U.S. patent application number 13/873391 was filed with the patent office on 2013-09-12 for stabilizing compositions for antibiotics and methods of use.
This patent application is currently assigned to TARO PHARMACEUTICALS NORTH AMERICA, INC.. The applicant listed for this patent is TARO PHARMACEUTICALS NORTH AMERICA, INC.. Invention is credited to Satish Asotra, Shen Gao, Daniel A. Moros.
Application Number | 20130237512 13/873391 |
Document ID | / |
Family ID | 39230807 |
Filed Date | 2013-09-12 |
United States Patent
Application |
20130237512 |
Kind Code |
A1 |
Gao; Shen ; et al. |
September 12, 2013 |
STABILIZING COMPOSITIONS FOR ANTIBIOTICS AND METHODS OF USE
Abstract
The present invention is directed to improved liquid antibiotic
formulations. In some embodiments, the present invention is
directed to a composition comprising an antibiotic in a liquid
comprising triglycerides, wherein the composition has less than
about 5% water (w/v).
Inventors: |
Gao; Shen; (Bolton, CA)
; Moros; Daniel A.; (Larchmont, NY) ; Asotra;
Satish; (Brampton, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
TARO PHARMACEUTICALS NORTH AMERICA, INC. |
Grand Cayman |
|
KY |
|
|
Assignee: |
TARO PHARMACEUTICALS NORTH AMERICA,
INC.
Grand Cayman
KY
|
Family ID: |
39230807 |
Appl. No.: |
13/873391 |
Filed: |
April 30, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13299829 |
Nov 18, 2011 |
8461143 |
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13873391 |
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11902925 |
Sep 26, 2007 |
8106040 |
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13299829 |
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60847093 |
Sep 26, 2006 |
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Current U.S.
Class: |
514/192 ;
514/210.06 |
Current CPC
Class: |
A61P 43/00 20180101;
A61K 31/424 20130101; A61K 9/0095 20130101; A61K 31/43 20130101;
A61K 45/06 20130101; A61K 2300/00 20130101; A61K 31/43 20130101;
A61P 31/00 20180101; A61K 2300/00 20130101; A61K 31/424 20130101;
A61P 31/04 20180101 |
Class at
Publication: |
514/192 ;
514/210.06 |
International
Class: |
A61K 31/43 20060101
A61K031/43; A61K 31/424 20060101 A61K031/424 |
Claims
1-25. (canceled)
26. A liquid pharmaceutical composition comprising a
.beta.-lactamase inhibitor; one or more of dried silicon dioxide,
dried colloidal silicon dioxide and dried magnesium trisilicate;
and a low moisture content medium chain triglyceride vehicle,
wherein the composition is a liquid, the concentration of medium
chain triglycerides ranges from about 50% to about 99% (w/v) of the
composition, and the composition contains less than about 1.0%
(w/v) water.
27. The composition of claim 26, wherein the composition is a
suspension.
28. The composition of claim 26, wherein the one or more of silicon
dioxide, colloidal silicon dioxide and magnesium trisilicate are
dried prior to inclusion in the pharmaceutical composition.
29. The composition of claim 26, wherein the medium chain
triglycerides contain less than about 0.1% (w/w) water.
30. The composition of claim 26, wherein the composition is
suitable for oral delivery.
31. The composition of claim 26, wherein the .beta.-lactamase
inhibitor is selected from the group consisting of clavulanic acid,
sulbactam, tazobactam, and mixtures thereof.
32. The composition of claim 26, wherein the .beta.-lactamase
inhibitor is clavulanic acid.
33. The composition of claim 26, wherein the .beta.-lactamase
inhibitor is stable for at least about ten days when stored at a
temperature of about 20.degree. C. to about 25.degree. C.
34. A liquid pharmaceutical composition, comprising a
.beta.-lactamase inhibitor, one or more dried hygroscopic
excipients and a low moisture content medium chain triglyceride
vehicle, wherein the composition is a liquid and the composition
contains less than about 1.0% (w/v) water.
35. The composition of claim 34, wherein the composition is a
suspension.
36. The composition of claim 34, wherein the .beta.-lactamase
inhibitor is selected from the group consisting of clavulanic acid,
sulbactam, tazobactam, and mixtures thereof.
37. The composition of claim 34, wherein the .beta.-lactamase
inhibitor is clavulanic acid.
38. The composition of claim 34, wherein the one or more
hygroscopic excipients comprise one or more of silicon dioxide,
colloidal silicon dioxide and magnesium trisilicate.
39. The composition of claim 34, wherein the hygroscopic excipients
are dried prior to inclusion in the pharmaceutical composition.
40. The composition of claim 34, wherein the medium chain
triglycerides contain less than about 0.1% (w/w) water.
41. The composition of claim 34, wherein the concentration of
medium chain triglycerides is from about 50% (w/v) to about 99%
(w/v).
42. The composition of claim 34, wherein the .beta.-lactamase
inhibitor is stable for at least about ten days when stored at a
temperature of about 20.degree. C. to about 25.degree. C.
43. The composition of claim 34, wherein the composition is
suitable for oral delivery.
44. A liquid pharmaceutical composition for oral delivery
consisting essentially of a .beta.-lactamase inhibitor, one or more
of silicon dioxide, colloidal silicon dioxide and magnesium
trisilicate, and a low moisture content medium chain triglyceride
vehicle, wherein the composition is a liquid, the concentration of
medium chain triglycerides ranges from about 50% to about 99% (w/v)
of the composition, and the composition contains less than about
1.0% (w/v) water.
Description
FIELD OF THE INVENTION
[0001] The present invention is directed to improved liquid
antibiotic formulations. In some embodiments, the present invention
is directed to a composition comprising an antibiotic in a liquid
comprising triglycerides, wherein the composition has less than
about 5% water (w/v).
BACKGROUND OF THE INVENTION
[0002] .beta.-Lactam antibiotics are commonly prescribed
antibiotics that are active against both gram-positive and
gram-negative organisms. See Goodman and Gilman's, The
Pharmacological Basis of Therapeutics, Ninth Ed., 1996 (Goodman and
Gilman's). Penicillins include penicillins G and V which are active
against gram-positive cocci, naficillin which is active against
penicillinase-producing Staphylococcus aureus and ampicillin which
has an improved gram-negative spectrum of activity. Unfortunately,
bacterial resistance to .beta.-lactam antibiotics is growing. A
major mechanism of resistance involves the production of
.beta.-lactamases by the bacteria. .beta.-lactamases cleave the
.beta.-lactam ring generating penicilloic acid, which is not
bacteriocidal.
[0003] .beta.-lactamases can be inhibited by molecules which bind
to the .beta.-lactamases, acting as competitive substrates for the
enzymes. One such molecule, clavulanic acid, binds irreversibly to
the .beta.-lactamases, irreversibly inhibiting the enzyme.
