U.S. patent application number 11/895374 was filed with the patent office on 2008-03-06 for stabilized difloxacin injectable solution.
This patent application is currently assigned to WYETH. Invention is credited to Henderik W. Frijlink.
Application Number | 20080058371 11/895374 |
Document ID | / |
Family ID | 27668974 |
Filed Date | 2008-03-06 |
United States Patent
Application |
20080058371 |
Kind Code |
A1 |
Frijlink; Henderik W. |
March 6, 2008 |
Stabilized difloxacin injectable solution
Abstract
An antibacterial formulation suitable for injection into animals
containing approximately 2-10% w/v difloxacin HCl, L-arginine base,
propylene glycol, ethanol and/or benzyl alcohol, and water. The
formulation is a solution having a pH of form 9 to 10. The
formulation produces little or no tissue damage or irritation at
the injection site.
Inventors: |
Frijlink; Henderik W.; (KM
Eelde, NL) |
Correspondence
Address: |
Anne M. Rosenblum, Esq
Suite 212
163 Delaware Avenue
Delmar
NY
12054
US
|
Assignee: |
WYETH
Madison
NJ
|
Family ID: |
27668974 |
Appl. No.: |
11/895374 |
Filed: |
August 24, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11071824 |
Mar 3, 2005 |
7273870 |
|
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11895374 |
Aug 24, 2007 |
|
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10346597 |
Jan 17, 2003 |
6872723 |
|
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11071824 |
Mar 3, 2005 |
|
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60352764 |
Jan 28, 2002 |
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Current U.S.
Class: |
514/312 |
Current CPC
Class: |
A61K 31/495 20130101;
A61K 47/10 20130101; A61K 47/183 20130101; A61P 31/04 20180101;
A61K 31/4709 20130101 |
Class at
Publication: |
514/312 |
International
Class: |
A61K 31/4709 20060101
A61K031/4709; A61P 31/04 20060101 A61P031/04 |
Claims
1-8. (canceled)
9. (canceled)
9. (canceled)
10-14. (canceled)
15: A method of treating a bacterial infection in an animal in need
thereof comprising the step of administering to the animal by
injection a therapeutically effective amount of a pharmaceutical
composition comprising about 2-10% w/v difloxacin HCl; 5-20% w/v
L-arginine base; about 5-15% w/v ethanol; up to about 10% w/v of an
anti-microbial preservative; propylene glycol, glycerol, a soluble
polyethylene glycol, or a combination thereof; and water, wherein
said composition has a pH in the approximate range of 9-10.
16: The method according to claim 15, wherein the composition
comprises about 4-6% w/v difloxacin HCl.
17: The method according to claim 16, wherein the composition
comprises approximately 20-40% propylene glycol and 5-15%
L-arginine base; and the anti-microbial preservative is selected
from the group consisting of benzyl alcohol, phenol, chlorocresol
and a mixture thereof.
18: The method according to claim 15, wherein the pH of the
composition is in the approximate range of 9.1-9.6.
19: The method according to claim 16, wherein the pH of the
composition is in the approximate range of 9.1-9.6.
20: The method according to claim 17, wherein the pH of the
composition is in the approximate range of 9.1-9.6.
21: The method according to claim 17, wherein the preservative of
the composition is benzyl alcohol.
22: The method according to claim 15, wherein the composition
further comprises potassium hydroxide.
23: The method according to claim 22, wherein the preservative of
the composition is benzyl alcohol and the pH of the composition is
in the approximate range of 9.1-9.6.
24: A method of treating a bacterial infection in an animal in need
thereof comprising the step of administering to the animal by
injection a therapeutically effective amount of a pharmaceutical
composition comprising about 5% w/v difloxacin HCl; 10% w/v
L-arginine base; about 10% w/v ethanol; about 5% w/v benzyl
alcohol; about 30% w/v propylene glycol; and water, wherein said
composition has a pH in the approximate range of 9.1-9.6.
Description
[0001] This application claims priority from copending provisional
application Ser. No. 60/352,764, filed on Jan. 28, 2002, the entire
disclosure of which is hereby incorporated by reference. This
invention relates to the field of formulations for the antibiotic
compound difloxacin, especially formulations suitable to be
injected into animals.
FIELD OF THE INVENTION
Background of the Invention
[0002] Difloxacin, also known as
6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-7-(4-methyl-1-piperadinyl)
4-oxo-3-quinolinecarboxylic acid, is an antibiotic compound useful
against a wide range of bacteria in animals. However, it is not
highly soluble in water, which makes difloxacin difficult to
formulate for administration by injection. Difloxacin is soluble in
some high pH formulations, but high pH formulations tend to damage
or irritate the tissue at the injection site.
[0003] U.S. Pat. No. 4,772,605 teaches alkaline aqueous
formulations for quinolinecarboxylic acids which contain arginine
and a base, and may contain an alcohol and/or other ingredients.
Formulations containing difloxacin are not disclosed in this
patent.
[0004] U.S. Pat. No. 5,756,506 teaches the administration of a
single high dose of a fluoroquinolone composition, especially an
enrofloxacin composition, for treating bacterial infections in
animals.
