DESC:RELATED PATENT APPLICATIONS
This application claims the priority to and benefit of Indian Provisional Patent
Application No. 201721013819 filed on April 18, 2017; 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 treating or
preventing bacterial infections.
BACKGROUND OF THE INVENTION
Bacterial infections continue to remain one of the major causes contributing towards
human diseases. One of the key challenges in treatment of bacterial infections is the ability
of bacteria to develop resistance to one or more antibacterial agents over time. Examples of
such bacteria that have developed resistance to typical antibacterial agents include: Penicillinresistant
Streptococcus pneumoniae, Vancomycin-resistant Enterococci, and Methicillinresistant
Staphylococcus aureus. The problem of emerging drug-resistance in bacteria is often
tackled by switching to newer antibacterial agents, which can be more expensive and
sometimes more toxic. Additionally, this may not be a permanent solution as the bacteria
often develop resistance to the newer antibacterial agents as well in due course. In general,
bacteria are particularly efficient in developing resistance, because of their ability to multiply
very rapidly and pass on the resistance genes as they replicate.
Treatment of infections caused by resistant bacteria remains a key challenge for the
clinician community. One example of such challenging pathogen is Acinetobacter baumannii
(A. baumannii), which continues to be an increasingly important and demanding species in
healthcare settings. The multidrug resistant nature of this pathogen and its unpredictable
susceptibility patterns make empirical and therapeutic decisions more difficult. A. baumannii
is associated with infections such as pneumonia, bacteremia, wound infections, urinary tract
infections and meningitis.
3
Therefore, there is a need for development of newer ways to treat infections that are
becoming resistant to known therapies and methods. Surprisingly, it has been found that a
compositions comprising meropenem and certain nitrogen containing bicyclic compounds
(disclosed in PCT/IB2012/054706) exhibit unexpectedly synergistic antibacterial activity,
even against highly resistant bacterial strains.
SUMMARY OF THE INVENTION
Accordingly, there are provided pharmaceutical compositions comprising: (a)
meropenem or a pharmaceutically acceptable derivative thereof, and (b) a compound of
Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof:
N
N
O
SO3H
O
NC
Formula (I)
In one general aspect, there are provided pharmaceutical compositions comprising: (a)
meropenem or a pharmaceutically acceptable derivative thereof, and (b) a compound of
Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof; wherein a
compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative
thereof is present in the composition in an amount from about 0.125 gram to about 4 gram per
gram of meropenem or a pharmaceutically acceptable derivative thereof.
In yet another general aspect, there are provided methods for treating or preventing a
bacterial infection in a subject, said methods comprising administering to said subject an
effective amount of a pharmaceutical composition comprising: (a) meropenem or a
pharmaceutically acceptable derivative thereof; and (b) a compound of Formula (I) or a
stereoisomer or a pharmaceutically acceptable derivative thereof.
4
In another general aspect, there are provided methods for treating or preventing a
bacterial infection in a subject, said methods comprising administering to said subject an
effective amount of a pharmaceutical composition comprising: (a) meropenem or a
pharmaceutically acceptable derivative thereof, and (b) a compound of Formula (I) or a
stereoisomer or a pharmaceutically acceptable derivative thereof; wherein a compound of
Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof is present in
the composition in an amount from about 0.125 gram to about 4 gram per gram of
meropenem or a pharmaceutically acceptable derivative thereof.
In yet another general aspect, there are provided methods for treating or preventing a
bacterial infection in a subject, said methods comprising administering to said subject an
effective amount of: (a) meropenem or a pharmaceutically acceptable derivative thereof; and
(b) a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative
thereof.
In another general aspect, there are provided methods for treating or preventing a
bacterial infection in a subject, said methods comprising administering to said subject an
effective amount of: (a) meropenem or a pharmaceutically acceptable derivative thereof, and
(b) a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative
thereof; wherein a compound of Formula (I) or a stereoisomer or a pharmaceutically
acceptable derivative thereof is administered in an amount from about 0.125 gram to about 4
gram per gram of meropenem or a pharmaceutically acceptable derivative thereof.
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
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
5
modifications of the inventive features illustrated herein, which would occur to one skilled 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 as if fully
rewritten herein.
The inventors have surprisingly discovered that a pharmaceutical composition
comprising: (a) meropenem or a pharmaceutically acceptable derivative thereof, and (b) a
compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative
thereof exhibits unexpectedly improved antibacterial efficacy, even against highly resistant
bacteria, including those producing extended spectrum beta-lactamase enzymes (ESBLs).