Clinically, the addition of .beta.-lactamase inhibitors to
penicillins is very important because it extends the spectrum of
bacteriocidal activity. For example, the combination of amoxicillin
and clavulanic acid is effective against the
.beta.-lactamase-producing strains of staphylococci, H. influenza,
gonococci and E. coli. The addition of clavulanic acid to
ticarcillin extends its bacteriocidal activity to include aerobic
gram-negative bacilli, Staphylococcus aureus as well as Bacteroides
species. Other .beta.-lactamases inhibitors include, sulbactam and
tazobactam.
[0004] Unfortunately, .beta.-lactamase inhibitors such as
clavulanic acid are unstable in aqueous media. U.S. Pat. No.
6,177,421. Clavulanic acid is susceptible to hydrolytic
degradation. There exists a narrow range of pH and temperature
where the molecule is most stable. Wildfeuer et al.
Arzneimittelforschung 41(1):70-73 (1991).
[0005] Given the growth of antibiotic resistant bacteria and the
importance of penicillins as a first-line therapy, there exists a
continuing need to develop formulations containing .beta.-lactamase
inhibitors that are stable.
SUMMARY OF THE INVENTION
[0006] The present invention is directed to a composition
comprising an antibiotic in a liquid comprising triglycerides,
wherein the composition has less than about 5% water (w/v). In some
embodiments, the antibiotic is selected from the group consisting
of a penicillin, a cephalosporin, a carbapenem, and mixtures
thereof. In some embodiments, the antibiotic is a penicillin
selected from the group consisting of penicillin G, penicillin V,
methicillin, nafcillin, oxacillin, cloxacillin, dicloacllin,
ampicillin, amoxicillin, carbenicillin, ticarcillin, piperacillin,
meziocillin, aziocillin, and mixtures thereof.
[0007] The triglycerides can be selected from the group consisting
of short chain triglycerides, medium chain triglycerides, and long
chain triglycerides. In some embodiments, the triglycerides are
medium chain triglycerides.
[0008] In some embodiments, the triglycerides can be about 5% (w/v)
to about 99% (w/v), about 25% (w/v) to about 99% (w/v), about 50%
(w/v) to about 99% (w/v), about 75% (w/v) to about 99% (w/v), about
85% (w/v) to about 99% (w/v), or about 95% (w/v) to about 99% (w/v)
of the composition.
[0009] In some embodiments, the composition has less than about 1%
water (w/v), in another embodiment there is less than about 0.5%
water (w/v), and in a third embodiment there is less than about
0.1% water (w/v). The composition can also be a dry triglyceride
liquid formulation in some embodiments.
[0010] The composition of the present invention can further
comprise a .beta.-lactamase inhibitor, for example, clavulanic
acid. In some embodiments, the compositions of the present
invention comprise clavulanic acid, amoxicillin, and medium chain
triglycerides.
[0011] The present invention is further directed to a composition
comprising a penicillin and a .beta.-lactamase inhibitor in a
liquid comprising medium chain triglycerides, wherein the
concentration of triglycerides ranges from about 5% (w/v) to about
95% (w/v), and wherein the composition has less than about 5% water
(w/v). In some embodiments, the penicillin is amoxicillin and the
.beta.-lactamase inhibitor is clavulanic acid. In some embodiments,
the concentration of amoxicillin ranges from about 50 mg/5 ml to
about 800 mg/5 ml and clavulanic acid ranges from about 10 mg/5 ml
to about 80 mg/5 ml.
[0012] The present invention is also directed to a composition
comprising a penicillin and a .beta.-lactamase inhibitor, wherein
the penicillin and .beta.-lactamase inhibitor are in a liquid
comprising medium chain triglycerides, wherein the concentration of
triglycerides can be about 70% (w/v) to about 99% (w/v).
[0013] In some embodiments, the penicillin or antibiotic is stable
for at least about ten days when stored at a temperature of about
20.degree. C. to about 25.degree. C.
[0014] The present invention is also directed to kits comprising
any embodiment of the compositions of the present invention. For
example, the present invention is directed to a kit comprising a
composition comprising an antibiotic which can be mixed with a
liquid comprising triglycerides, wherein the composition has less
than about 5% water (w/v). In some embodiments, the kit comprises
(a) a first container comprising a therapeutically effective amount
of an antibiotic and (b) a second container comprising a
pharmaceutically acceptable carrier, excipient, diluent or
combination thereof. In some embodiments, at least one container
can be made of high density polyethylene.
[0015] The present invention is also directed to methods of using
the compositions of the present invention. For example, the present
invention is directed to a method of treating a microbial infection
in a mammal, the method comprising administering a composition
comprising an antibiotic in a liquid comprising triglycerides,
wherein the composition has less than about 5% water (w/v) to the
mammal in need thereof.
DESCRIPTION OF THE DRAWINGS
[0016] FIG. 1 (A, B, C, and D) illustrates exemplary embodiments of
the present invention.
DETAILED DESCRIPTION
[0017] The headings below are provided solely for organizational
purposes and are not intended to impart any division or meaning to
this document, unless specifically indicated.
Compositions
[0018] The present invention is directed to compositions comprising
an antibiotic compound in a liquid comprising triglycerides,
wherein the composition has less than about 5% water (w/v). In some
embodiments, the composition can further comprise a
.beta.-lactamase inhibitor. The antibiotic compound can be in
suspension or in solution in the liquid comprising
triglycerides.
[0019] The term "antibiotic" encompasses any pharmaceutically
acceptable compound that can inhibit the growth of or destroy
bacteria and/or other microbes, regardless of whether the compound
is produced in a microorganism or produced synthetically. This term
encompasses disinfectants, antiseptics, and any other antimicrobial
compounds. For example, the term "antibiotic" encompasses
penicillin and all its derivatives.
[0020] Suitable antibiotics for use in the present invention
include, but are not limited to, the .beta.-lactam class of
antibiotics which comprises penicillins, cephalosporins, and
carbapenems. .beta.-lactam antibiotics are useful as antimicrobial
agents. These compounds inhibit the synthesis of the bacterial
peptidoglycan cell wall and are active against both gram-positive
and gram-negative cell walls.
[0021] Penicillins can be generally classified based on their
spectrum of microbial activity. Penicillin G and penicillin V are
highly active against strains of gram-positive cocci. However,
these drugs are readily hydrolyzed by penicillinase making them
ineffective against most strains of Staphylococcus aureus. In some
embodiments, the antibiotic of the present invention is penicillin
G, penicillin V, or a mixture thereof.
[0022] Penicillinase-resistant penicillins tend to have less potent
antimicrobial activity against microbes sensitive to penicillin G
but these penicillins are active against Staphylococcus aureus.
Exemplary penicillinase-resistant penicillins include, but are not
limited to, methicillin, nafcillin, oxacillin, cloxacillin, and
dicloxacillin. In some embodiments, the antibiotic of the present
invention is methicillin, nafcillin, oxacillin, cloxacillin,
dicloxacillin, or a mixture thereof.
[0023] Another group of penicillins include those whose spectrum of
antimicrobial activity extends to include gram-negative organisms
such as Haemophilus influenza, E. coli, and Proteus mirabilis.
