DESC:Field of Invention
The present invention relates to an antibiotic pharmaceutical composition for the treatment of antibiotic resistant infection.
Background
Antimicrobial resistance is a well-known phenomenon which is a great concern 5 to public health affecting humans worldwide. Antibacterial resistance (ABR) is a major subset of antimicrobial resistance which occurs in bacteria where they no longer response to antibiotics possessing serious threat to human and animal welfare. There are four primary mechanism of antibiotic resistances: (1) Enzymatic inactivation of the antibiotic, (2) Drug excretion by activation of efflux 10 pumps, (3) Decreased uptake of the antibiotic by changes in the outer membrane permeability and (4) target site modification
Prior arts are present which teaches methods to block the aforementioned mechanisms of antibiotic resistance. In addition, to enhance the antimicrobial action of the drug, a great deal of research has recently been devoted to 15 exploring the potential of targeting bacterial pathogenicity. For example, to overcome Enzymatic inactivation, a new class of drugs called â-lactamase inhibitors have been developed which are used in combination with antibiotic to overcome MDR bacteria. Blocking the enzymatic inactivation of â-lactam by â-lactamase inhibitors has been reported to be the most validated approach with 20 numerous compounds, such as clavulanic acid, sulbactam and tazobactam
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[Gonzalez-Bello, C, Antibiotic adjuvants-A strategy to unlock bacterial resistance to antibiotics, Bioorganic & Medicinal Chemistry Letters, 27(2017) 4221-28]. But resistance against this combination has also been emerging. For e.g Wung Y. et al has reported on the resistance developed against the Antibiotic and â-lactamase inhibitor of Ceftazidime and Avibactam respectively [ Wang Y, Wang J, Wang R, 5 Cai Y. Resistance to ceftazidime-avibactam and underlying mechanisms. J Glob Antimicrob Resist. 2020 Sep;22:18-27]. Avibactam is a Diazabicycloocatane is a type of â-lactamase inhibitor which when combined with antibiotic (ceftazidime), has been shown to present inhibitory activity against most class A and C enzymes and has also proved to inhibit penicillin-binding proteins. 10
Thus there arises a need in the art to develop a therapy that can simultaneously act on all or multiple mechanism of antibiotic resistance. A way of achieving the same is combination therapy with agents having complementary mechanisms of action formulated in a single-dose form. Such a formulation has unique advantages such as complementary mechanism of action, synergistic effects, 15 better tolerability, elongated product life-cycle management, and cost savings. Use of such a formulation is a rational approach for achieving optimal therapeutic benefits while minimizing pill-burden. Greater convenience with decreased pill-burden leads to improved adherence, resulting in superior clinical outcomes and greater cost-effectiveness. 20
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A key step in designing of the combination is selection of effective and well- tolerated treatments. Moreover, it is essential that the components have complementary mechanisms of action and compatible pharmacokinetic profiles.
The inventors of present invention have surprisingly found that targeting more than one mechanism of antibiotic resistance can provide a more synergistic 5 effect. Thus the present invention provides a composition comprising an antibiotic and a synergistic combination of Diazabicycloocatane â–lactamase inhibitor and one or more antibacterial potentiator/enhancers, wherein the synergistic combination provides synergistic effects by:
i. By protecting antibiotic from degradation of certain â-lactamases 10
ii. By using outer membrane permeabilizers to improve the antibiotic intake.
The Diazabicycloocatane inactivate â-lactamases and protect the antibiotics from degradation and whereas antibacterial potentiator/enhancers destabilizes the outer membrane of bacteria and improves the uptake of antibiotics and 15 improves the efficacy of antibiotics against the resistance without altering the pharmacological activity of antibiotics.
Objective
An objective of the present invention is to provide a pharmaceutical composition comprising an antibiotic and one or more ingredients that increases or enhances 20 the activity of the antibiotic.
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An objective of the present invention is to provide a pharmaceutical composition comprising an antibiotic and a synergistic combination of antibacterial potentiator/enhancers.
Another objective of the present invention is to provide a pharmaceutical composition comprising an antibiotic, and a synergistic combination of 5 diazabicycloocatane â-lactamase inhibitor and antibacterial potentiator/enhancers, wherein the antibiotic potentiator/enhanchers are an outer membrane permealiblizer.