The term “infection” or “bacterial infection” as used herein 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 presence of other floras, which are not desirable. The term “infection” includes
infection caused by bacteria.
The term “treat”, “treating” or “treatment” as used herein refers to administration of a
medicament, including a pharmaceutical composition, or one or more pharmaceutically active
ingredients, for 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 pharmaceutically active ingredients discussed herein, with or without additional
pharmaceutically active or inert ingredients, in order to: (i) reduce or eliminate either a
bacterial infection, or one or more symptoms of a bacterial infection, or (ii) retard progression
of a bacterial infection, or one or more symptoms of a bacterial infection, or (iii) reduce
severity of a bacterial infection, or one or more symptoms of a bacterial infection, or (iv)
suppress clinical manifestation of a bacterial infection, or (v) suppress manifestation of
adverse symptoms of a bacterial infection.
6
The terms “pharmaceutically effective amount” or “therapeutically effective amount”
or “effective amount” as used herein refer 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 effective amount” or “pharmaceutically effective amount” or “effective
amount” of an antibacterial agent or a pharmaceutical composition is the amount of the
antibacterial agent 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). Such 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 particular type of the antibacterial agent used. For prophylactic
treatments, a prophylactically effective amount is that amount which would be effective in
preventing the bacterial infection.
The term “administration” or “administering” refers to and includes delivery of a
composition, or one or more pharmaceutically active ingredients to a subject, including for
example, by any appropriate method, which serves to deliver the composition or its active
ingredients or other pharmaceutically active ingredients to the site of infection. The method
of administration may vary depending on various factors, such as for example, the
components of the pharmaceutical composition or type/nature of the pharmaceutically active
or inert ingredients, 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 nonlimiting
examples of ways to administer a composition or a pharmaceutically active
ingredient to a subject according to this invention include oral, intravenous, topical,
intrarespiratory, intraperitoneal, intramuscular, parenteral, sublingual, transdermal, intranasal,
aerosol, intraocular, intratracheal, intrarectal, vaginal, gene gun, dermal patch, eye drop and
mouthwash. In case of a pharmaceutical composition comprising more than one ingredients
(active or inert), one of the ways of 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 or 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 composition as a whole provides
a synergistic and/or desired effect.
7
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 the
microorganism, including the processes that keep the microorganism alive.
The term, “effectiveness” as used herein refers to ability of a treatment, or a
composition, or one or more pharmaceutically active ingredients to produce a desired
biological effect in a subject. For example, the term “antibacterial effectiveness” of a
composition or of an antibacterial agent refers to the ability of the composition or the
antibacterial agent to prevent or treat 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, 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 environment. The term “antibacterial agent” also refers to compounds
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” or “beta-lactamase enzyme” 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
hydrolyse the beta-lactam ring in a beta-lactam compound, either partially or completely.
The term “extended spectrum beta-lactamase” (ESBL) as used herein includes those
beta-lactamase enzymes, which are capable of conferring bacterial resistance to various betalactam
antibacterial agents such as penicillins, cephalosporins, aztreonam and the like.
8
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 “colony forming units” or “CFU” as used herein refers to an estimate of
number of viable bacterial cells per ml of the sample. Typically, a “colony of bacteria” refers
to a mass of individual bacteria growing together.
The term “pharmaceutically inert ingredient” or “carrier” or “excipient” refers to and
includes compounds or materials used to facilitate administration of a compound, for
example, to increase the solubility of the compound. Typical, non-limiting examples of solid
carriers include starch, lactose, dicalcium phosphate, sucrose, and kaolin. Typical, nonlimiting
examples of liquid carriers include sterile water, saline, buffers, non-ionic
surfactants, and edible oils. In addition, various adjuvants commonly used in the art may also
be included. These and other such compounds are described in literature, e.g., in the Merck
Index (Merck & Company, Rahway, N.J.). Considerations for inclusion of various
components in pharmaceutical compositions are described, e.g., in Gilman et al. (Goodman
and Gilman’s: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press., 1990),
which is incorporated herein by reference in its entirety.
The term “subject” as used herein refers to 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” include humans, cats, dogs, horses, sheep,
bovine cows, pigs, lambs, rats, mice and guinea pigs.
The term “pharmaceutically acceptable derivative” as used herein refers to and
includes any pharmaceutically acceptable salt, pro-drug, metabolite, ester, ether, hydrate,
polymorph, solvate, complex, and adduct of a compound described herein which, upon
administration to a subject, is capable of providing (directly or indirectly) the parent
compound. For example, the term “antibacterial agent or a pharmaceutically acceptable
derivative thereof” includes all derivatives of the antibacterial agent (such as salts, pro-drugs,
metabolites, esters, ethers, hydrates, polymorphs, solvates, complexes, and adducts) which,
upon administration to a subject, are capable of providing (directly or indirectly) the
antibacterial agent.