However, these drugs are hydrolyzed by .beta.-lactamases that are
found in increasing numbers of gram-negative bacteria. In some
embodiments, the antibiotic of the present invention is ampicillin,
amoxicillin, bacampicillin, or a mixture thereof.
[0024] Still other penicillins, such as, carbenicillin,
carbenicillin indanyl, and ticarcillin are classified together
because their spectrum of antimicrobial activity includes
Pseudomonas, Enterobacter, and Proteus species. Other
extended-spectrum penicillins include mezlocillin and piperacillin,
which have activity against Pseudomonas, Klebsiella, and other
gram-negative microbes. However, these drugs are also hydrolyzed by
.beta.-lactamases. In some embodiments, the antibiotic of the
present invention is carbenicillin, carbenicillin indanyl,
ticarcillin, mezlocillin, piperacillin, or a mixture thereof.
[0025] The present invention is also directed to using
cephalosporins. Cephalosporins can be categorized depending on
their generation, as described in Goodman and Gilman's. First
generation cephalosporins include cephalothin, cefazolin,
cephalexin, and cefadroxil. Second generation cephalosporins
include cefamandole, cefoxitin, cefaclor, cefuroxime, cefuroxime
axetil, loracarbef, cefonicid, cefotetan, and ceforamide. Third
generation cephalosporins include cefoxatime, cefopodoxime
proxetil, cefizoxime, cefoperazone, and ceftazidime. Finally, an
exemplary fourth generation cephalosporin is cefepime.
[0026] In some embodiments, the antibiotic of the present invention
is cephalothin, cefazolin, cephalexin, cefadroxil, cefamandole,
cefoxitin, cefaclor, cefuroxime, cefuroxime axetil, loracarbef,
cefonicid, cefotetan, ceforamide, cefoxatime, cefopodoxime
proxetil, cefizoxime, cefoperazone, ceftazidime, cefepime, or a
mixture thereof.
[0027] The present invention is further directed to using
.beta.-lactam antibiotics other than penicillins or cephalosporins.
These other .beta.-lactam antibiotics include those compounds that
have a .beta.-lactam structure but are not considered a penicillin
or cephalosporin. For example, the carbapenems which include
imipenem, meropenem, and aztreonam. In some embodiments, the
antibiotic of the present invention is imipenem, meropenem,
aztreonam, or a mixture thereof. As one of skill in the art will
appreciate, the above list of antibiotics is not exhaustive and
other antibiotics which are not mentioned are also encompassed
within the present invention.
[0028] In some embodiments, the compositions of the present
invention can comprise more than one antibiotic. For example, the
present invention is also directed to a composition comprising more
than one antibiotic in a liquid comprising triglycerides, wherein
the composition has less than about 5% water (w/v). In some
embodiments, the present invention comprises 2, 3, 4, or 5 or more
antibiotics in combination. The antibiotics used in the embodiments
of the present invention that comprise more than one antibiotic can
be selected from a group consisting of, but not limited to, a
penicillin, a cephalosporin, a carbapenem, or a mixture
thereof.
[0029] The embodiments of the present invention that include more
than one antibiotic can be useful for treating mammals with an
infection from more than one bacteria or other microbe. For
example, a physician may prescribe a penicillin such as
carbenicillin to treat an infection caused by Pseudomonas and a
second antibiotic to treat an infection caused by a different
microbe that carbenicillin cannot treat.
[0030] The above .beta.-lactam antibiotics are susceptible to
inactivation by .beta.-lactamase. The .beta.-lactamase enzyme opens
the .beta.-lactam ring in penicillin or other .beta.-lactam
antibiotics. This change produces penicillonic acid (from
penicillins) and eliminates the antibiotic properties of
penicillin. Similar attacks reduce the ability of other
.beta.-lactam antibiotics to treat microbe caused diseases. See
Despande et. al, Degradation of .beta.-lactam Antibiotics, Current
Science, 87:12 1684-1695 (2004).
[0031] This presents a problem for treating those bacteria and
other microbes that have the ability to produce .beta.-lactamase as
a defense mechanism. For example, if a physician administers a
.beta.-lactam antibiotic to treat microbes that produce
.beta.-lactamase, the therapeutic effect of the antibiotic with be
reduced or there will be no effect.
[0032] To overcome this problem, the antibiotic can be administered
in combination with a .beta.-lactamase inhibitor. A
".beta.-lactamase inhibitor" is a compound that can bind
.beta.-lactamase thereby preventing it from inactivating the
antibiotic. As one of skill in the art will appreciate, this term
encompasses all forms of the compound including, for example,
acids, bases, salts, and esters thereof, as well as polymorph
crystal forms. In some embodiments, a ".beta.-lactamase inhibitor"
refers to a pharmaceutically acceptable salts selected from, but
not limited to, alkali metal salts such as sodium or potassium,
alkaline earth salts or an ammonium salt (all of which are herein
referred to as a pharmaceutically acceptable salts).
[0033] In some embodiments, the compositions of the present
invention further comprise a .beta.-lactamase inhibitor. The
.beta.-lactamase inhibitor can be clavulanic acid, sulbactam,
tazobactam, or mixtures thereof, as well as the salts and esters of
these compounds. In some embodiments, the .beta.-lactamase
inhibitor is potassium clavulanate.
[0034] These .beta.-lactamase inhibitors are often prescribed in
association with amino- and ureidopenicillins for treating
gram-negative infections. See Naas et al., Integration of a
Transposon TnI-Encoded Inhibitor-Resistant .beta.-Lactamase Gene,
bla.sub.TEM-67 from Proteus mirabilis, into the Escherichia coli
Chromosome, Antimicrobial Agents and Chemotherapy, 47:1 p. 19-26,
(2003). For example, clavulanic acid has been combined with
amoxicillin to form an oral preparation (AUGMENTIN.RTM., available
from GlaxoSmithKline, Research Triangle Park, N.C.) and with
tiarcillin as a parenteral preparation (TIMENTIN.RTM., available
from GlaxoSmithKline, Research Triangle Park, N.C.).
[0035] These products suffer from poor stability because of the
water content of their formulations. This is a major problem for
clavulanic acid and its salts because they are extremely sensitive
to the presence of water and undergo rapid hydrolytic degradation,
both as a dry-powder and in a reconstituted state. In particular,
in aqueous solutions, clavulanic acid is unstable and beaks down
reducing the amount available to bind .beta.-lactamases.
[0036] For example, when amoxicillin and clavulanic acid are used
together, the mixture can be reconstituted in water before it is
administered to a patient. Even when stored at 4.degree. C., the
clavulanic acid degrades rapidly, reducing its effectiveness.
[0037] In some embodiments, the compositions of the present
invention comprise less than 90%, 80%, 70%, 60%, 50%, 40%, 30%,
20%, or 10% water (w/v). The present invention can also comprise
less than 5%, 4%, 3%, 2%, 1%, 0.1%, 0.01% (w/v) or be completely
free of water. These low water embodiments can be used with water
labile components, for example, clavulanic acid.
