1
FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION
ANTIBACTERIAL COMPOSITIONS AND METHODS
2. APPLICANT
(a). NAME: WOCKHARDT LIMITED
(b). NATIONALITY: INDIAN
(c). ADDRESS: D-4, M. I. D. C INDUSTRIAL AREA,
CHIKALTHANA, AURANGABAD – 431006,
MAHARASHTRA, INDIA.
The following specification particularly describes the invention and the manner in
which it is to be performed.
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ANTIBACTERIAL COMPOSITIONS AND METHODS
RELATED PATENT APPLICATIONS
This application claims priority to and benefit of the Indian Patent Application No.
201621011248 filed on March 31, 2016, the disclosures of which are incorporated herein by
reference in its entirety as if fully rewritten herein.
FIELD OF THE INVENTION
The invention relates to antibacterial compositions and methods for treatment, control or
prevention of bacterial infections.
BACKGROUND OF THE INVENTION
Infections caused by bacteria continue to remain an area of serious concern worldwide. One
of the key challenges in the treatment, control or prevention of bacterial infections is the ability of
bacteria to develop resistance to one or more antibacterial agents over time. Representative
examples of such bacteria that have developed resistance to typical antibacterial agents include:
Penicillin-resistant Streptococcus pneumoniae, Vancomycin-resistant Enterococci, and Methicillinresistant
Staphylococcus aureus. The problem of emerging drug-resistance in bacteria is often
tackled by switching over to newer antibacterial agents. However, development of new antibacterial
agents can be expensive and may not be always a permanent solution as bacteria often develop
resistance to the newer antibacterial agents in due course. In general, bacteria are often efficient in
developing resistance to antibacterial agent because of their ability to multiply very rapidly and pass
on the resistance genes as they replicate. Bacteria develop resistance to existing antibacterial agents
through various mechanisms including production of beta lactamases, mutations in the target PBPs,
development of efflux pumps, and decreased expression of outer membrane proteins or porins. For
example, in response to the continued exposure to a variety of beta-lactam antibacterial agents,
bacteria have developed several types of beta lactamases that are capable of hydrolyzing
antibacterial agents belonging to penicillins, cephalosporins, monobactams and even carbapenems.
There is an urgent need for development of newer ways to treat bacterial infections, and in
particular, infections caused by bacteria that have acquired resistance to one or more of the existing
antibacterial agents. A composition comprising at least one antibacterial agent and tazobactam was
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disclosed in PCT International Patent Application No. PCT/IB2011/053398. For example, a
composition comprising cefepime and tazobactam exhibited a synergistic antibacterial effect against
a wide variety of bacteria. However, a combination of cefepime and tazobactam when administered
intravenously caused inflammation of veins (the effect also known as phlebitis). The inventors have
now surprisingly discovered that it is possible to use a composition comprising cefepime and
tazobactam parenterally without causing phlebitis by adding a specific amount of arginine or a
pharmaceutically acceptable thereof to the composition, and also by using a specific administration
regime. The specific amount of each ingredient in the composition, and the administration regime
was surprisingly found to result in unexpected synergy, thereby making such compositions and/or
therapy effective against several resistant bacteria.
SUMMARY OF THE INVENTION
Accordingly, there is provided a method for treating bacterial infection in a subject by
parenteral administration of active ingredients, said active ingredients comprising: (a) about 0.50
gram to about 6 gram of cefepime or a pharmaceutically acceptable salt thereof, (b) about 0.10 to
1.5 gram arginine or a pharmaceutically acceptable salt thereof, per gram of cefepime or a
pharmaceutically acceptable salt thereof, and (c) about 0.50 gram to about 6 gram of tazobactam or
a pharmaceutically acceptable salt thereof; said method further characterized in that the ingredients
are administered parenterally over a period of about 15 minutes to about 24 hours.
In another general aspect, there is provided use of active ingredients in a method for treating
bacterial infection in a subject, said active ingredients comprising: (a) about 0.50 gram to about 6
gram of cefepime or a pharmaceutically acceptable salt thereof, (b) about 0.10 to 1.5 gram arginine
or a pharmaceutically acceptable salt thereof, per gram of cefepime or a pharmaceutically
acceptable salt thereof, and (c) about 0.50 gram to about 6 gram of tazobactam or a
pharmaceutically acceptable salt thereof; said method comprising that the active ingredients are
administered parenterally over a period of about 15 minutes to about 24 hours.
The details of one or more embodiments of the invention are set forth in the description
below. Other features, objects and advantages of the invention will be apparent from the following
description, including claims.
DETAILED DESCRIPTION OF THE INVENTION
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Reference will now be made to the exemplary embodiments, and specific language will be
used herein to describe the same. It should nevertheless be understood that no limitation of the
scope of the invention is thereby intended. Alterations and further modifications of the inventive
features illustrated herein, and additional applications of the principles of the invention as illustrated
herein, which would occur to one of ordinary skills in the relevant art and having possession of this
disclosure, are to be considered within the scope of the invention. It must be noted that, as used in
this specification and the appended claims, the singular forms “a”, “an”, and “the” include plural
referents unless the content clearly dictates otherwise. All references including patents, patent
applications, and literature cited in the specification are expressly incorporated herein by reference
in their entirety.
The inventors have now surprisingly discovered that it is possible to use a composition
comprising cefepime and tazobactam parenterally without causing phlebitis by adding a specific
amount of arginine or a pharmaceutically acceptable thereof to the composition, and also by using a
specific administration regime. The specific amount of each ingredient in the composition, and the
administration regime was surprisingly found to result in unexpected synergy, thereby making such
compositions and/or therapy effective against several resistant bacteria.
The term “pharmaceutically acceptable salt” as used herein refers to one or more salts of a
given compound which possesses the desired pharmacological activity of the free compound and
which are neither biologically nor otherwise undesirable. In general, the “pharmaceutically
acceptable salts” refer to and include those salts that are suitable for use in contact with the tissues
of human and animals without undue toxicity, irritation, allergic response and the like, and are
commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well
known in the art. For example, S. M. Berge, et al. (J. Pharmaceutical Sciences, 66: 1-19 (1977)),
incorporated herein by reference in its entirety, describes various pharmaceutically acceptable salts
in details.