9
The term “pharmaceutically acceptable salt” as used herein refers to one or more salts
of a given compound which possesses desired pharmacological activity of the free compound
and which is neither biologically nor otherwise undesirable. In general, the term
“pharmaceutically acceptable salts” refer to 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 “stereoisomer” as used herein refers to and includes isomeric molecules that
have the same molecular formula but differ in positioning of atoms and/or functional groups
in the space. Stereoisomers may further be classified as enantiomers (where different isomers
are mirror-images of each other) and diastereomers (where different isomers are not mirrorimages
of each other). Diastereomers include isomers such as conformers, meso compounds,
cis-trans (E-Z) isomers, and non-enantiomeric optical isomers.
A person of skills in the art would appreciate that various compounds described
herein (including, for example a compound of Formula (I) and meropenem) can exist and are
often used as their pharmaceutically acceptable derivatives (such as salts, pro-drugs,
metabolites, esters, ethers, hydrates, polymorphs, solvates, complexes, and adducts).
In one general aspect, there are provided pharmaceutical compositions comprising: (a)
meropenem or a pharmaceutically acceptable derivative thereof, and (b) a compound of
Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof:
N
N
O
SO3H
O
NC
Formula (I)
10
Compound of Formula (I), according to the invention can be used in various forms
including as such, a stereoisomer or a pharmaceutically acceptable derivative thereof. A
compound of Formula (I) (CAS Registry Number: 1427462-70-1) may also be known
chemically by different names including the following: (a) “trans-7-oxo-6-(sulphooxy)-1,6-
diazabicyclo[3.2.1]octane-2-carbonitrile”; (b) “(2S, 5R)-7-oxo-6-(sulphooxy)-1,6-
diazabicyclo[3.2.1]octane-2-carbonitrile”; or (c) “Sulphuric acid, mono[(1R,2S,5R)-2-cyano-
7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl] ester”. A reference to “a compound of Formula (I)” is
intended to include compounds chemically known as: (a) “trans-7-oxo-6-(sulphooxy)-1,6-
diazabicyclo[3.2.1]octane-2-carbonitrile”; (b) “(2S, 5R)-7-oxo-6-(sulphooxy)-1,6-
diazabicyclo[3.2.1]octane-2-carbonitrile”; or (c) “Sulphuric acid, mono[(1R,2S,5R)-2-cyano-
7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl] ester”.
Compound of Formula (I) may also be used in the form of its stereoisomer or a
pharmaceutically acceptable derivative thereof. Typical, non-limiting examples of suitable
pharmaceutically acceptable derivatives of a compound of Formula (I) include its sodium salt
(also known as “sodium salt of sulphuric acid, mono[(1R,2S,5R)-2-cyano-7-oxo-1,6-
diazabicyclo[3.2.1]oct-6-yl] ester” or “sulphuric acid, mono[(1R,2S,5R)-2-cyano-7-oxo-1,6-
diazabicyclo[3.2.1]oct-6-yl] ester, sodium salt (1:1); CAS Registry Number: 1427462-59-6”);
potassium salt (also known as “potassium salt of sulphuric acid, mono[(1R,2S,5R)-2-cyano-
7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl] ester” or “sulphuric acid, mono[(1R,2S,5R)-2-cyano-
7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl] ester, potassium salt (1:1); CAS Registry Number:
1427462-60-9”); and other salts such as “1-Butanaminium, N,N,N-tributyl-, (1R,2S,5R)-2-
cyano-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl sulphate (1:1); CAS Registry Number:
1427462-72-3”.
In another general aspect, there are provided pharmaceutical compositions
comprising: (a) meropenem or a pharmaceutically acceptable derivative thereof, and (b) a
compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative
thereof; wherein a compound of Formula (I) or a stereoisomer or a pharmaceutically
acceptable derivative thereof is present in the composition in an amount from about 0.125
gram to about 4 gram per gram of meropenem or a pharmaceutically acceptable derivative
thereof.
11
Both, meropenem and a compound of Formula (I) may be present in the composition
in their free forms or in the form of their pharmaceutically acceptable derivatives (such as
salts, pro-drugs, metabolites, esters, ethers, hydrates, polymorphs, solvates, complexes, or
adducts).