[0038] According to the present invention, surprisingly, the
addition of triglycerides to a liquid suspension containing an
antibiotic, e.g. a .beta.-lactam, and a .beta.-lactamase inhibitor,
e.g. clavulanic acid, prevents degradation of the clavulanic
acid.
[0039] Triglycerides (also known as triacylglycerol or
triacylglyceride) are glycerides in which the glycerol is
esterified with three fatty acids. Triglycerides are the main
constituent of vegetable oil and animal fats. The general chemical
structure of triglycerides is shown below:
##STR00001##
R', R'', and R''' are alkyl chains (C.sub.1-C.sub.n).
[0040] Chain lengths of the fatty acids in naturally occurring
triglycerides may range from 3 to 24 carbon atoms, but lengths of
16 and 18 carbon atoms are most common. Shorter chain lengths may
be found in some substances (butyric acid in butter). Most
naturally occurring fats contain a complex mixture of individual
triglycerides. Based on their chain length, triglycerides can be
divided into three categories: (i) short chain triglycerides (SCT);
(ii) medium chain triglycerides (MCT); and (iii) long chain
triglycerides (LCT).
[0041] Short chain triglycerides are triglycerides having short
chain fatty acids, e.g., C.sub.2-C.sub.6. For example, one short
chain triglyceride is glyceryl tributyrate.
[0042] Medium chain triglycerides have fatty acids ranging from
about C.sub.8 to about C.sub.10. Some exemplary commercially
available medium chain triglycerides are LABRAFAC.RTM. (available
from Gattefosse Pharma, Saint-Priest Cedex, France) CAPTEX.RTM.
(available from Parchem, White Plains, N.Y.), NESATOL.RTM.
(available from Kreglinger Europe, Antwerp, Belgium) WAGLINOL.RTM.
(available from Industrial Quimica Lasem, S. A., Barcelona, Spain),
BERGABEST.RTM. (available from Sternchemie, Hamburg, Germany),
MIGLYOL.RTM. (available from Universal Preserv-A-Chem, Inc.,
Edison, N.J.), NEOBEE.RTM. (available from Stepan Company,
Northfield, Ill.), and CRODAMOL.RTM. (available from Croda, Edison,
N.J.).
[0043] Triglycerides longer than a medium chain triglyceride, e.g.
C.sub.11 to C.sub.x are called long chain triglycerides. One
exemplary long chain triglyceride is castor oil.
[0044] The compositions of the present invention can comprise a
short chain, medium chain, or long chain triglyceride. In some
embodiments, the triglyceride is a medium chain triglyceride. In
some embodiments of the present invention, the use of a medium
chain triglyceride can increase the bioavailability of a drug. See
Ueda et al., Effect of Ethyl Cellulose in a Medium-Chain
Triglyceride on the Bioavailability of Ceftizoxime, J Pharm Sci.
72(4):454-8 (1983).
[0045] The present invention can also comprise a mixture of
triglycerides. In some embodiments, the mixture of triglycerides
comprises a mixture of a short chain and a medium chain, a short
chain and a long chain, or a medium chain and a long chain.
Further, the mixture of triglycerides can comprise more than one
short chain, more than one medium chain, or more than one long
chain.
[0046] The compositions of the present invention can comprise about
1% to about 99% triglycerides (w/v). In some embodiments, the
inactive components of the present invention comprise about 1% to
about 25%, about 25% to about 50%, about 50% to about 75%, or about
75% to about 100% triglycerides (w/v). In some embodiments, the
composition comprises about 99%, about 95%, about 90%, about 85%,
about 80%, about 75%, about 70%, about 65%, about 60%, about 55%,
about 50%, about 45%, about 40%, about 35%, about 30%, about 25%,
about 20%, about 15%, about 10%, or about 5% of triglycerides
(w/v). The term "about" refers to plus or minus 10% of the
indicated number. For example, "about 10%" indicates a range of 9%
to 11%.
[0047] In some embodiments, the triglycerides are selected from the
group consisting of, but not limited to, vegetable oils, fish oils,
animal fats, hydrogenated vegetable oils, partially hydrogenated
vegetable oils, synthetic triglycerides, modified triglycerides,
fractionated triglycerides, medium and long-chain triglycerides,
structured triglycerides, and mixtures thereof.
[0048] In some embodiments, the triglycerides can be almond oil;
babassu oil; borage oil; blackcurrant seed oil; canola oil; castor
oil; coconut oil; corn oil; cottonseed oil; evening primrose oil;
grapeseed oil; groundnut oil; mustard seed oil; olive oil; palm
oil; palm kernel oil; peanut oil; rapeseed oil; safflower oil;
sesame oil; shark liver oil; soybean oil; sunflower oil;
hydrogenated castor oil; hydrogenated coconut oil; hydrogenated
palm oil; hydrogenated soybean oil; hydrogenated vegetable oil;
hydrogenated cottonseed and castor oil; partially hydrogenated
soybean oil; partially soy and cottonseed oil; glyceryl
tricaproate; glyceryl tricaprylate; glyceryl tricaprate; glyceryl
triundecanoate; glyceryl trilaurate; glyceryl trioleate; glyceryl
trilinoleate; glyceryl trilinolenate; glyceryl
tricaprylate/caprate; glyceryl tricaprylate/caprate/laurate;
glyceryl tricaprylate/caprate/linoleate; and glyceryl
tricaprylate/caprate/stearate.
[0049] In addition to triglycerides, the compositions of the
present invention can further comprise stabilizing agents. A
"stabilizing agent" is a compound that can prevent or slow the
degradation of the antibiotic or .beta.-lactamase inhibitor while
in storage.
[0050] In some embodiments, the compositions of the present
invention are stable for at least about ten days when stored at a
temperature of about 20.degree. C. to about 25.degree. C. In some
embodiments, the compositions of the present invention are stable
for about ten days to about 31 days when stored at a temperature of
about 20.degree. C. to about 25.degree. C.
[0051] That is, the compositions of the present invention are
stable at a temperature of about 20.degree. C. to about 25.degree.
C. during a course of antibiotic treatment. In some embodiments,
the compositions of the present invention do not require
refrigeration during a course of antibiotic treatment. A course of
antibiotic treatment can be, but is not limited to, about 1, about
3, about 5, about 7, about 10 days, or about 31 days. Further a
course of antibiotic treatment can be as long as the antibiotics
are prescribed for use by a medical professional authorized to
prescribe antibiotics. This can length can be determined based on
the needs and characteristics of the individual patient. For
example, if the patient is immunosuppressed or immunocompromised
then the course of antibiotic treatment can be longer than a week,
a month, or a year, depending on the patient's condition.
[0052] The present invention can further comprise a
pharmaceutically acceptable excipient other than the triglycerides
previously mentioned. An "excipient" refers to a substance that is
used in the formulation of pharmaceutical compositions, and, by
itself, generally has little or no therapeutic value. Various
excipients can be used in the invention, including those described
in Remington: The Science and Practice of Pharmacy, 21.sup.st Ed.