The term “infection” or “bacterial infection” as used herein refers to and includes presence
of bacteria, in or on a subject, which, if its growth were inhibited, would result in a benefit to the
subject. As such, the term “infection” in addition to referring to the presence of bacteria also refers
to normal flora, which is not desirable. The term “infection” includes infections caused by bacteria.
The term “treat”, “treating” or “treatment” as used herein refers to administering a
medicament, including a pharmaceutical composition, or one or more active ingredients, for
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prophylactic and/or therapeutic purposes. The term “prophylactic treatment” refers to treating a
subject who is not yet infected, but who is susceptible to, or otherwise at a risk of infection
(preventing the bacterial infection). The term “therapeutic treatment” refers to administering
treatment to a subject already suffering from infection. The terms “treat”, “treating” or “treatment”
as used herein also refer to administering compositions or one or more of active ingredients
discussed herein, with or without additional active or inert ingredients, in order to: (i) reduce or
eliminate either a bacterial infection or one or more symptoms of the bacterial infection, or (ii)
retard the progression of a bacterial infection or of one or more symptoms of the bacterial infection,
or (iii) reduce the severity of a bacterial infection or of one or more symptoms of the bacterial
infection, or (iv) suppress the clinical manifestation of a bacterial infection, or (v) suppress the
manifestation of adverse symptoms of the bacterial infection.
The term “pharmaceutically effective amount” or “therapeutically effective amount” or
“effective amount” as used herein refers to an amount, which has a therapeutic effect or is the
amount required to produce a therapeutic effect in a subject. For example, a therapeutically or
pharmaceutically effective amount of an active ingredient or a pharmaceutical composition is the
amount of the active ingredient or the pharmaceutical composition required to produce a desired
therapeutic effect as may be judged by clinical trial results, model animal infection studies, and/or
in vitro studies (e.g. in agar or broth media). The pharmaceutically effective amount depends on
several factors, including but not limited to, the microorganism (e.g. bacteria) involved,
characteristics of the subject (for example height, weight, sex, age and medical history), severity of
infection and the particular type of the antibacterial agent or active ingredient used. For
prophylactic treatments, a therapeutically or prophylactically effective amount is that amount which
would be effective in preventing a microbial (e.g. bacterial) infection. The active ingredients and/or
pharmaceutical compositions according to the invention are used in amounts that are effective in
providing the desired therapeutic effect or result.
The term “administration” or “administering” includes delivery of a composition, or one or
more of active ingredients to a subject, including for example, by any appropriate methods, which
serves to deliver the composition or the active ingredients to the site of the infection. The method of
administration may vary depending on various factors, such as for example, the components of the
pharmaceutical composition or the nature of the active and/or inert ingredients, the site of the
potential or actual infection, the microorganism involved, severity of the infection, age and physical
condition of the subject and a like. Some non-limiting examples of ways to administer a
composition or active ingredients to a subject according to the invention include oral, intravenous,
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topical, intra-respiratory, intra-peritoneal, intra-muscular, parenteral, sublingual, transdermal,
intranasal, aerosol, intra-ocular, intra-tracheal, intra-rectal, vaginal, gene gun, dermal patch, eye
drop, ear drop or mouthwash. In case of a pharmaceutical composition comprising more than one
ingredient (active or inert), one way to administering such composition is by admixing the
ingredients (e.g. in the form of a suitable unit dosage form such as tablet, capsule, solution, powder
and a like) and then administering the dosage form. Alternatively, the ingredients may also be
administered separately (simultaneously or one after the other) as long as these ingredients reach
beneficial therapeutic levels such that the desired therapeutic effect is achieved.
The term “parenteral administration” refers to and includes a route of administration that
does not involve gastrointestinal tract directly. Typical, non-limiting examples of parenteral route of
administration includes intravenous (into a vein), intra-arterial (into an artery), intraosseous infusion
(into the bone marrow), intra-muscular, intracerebral, intrathecal, subcutaneous administration. In
general, the parenteral administration is performed by injecting or infusing the composition or the
active ingredient(s) directly into a subject without direct involvement of the gastrointestinal tract.
The term “growth” as used herein refers to a growth of one or more microorganisms and
includes reproduction or population expansion of the microorganism (e.g. bacteria). The term
“growth” also includes maintenance of on-going metabolic processes of a microorganism (e.g.
bacteria), including processes that keep the microorganism alive.
The term, “effectiveness” as used herein refers to the ability of a treatment or a composition
or one or more active ingredients to produce a desired biological effect in a subject. For example,
the term “antibacterial effectiveness” of a composition or an antibacterial agent refers to the ability
of the composition or the antibacterial agent to treat or prevent the microbial (e.g. bacterial)
infection in a subject.
The term “synergistic” or “synergy” as used herein refers to the interaction of two or more
agents so that their combined effect is greater than their individual effects.
The term “antibacterial agent” as used herein refers to any substance, compound or a
combination of substances or a combination of compounds capable of: (i) inhibiting, reducing or
preventing growth of bacteria; (ii) inhibiting or reducing ability of a bacteria to produce infection in
a subject; or (iii) inhibiting or reducing ability of bacteria to multiply or remain infective in the
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environment. The term “antibacterial agent” also refers to a compound capable of decreasing
infectivity or virulence of bacteria.
The term “beta-lactam antibacterial agent” as used herein refers to compounds with
antibacterial properties and containing a beta-lactam nucleus in their molecular structure.
The term “beta-lactamase” as used herein refers to any enzyme or protein or any other
substance that breaks down a beta-lactam ring. The term “beta-lactamase” includes enzymes that
are produced by bacteria and have the ability to hydrolyze the beta-lactam ring in a beta-lactam
compound, either partially or completely.
The term “beta-lactamase inhibitor” as used herein refers to a compound capable of
inhibiting activity of one or more beta-lactamase enzymes, either partially or completely.