Individual amounts of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and meropenem or pharmaceutically
acceptable derivative thereof in the composition may vary depending on clinical
requirements. In some embodiments, a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof in the composition is present in an amount
from about 0.01 gram to about 10 gram. In some other embodiments, meropenem or a
pharmaceutically acceptable derivative thereof in the composition is present in an amount
from about 0.01 gram to about 10 gram.
In some embodiments, the pharmaceutical composition according to the invention
comprises about 0.125 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 0.5 gram of meropenem or a
pharmaceutically acceptable derivative thereof.
In some embodiments, the pharmaceutical composition according to the invention
comprises about 0.25 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 0.5 gram of meropenem or a
pharmaceutically acceptable derivative thereof.
In some other embodiments, the pharmaceutical composition according to the
invention comprises about 0.5 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 0.5 gram of meropenem or a
pharmaceutically acceptable derivative thereof.
In some embodiments, the pharmaceutical composition according to the invention
comprises about 1 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 0.5 gram of meropenem or a
pharmaceutically acceptable derivative thereof.
12
In some embodiments, the pharmaceutical composition according to the invention
comprises about 2 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 0.5 gram of meropenem or a
pharmaceutically acceptable derivative thereof.
In some other embodiments, the pharmaceutical composition according to the
invention comprises about 0.125 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 1 gram of meropenem or a
pharmaceutically acceptable derivative thereof.
In some other embodiments, the pharmaceutical composition according to the
invention comprises about 0.25 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 1 gram of meropenem or a
pharmaceutically acceptable derivative thereof.
In some embodiments, the pharmaceutical composition according to the invention
comprises about 0.5 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 1 gram of meropenem or a
pharmaceutically acceptable derivative thereof.
In some embodiments, the pharmaceutical composition according to the invention
comprises about 1 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 1 gram of meropenem or a
pharmaceutically acceptable derivative thereof.
In some embodiments, the pharmaceutical composition according to the invention
comprises about 2 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 1 gram of meropenem or a
pharmaceutically acceptable derivative thereof.
In some embodiments, the pharmaceutical composition according to the invention
comprises about 4 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 1 gram of meropenem or a
pharmaceutically acceptable derivative thereof.
13
In some embodiments, the pharmaceutical composition according to the invention
comprises about 0.125 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 2 gram of meropenem or a
pharmaceutically acceptable derivative thereof.
In some embodiments, the pharmaceutical composition according to the invention
comprises about 0.250 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 2 gram of meropenem or a
pharmaceutically acceptable derivative thereof.
In some embodiments, the pharmaceutical composition according to the invention
comprises about 0.5 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 2 gram of meropenem or a
pharmaceutically acceptable derivative thereof.
In some embodiments, the pharmaceutical composition according to the invention
comprises about 1 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 2 gram of meropenem or a
pharmaceutically acceptable derivative thereof.
In some embodiments, the pharmaceutical composition according to the invention
comprises about 2 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 2 gram of meropenem or a
pharmaceutically acceptable derivative thereof.
In some embodiments, the pharmaceutical composition according to the invention
comprises about 4 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 2 gram of meropenem or a
pharmaceutically acceptable derivative thereof.
The pharmaceutical compositions according to the invention may include one or more
pharmaceutically acceptable carriers or excipients or the like. Typical, non-limiting examples
of such carriers or excipients include mannitol, lactose, starch, magnesium stearate, sodium
14
saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatine, sucrose, magnesium
carbonate, wetting agents, emulsifying agents, solubilizing agents, buffering agents,
lubricants, preservatives, stabilizing agents, binding agents and the like.
The pharmaceutical compositions or the active ingredients according to the present
invention may be formulated into a variety of dosage forms, such as solid, semi-solid, liquid
and aerosol dosage forms. Typical, non-limiting examples of some dosage forms include
tablets, capsules, powders, solutions, suspensions, suppositories, aerosols, granules,
emulsions, syrups, elixirs and the like.
In some embodiments, pharmaceutical compositions according to the invention are in
the form of a powder or a solution. In some other embodiments, pharmaceutical compositions
according to the invention are present in the form of a powder or a solution that can be
reconstituted by addition of a compatible reconstitution diluent prior to administration. In
some other embodiments, pharmaceutical compositions according to the invention are in the
form of a frozen composition that can be diluted with a compatible reconstitution diluent
prior to administration. Typical, non-limiting example of suitable compatible reconstitution
diluent includes water.
In some other embodiments, pharmaceutical compositions according to the invention
are present in the form ready to use for parenteral administration.