[0005] Japanese patent application no. 232024 (1993), published as
no. JP 07082141, discloses an injectable aqueous formulation
containing difloxacin, a base, and propylene glycol, and optionally
benzyl alcohol. This formulation allegedly reduces tissue damage at
the injection site.
SUMMARY OF THE INVENTION
[0006] The present invention is a formulation suitable for
injection into animals comprising approximately 2-10% w/v
difloxacin HCl, L-arginine base, propylene glycol, ethanol and/or
benzyl alcohol, and water. The present invention also comprises a
method for making such a formulation.
[0007] It is an object of the present invention to provide a
difloxacin formulation which is suitable for injection into animals
and which will not significantly damage the tissue at the injection
site.
[0008] Other objects and advantages of the present invention will
be apparent to those skilled in the art from the disclosure below
and the appended claims.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0009] A preferred embodiment of the present invention is a
formulation comprising approximately: 4-6% difloxacin HCl; 20-40%
propylene glycol; 5-15% L-arginine base; 5-15% ethanol; 0-10%
benzyl alcohol; and water. These percentages are on a weight/volume
(w/v) basis, i.e., g/ml. The measured pH is preferably in the
approximate range of 9-10, and more preferably in the approximate
range of 9.1-9.6.
[0010] A highly preferred embodiment of the present invention
comprises approximately: 5% (w/v) difloxacin HCl; 30% (w/v)
propylene glycol; 10% (w/v) L-arginine base; 10% (w/v) ethanol; 5%
(w/v) benzyl alcohol; and water.
[0011] The pH of the formulation may be adjusted to achieve the
desired level of alkalinity by addition of an acid or base. Any
suitable acid or base may be used. Bases such as potassium
hydroxide, and acids such as HCl, have been found to be highly
suitable for this purpose. Those skilled in the art will have no
difficulty identifying suitable bases or acids.
[0012] The desired pH level may be achieved not only with
L-arginine base, but alternatively with either glycine in
combination with KOH, or with diethanolamine. The use of L-arginine
is preferred I the practice of this invention.
[0013] Although propylene glycol is most preferred, it may be
partly or wholly replaced by similar compounds, such as glycerol
and soluble polyethylene glycols, e.g., polyethylene glycol 400,
and the like.
[0014] Benzyl alcohol may act as both a co-solvent and an
antimicrobial preservative in the formulation of this invention.
The benzyl alcohol may be partly or wholly replaced by one or more
other preservatives known in the art, such as chlorocresol and
phenol. However, benzyl alcohol is preferred.
[0015] Preferably, the formulation of this invention is made by
adding the difloxacin HCl and arginine to water at room
temperature, mixing until a uniform suspension is achieved, and
then mixing in the ethanol, benzyl alcohol and propylene glycol
until the solids dissolve. The exact temperature is not critical,
as long as it is not too cold to hinder dissolution of the solids
or hot enough to adversely affect the components of the formulation
or cause significant evaporation of the ethanol. A temperature of
approximately 10-30.degree. C. is suitable for formulating the
composition of this invention; a temperature of about 15-25.degree.
C. is preferred, and 18-25.degree. C. is more preferred. The pH may
be adjusted, if necessary, for example with HCl or KOH, to achieve
the desired level of alkalinity.
[0016] The arginine acts as a buffer and helps to achieve a
suitable pH at which the difloxacin will fully dissolve. In a
preferred embodiment of the invention, approximately 5-20% w/v
L-arginine is used; 5-15% is more preferred, and 10% is most
preferred. The glycol and alcohols are used to facilitate the
solubility of the difloxacin so that a higher pH is not needed. The
more moderate pH may prevent or reduce tissue damage and discomfort
at the injection site.
[0017] Formulations having a difloxacin concentration significantly
higher than about 5-6% may provide decreased bioavailability of
difloxacin after administration by injection. Formulations
containing greater than about 10% difloxacin may be made, but such
formulations may require a disadvantageously high pH level and may
have less desirable pharmacokinetics than formulations of this
invention.
[0018] Although the use of difloxacin HCl is described herein,
other forms of difloxacin may be used. If, for example, the base
difloxacin is used instead of difloxacin HCl, less argenine and/or
other base is needed to achieve the desired pH. Those skilled in
the art will easily be able to determine how much base is needed to
achieve a pH within the range set forth herein for this invention,
regardless of the form of the difloxacin. Those skilled in the art
will also recognize that other salts of difloxacin are
pharmaceutically suitable substitutes for the hydrochloride salt,
and will be able to identify and use such salts in this invention
without undue experimentation. The desired pH range can be
achieved, regardless of the form of difloxacin used, by using the
requisite amount of HCl or KOH to adjust pH.
[0019] The formulation of the present invention has the advantage
that it may be formulated without the need for heating to dissolve
the solid ingredients. In fact, heating may be detrimental to
dissolution of the difloxacin, since it may cause evaporation of a
significant amount of the ethanol.