The term “pharmaceutically inert ingredient” or “inert ingredient”, “carrier" or “excipient”
refers to a compound or material used to facilitate administration of a compound, including for
example, to increase the solubility of the compound. Typical, non-limiting examples of solid
carriers include, starch, lactose, di-calcium phosphate, sucrose, and kaolin and so on. Typical, nonlimiting
examples of liquid carriers include sterile water, saline, buffers, non-ionic surfactants, and
edible oils such as oil, peanut and sesame oils and so on. In addition, various adjuvants commonly
used in the art may be included. These and other such compounds are described in the literature, for
example, in the Merck Index (Merck & Company, Rahway, N.J.). Considerations for inclusion of
various components in pharmaceutical compositions are described, for example, in Gilman et al.
(Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed.,
Pergamon Press., which is incorporated herein by reference in its entirety.
The term “subject” as used herein refers to a vertebrate or invertebrate, including a mammal.
The term “subject” includes human, animal, a bird, a fish, or an amphibian. Typical, non-limiting
examples of a “subject” includes humans, cats, dogs, horses, sheep, bovine cows, pigs, lambs, rats,
mice and guinea pigs.
A person of skills in the art would appreciate that the compounds described herein can
generally exist or used in various pharmaceutically acceptable forms including in the form of their
pharmaceutically acceptable salts, pro-drugs, metabolites, esters, ethers, hydrates, polymorphs,
solvates, complexes, enantiomers, adducts or such other pharmaceutically acceptable derivatives. A
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reference to the compound, therefore, is intended to include it’s pharmaceutically acceptable salts,
pro-drugs, metabolites, esters, ethers, hydrates, polymorphs, solvates, complexes, enantiomers,
adducts or such other pharmaceutically acceptable derivative. For example, the terms “cefepime”,
“tazobactam”, or “arginine” includes their pharmaceutically acceptable salts, pro-drugs,
metabolites, esters, ethers, hydrates, polymorphs, solvates, complexes, enantiomers, adducts or such
other pharmaceutically acceptable derivatives. Each of cefepime or a pharmaceutically acceptable
salt thereof, tazobactam or a pharmaceutically acceptable salt thereof, and arginine or a
pharmaceutically acceptable salt thereof, is individually referred to as an “active ingredient” and
collectively referred to as “active ingredients”. The terms “pharmaceutical compositions” or
“composition” as used herein refer to and include the compositions according to the invention.
In one general aspect, there is provided a method for treating bacterial infection in a subject
by parenteral administration of active ingredients, said active ingredients comprising: (a) about 0.50
gram to about 6 gram of cefepime or a pharmaceutically acceptable salt thereof, (b) about 0.10 to
1.5 gram arginine or a pharmaceutically acceptable salt thereof, per gram of cefepime or a
pharmaceutically acceptable salt thereof, and (c) about 0.50 gram to about 6 gram of tazobactam or
a pharmaceutically acceptable salt thereof; said method further characterized in that the ingredients
are administered parenterally over a period of about 15 minutes to about 24 hours.
In another general aspect, there is provided use of active ingredients in a method for treating
bacterial infection in a subject, said active ingredients comprising: (a) about 0.50 gram to about 6
gram of cefepime or a pharmaceutically acceptable salt thereof, (b) about 0.10 to 1.5 gram arginine
or a pharmaceutically acceptable salt thereof, per gram of cefepime or a pharmaceutically
acceptable salt thereof, and (c) about 0.50 gram to about 6 gram of tazobactam or a
pharmaceutically acceptable salt thereof; said method comprising that the active ingredients are
administered parenterally over a period of about 15 minutes to about 24 hours.
In some embodiments, tazobactam is present as tazobactam sodium. In some other
embodiments, cefepime is present as cefepime hydrochloride. In some embodiments, arginine is
present as arginine hydrochloride.
In some embodiments, there is provided a method for treating bacterial infection in a subject
by parenteral administration of active ingredients, said active ingredients comprising: (a) about 0.50
gram to about 6 gram of cefepime or a pharmaceutically acceptable salt thereof, (b) about 0.50 to
0.90 gram arginine or a pharmaceutically acceptable salt thereof, per gram of cefepime or a
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pharmaceutically acceptable salt thereof, and (c) about 0.50 gram to about 6 gram of tazobactam or
a pharmaceutically acceptable salt thereof; said method comprising that the active ingredients are
administered parenterally over a period of about 15 minutes to about 24 hours.
In some embodiments, there is provided a method for treating bacterial infection in a subject
by parenteral administration of active ingredients, said active ingredients comprising: (a) about 0.50
gram to about 6 gram of cefepime or a pharmaceutically acceptable salt thereof, (b) about 0.70 to
0.80 gram arginine or a pharmaceutically acceptable salt thereof, per gram of cefepime or a
pharmaceutically acceptable salt thereof, and (c) about 0.50 gram to about 6 gram of tazobactam or
a pharmaceutically acceptable salt thereof; said method comprising that the active ingredients are
administered parenterally over a period of about 15 minutes to about 24 hours.
In some embodiments, there is provided a method for treating bacterial infection in a subject
by parenteral administration of active ingredients, said active ingredients comprising: (a) about 0.50
gram to about 3 gram of cefepime or a pharmaceutically acceptable salt thereof, (b) about 0.10 to
1.5 gram arginine or a pharmaceutically acceptable salt thereof, per gram of cefepime or a
pharmaceutically acceptable salt thereof, and (c) about 0.50 gram to about 3 gram of tazobactam or
a pharmaceutically acceptable salt thereof; said method comprising that the active ingredients are
administered parenterally over a period of about 15 minutes to about 24 hours.
In some embodiments, there is provided a method for treating bacterial infection in a subject
by parenteral administration of active ingredients, said active ingredients comprising: (a) about 0.50
gram to about 3 gram of cefepime or a pharmaceutically acceptable salt thereof, (b) about 0.50 to
0.90 gram arginine or a pharmaceutically acceptable salt thereof, per gram of cefepime or a
pharmaceutically acceptable salt thereof, and (c) about 0.50 gram to about 3 gram of tazobactam or
a pharmaceutically acceptable salt thereof; said method comprising that the active ingredients are
administered parenterally over a period of about 15 minutes to about 24 hours.