The compositions according to the invention can be formulated into various dosage
forms wherein the active ingredients and/or excipients may be present either together (e.g. as
an admixture) or as separate components. When the various ingredients in the composition
are formulated as a mixture, such compositions can be delivered by administering such a
mixture to a subject using any suitable route of administration. Alternatively, pharmaceutical
compositions according to the invention may also be formulated into a dosage form wherein
one or more ingredients (such as active or inactive ingredients) are present as separate
components. The composition or dosage form wherein the ingredients do not come as a
mixture, but come as separate components, such composition/dosage form may be
administered in several ways. In one possible way, the ingredients may be mixed in the
desired proportions and the mixture is reconstituted in suitable reconstitution diluent and is
then administered as required. Alternatively, the components or the ingredients (active or
15
inert) may be separately administered (simultaneously or one after the other) in appropriate
proportion so as to achieve the same or equivalent therapeutic level or effect as would have
been achieved by administration of the equivalent mixture.
In some embodiments, pharmaceutical compositions according to the invention are
formulated into a dosage form such that a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and meropenem or a pharmaceutically
acceptable derivative thereof, are present in the composition as admixture or as a separate
components. In some other embodiments, pharmaceutical compositions according to the
invention are formulated into a dosage form such that a compound of Formula (I) or a
stereoisomer or a pharmaceutically acceptable derivative thereof, and meropenem or a
pharmaceutically acceptable derivative thereof, are present in the composition as separate
components.
In one general aspect, pharmaceutical compositions according to the invention are
used in treatment or prevention of a bacterial infection.
In another general aspect, there are provided methods for treating or preventing a
bacterial infection in a subject, said method comprising administering to said subject
effective amount of a pharmaceutical composition according to the invention. In case of
dosage forms wherein a compound of Formula (I) or a stereoisomer or a pharmaceutically
acceptable derivative thereof, and meropenem or a pharmaceutically acceptable derivative
thereof, are present in the composition as separate components; a compound of Formula (I) or
a stereoisomer or a pharmaceutically acceptable derivative thereof may be administered
before, after or simultaneously with the administration of meropenem or a pharmaceutically
acceptable derivative thereof.
In yet another general aspect, there are provided methods for treating or preventing
bacterial infections in a subject, said methods comprising administering to said subject an
effective amount of: (a) meropenem or a pharmaceutically acceptable derivative thereof, and
(b) a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative
thereof:
16
N
N
O
SO3H
O
NC
Formula (I)
In another general aspect, there are provided methods for treating or preventing
bacterial infections in a subject, said methods comprising administering to said subject an
effective amount of: (a) meropenem or a pharmaceutically acceptable derivative thereof, and
(b) a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative
thereof; wherein amount of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof administered is from about 0.125 gram to
about 4 gram per gram of meropenem or a pharmaceutically acceptable derivative thereof.
In some embodiments, there is provided a method for treating or preventing a
bacterial infection in a subject, said method comprising administering to said subject: (a)
meropenem or a pharmaceutically acceptable derivative thereof, and (b) a compound of
Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, in any of
the following amounts:
(i) about 0.125 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 0.5 gram of meropenem or a
pharmaceutically acceptable derivative thereof;
(ii) about 0.25 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 0.5 gram of meropenem or a
pharmaceutically acceptable derivative thereof;
(iii) about 0.5 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 0.5 gram of meropenem or a
pharmaceutically acceptable derivative thereof;
17
(iv) about 1 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 0.5 gram of meropenem or a
pharmaceutically acceptable derivative thereof;
(v) about 2 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 0.5 gram of meropenem or a
pharmaceutically acceptable derivative thereof;
(vi) about 0.125 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 1 gram of meropenem or a
pharmaceutically acceptable derivative thereof;
(vii) about 0.25 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 1 gram of meropenem or a
pharmaceutically acceptable derivative thereof;
(viii) about 0.5 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 1 gram of meropenem or a
pharmaceutically acceptable derivative thereof;
(ix) about 1 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 1 gram of meropenem or a
pharmaceutically acceptable derivative thereof;
(x) about 2 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 1 gram of meropenem or a
pharmaceutically acceptable derivative thereof;
(xi) about 4 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 1 gram of meropenem or a
pharmaceutically acceptable derivative thereof;
(xii) about 0.125 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 2 gram of meropenem or a
pharmaceutically acceptable derivative thereof;
18
(xiii) about 0.25 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 2 gram of meropenem or a
pharmaceutically acceptable derivative thereof;
(xiv) about 0.5 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 2 gram of meropenem or a
pharmaceutically acceptable derivative thereof;
(xv) about 1 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 2 gram of meropenem or a
pharmaceutically acceptable derivative thereof;
(xvi) about 2 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 2 gram of meropenem or a
pharmaceutically acceptable derivative thereof; or
(xvii) about 4 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 2 gram of meropenem or a
pharmaceutically acceptable derivative thereof.