(2006). Excipients include, but are not limited to, antioxidants,
anti-bacterial agents that prevent the decay of the formulation
itself as opposed to those exhibiting a therapeutic effect,
preservatives, chelating agents, buffering agents, agents for
adjusting toxicity, colorings, flavorings and diluting agents,
emulsifying and suspending agents, and other substances with
pharmaceutical applications.
[0053] The term "pharmaceutically acceptable" excipient refers to
those compounds, materials, compositions, and/or dosage forms which
are, within the scope of sound medical judgment, suitable for
contact with the tissues of human beings and animals without
excessive toxicity, irritation, allergic response, or other problem
complications commensurate with a reasonable benefit/risk ratio. In
some embodiments, the term "pharmaceutically acceptable" means
approved by a regulatory agency of the Federal or a state
government or listed in the U.S. Pharmacopoeia or other generally
recognized international pharmacopoeia for use in animals, and more
particularly in humans. In some embodiments, the excipients used in
the compositions of the present invention are pharmaceutically
acceptable.
[0054] In some embodiments, at least one of the excipients included
in the liquid formulation can be further dried to reduce its
moisture content. In some embodiments, the formulation uses dried
silicon dioxide, colloidal silicon dioxide, magnesium trisilicate,
or combinations of these excipients. The drying can be done using
any method known to one of skill in the art, for example, by
placing the excipient in a 105.degree. C. oven overnight.
[0055] The dried excipients can be combined with low moisture
content medium chain triglycerides (e.g., a moisture content of
about 0.0275% w/w). For example, dried silicon dioxide, dried
colloidal silicon dioxide and dried magnesium trisilicate and low
moisture medium chain triglyceride oil (e.g. 0.0275%, w/w) can be
used as part of a low moisture liquid formulation suitable for
delivering an active ingredient, such as an antibiotic.
[0056] Some embodiments of the present invention are directed to
dry or dehydrated triglyceride liquid formulations comprising an
antibiotic. The terms "dry triglyceride liquid formulations" or
"dehydrated triglyceride liquid formulations" both refer to
pharmaceutical formulations comprising a triglyceride that are
substantially free, and in some cases totally free, of water, and
can be considered to be dehydrated. These formulations can also be
considered anhydrous. Such formulations can be prepared using low
moisture content medium chain triglycerides and powdered excipients
with low moisture contents. The powdered excipients can be further
dried to reduce their moisture content. As is evident, the term
"dry" is used in relation to a liquid to mean that the liquid and
its contents have a low or a reduced water content. This use of the
term "dry" is not intended to mean the liquid is devoid of
fluid-like characteristics, e.g., it has become a powder.
[0057] The dry triglyceride liquid formulations of present
invention are particularly useful in preventing hydrolytic
degradation of clauvanic acid and/or potassium clauvanate when they
are in a reconstituted antibiotic formulation. While not wishing to
be bound to a single theory, the drying or desiccation of the
excipients is believed to maximize their hygroscopic behavior in
the reconstituted formulation. For example, silicon dioxide is very
hygroscopic and adsorbs large quantities of water up to 30% (w/w)
with a relative humidity of around 80% (w/w). This adsorbtive
ability is impaired if the silicon dioxide is exposed to humidity
or other water before it becomes part of the reconstituted
formulation. However, in its dried form, it is believed to adsorb
water from within the formulation, which reduces the hydrolytic
degradation of clauvanic acid and/or potassium clauvanate when they
are in a reconstituted antibiotic formulation.
Methods of Treating
[0058] The compositions of the present invention can be
administered to any mammal in need of the composition that can
experience the beneficial effects of the compounds of the
invention. Such mammals include humans and non-humans, such as pets
and farm animals. Accordingly, the present invention is directed to
methods of treating a microbial infection in a mammal, the method
comprising administering a composition comprising an antibiotic in
a liquid comprising triglycerides, wherein the composition has less
than about 5% water (w/v), to the mammal in need thereof.
[0059] Various patients can find utility in the present invention.
In some embodiments, the patient is a child. In some embodiments,
the patient is about 55 years of age or older. In some embodiments,
the patient has a bacterial infection. In some embodiments, the
patient has a condition that compromises their immune system, e.g.,
AIDS or advanced stage cancer.
[0060] The dosage of the antibiotic administered will be dependent
upon the age, health, and weight of the recipient, kind of
concurrent treatment, if any, the frequency of treatment, and the
nature of the effect desired. The compositions of the present
invention can contain a quantity of a compound(s) according to this
invention in an amount effective to treat the condition, disorder
or disease of the subject being treated. One of ordinary skill in
the art will appreciate that a method of administering
pharmaceutically effective amounts of the antibiotic to a patient
in need thereof can be determined empirically, or by standards
currently recognized in the medical arts. It will be understood
that, when administered to, for example, a human patient, the total
daily dosage of the agents of the compositions of the present
invention will be decided within the scope of sound medical
judgment by the attending physician.
[0061] The specific therapeutically effective dose level for any
particular patient will depend upon a variety of factors: the type
and degree of the cellular response to be achieved; activity of the
specific agent or composition employed; the specific agents or
composition employed; the age, body weight, general health, gender
and diet of the patient; the time of administration, route of
administration, and rate of excretion of the agent; the duration of
the treatment; drugs used in combination or coincidental with the
specific agent; and like factors well known in the medical arts.
For example, it is well within the skill of the art to start doses
of the agents at levels lower than those required to achieve the
desired therapeutic effect and to gradually increase the dosages
until the desired effect is achieved.
[0062] In some embodiments, the compositions of the present
invention can be administered in combination with another
therapeutic agent. Accordingly, the compositions of the present
invention can also include one or more additional therapeutic
agents such as, but not limited to, hydrophilic drugs, hydrophobic
drugs, hydrophilic macromolecules, cytokines, peptidomimetics,
peptides, proteins, toxoids, sera, antibodies, vaccines,
nucleosides, nucleotides, nucleoside analogs, genetic materials
and/or combinations thereof.
[0063] Additional examples of therapeutic agents that can be used
in the pharmaceutical compositions of the present invention
include, but are not limited to, other antineoplastic agents,
analgesics and anti-inflammatory agents, anti-anginal agents,
antihelmintics, anti-arrythmic agents, anti-arthritic agents,
anti-asthma agents, anti-viral agents, anti-coagulants,
anti-depressants, antidiabetic agents, anti-epileptic agents,
anti-emetics, anti-fungal agents, anti-gout agents,
anti-hypertensive agents, anti-malarial agents, antimigraine
agents, anti-muscarinic agents, anti-Parkinson's agents,
anti-protozoal agents, anti-thyroid agents, thyroid therapeutic
agents, anti-tussives, anxiolytic agents, hypnotic agents,
neuroleptic agents, beta-blockers, cardiac inotropic agents,
corticosteroids, diuretics, gastrointestinal agents, histamine
H.sub.2-receptors antagonists, immunosuppressants, keratolytics,
lipid regulating agents, muscle relaxants, nutritional agents,
cytokines, peptidomimetics, peptides, proteins, toxoids, sera,
sedatives, sex hormones, sex hormone antagonists or agonists,
stimulants antibodies, vaccines, nucleosides, nucleoside analogs
and genetic materials. Amphiphilic therapeutic agents and
nutritional agents can also be included.