In some embodiments, there is provided a method for treating bacterial infection in a subject
by parenteral administration of active ingredients, said active ingredients comprising: (a) about 0.50
gram to about 3 gram of cefepime or a pharmaceutically acceptable salt thereof, (b) about 0.70 to
0.80 gram arginine or a pharmaceutically acceptable salt thereof, per gram of cefepime or a
pharmaceutically acceptable salt thereof, and (c) about 0.50 gram to about 3 gram of tazobactam or
a pharmaceutically acceptable salt thereof; said method comprising that the active ingredients are
administered parenterally over a period of about 15 minutes to about 24 hours.
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In some embodiments, there is provided a method for treating bacterial infection in a subject
by parenteral administration of active ingredients, said active ingredients comprising: (a) about 1
gram of cefepime or a pharmaceutically acceptable salt thereof, (b) about 0.70 to 0.80 gram arginine
or a pharmaceutically acceptable salt thereof, per gram of cefepime or a pharmaceutically
acceptable salt thereof, and (c) about 1 gram of tazobactam or a pharmaceutically acceptable salt
thereof; said method comprising that the active ingredients are administered parenterally over a
period of about 15 minutes to about 24 hours.
In some embodiments, there is provided a method for treating bacterial infection in a subject
by parenteral administration of active ingredients, said active ingredients comprising: (a) about 2
gram of cefepime or a pharmaceutically acceptable salt thereof, (b) about 0.70 to 0.80 gram arginine
or a pharmaceutically acceptable salt thereof, per gram of cefepime or a pharmaceutically
acceptable salt thereof, and (c) about 2 gram of tazobactam or a pharmaceutically acceptable salt
thereof; said method comprising that the active ingredients are administered parenterally over a
period of about 15 minutes to about 24 hours.
In some other embodiments, there is provided a method for treating bacterial infection in a
subject by parenteral administration of active ingredients in any of the following amounts over a
period of about 15 minutes to about 250 minutes:
(i) (a) about 0.50 gram to about 6 gram of cefepime or a pharmaceutically acceptable
salt thereof, (b) about 0.10 to 1.5 gram arginine or a pharmaceutically acceptable salt thereof, per
gram of cefepime or a pharmaceutically acceptable salt thereof, and (c) about 0.50 gram to about 6
gram of tazobactam or a pharmaceutically acceptable salt thereof;
(ii) (a) about 0.50 gram to about 6 gram of cefepime or a pharmaceutically acceptable
salt thereof, (b) about 0.50 to 0.90 gram arginine or a pharmaceutically acceptable salt thereof, per
gram of cefepime or a pharmaceutically acceptable salt thereof, and (c) about 0.50 gram to about 6
gram of tazobactam or a pharmaceutically acceptable salt thereof;
(iii) (a) about 0.50 gram to about 6 gram of cefepime or a pharmaceutically acceptable
salt thereof, (b) about 0.70 to 0.80 gram arginine or a pharmaceutically acceptable salt thereof, per
gram of cefepime or a pharmaceutically acceptable salt thereof, and (c) about 0.50 gram to about 6
gram of tazobactam or a pharmaceutically acceptable salt thereof;
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(iv) (a) about 0.50 gram to about 3 gram of cefepime or a pharmaceutically acceptable
salt thereof, (b) about 0.10 to 1.5 gram arginine or a pharmaceutically acceptable salt thereof, per
gram of cefepime or a pharmaceutically acceptable salt thereof, and (c) about 0.50 gram to about 3
gram of tazobactam or a pharmaceutically acceptable salt thereof;
(v) (a) about 0.50 gram to about 3 gram of cefepime or a pharmaceutically acceptable
salt thereof, (b) about 0.50 to 0.90 gram arginine or a pharmaceutically acceptable salt thereof, per
gram of cefepime or a pharmaceutically acceptable salt thereof, and (c) about 0.50 gram to about 3
gram of tazobactam or a pharmaceutically acceptable salt thereof;
(vi) (a) about 0.50 gram to about 3 gram of cefepime or a pharmaceutically acceptable
salt thereof, (b) about 0.70 to 0.80 gram arginine or a pharmaceutically acceptable salt thereof, per
gram of cefepime or a pharmaceutically acceptable salt thereof, and (c) about 0.50 gram to about 3
gram of tazobactam or a pharmaceutically acceptable salt thereof;
(vii) (a) about 1 gram of cefepime or a pharmaceutically acceptable salt thereof, (b) about
0.70 to 0.80 gram arginine or a pharmaceutically acceptable salt thereof, per gram of cefepime or a
pharmaceutically acceptable salt thereof, and (c) about 1 gram of tazobactam or a pharmaceutically
acceptable salt thereof; or
(viii) (a) about 2 gram of cefepime or a pharmaceutically acceptable salt thereof, (b) about
0.70 to 0.80 gram arginine or a pharmaceutically acceptable salt thereof, per gram of cefepime or a
pharmaceutically acceptable salt thereof, and (c) about 2 gram of tazobactam or a pharmaceutically
acceptable salt thereof.