In some embodiments, in the methods according to the invention, a compound of
Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof is
administered in an amount from about 0.01 gram to about 10 gram. In some other
embodiments, in the methods according to the invention, meropenem or a pharmaceutically
acceptable derivative thereof is administered in an amount from about 0.01 gram to about 10
gram.
In some embodiments, in the methods according to the invention, a compound of
Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof is
administered before, after or simultaneously with the administration of meropenem or a
pharmaceutically acceptable derivative thereof.
19
In the methods according to the invention, the pharmaceutical composition and/or
other pharmaceutically active ingredients disclosed herein may be administered by any
appropriate method, which serves to deliver the composition, or its constituents, or the active
ingredients to the desired site. The method of administration can vary depending on various
factors, such as for example, the components of the pharmaceutical composition and the
nature of the active ingredients, the site of the potential or actual infection, the microorganism
(e.g. bacteria) involved, severity of infection, age and physical condition of the subject. Some
non-limiting examples of administering the composition to a subject according to this
invention include oral, intravenous, topical, intrarespiratory, intraperitoneal, intramuscular,
parenteral, sublingual, transdermal, intranasal, aerosol, intraocular, intratracheal, intrarectal,
vaginal, gene gun, dermal patch, eye drop, ear drop or mouthwash. In some embodiments, the
compositions or one or more active ingredients according to the invention are administered
parenterally.
In some embodiments, in the compositions and methods according to the invention, a
compound of Formula (I) is “(2S, 5R)-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-
carbonitrile”. In some other embodiments, in the compositions and methods according to the
invention, a compound of Formula (I) is: “sulphuric acid, mono[(1R,2S,5R)-2-cyano-7-oxo-
1,6-diazabicyclo[3.2.1]oct-6-yl] ester”. In some embodiments, in compositions and methods
according to the invention, a compound of Formula (I) is present as a sodium or potassium
salt of “sulphuric acid, mono[(1R,2S,5R)-2-cyano-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]
ester”.
In some embodiments, there is provided a method for increasing antibacterial
effectiveness of meropenem or a pharmaceutically acceptable derivative thereof in a subject,
said method comprising co-administering meropenem or a pharmaceutically acceptable
derivative thereof, with a compound of Formula (I) or a stereoisomer or a pharmaceutically
acceptable derivative thereof. In some other embodiments, there is provided a method for
increasing antibacterial effectiveness of meropenem or a pharmaceutically acceptable
derivative thereof in a subject, said method comprising co-administering meropenem or a
pharmaceutically acceptable derivative thereof, with a compound of Formula (I) or a
stereoisomer or a pharmaceutically acceptable derivative thereof, wherein the amount of a
compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative
20
thereof is from about 0.125 gram to about 4 gram per gram of meropenem or a
pharmaceutically acceptable derivative thereof.
A wide variety of bacterial infections can be treated or prevented using compositions
and methods according to the invention. Typical, non-limiting examples of bacterial
infections that can be treated or prevented using methods and/or pharmaceutical compositions
according to the invention include E. coli infections, Yersinia pestis (pneumonic plague),
staphylococcal infection, mycobacteria infection, bacterial pneumonia, Shigella dysentery,
Serratia infections, Candida infections, Cryptococcal infection, anthrax, tuberculosis or
infections caused by Pseudomonas aeruginosa, Acinetobacter baumannii or methicillin
resistant Staphylococcus aurues (MRSA) etc.
The pharmaceutical compositions and methods according to the invention are useful
in treatment or prevention of several infections, including for example, skin and soft tissue
infections, febrile neutropenia, urinary tract infection, intraabdominal infections, respiratory
tract infections, pneumonia (nosocomial), bacteremia meningitis, surgical infections and the
like.
In some embodiments, pharmaceutical compositions and methods according to the
invention are used in treatment or prevention of infections caused by resistant bacteria. In
some other embodiments, the compositions and methods according to the invention are used
in treatment or prevention of infections caused by bacteria producing one or more betalactamase
enzymes.
In general, the pharmaceutical compositions and methods disclosed herein are also
effective in preventing or treating infections caused by bacteria that are considered to be less
or not susceptible to one or more of known antibacterial agents or their known compositions.
Some non-limiting examples of such bacteria known to have developed resistance to various
antibacterial agents include Acinetobacter, Escherichia coli, Pseudomonas aeruginosa,
Staphylococcus aureus, Enterobacter, Klebsiella, Citrobacter and a like.