[0020] The formulation of this invention is stable when stored
under normal conditions used in the art. The storage temperature
may be lower than 10.degree. C., e.g., 5.degree. C. or less, as
long as a precipitate does not form. Those skilled in the art will
have no difficulty determining suitable storage temperatures.
[0021] The present invention provides a formulation in which the
difloxacin is completely dissolved, which minimizes tissue damage
at the injection site, and which has the advantage of rapid and
essentially complete bioavailability of the active ingredient. The
production of the formulation of this invention is quite robust,
especially when ethanol is used as the solvent; it has been found
that if the pH rises temporarily above 11.0 during production,
ethanol prevents insoluble precipitates from forming.
[0022] The pH of the solution of this invention is believed to be
very important in providing a formulation that: (a) minimizes
damage or irritation to the tissue at the injection site; (b)
dissolves the difloxacin; and, (c) produces a relatively high blood
plasma level of difloxacin in the first two hours after
administration by injection.
[0023] The various advantages of this invention are achieved using
a combination of ingredients which facilitate dissolution of the
difloxacin at a relatively moderate level of alkalinity, and which
cause minimal irritation at the injection site. Surprisingly,
although the formulation of this invention contains high levels of
several ingredients that are known to be irritating to tissue, the
combination of ingredients in the present invention result in an
unexpectedly low level of irritation.
[0024] The following examples are presented to illustrate certain
embodiments of the present invention, but should not be construed
as limiting the scope of this invention.
Example 1
[0025] The following ingredients are used to create a difloxacin
solution for injection: TABLE-US-00001 % (m/v) difloxacin HCl 5.46
(=5.0% free base) propylene glycol 30.0 benzyl alcohol 5.0 ethanol
10.0 L-arginine base 10.0 water q.s. to 100%.
About 80% of the water for injection is charged to a vessel and
maintained at 18-25.degree. C. The arginine and difloxacin HCl are
added with mixing to form a uniform suspension, and the vessel is
purged with nitrogen gas. The ethanol, propylene glycol and benzyl
alcohol are added and the composition is mixed until the solids
dissolve. The rest of the water for injection is added with mixing
to reach the full volume. The solution is sterilized using
saturated steam at 121.degree. C. for 30 minutes. The pH of the
solution is 9.3. The solution is clear and no precipitate is
observed. The osmolarity (mOsmol/Kg, after a 10-fold dilution with
water for injection) is 723.
Example 2
[0026] Compositions having 2.5% and 6% difloxacin (w/v) are
prepared according to the procedure of Example 1, and the pH is
adjusted with either KOH or HCl, if necessary, to reach a pH of
9.9. In these solutions, the percentage of the ingredients other
than difloxacin and water are the same as in Example 1.
Example 3
[0027] The three difloxacin compositions prepared according to
Examples 1 and 2 are used in an experiment to study the
pharmacokinetics of these formulations when injected into sheep.
Twelve male lambs about 10 months old are divided into three groups
of four; a different formulation of Examples 1 and 2 is
administered to each group. The lambs are each injected with one of
the formulations at a dose of 2.5 mg/kg body weight, and blood
samples are taken at 1, 2, 4, 6, 10 and 24 hours after injection.
Mean plasma levels (.mu.g/ml) for these samples are provided in the
table below: TABLE-US-00002 Hours after injection: 1 2 4 6 10 24
2.5% difloxacin formulation 877 860 648 500 339 131 5% difloxacin
formulation 1097 1108 812 578 371 98 6% difloxacin formulation 617
705 658 547 381 142
These formulations do not produce significant tissue damage or
swelling at the injection site. The 5% difloxacin formulation
having a measured pH=9.3 produces a significantly higher level of
difloxacin in the blood in the first 1-4 hours after injection than
either the 2.5% or 6% formulations having a measured pH of 9.9.
Example 4
[0028] A formulation is prepared according to Example 1, except
that the difloxacin content is doubled to form a 10% w/v solution,
and the final pH is 9.9.
Examples 5 & 6
[0029] Two 5% w/v difloxacin formulations are prepared according to
Example 1, except that the final pH is 9.1 and 9.6, respectively.
The pH is adjusted using KOH or HCl to obtain the desired pH
value.
Comparative Example
[0030] A 5% difloxacin formulation is made according to the
procedure in Example 1, with the exception that the ethanol is
omitted and the final pH is 9.9. This formulation is administered
to three male lambs in accordance with the procedure of Example 3,
with the following results: TABLE-US-00003 Hours after injection: 1
2 4 6 10 24 Mean blood plasma 783 955 824 650 438 117. level
(.mu.g/ml)
The blood plasma level in the first two hours is less than that
produced by administering the formulation of Example 1. These
results indicate that the use of ethanol and a lower pH according
to the present invention provides a superior formulation compared
to the formulation of this Comparative Example having the same
difloxacin content.
[0031] Many variations of the present invention not illustrated
herein will occur to those skilled in the art. The present
invention is not limited to the embodiments illustrate and
described herein, but encompasses all the subject matter within the
scope of the appended claims and equivalents thereof.
* * * * *