In some other embodiments, there is provided a method for treating bacterial infection in a
subject by parenteral administration of active ingredients in any of the following amounts over a
period of about 30 minutes to about 120 minutes:
(i) (a) about 0.50 gram to about 6 gram of cefepime or a pharmaceutically acceptable
salt thereof, (b) about 0.10 to 1.5 gram arginine or a pharmaceutically acceptable salt thereof, per
gram of cefepime or a pharmaceutically acceptable salt thereof, and (c) about 0.50 gram to about 6
gram of tazobactam or a pharmaceutically acceptable salt thereof;
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(ii) (a) about 0.50 gram to about 6 gram of cefepime or a pharmaceutically acceptable
salt thereof, (b) about 0.50 to 0.90 gram arginine or a pharmaceutically acceptable salt thereof, per
gram of cefepime or a pharmaceutically acceptable salt thereof, and (c) about 0.50 gram to about 6
gram of tazobactam or a pharmaceutically acceptable salt thereof;
(iii) (a) about 0.50 gram to about 6 gram of cefepime or a pharmaceutically acceptable
salt thereof, (b) about 0.70 to 0.80 gram arginine or a pharmaceutically acceptable salt thereof, per
gram of cefepime or a pharmaceutically acceptable salt thereof, and (c) about 0.50 gram to about 6
gram of tazobactam or a pharmaceutically acceptable salt thereof;
(iv) (a) about 0.50 gram to about 3 gram of cefepime or a pharmaceutically acceptable
salt thereof, (b) about 0.10 to 1.5 gram arginine or a pharmaceutically acceptable salt thereof, per
gram of cefepime or a pharmaceutically acceptable salt thereof, and (c) about 0.50 gram to about 3
gram of tazobactam or a pharmaceutically acceptable salt thereof;
(v) (a) about 0.50 gram to about 3 gram of cefepime or a pharmaceutically acceptable
salt thereof, (b) about 0.50 to 0.90 gram arginine or a pharmaceutically acceptable salt thereof, per
gram of cefepime or a pharmaceutically acceptable salt thereof, and (c) about 0.50 gram to about 3
gram of tazobactam or a pharmaceutically acceptable salt thereof;
(vi) (a) about 0.50 gram to about 3 gram of cefepime or a pharmaceutically acceptable
salt thereof, (b) about 0.70 to 0.80 gram arginine or a pharmaceutically acceptable salt thereof, per
gram of cefepime or a pharmaceutically acceptable salt thereof, and (c) about 0.50 gram to about 3
gram of tazobactam or a pharmaceutically acceptable salt thereof;
(vii) (a) about 1 gram of cefepime or a pharmaceutically acceptable salt thereof, (b) about
0.70 to 0.80 gram arginine or a pharmaceutically acceptable salt thereof, per gram of cefepime or a
pharmaceutically acceptable salt thereof, and (c) about 1 gram of tazobactam or a pharmaceutically
acceptable salt thereof; or
(viii) (a) about 2 gram of cefepime or a pharmaceutically acceptable salt thereof, (b) about
0.70 to 0.80 gram arginine or a pharmaceutically acceptable salt thereof, per gram of cefepime or a
pharmaceutically acceptable salt thereof, and (c) about 2 gram of tazobactam or a pharmaceutically
acceptable salt thereof.
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In some other embodiments, there is provided a method for treating bacterial infection in a
subject by parenteral administration of active ingredients in any of the following amounts over a
period of about 30 minutes to about 90 minutes:
(i) (a) about 0.50 gram to about 6 gram of cefepime or a pharmaceutically acceptable
salt thereof, (b) about 0.10 to 1.5 gram arginine or a pharmaceutically acceptable salt thereof, per
gram of cefepime or a pharmaceutically acceptable salt thereof, and (c) about 0.50 gram to about 6
gram of tazobactam or a pharmaceutically acceptable salt thereof;
(ii) (a) about 0.50 gram to about 6 gram of cefepime or a pharmaceutically acceptable
salt thereof, (b) about 0.50 to 0.90 gram arginine or a pharmaceutically acceptable salt thereof, per
gram of cefepime or a pharmaceutically acceptable salt thereof, and (c) about 0.50 gram to about 6
gram of tazobactam or a pharmaceutically acceptable salt thereof;
(iii) (a) about 0.50 gram to about 6 gram of cefepime or a pharmaceutically acceptable
salt thereof, (b) about 0.70 to 0.80 gram arginine or a pharmaceutically acceptable salt thereof, per
gram of cefepime or a pharmaceutically acceptable salt thereof, and (c) about 0.50 gram to about 6
gram of tazobactam or a pharmaceutically acceptable salt thereof;
(iv) (a) about 0.50 gram to about 3 gram of cefepime or a pharmaceutically acceptable
salt thereof, (b) about 0.10 to 1.5 gram arginine or a pharmaceutically acceptable salt thereof, per
gram of cefepime or a pharmaceutically acceptable salt thereof, and (c) about 0.50 gram to about 3
gram of tazobactam or a pharmaceutically acceptable salt thereof;
(v) (a) about 0.50 gram to about 3 gram of cefepime or a pharmaceutically acceptable
salt thereof, (b) about 0.50 to 0.90 gram arginine or a pharmaceutically acceptable salt thereof, per
gram of cefepime or a pharmaceutically acceptable salt thereof, and (c) about 0.50 gram to about 3
gram of tazobactam or a pharmaceutically acceptable salt thereof;
(vi) (a) about 0.50 gram to about 3 gram of cefepime or a pharmaceutically acceptable
salt thereof, (b) about 0.70 to 0.80 gram arginine or a pharmaceutically acceptable salt thereof, per
gram of cefepime or a pharmaceutically acceptable salt thereof, and (c) about 0.50 gram to about 3
gram of tazobactam or a pharmaceutically acceptable salt thereof;
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(vii) (a) about 1 gram of cefepime or a pharmaceutically acceptable salt thereof, (b) about
0.70 to 0.80 gram arginine or a pharmaceutically acceptable salt thereof, per gram of cefepime or a
pharmaceutically acceptable salt thereof, and (c) about 1 gram of tazobactam or a pharmaceutically
acceptable salt thereof; or
(viii) (a) about 2 gram of cefepime or a pharmaceutically acceptable salt thereof, (b) about
0.70 to 0.80 gram arginine or a pharmaceutically acceptable salt thereof, per gram of cefepime or a
pharmaceutically acceptable salt thereof, and (c) about 2 gram of tazobactam or a pharmaceutically
acceptable salt thereof.
In some embodiments, the active ingredients are administered simultaneously or one after
the other.
In some other embodiments, the active ingredients are administered in the form of a
solution, the solution being obtained by adding the active ingredients to a compatible liquid diluent.
In some embodiments, each of the active ingredients is administered independently in the
form of a solution, the solution being obtained by dissolving the active ingredient in a compatible
liquid diluent.
