days.
[0401] The present invention is not to be limited in scope by the
specific embodiments disclosed in the examples which are intended
as illustrations of a few aspects of the invention and any
embodiments that are functionally equivalent are within the scope
of this invention. Indeed, various modifications of the invention
in addition to those shown and described herein will become
apparent to those skilled in the art and are intended to fall
within the scope of the appended claims.
[0402] A number of references have been cited, the entire
disclosure of which are incorporated herein by reference.
* * * * *