21
EXAMPLES
The following examples illustrate 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
embodiments of the invention.
The antibacterial activity of combinations according to the invention was investigated
against various bacterial strains. In a typical study, minimum inhibitory concentrations (MIC)
were determined using Muller Hinton Agar (MHA) (BD, USA) according to Clinical and
Laboratory Standards Institute (CLSI) recommendations, (Clinical and Laboratory Standards
Institute (CLSI), Performance Standards for Antimicrobial Susceptibility Testing, 20th
Informational Supplement, M 100-S20, Volume 30, No. 1, 2010). In short, the inocula were
adjusted to deliver about 104 colony forming units (CFU) per spot with a multipoint
inoculator (Applied Quality Services, UK). The plates were pored with doubling
concentration range of the test combinations according to invention containing MHA. The
plates were inoculated and were incubated at 35ºC for 18 hours. MICs were read as the
lowest concentration of drug that completely inhibited bacterial growth.
Example 1
The results of antibacterial activity of combination of meropenem and the compound
of Formula (I) against highly resistant strains like Acinetobacter baumannii harbouring
carbapenem hydrolyzing (CHDL) OXA beta-lactamases, K. pneumonia harbouring Klebsiella
pneumonia carbapenemases (KPC) and Enterobacter cloacae harbouring Klebsiella
pneumonia carbapenemases are given in Table 1. As may be seen, the data in Table 1 reveals
that both meropenem and compound of Formula (I) when used alone exhibited higher MIC
values. However, the MIC values of meropenem lowered significantly in presence of the
compound of Formula (I) (at 4 and 8 mcg/ml). The MIC values of meropenem reduced from
22
8 - 256 mcg/ml to about 0.12 - 2 mcg/ml in presence of the compound of Formula (I) (at 4
and 8 mcg/ml).
The results given in the Table 1, clearly and surprisingly demonstrate the potent
antibacterial activity of combinations comprising meropenem and a compound of Formula (I)
against highly resistant bacterial strains. Thus, combination of meropenem and a compound
of Formula (I) has tremendous beneficial effect in inhibiting highly resistant bacterial strains
demonstrating the noteworthy therapeutic advance in the treatment of infections caused by
such pathogens.
Table 1: Antimicrobial activity of the composition according to invention against various resistant bacterial
strains
Organisms Resistance
mechanisms
MIC (µg/ml)
Meropenem Compound of
Formula (I)
MIC of
Meropenem in
presence of
compound of
Formula (I)
(4 µg/ml)
MIC of
Meropenem in
presence of
compound of
Formula (I)
(8 µg/ml)
NCTC Acinetobacter
baumannii 13301
CHDL OXA-23
16 > 64 2 2
NCTC Acinetobacter
baumannii 13304
CHDL OXA-26 16 > 64 1 1
NCTC Acinetobacter
baumannii 13305
CHDL OXA-27 8 > 64 1 1
Acinetobacter
baumannii SL98
CHDL OXA-23 16 > 64 1 1
Acinetobacter
baumannii 1466116
CHDL OXA-23 32 > 64 2 2
K. pneumoniae J234 KPC 256 > 64 0.5 0.25
K. pneumoniae J235 KPC 128 > 64 0.25 0.25
K. pneumoniae J236 KPC 256 > 64 0.5 0.5
K. pneumoniae J237 KPC 32 > 64 0.12 0.12
K. pneumoniae J238 KPC 128 > 64 0.25 0.25
Enterobacter cloacae
J222
KPC 64 > 64 0.25 0.25
Example 2
Sterile Meropenem was aseptically blended or mixed with sterile compound of
Formula (I) for about 30 minutes at 8 rpm to obtain sterile dry powder for injection
23
(compositions shown in Table 1). Each single vial of this formulation may be reconstituted
with suitable reconstitution diluent prior to administration.
Table 1. Parenteral composition comprising Meropenem and compound of Formula (I)
Sr. Ingredient
Quantity
per vial
(1.5 g/vial)
Quantity
per vial
(2 g/vial)
Quantity
per vial
(3 g/vial)
Quantity
per vial
(4 g/vial)
1. Sterile Meropenem for Injection
USP
1 g 1 g 2 g 2 g
2. Sterile compound of Formula (I) 0.5 g 1 g 1 g 2 g
3. Buffering agent q.s q.s q.s. q.s. ,CLAIMS:1. A pharmaceutical composition comprising: (a) meropenem or a
pharmaceutically acceptable derivative thereof, and (b) a compound of Formula (I) or a
stereoisomer or a pharmaceutically acceptable derivative thereof:
N
N
O
SO3H
O
NC
Formula (I)
2. A pharmaceutical composition as claimed in Claim 1, wherein a compound of
Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof is present in
the composition in an amount from about 0.125 gram to about 4 gram per gram of
meropenem or a pharmaceutically acceptable derivative thereof.