A wide variety of liquid diluents can be used. Typical, non-limiting example of liquid
diluent includes water for injection, 0.9% sodium chloride solution, 5% dextrose solution, normal
saline solution and a like.
In some embodiments the active ingredients according to the invention are administered in
the form of a solution as described herein, said solution having a pH within a range between about
6.5 to about 8.
The active ingredients according to the invention can be administered at varied time
intervals depending upon the specific requirement or the desired therapeutic effect. In some
embodiments, the active ingredients according to the invention are administered one, two, three or
four times a day. In some other embodiments, the active ingredients according to the invention are
administered every 4 hours, 6 hours, 8 hours, 12 hours or 24 hours.
15
The active ingredients according to the invention may also be administered in combination
with one or more pharmaceutically acceptable carriers or excipients or inert ingredients. Typical,
non-limiting examples of such carriers or excipients or inert ingredients include mannitol, lactose,
starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose,
gelatin, sucrose, magnesium carbonate, wetting agents, emulsifying agents, solubilizing agents,
buffering agents, lubricants, stabilizing agents, binding agents and a like.
In some embodiments, the active ingredients according to the invention are administered in
combination with one or more buffering agent. Typical non-limiting examples of buffering agents
include aluminum hydroxide, aluminum hydroxide/magnesium carbonate co-precipitate, aluminum
hydroxide/sodium bicarbonate co-precipitate, aluminium glycinate, aluminium magnesium
hydroxide, aluminium phosphate, calcium acetate, calcium carbonate, calcium formate, calcium
bicarbonate, calcium borate, calcium citrate, calcium gluconate, calcium glycerophosphate, calcium
hydroxide, calcium chloride, calcium lactate, calcium phthalate, calcium phosphate, calcium
succinate, calcium tartrate, calcium propionate, dibasic sodium phosphate, dipotassium hydrogen
phosphate, dipotassium phosphate, disodium hydrogen phosphate, disodium succinate, dry
aluminum hydroxide gel, magnesium acetate, magnesium aluminate, magnesium borate,
magnesium bicarbonate, magnesium hydroxide, magnesium carbonate, magnesium citrate,
magnesium gluconate, magnesium lactate, magnesium metasilicate aluminate, magnesium oxide,
magnesium phthalate, magnesium phosphate, magnesium silicate, magnesium succinate,
magnesium tartrate, potassium acetate, potassium carbonate, potassium bicarbonate, potassium
borate, potassium citrate, potassium metaphosphate, potassium phthalate, potassium phosphate,
potassium polyphosphate, potassium pyrophosphate, potassium succinate, potassium tartrate,
sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate, sodium citrate, sodium
gluconate, sodium hydrogen phosphate, sodium hydroxide, sodium lactate, sodium phthalate,
sodium phosphate, sodium polyphosphate, sodium pyrophosphate, sodium sesquicarbonate, sodium
succinate, sodium tartrate, sodium tripolyphosphate, synthetic hydrotalcite, tetrapotassium
pyrophosphate, tetrasodium pyrophosphate, tripotassium phosphate, trisodium phosphate,
trometamol, trihydroxymethylaminomethane, an amino acid such as alanine, arginine, asparagine,
aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine,
methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine or the optically
active isomers thereof, or the racemic mixtures thereof, an acid salt of an amino acid, an alkali slat
of an amino acid or mixtures thereof.
16
In another general aspect, there are provided methods for treatment, control or prevention of
bacterial infection using the active ingredients according to the invention. In some embodiments,
there is provided a method for treatment, control or prevention of bacterial infection in a subject,
said method comprising administering to said subject an effective amount of active ingredients
according to the invention.
In some embodiments, the active ingredients according to the invention are used in
treatment, control or prevention of bacterial infection.
In other embodiments, the active ingredients according to the invention are administered by
any appropriate method, which serves to deliver the composition or its constituents to the desired
site. In case of methods using administration of active ingredients, the active ingredients may also
be administered by any appropriate method. The method of administration can vary depending on
various factors, such as for example, the nature of the active ingredients or the composition, the site
of the potential or actual infection, the microorganism involved, severity of infection, age and
physical condition of the subject and so on. In some embodiments, the active ingredients according
to the invention are administered parenterally. Some non-limiting examples of administration
methods according to the invention include intravenous, intraperitoneal, intramuscular, parenteral,
intratracheal, intrarectal and a like.
In another general aspect, the active ingredients according to the invention are used in
prophylactic treatment of a subject, comprising administering to a subject at risk of infection caused
by bacteria, a prophylactically effective amount the active ingredients according to the invention.
In general, the active ingredients according to the invention are effective against infections
caused by a wide variety of bacteria, including those exhibiting resistance to one or more of known
antibacterial agents or compositions. Some non-limiting examples of infections that can be treated,
controlled or prevented using the compositions and methods according the invention include
infections caused by bacteria belonging to genus Escherichia, Staphylococcus, Streptococcus,
Haemophilus, Klebsiella, Moraxella, Enterobacter, Proteus, Serratia, Pseudomonas, Acinetobacter,
Citrobacter, Stenotrophomonas, Bacteroides, Prevotella, Fusobacterium, Clostridium.
In general, the active ingredients according to the invention are useful in treatment, control
or prevention of several infections, including, for example, skin and soft tissue infections, febrile
neutropenia, urinary tract infections, intraabdominal infections, respiratory tract infections,
17
pneumonia (nosocomial), bacteremia, meningitis, diabetic foot infections, bone and joint infections,
surgical site infections, Shigella dysentery and the like.
It will be readily apparent to one skilled in the art that varying substitutions and
modifications may be made to the compositions and/or to the methods disclosed herein without
departing from the scope and spirit of the invention. For example, those skilled in the art will
recognize that the invention may be practiced using a variety of different ways within the described
generic descriptions.