[0064] The terms "treat" and "treatment" refer to both therapeutic
treatment and prophylactic or preventative measures, wherein the
object is to prevent or slow down (lessen) an undesired
physiological condition, disorder or disease, or obtain beneficial
or desired clinical results. For purposes of this invention,
beneficial or desired clinical results include, but are not limited
to, alleviation of symptoms; diminishment of extent of condition,
disorder or disease; stabilization (i.e., not worsening) of the
state of condition, disorder or disease; delay in onset or slowing
of condition, disorder or disease progression; amelioration of the
condition, disorder or disease state, remission (whether partial or
total), whether detectable or undetectable; or enhancement or
improvement of condition, disorder or disease. Treatment includes
eliciting a clinically significant response, without excessive
levels of side effects. Treatment also includes prolonging survival
as compared to expected survival if not receiving treatment. In
some embodiments, the present invention is directed to a method of
treating a microbial infection in a mammal, the method comprising
administering a composition comprising an antibiotic in a liquid
comprising triglycerides, to the mammal in need thereof.
[0065] A "pharmaceutically effective amount" means an amount
effective to provide a therapeutic effect during a period of
treatment. The effect can be the treatment of a bacterial infection
or other microbe-caused disease state or condition. In some
embodiments, the present infection is directed to a
pharmaceutically effective amount of an antibiotic is administered
to a mammal in need thereof.
[0066] As discussed previously, the methods and compositions of the
present invention can be used to treat microbial caused diseases.
In some embodiments, the methods and compositions of the present
invention can be used to treat otitis media. Otitis media is an
infection or inflammation of the middle ear caused by viral or
bacterial infections. It is estimated that 75% of children
experience at least one episode of otitis media by their third
birthday, however, this infection is not limited to children.
Otitis media can be treated using antibiotics. See Berman et al.,
Otitis media-related antibiotic prescribing patterns, outcomes, and
expenditures in a pediatric medicaid population, Pediatrics, 102(1
Pt 1):157 (1998); Glasziou et al., Antibiotics for acute otitis
media in children, Cochr ane Database Syst Rev. (2):CD000219
(2000). Thus, in some embodiments, the compositions of the present
invention can be administered to a patient with otitis media to
treat the infection.
Kits
[0067] The present invention is also directed to kits comprising a
composition of the present invention. In some embodiments, the kits
of the present invention further comprise a container or other
means for holding the compositions of the present invention. In
some embodiments, there is one container, two containers, three
containers, or more than three containers.
[0068] Traditional aqueous based antibiotic formulations can be
prepared at the pharmacy by mixing a measured amount of the
powdered components with water. These formulations require
refrigeration after mixing.
[0069] The kits of the present invention can be used to prepare the
pharmaceutical compositions in a manner distinct from traditional
kits. The medium chain triglycerides can be in a container separate
from the powdered components, which can be in their own distinct
container. The powdered components can comprise an antibiotic and
clavulanic acid, or another .beta.-lactamase inhibitor, either
together or in separate containers. This allows the pharmacist to
either pour the powders into the container with the liquid or vice
versa. Storing the liquid and powder components in separate
containers within a kit helps keep all the formulary components
moisture-free because each container is only opened at the time of
reconstitution, limiting the exposure to moisture in the
environment.
[0070] Thus, in some embodiments, the kit comprises (a) a first
container or other means for containing a therapeutically effective
amount of the composition of the present invention and (b) a second
container or other means for containing a pharmaceutically
acceptable carrier, excipient, diluent or combination thereof. For
example, the powdered portion of the formulation is stored in one
container while the liquid is stored in a separate container.
Optionally, the kit can have additional containers or other means
for containing comprising a therapeutically effective amount of
additional agents or excipients.
[0071] In some embodiments, the kit comprises a container or other
means for containing for the separate compositions, such as, a
divided bottle or a divided foil packet, however, the separate
compositions can also be contained within a single, undivided
container. Typically, the kit contains directions for
administration of the separate components. The kit form is
particularly advantageous when the separate components are
preferably administered at different dosage intervals, or when
titration of the individual components of the combination is
desired by the prescribing physician.
[0072] In some embodiments, the antibiotic is in one container or
other means for containing and the triglycerides are in another.
The physician or pharmacist can then mix the two components to form
a composition comprising an antibiotic in a liquid comprising
triglycerides, wherein the composition has less than about 5% water
(w/v). Any powdered excipients desired for the formulation can be
present with the triglycerides (e.g., in a solution or a
suspension) or they can be in a mixture with the antibiotic. The
.beta.-lactamase inhibitor may be in a container with the
antibiotic or separate from the antibiotic in another container
with powder.
[0073] In some embodiments, the kit of the present invention can
further comprise an additional container or means for containing
comprising a therapeutically effective amount of an agent selected
from the group consisting of hydrophilic drugs, hydrophobic drugs,
hydrophilic macromolecules, cytokines, peptidomimetics, peptides,
proteins, toxoids, sera, antibodies, vaccines, nucleosides,
nucleotides, nucleoside and/or nucleotide analogs, genetic
materials and combinations thereof.
[0074] In some embodiments, the container or other means for
containing of the kit is a bottle. This bottle can be
moisture-proof, including a moisture proof cap. It is also
important to select a bottle that will not be permeable to the
triglycerides of the present invention, in particular, to the
medium chain triglycerides. Some polymers that are suitable for
aqueous solutions would not be suitable for use in the kits of the
present invention.
[0075] Suitable containers or other means for containing include,
but are not limited to, bottles made of high density polyethylene
(HDPE), polypropylene (PP), glass, and metal. HDPE bottles are
particularly suited for the present invention because molecules of
HDPE have fewer branches and side chains which leads to higher
density and smaller pores. This makes it an effective barrier to
contain medium chain triglycerides within the bottle as well as an
effective barrier to prevent an influx of water. Accordingly, in
some embodiments, the container is a HDPE bottle.
[0076] As one of skill in the art will appreciate, the container is
not limited to HDPE bottles. Table 1 shows a comparison of the
properties of some more bottles contemplated for use in the present
invention.
TABLE-US-00001 TABLE 1 Bottle PET PETG HDPE LDPE PP Moisture Fair
to Fair to Good to Good Good to barrier Good Good Excellent
Excellent Oxygen Good Good Poor Poor Poor barrier Clarity Clear
Clear Opaque Opaque Translucent
[0077] A method according to the present invention comprises
preparing a pharmaceutical composition by combining a dehydrated
triglyceride with a powdered antibiotic and, optionally, a
.beta.-lactamase inhibitor such as clavulanic acid. Any of the kits
of the present invention are useful in this method.