Another objective of the present invention is to provide a synergistic combination of ingredient that synergistically complements the activity of an 10 antibiotic, wherein the synergistic combination provides synergistic effects by:
i. By protecting antibiotic from degradation of certain â-lactamases
ii. By using outer membrane permeabilizers to improve the antibiotic intake.
Summary 15
A pharmaceutical composition comprising an antibiotic and a synergistic combination of a Diazabicycloocatane â-lactamase inhibitor and an outer membrane permeabilizer (OMP), wherein the Diazabicycloocatane â-lactamase inhibitor acts by protecting antibiotic from degradation of certain â-lactamases and the OMP by permeabilizing the outer membrane to improve the antibiotic 20 intake.
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Description
Those skilled in the art will be aware that the present disclosure is subject to variations and modifications other than those specifically described. It is to be understood that the present disclosure includes all such variations and modifications. The disclosure also includes all such compositions, components of 5 the composition, referred to or indicated in this specification, individually or collectively and all combinations of any or more of such components or composition.
Definitions
For convenience, before further description of the present disclosure, certain 10 terms employed in the specification, and examples are collected here. These definitions should be read in the light of the remainder of the disclosure and understood as by a person of skill in the art. The terms used herein have their meanings recognized and known to those of skill in the art, however, for convenience and completeness, particular terms and their meanings are set 15 forth below.
The articles “a”, “an” and “the” are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.
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The terms “comprise” and “comprising” are used in the inclusive, open sense, meaning that additional elements may be included. It is not intended to be construed as “consists of only”.
Throughout this specification, unless the context requires otherwise the word “comprise”, and variations such as “comprises” and “comprising”, will be 5 understood to imply the inclusion of a stated element or step or group of element or steps but not the exclusion of any other element or step or group of element or steps.
The term “including” is used to mean “including but not limited to”. “Including” and “including but not limited to” are used interchangeably. 10
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the disclosure, the preferred methods, and materials are now described. All 15 publications mentioned herein are incorporated herein by reference.
The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purposes of exemplification only. Functionally equivalent products and processes are clearly within the scope of the disclosure, as described herein. 20
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The term “pharmaceutical composition” refers to delivery system in which active agents are delivered to the patients. This could be in the form of tablet, capsule, injection, liquid etc.
The term “pharmaceutically acceptable excipient” refers to inert substances other than active ingredients which are used in the preparation of 5 pharmaceutical products.
The term “parenteral” refers to drug delivery system in which the active agent(s) are directly administered into blood stream in form of injection surpassing first pass metabolism.
The term “excipients” as used herein means a component of a pharmaceutical 10 product that is not an active ingredient. The excipients that are useful in preparing a pharmaceutical composition are generally safe and non-toxic.
The term “Enzymatic inactivation of the antibiotic” as used herein describes the inactivation of activity of an antibiotic by cellular enzyme. For example, â-lactamase enzymes inactivate the activity of antibiotics by hydrolysing the 15 antibiotic and also represent one the most prevalent causes of antibiotic resistance.
The term “Drug excretion by activation of efflux pumps” as uses herein refers to proteins, which are able to eliminate a wide variety of compounds from the periplasm to the outside cell, are activated by the bacteria to eliminate the 20 antibiotic.
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“Outer membrane permeabilizer” (OMP) as used herein refers to cationic and amphiphilic or are chelators that destabilize the outer layer of the outer membrane of the bacteria by either interaction with the polyanionic lipopolysaccharides or by capture of outer layer cations respectively. Thereby making that region of the bacterial outer-membrane permeable to antibiotic. 5
“Target site modification” as used herein refers to the changes in the target site of the antibiotic that decreases or destroy the binding efficiency of the antibiotic and therefore limit is potency.
In an embodiment the present invention provides a pharmaceutical composition comprising a synergistic combination of an antibiotic with one or more 10 ingredient that enhances the activity or efficacy of the antibiotic.
In an embodiment the ingredients that enhances the activity or efficacy of the antibiotic are selected from ingredients that inactivates or inhibit or counters the (1) Enzymatic inactivation of the antibiotic, (2) Drug excretion by activation of efflux pumps, (3) Decreased uptake of the antibiotic by changes in the outer 15 membrane permeability and (4) target site modification.