EXAMPLES
The following examples illustrate the embodiments of the invention that are presently best
known. However, it is to be understood that the following are only exemplary or illustrative of the
application of the principles of the present invention. Numerous modifications and alternative
compositions, methods, and systems may be devised by those skilled in the art without departing
from the spirit and scope of the present invention. The appended claims are intended to cover such
modifications and arrangements. Thus, while the present invention has been described above with
particularity, the following examples provide further detail in connection with what are presently
deemed to be the most practical and preferred embodiments of the invention
The efficacy of methods according to the invention was investigated using neutropenic
murine lung infection model at doses which are corresponding to clinical doses of 2 gram of
cefepime and 2 gram of tazobactam q8h, and 30 to 90 min infusion. The protocol employed is a
widely employed approach to predict clinical efficacy of a given dosing regimen through mouse
models of infection. In a typical study, male and female Swiss albino mice weighing 25-27 gram
were rendered neutropenic with 150 and 100 mg/kg intraperitoneal injections of cyclophosphamide
(Endoxan-Asta) given 1 and 4 day prior to infection. Two hours prior to the initiation of
antimicrobial therapy, mice were instilled via intranasal route with 80 µl of bacterial suspension,
containing approximately 106
log10 CFU/ml of infecting pathogen (K. pneumoniae H524).
Beginning 2 hours after infection, groups of 6 mice were administered (subcutaneous route)
humanized doses of the cefepime and tazobactam. All doses were administered as 0.250 ml
subcutaneous injections at a frequency of q1h (every one hour) and q2h (2 hourly) dosing intervals
over 24 hours. Lungs from all the animals including untreated animals were harvested 3 hours post
last dose of regimen and individually homogenized in 3 ml normal saline. Bacterial count in
homogenized lungs were determined and expressed in colony forming unit (CFU) per lung.
18
Bacterial load in lungs of untreated animals enumerated at the time of initiation of therapy (2 hours
post infections) served as reference count to quantify the magnitude of antibacterial effect realized
through applied dosing regimens.
Cefepime + tazobactam
dose (mg/kg)
Dosing
regimen
Total daily dose
(mg/kg)
Corresponding clinical dose
50 + 50 q1h 1200 2 gram of cefepime + 2 gram of tazobactam
(90 min infusion)
100 + 100 q2h 1200 2 gram of cefepime + 2 gram of tazobactam
(30 min infusion)
To mimic 90 min infusion in human, cefepime + tazobactam combination was administered
every 1 hour over 24 hours. Similarly, to mimic 30 min infusion in human, the combination was
administered every 2 hours over 24 hours. The results obtained showed that, at a dose of 50 mg/kg
q1h mimicking 90 min infusion in humans resulted into 4.5 log kill of bacteria per lung over initial
bacterial lung load. While 100 mg/kg q2h mimicking 30 min infusion resulted into just 1.9 log kill.
The improvement in bactericidal effect by 90 min infusion is better than that obtained with a 30 min
infusion.
19
Claims
1. A method for treating bacterial infection in a subject by parenteral administration of
active ingredients, said active ingredients comprising: (a) about 0.50 gram to about 6 gram of
cefepime or a pharmaceutically acceptable salt thereof, (b) about 0.10 to 1.5 gram arginine or a
pharmaceutically acceptable salt thereof, per gram of cefepime or a pharmaceutically acceptable
salt thereof, and (c) about 0.50 gram to about 6 gram of tazobactam or a pharmaceutically
acceptable salt thereof; said method further characterized in that the ingredients are administered
parenterally over a period of about 15 minutes to about 24 hours.
2. The method according to Claim 1, wherein the active ingredients are administered in
the following amounts: (a) about 0.50 gram to about 6 gram of cefepime or a pharmaceutically
acceptable salt thereof, (b) about 0.50 to 0.90 gram arginine or a pharmaceutically acceptable salt
thereof, per gram of cefepime or a pharmaceutically acceptable salt thereof, and (c) about 0.50 gram
to about 6 gram of tazobactam or a pharmaceutically acceptable salt thereof.
3. The method according to Claim 1, wherein the active ingredients are administered in
the following amounts: (a) about 0.50 gram to about 6 gram of cefepime or a pharmaceutically
acceptable salt thereof, (b) about 0.70 to 0.80 gram arginine or a pharmaceutically acceptable salt
thereof, per gram of cefepime or a pharmaceutically acceptable salt thereof, and (c) about 0.50 gram
to about 6 gram of tazobactam or a pharmaceutically acceptable salt thereof.
4. The method according to Claim 1, wherein the active ingredients are administered in
the following amounts: (a) about 0.50 gram to about 3 gram of cefepime or a pharmaceutically
acceptable salt thereof, (b) about 0.10 to 1.5 gram arginine or a pharmaceutically acceptable salt
thereof, per gram of cefepime or a pharmaceutically acceptable salt thereof, and (c) about 0.50 gram
to about 3 gram of tazobactam or a pharmaceutically acceptable salt thereof.
5. The method according to Claim 1, wherein the active ingredients are administered in
the following amounts: (a) about 0.50 gram to about 3 gram of cefepime or a pharmaceutically
acceptable salt thereof, (b) about 0.50 to 0.90 gram arginine or a pharmaceutically acceptable salt
thereof, per gram of cefepime or a pharmaceutically acceptable salt thereof, and (c) about 0.50 gram
to about 3 gram of tazobactam or a pharmaceutically acceptable salt thereof.
20
6. The method according to Claim 1, wherein the active ingredients are administered in
the following amounts: (a) about 0.50 gram to about 3 gram of cefepime or a pharmaceutically
acceptable salt thereof, (b) about 0.70 to 0.80 gram arginine or a pharmaceutically acceptable salt
thereof, per gram of cefepime or a pharmaceutically acceptable salt thereof, and (c) about 0.50 gram
to about 3 gram of tazobactam or a pharmaceutically acceptable salt thereof.
7. The method according to Claim 1, wherein the active ingredients are administered in
the following amounts: (a) about 1 gram of cefepime or a pharmaceutically acceptable salt thereof,
(b) about 0.70 to 0.80 gram arginine or a pharmaceutically acceptable salt thereof, per gram of
cefepime or a pharmaceutically acceptable salt thereof, and (c) about 1 gram of tazobactam or a
pharmaceutically acceptable salt thereof.