[0078] The following examples are further illustrative of the
present invention, but are not to be construed to limit the scope
of the present invention.
Example 1
[0079] The compositions of the present invention have better
stability than aqueous solutions containing clavulanic acid. To
demonstrate this, samples of some embodiments of the present
invention are prepared at potassium clavulanate concentrations of
15 mg/5 mL, 35 mg/5 mL and 90 mg/5 mL. Each sample is dispersed in
a vehicle of medium chain triglycerides and water. Further, the
above sample preparation is repeated with the addition of
amoxicillin at 250 mg/5 mL. Table 2 shows the ratios of MCT:water
that are used in each sample prepared.
TABLE-US-00002 TABLE 2 Potassium clavulanate MCT:Water 15 mg 35 mg
90 mg (Diluent) (Ratio ~17) (Ratio ~7) (Ratio ~3) 1:3 No
amoxicillin No amoxicillin No amoxicillin (pH per USP Amoxicillin
Amoxicillin Amoxicillin between 250 mg/5 mL 250 mg/5 mL 250 mg/5 mL
3.8 to 6.6) 1:1 No amoxicillin No amoxicillin No amoxicillin (pH
per USP Amoxicillin Amoxicillin Amoxicillin between 250 mg/5 mL 250
mg/5 mL 250 mg/ 5 mL 3.8 to 6.6) 3:1 No amoxicillin No amoxicillin
No amoxicillin (pH per USP Amoxicillin Amoxicillin Amoxicillin
between 250 mg/5 mL 250 mg/5 mL 250 mg/ 5 mL 3.8 to 6.6) 100% MCT
No amoxicillin No amoxicillin No amoxicillin Amoxicillin
Amoxicillin Amoxicillin 250 mg/5 mL 250 mg/5 mL 250 mg/ 5 mL
[0080] The pH of the samples is controlled so that the mixture of
amoxicillin and potassium clavulanate have a pH of about 3.8 to
about 6.6. Solutions of pure amoxicillin (2 mg/ml) have an optimum
pH range of about 3.8 to about 6.0 and solutions of pure
clavulanate potassium (1% solution) have an optimum pH range of
about 3.8 to about 8.0.
[0081] These samples are stored at both a temperature of about
20.degree. C. to about 25.degree. C. and under refrigeration (about
4.degree. C.) and are tested for pH and the amount of amoxicillin
and clavulanate. The samples to be tested for pH and the amount of
amoxicillin and clavulanate at the following time points: 0 day
(day of reconstitution), 5 day, 10 day, 15 day, 1 month, 2 months
and 3 months after reconstitution.
[0082] The pH is measured using any technique known to one of skill
in the art. For example, using the methods described in the U.S.
Pharmacopoeia.
[0083] The amount of amoxicillin and clavulanate are measured using
HPLC or other assay capable of measuring the amount of amoxicillin
and clavulanate. Quantification of the compounds by HPLC is used to
determine the unknown concentration of both amoxicillin and
clavulanate in the samples. The samples are injected (about 10-20
.mu.l) into a liquid chromatograph equipped with a 210-nm detector
and a 4-mm.times.30-cm column that contains 3- to 10-.mu.m packing
L1. See U.S. Pharmacopoeia. The peaks of the sample are compared to
the injection of a series of known concentrations of the standard
compound solution (e.g., about 10 .mu.l of amoxicillin and/or about
20 .mu.l of clavulanate) onto the HPLC for detection. The
chromatograph of these known concentrations gives a series of peaks
that correlate to the concentration of the samples that are
injected. The chromatogram is recorded and the responses for the
major peaks are measured. One of skill in the art can then
determine the percentage of clavulanate or amoxicillin in the
solution using the methods described in the U.S. Pharmacopoeia or
other equivalent method.
[0084] Further, for in vivo studies testing the stability of the
samples, high-performance liquid chromatographic methods using
ultraviolet detection at 220 nm can be used for the simultaneous
determination of amoxicillin and clavulanic acid in human or dog
plasma. See Hoizey et al., J Pharm Biomed Anal. 15; 30(3):661-6
(2002); Choi et al., J Pharm Biomed Anal. 1; 35(1):221-31
(2004).
[0085] As one of skill in the art will appreciate, the stability of
the composition can be tested using methods other than HPLC. For
example, bioassays and spectrophotometric methods could be used in
place of HPLC or in addition to HPLC to determine the stability of
the composition. Thus, testing using zone of inhibition assays,
cell proliferation assays (e.g., using colorimetric dyes), and
other equivalent methods are also encompassed by the present
invention.
Example 2
[0086] The formulations in FIG. 1A-D depict embodiments of the
present invention. These formulations can be prepared by using the
following exemplary methods.
[0087] The formulation depicted in FIG. 1A can be prepared by
adding sorbitan monostearate and BHT to medium chain triglycerides
to form a mixture, heating the mixture to 55.degree. C., and then
mixing the mixture until the components have dissolved. The
resulting oil suspension is then cooled to a temperature of about
20.degree. C. to about 25.degree. C.
[0088] Next, the amoxicillin trihydrate, potassium
clavulanate/silicon dioxide blend (1:1 blend), silicon dioxide
(63FP), and colloidal silicon dioxide are weighed into the amounts
listed in FIG. 1A and then mixed in a container, such as, a glass
bottle to form a dry blend. The oil suspension is then added to the
container. The container is shaken to suspend the dry blend in the
oil suspension.
[0089] The formulation depicted in FIG. 1B can be prepared by
adding sorbitan monostearate and BHT to medium chain triglycerides
to form a mixture, heating the mixture to 55.degree. C., and then
mixing the mixture until the components have dissolved. The
resulting oil suspension is then cooled to a temperature of about
20.degree. C. to about 25.degree. C.
[0090] Next, the amoxicillin trihydrate, potassium
clavulanate/silicon dioxide blend (1:1 blend), silicon dioxide
(244FP), and colloidal silicon dioxide are weighed into the amounts
listed in FIG. 1B and then mixed in a container, such as, a glass
bottle to form a dry blend. The oil suspension is then added to the
container. The container is shaken to suspend the dry blend in the
oil suspension.
[0091] The formulation depicted in FIG. 1C can be prepared by
adding sorbitan monostearate and BHT to medium chain triglycerides
to form a mixture, heating the mixture to 55.degree. C., and then
mixing the mixture until the components have dissolved. The
resulting oil suspension is then cooled to a temperature of about
20.degree. C. to about 25.degree. C.
[0092] Next, the amoxicillin trihydrate, potassium
clavulanate/silicon dioxide blend (1:1 blend), silicon dioxide
(72FP), and colloidal silicon dioxide are weighed into the amounts
listed in FIG. 1C and then mixed in a container, such as, a glass
bottle to form a dry blend. The oil suspension is then added to the
container. The container is shaken to suspend the dry blend in the
oil suspension.