3. A pharmaceutical composition as claimed in any of the Claims 1 or 2, wherein
a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative
thereof is present in the composition in an amount from about 0.01 gram to about 10 gram.
4. A pharmaceutical composition as claimed in any of the Claims 1 or 2, wherein
meropenem or a pharmaceutically acceptable derivative thereof is present in the composition
in an amount from about 0.01 gram to about 10 gram.
5. A pharmaceutical composition as claimed in any of the Claims 1 to 4,
comprising: (a) meropenem or a pharmaceutically acceptable derivative thereof, and (b) a
compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative
thereof, in any of the following amounts:
(i) about 0.125 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 0.5 gram of meropenem or a
pharmaceutically acceptable derivative thereof;
25
(ii) about 0.25 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 0.5 gram of meropenem or a
pharmaceutically acceptable derivative thereof;
(iii) about 0.5 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 0.5 gram of meropenem or a
pharmaceutically acceptable derivative thereof;
(iv) about 1 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 0.5 gram of meropenem or a
pharmaceutically acceptable derivative thereof;
(v) about 2 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 0.5 gram of meropenem or a
pharmaceutically acceptable derivative thereof;
(vi) about 0.125 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 1 gram of meropenem or a
pharmaceutically acceptable derivative thereof;
(vii) about 0.25 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 1 gram of meropenem or a
pharmaceutically acceptable derivative thereof;
(viii) about 0.5 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 1 gram of meropenem or a
pharmaceutically acceptable derivative thereof;
(ix) about 1 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 1 gram of meropenem or a
pharmaceutically acceptable derivative thereof;
26
(x) about 2 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 1 gram of meropenem or a
pharmaceutically acceptable derivative thereof;
(xi) about 4 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 1 gram of meropenem or a
pharmaceutically acceptable derivative thereof;
(xii) about 0.125 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 2 gram of meropenem or a
pharmaceutically acceptable derivative thereof;
(xiii) about 0.25 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 2 gram of meropenem or a
pharmaceutically acceptable derivative thereof;
(xiv) about 0.5 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 2 gram of meropenem or a
pharmaceutically acceptable derivative thereof;
(xv) about 1 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 2 gram of meropenem or a
pharmaceutically acceptable derivative thereof;
(xvi) about 2 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 2 gram of meropenem or a
pharmaceutically acceptable derivative thereof; or
(xvii) about 4 gram of a compound of Formula (I) or a stereoisomer or a
pharmaceutically acceptable derivative thereof, and about 2 gram of meropenem or a
pharmaceutically acceptable derivative thereof.
6. A pharmaceutical composition as claimed in any of the Claims 1 to 5, wherein
a compound of Formula (I) is: “(2S, 5R)-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-
2-carbonitrile”.
27
7. A pharmaceutical composition as claimed in any of the Claims 1 to 5, wherein
a compound of Formula (I) is: “sulphuric acid, mono[(1R,2S,5R)-2-cyano-7-oxo-1,6-
diazabicyclo[3.2.1]oct-6-yl] ester”.
8. A pharmaceutical composition as claimed in any of the Claims 1 to 5, wherein
a compound of Formula (I) is present as a sodium or potassium salt of “sulphuric acid,
mono[(1R,2S,5R)-2-cyano-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl] ester”.
9. A pharmaceutical composition as claimed in any of the Claims 1 to 8, wherein
the composition is formulated into a dosage form such that a compound of Formula (I) or a
stereoisomer or a pharmaceutically acceptable derivative thereof, and meropenem or a
pharmaceutically acceptable derivative thereof, are present in the composition as admixture
or as separate components.
10. A pharmaceutical composition as claimed in Claim 9, wherein the
composition is formulated into a dosage form such that a compound of Formula (I) or a
stereoisomer or a pharmaceutically acceptable derivative thereof, and meropenem or a
pharmaceutically acceptable derivative thereof, are present in the composition as separate
components.
11. A pharmaceutical composition as claimed in any of the Claims 1 to 10,
wherein the composition is in form of a powder or a solution.
12. A pharmaceutical composition as claimed in Claim 11, wherein the
composition is in the form of a powder or a solution that can be reconstituted by addition of a