8. The method according to Claim 1, wherein the active ingredients are administered in
the following amounts: (a) about 2 gram of cefepime or a pharmaceutically acceptable salt thereof,
(b) about 0.70 to 0.80 gram arginine or a pharmaceutically acceptable salt thereof, per gram of
cefepime or a pharmaceutically acceptable salt thereof, and (c) about 2 gram of tazobactam or a
pharmaceutically acceptable salt thereof.
9. The method according to any one of the Claims 1 to 8, wherein the active ingredients
are administered parenterally over a period of about 15 minutes to about 250 minutes.
10. The method according to any one of the Claims 1 to 8, wherein the active ingredients
are administered parenterally over a period of about 30 minutes to about 120 minutes.
11. The method according to any one of the Claims 1 to 8, wherein the active ingredients
are administered parenterally over a period of about 30 minutes to about 90 minutes.
12. The method according to any one of the Claims 1 to 11, wherein the ingredients are
administered simultaneously or one after the other.
13. The method according to any one of the Claims 1 to 12, wherein active ingredients
are administered in the form of a solution, the solution being obtained by adding the active
ingredients to a compatible liquid diluent.
21
14. The method according to any one of the Claims 1 to 12, wherein each of the active
ingredients is administered independently in the form of a solution, the solution being obtained by
dissolving the active ingredient in a compatible liquid diluent.
15. The method according to any one of the Claims 1 to 14, wherein the active
ingredients are administered one, two, three or four times a day.
16. The method according to any one of the Claims 1 to 14, wherein the active
ingredients are administered every 6 hours, 8 hours, 12 hours or 24 hours.
17. Use of active ingredients in a method for treating bacterial infection in a subject, said
active ingredients comprising: (a) about 0.50 gram to about 6 gram of cefepime or a
pharmaceutically acceptable salt thereof, (b) about 0.10 to 1.5 gram arginine or a pharmaceutically
acceptable salt thereof, per gram of cefepime or a pharmaceutically acceptable salt thereof, and (c)
about 0.50 gram to about 6 gram of tazobactam or a pharmaceutically acceptable salt thereof; said
method comprising that the active ingredients are administered parenterally over a period of about
15 minutes to about 24 hours.
18. The use according to Claim 17, wherein the active ingredients comprise: (a) about
0.50 gram to about 6 gram of cefepime or a pharmaceutically acceptable salt thereof, (b) about 0.50
to 0.90 gram arginine or a pharmaceutically acceptable salt thereof, per gram of cefepime or a
pharmaceutically acceptable salt thereof, and (c) about 0.50 gram to about 6 gram of tazobactam or
a pharmaceutically acceptable salt thereof.
19. The use according to Claim 17, wherein the active ingredients comprise: (a) about
0.50 gram to about 6 gram of cefepime or a pharmaceutically acceptable salt thereof, (b) about 0.70
to 0.80 gram arginine or a pharmaceutically acceptable salt thereof, per gram of cefepime or a
pharmaceutically acceptable salt thereof, and (c) about 0.50 gram to about 6 gram of tazobactam or
a pharmaceutically acceptable salt thereof.
20. The use according to Claim 17, wherein the active ingredients comprise: (a) about
0.50 gram to about 3 gram of cefepime or a pharmaceutically acceptable salt thereof, (b) about 0.10
to 1.5 gram arginine or a pharmaceutically acceptable salt thereof, per gram of cefepime or a
pharmaceutically acceptable salt thereof, and (c) about 0.50 gram to about 3 gram of tazobactam or
a pharmaceutically acceptable salt thereof.
22
21. The use according to Claim 17, wherein the active ingredients comprise: (a) about
0.50 gram to about 3 gram of cefepime or a pharmaceutically acceptable salt thereof, (b) about 0.50
to 0.90 gram arginine or a pharmaceutically acceptable salt thereof, per gram of cefepime or a
pharmaceutically acceptable salt thereof, and (c) about 0.50 gram to about 3 gram of tazobactam or
a pharmaceutically acceptable salt thereof.
22. The use according to Claim 17, wherein the active ingredients comprise: (a) about
0.50 gram to about 3 gram of cefepime or a pharmaceutically acceptable salt thereof, (b) about 0.70
to 0.80 gram arginine or a pharmaceutically acceptable salt thereof, per gram of cefepime or a
pharmaceutically acceptable salt thereof, and (c) about 0.50 gram to about 3 gram of tazobactam or
a pharmaceutically acceptable salt thereof.
23. The use according to Claim 17, wherein the active ingredients comprise: (a) about 1
gram of cefepime or a pharmaceutically acceptable salt thereof, (b) about 0.70 to 0.80 gram arginine
or a pharmaceutically acceptable salt thereof, per gram of cefepime or a pharmaceutically
acceptable salt thereof, and (c) about 1 gram of tazobactam or a pharmaceutically acceptable salt
thereof.
24. The use according to Claim 17, wherein the active ingredients comprise: (a) about 2
gram of cefepime or a pharmaceutically acceptable salt thereof, (b) about 0.70 to 0.80 gram arginine
or a pharmaceutically acceptable salt thereof, per gram of cefepime or a pharmaceutically
acceptable salt thereof, and (c) about 2 gram of tazobactam or a pharmaceutically acceptable salt
thereof.
25. The use according to any one of Claims 17 to 24, wherein the active ingredients are
administered parenterally over a period of about 15 minutes to about 250 minutes.
26. The use according to any one of Claims 17 to 24, wherein the active ingredients are
administered parenterally over a period of about 30 minutes to about 120 minutes.
27. The use according to any one of Claims 17 to 24, wherein the active ingredients are
administered parenterally over a period of about 30 minutes to about 90 minutes.
28. The use according to any one of Claims 17 to 24, wherein the ingredients are
administered simultaneously or one after the other.
23
29. The use according to any one of Claims 17 to 24, wherein the active ingredients are
administered one, two, three or four times a day.
30. The use according to any one of Claims 17 to 24, wherein the active ingredients are
administered every 6 hours, 8 hours, 12 hours or 24 hours.