[0093] The formulation depicted in FIG. 1D can be prepared by
adding sorbitan monostearate, BHA, and BHT to medium chain
triglycerides to form a mixture, heating the mixture to 55.degree.
C., and then mixing the mixture until the components have
dissolved. The resulting oil suspension is then cooled to a
temperature of about 20.degree. C. to about 25.degree. C.
[0094] Next, the amoxicillin trihydrate, potassium
clavulanate/silicon dioxide blend (1:1 blend), silicon dioxide
(63FP), and colloidal silicon dioxide are weighed into the amounts
listed in FIG. 1D and then mixed in a container, such as, a glass
bottle to form a dry blend. The oil suspension is then added to the
container. The container is shaken to suspend the dry blend in the
oil suspension.
Example 3
[0095] Reconstituted suspensions of the present invention, as
listed in FIG. 1A-C and prepared according to Example 2, can be
tested for stability at a temperature of about 20.degree. C. to
about 25.degree. C. and compared to the brand product
(Augmentin.RTM.) which is stored at about 4.degree. C. The
following data represents the observed results of this stability
test.
TABLE-US-00003 TABLE 3 Time point Formulation in Formulation in
Formulation in (days) FIG. 1A FIG. 1 C Fig. 1B Augmentin .RTM. 0
Off-white to Off-white to Off-white to Cream colored cream colored
cream colored cream colored viscous suspension, settles suspension,
settles suspension, settles suspension. quickly less quickly than
less quickly than the formulation in the formulation in FIG. 1A
FIG. 1C 1 Off-white to Off-white to Off-white to Cream colored
cream colored cream colored cream colored viscous suspension,
settles suspension, settles suspension, settles suspension. quickly
less quickly than less quickly than the formulation in the
formulation in FIG. 1A FIG. 1C 5 Yellow colored Yellow colored
Yellow colored Cream colored suspension, settles suspension,
settles suspension, settles viscous quickly less quickly than less
quickly than suspension. the formulation in the formulation in FIG.
1A FIG. 1C
Example 4
[0096] The formulations described in FIG. 1A-C can be tested to
determine the degradation of clavulanic acid and amoxicillin. These
formulations can be prepared as described in Example 2 and then
stored at a temperature of about 20.degree. C. to about 25.degree.
C. The brand product (Augmentin.RTM.) can be prepared according to
its labeling instructions and stored at a temperature of about
4.degree. C. as the product labeling recommends.
[0097] At time points of 0 days (reconstitution of powder), 1 day,
5 days, and 8 days the following results were obtained using the
HPLC methods described in the US Pharmacopoeia. Samples are
withdrawn for assay from the top and bottom of the bottle to assess
the homogeneity of the suspension.
TABLE-US-00004 TABLE 4 Syloid Type % Clav. % Amoxi. (Silcon
Formulation 0 1 5 8 0 1 5 8 Gel) Sample Info in FIG. 1. Day Day Day
Day Day Day Day Day 63FP Sample 1- FIG. 1A 125.3 108.6 98.3 107.7
107.3 105.3 104.2 101.9 Bottom Sample 2- FIG. 1A 101.5 106.7 99.5
95.9 99.6 108.0 105.3 97.3 Top 72FP Sample 3- FIG. 1C 215.3 99.2
99.7 94.9 165.2 100.0 107.1 98.8 Bottom Sample 4- FIG. 1C 104.0
103.0 93.4 92.3 100.0 104.6 101.2 97.1 Top 244FP Sample 5- FIG. 1B
108.0 106.0 103.5 93.6 98.9 99.6 110.4 98.8 Bottom Sample 6- FIG.
1B 106.0 105.7 100.3 94.4 99.6 103.3 107.1 99.0 Top NA Augmentin
.RTM.- N/A 112.5 113.4 103.3 97.7 101.0 111.0 104.3 98.1 1Bottom NA
Augmentin .RTM.- N/A 115.7 112.9 103.2 97.5 103.0 110.0 104.6 98.5
2 Top
[0098] As illustrated in Table 4, the sample containing 244FP (the
formulation shown in FIG. 1B) had approximately 13% clavulanic acid
degradation after 8 days at a temperature of about 20.degree. C. to
about 25.degree. C. The brand product had approximately 15%
clavulanic acid degradation after 8 days despite being stored at
4.degree. C.
Example 5
[0099] The inventors have also tested the formulation stability of
formulations of the present invention which use pre-dried powdered
excipients. For this test, part of the powdered components in the
test formulation, including silicon dioxide, colloidal silicon
dioxide and magnesium tricilicate, were dried in 105.degree. C.
oven overnight to reduce their water content. As a comparison, the
samples (powders) of these materials from the same containers
without drying were also studied.
[0100] Various medium chain triglyceride (MCT) oil samples with
different moisture levels of 0.0275, 0.05, 0.1 and 0.15% (w/w) were
evaluated for determining the stability of the formulation after
reconstitution.
[0101] The stability of a formulation (600 mg/42.9 mg) was
monitored using color change as an indicator of formulation
stability. In general, the whiter the formulation appears, the more
stable the formulation. It has been observed that for the
formulations without pre-dried powders, the reconstituted
suspension of the product became dark yellow on the second day
after reconstitution, irrespective of the moisture level of MCT
oil.
[0102] However, the formulations using pre-dried powders (silicon
dioxide, colloidal silicon dioxide and magnesium trisilicate) did
not show any color change for 3 days at all moisture levels of MCT
oil after reconstitution. After 3 days following reconstitution,
gradual color changes were observed in the formulations containing
high moisture level MCT oil, whereas no color change or slight
off-white was seen in 0.0275% MCT oil formulations for 21 days kept
at room temperature(23.+-.2.degree. C.).
[0103] Similar observations were obtained on 200/28.5 mg
formulation. The observation difference was the color change of the
200/28.5 mg formulations was faster than the 600/42.9 mg
formulations. This may be attributed to the fact that the 200/28.5
mg formulation has far less amount of dry powders than the 600/42.9
mg formulation.
[0104] These examples illustrate possible embodiments of the
present invention. As one of skill in the art will appreciate,
because of the versatility of the compositions, kits, and methods
of using the compositions disclosed herein, the compositions, kits,
and methods can be used in other similar ways to those described
herein. Thus, while the invention has been particularly shown and
described with reference to some embodiments thereof, it will be
understood by those skilled in the art that they have been
presented by way of example only, and not limitation, and various
changes in form and details can be made therein without departing
from the spirit and scope of the invention. Therefore, the breadth
and scope of the present invention should not be limited by any of
the above-described exemplary embodiments, but should be defined
only in accordance with the following claims and their
equivalents.
[0105] All documents cited herein, including journal articles or
abstracts, published or corresponding U.S. or foreign patent
applications, issued or foreign patents, or any other documents,
are each entirely incorporated by reference herein, including all
data, tables, figures, and text presented in the cited
documents.
* * * * *