In another embodiment the present invention provides a pharmaceutical composition comprising a combination of an antibiotic with one or more ingredient that synergistically increases or enhances the activity or efficacy of the antibiotic, wherein the ingredient that enhances the activity or efficacy of the 20 antibiotic by protecting antibiotic from Enzymatic inactivation or degradation of
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certain â-lactamases and by using outer membrane permeabilizers (OMP) to improve the antibiotic intake.
In another embodiment the ingredients that protect the antibiotics from enzymatic inactivation or degradation are selected from â-lactamases inhibitor, preferably Diazabicycloocatane â-lactamases inhibitors. In another embodiment 5 the OMP’s are selected from polyamines or amino acid, preferably polyamines and wherein the polyamines are EDTA or salts thereof.
In another embodiment the present invention provides a pharmaceutical composition comprising a combination of antibiotic and a synergistic combination of a Diazabicycloocatane â-lactamases inhibitor and an OMP, and 10 wherein the OMP’s are selected polyamines or amino acids, preferably polyamines and wherein the polyamines are EDTA or salts thereof and wherein the amino acids is L-arginine.
In another embodiment the present invention provides a pharmaceutical composition comprising an antibiotic and synergistic combination of 15 Diazabicycloocatane â-lactamases inhibitor and polyamine, wherein the Diazabicycloocatane â-lactamases inhibitor is Avibactam or its pharmaceutically acceptable salts and wherein the polyamine is EDTA or its pharmaceutically acceptable salts.
In another embodiment the present invention provides a pharmaceutical 20 composition comprising a synergistic combination of an antibiotic agent with one
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or more ingredient that enhances the activity or efficacy of the antibiotic agent, further optionally comprises an ingredient that enhances the activity of the antibiotic potentiators.
In an embodiment the present invention relates to a pharmaceutical composition comprising an antibiotic, Avibactam and EDTA and wherein the 5 pharmaceutical composition further comprises pharmaceutically acceptable excipients.
In an embodiment the present invention provides pharmaceutical composition comprising:
i. 500 to 2000 mg antibiotics and; 10
ii. 100 to 1000 mg avibactam and;
iii. 0.4mg to 50 mg disodium EDTA
In an embodiment the examples of antibiotic that can be used in the present invention are selected from penem, penam, Carbapenem, Cephalosporins, Monobactam, Penicillins, Quinolones/Fluoroquinolones, tetracyclines or a 15 combination thereof
In an embodiment the examples of antibiotic that can be used in the present invention are selected from carbapenem, cephalosporins, Monobactam, Penicillins or a combination thereof.
In an embodiment the examples of carbapenem are Meropenem, Imipenem, 20 Ertapenem, Doripenem, Biapenem, Tebipenem or combination thereof.
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In an embodiment the examples of cephalosporins are selected from Cefadroxil, Cefazolin, Cephradine, Cephapirin, Cephalothin, Cefalexin, Cefaclor, Cefoxitin, Cefotetan, Cefamandole, Cefmetazole, Cefonicid, Loracarbef, Cefprozil, Cefuroxime, Cefixime, Cefdinir, Cefditoren, Cefopreazone, Cefotaxime, Cefpodoxime, Ceftazidime, Ceftibuten, Ceftizoxime, Moxalactam, Ceftriaxone, 5 Cefepime, Ceftaroline fosamil, Ceftobiprole.
In an embodiment the Mobobactams is Aztreonam or pharmaceutical acceptable salts thereof.
In an embodiment the penicillins are selected from amoxicillin, ampicillin, Azlocillin, Dicloxacillin, Flucoxacillin, Mezlocillin, Methicillin, Nafcillin, Oxacillin, 10 Penicillin G, Penicillin V, Piperacillin, Temocillin, Ticarcillin.
In an embodiment the antibiotic is present in the amount of 10 mg to 1 gm.
In another embodiment the antibiotic is present in the range of 1% to 70% w/v of the composition.
In an embodiment the Diazabicycloocatane â-lactamase inhibitor is present in 15 the range of 100 mg to 1000 mg.
In another embodiment the Diazabicycloocatane â-lactamase inhibitor is present in the range of 1% to 90% w/v of the composition.
In an embodiment of the OMP is present in the range of 0.1 mg to 50 mg.
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In another embodiment the OMP is present in the range of 0.01% to 10% w/v of the composition.
In an embodiment the present invention is present in the form of parenteral dosage form. In an another embodiment parenteral formulation are suitable in form of intravenous, intramuscular, subcutaneous, intradermal, intra-arterial 5 administration.
In an embodiment the parenteral composition comprises Meropenem sodium, avibactam sodium and disodium EDTA.
In an another embodiment the parenteral composition comprises Cefoperazone Sodium, avibactam sodium and disodium EDTA. 10
In an another embodiment the parenteral composition comprises Ceftazidime, avibactam sodium and disodium EDTA.
In an embodiment the parenteral formulation can be present in form of aqueous or non-aqueous solution, emulsion, suspension, dry powder or lyophilized powder. In a preferred embodiment the parenteral formulation is present in the 15 form of aqueous solution.
In an embodiment the parenteral formulation can be present in the form of vial, ampoule, pre-filled syringe or the likes thereof.
In an another embodiment the present formulation comprises pharmaceutical acceptable excipients selected from stabilizer, pH regulator, buffering agents, 20
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solvents, chelating agents, antioxidants, preservatives, surfactants, tonicity modifying agents, dispersing agents.
In another embodiment the present invention provides a process to prepare the pharmaceutical composition of the present invention.
Examples 5
Example 1 –
S. No
Ingredients
Label Claim
1.
Meropenem
Sodium (as Sodium Carbonate)
1000 mg/vial
90.2 mg/vial
2.
Avibactam Sodium (Sterile)
Equivalent to Avibactam
500 mg / vial
3.
Sterile disodium EDTA
0.4mg to 37 mg / vial
Example 2 -
S. No
Material Name
Label Claim
1.
Cefoperazone Sodium
(Sterile) eq. to Anhydrous Cefoperazone
1000mg / vial
2.
Avibactam Sodium (Sterile)
Equivalent to Avibactam
500 mg / vial
3.
Sterile disodium EDTA
0.4 mg to 37 mg / vial
10
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Example 3 -
S. No
Material Name
Label Claim
1.
Ceftazidime for Injection (Sterile) Eq. to Ceftazidime
(Sterile Mixture of Ceftazidime Pentahydrate/Sodium Carbonate)
2.0 g/vial
2.
Avibactam Sodium (Sterile)
eq.to Avibactam
0.5 g/vial
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Sterile disodium EDTA
0.4 mg- 37 mg / vial ,CLAIMS:A pharmaceutical composition comprising an antibiotic, Diazabicycloocatane â-lactamase inhibitor and an outer membrane permeabilizers
2. The pharmaceutical composition as claimed in claim 1 wherein the 5 antibiotic is selected from penem, penam, carbapenems, cephalosoporins, penicillins, monobactams
3. The pharmaceutical composition as claimed in claim 1 wherein the Diazabicycloocatane â-lactamase inhibitor is selected Avibactam.
4. The pharmaceutical composition as claimed in claim 1 wherein the outer 10 membrane permeabilizers is EDTA.
5. The pharmaceutical composition as claimed in claim 1 comprising:
i. 500 to 2000 mg antibiotics and;
ii. 100 to 1000 mg avibactam and;
iii. 0.4mg to 50 mg disodium EDTA 15
6. The pharmaceutical composition as claimed in 1-5 further comprises pharmaceutically acceptable excipients selected from stabilizer, pH regulator, buffering agents, solvents, chelating agents, antioxidants, preservatives, surfactants, tonicity modifying agents, dispersing agents.
7. The pharmaceutical composition as claimed in any of the above claims is 20 present in parenteral dosage form.
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8. A parenteral composition as claimed in claim 1-7 comprises Meropenem sodium, avibactam sodium and disodium EDTA.
9. A parenteral composition as claimed in claim 1-7 comprises Cefoperazone sodium, avibactam sodium and disodium EDTA.
10. A parenteral composition as claimed in claim 1-7 comprises Ceftazidime 5 sodium, avibactam sodium and disodium EDTA.
Dated this 28th May’2023