A pharmaceutical formulation of a beta-lactam antibiotic, an inhibiting agent and a chelating agent

Abstract

The present invention relates to a pharmaceutical drug formulation comprising of a beta-lactam, an inhibiting agent and a chelating agent. More particularly, the present invention relates to a pharmaceutical drug formulation comprising of a beta-lactam antibiotic, an inhibiting agent in a ratio of 4:1 and a chelating agent in an amount of 3 mg / mL with reduced minimum inhibitory concentration that is effective against bacterial infections.

Description

[0001] “A PHARMACEUTICAL FORMULATION OF A BETA-LACTAM

[0002] ANTIBIOTIC, AN INHIBITING AGENT AND A CHELATING AGENT”

[0003] FIELD OF THE INVENTION

[0004] The present invention relates to the field of pharmaceutical drugs. More particularly, the present invention relates to a pharmaceutical formulation comprising of a beta-lactam antibiotic, an inhibiting agent and a chelating agent in a desired ratio that is effective against multidrug resistant pathogens.

[0005] BACKGROUND OF THE INVENTION

[0006] Bacterial infections occur when bacteria enter into the living body. Once the bacteria enters the body, they increase in number thereby causing an immune reaction in the body. Serious bacterial infections are treated with antibiotics that either kill the bacteria or stop them from multiplying. The choice of the specific antibiotic to be taken depends on the type of bacteria that is causing the infection. Antibiotics that work against a wide range of bacteria are called broad-spectrum antibiotics. Antibiotic resistance is a growing problem, therefore, antibiotics must be used appropriately and as per the prescription. With the rise of many antibiotic-resistant strains of bacteria, various studies have been attempted for the effective management of bacterial infections. However, only few have antimicrobial activity against different bacteria due to the difficulty of combining different specificities while maintaining shelf stability.

[0007] JP7421504B2 discloses about a pharmaceutical formulation for use in a method for treating small intestinal bacterial overgrowth in a subject in need thereof. The method comprises orally administering to the subject an effective amount of a pharmaceutical formulation comprising of meropenem as an antimicrobial agent. However, the antimicrobial agent in the disclosed formulation exhibits a significantly higher range of minimum inhibitory concentration.

[0008] US10407467B2 discloses about the polymyxin compounds in combination therapy with a second active agent for treatment of a microbial infection. However, the combination therapy disclosed in the cited document fails to provide effective minimum inhibitory concentration. As carbapenems possess broad-spectrum activity against many gram-negative bacteria they remain the final-line drug of choice for extended-spectrum, p-lactamase-producing organisms. However, the increasing prevalence of carbapenem-resistant and carbapenemase-producing organisms is affecting the efficacy of carbapenem. Hence, seeking alternative treatment regimens has become a pressing issue. Thus, there remains a need to develop novel products against pathogenic bacteria.

[0009] Therefore, there is a need to develop a pharmaceutical drug formulation that possesses efficient stability to overcome the abovementioned shortcomings.

[0010] OBJECT OF THE INVENTION

[0011] The main object of the present invention is to provide a pharmaceutical drug formulation comprising of a beta-lactam antibiotic, an inhibiting agent and a chelating agent.

[0012] Another object of the present invention is to provide a pharmaceutical drug formulation comprising of a beta-lactam antibiotic and an inhibiting agent in a ratio of 4: 1 and a chelating agent in an amount of 3 mg / mE.

[0013] Yet another object of the present invention is to provide a pharmaceutical drug formulation for effective management of bacterial infections.

[0014] Yet another object of the present invention is to provide a pharmaceutical drug formulation with reduced minimum inhibitory concentration that is effective against bacterial infections.

[0015] Still another object of the present invention is to provide a pharmaceutical drug formulation that is stable and effective against multi drug resistant bacteria or pathogens.

[0016] SUMMARY OF THE INVENTION

[0017] The present invention relates to a pharmaceutical drug formulation comprising of a betalactam antibiotic and an inhibiting agent in a ratio of 4:1 and a chelating agent in an amount of 3 mg / mL that is effective against multidrug resistant pathogens. In an embodiment, the present invention provides a pharmaceutical drug formulation, comprising of: a beta-lactam antibiotic; and an inhibiting agent in a ratio of 4:1; and a chelating agent in an amount of 3 mg / mL.

[0018] Additionally, the pharmaceutical drug formulation is in the form of a tablet, a capsule, an injection, a suspension, a gel or a cream. Further, the pharmaceutical drug formulation of the present invention exhibits a minimum inhibitory concentration ranging from 0.004 to 0.88 pg / mL.

[0019] The present invention relates to a stable and effective pharmaceutical drug formulation of a beta-lactam antibiotic, an inhibiting agent and a chelating agent with reduced minimum inhibitory concentration.

[0020] The above objects and advantages of the present invention will become apparent from the hereinafter set forth brief description of the drawings, detailed description of the invention, and claims appended herewith.

[0021] DETAILED DESCRIPTION OF THE INVENTION

[0022] The present invention will now be described hereinafter with reference to the accompanying drawings in which a preferred embodiment of the invention is shown. This invention may, however, be embodied in many different forms and should not be construed as being limited to the embodiment set forth herein. Rather, the embodiment is provided so that this disclosure will be thorough, and will fully convey the scope of the invention to those skilled in the art.

[0023] The present invention now will be described hereinafter with reference to the detailed description, in which some, but not all embodiments of the invention are indicated. Indeed, the invention may be embodied in many different forms and shouldnot be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. Like numbers refer to like elements throughout. The present invention is described fully herein with nonlimiting embodiments and exemplary experimentation. The present invention provides a pharmaceutical drug formulation of a beta-lactam antibiotic and an inhibiting agent in a ratio of 4: 1 and a chelating agent in an amount of 3 mg / mL that is effective against multidrug resistant pathogens.

[0024] In a preferred embodiment, the present invention provides a pharmaceutical drug formulation, comprising of: a beta-lactam antibiotic; and an inhibiting agent in a ratio of 4:1; and a chelating agent in an amount of 3 mg / mL.

[0025] Here, said beta-lactam antibiotic is a carbapenem antibiotic; said inhibiting agent is avibactam; and said chelating agent is ethylene diamine tetraacetic acid (EDTA), diethylene triamine pentaacetic acid (DTP A) or hydroxyethyl ethylene diamine tetraacetic acid (HEDTA).

[0026] Additionally, the pharmaceutical drug formulation is in the form of a tablet, a capsule, an injection, a suspension, a gel or a cream. Further, the pharmaceutical drug formulation of the present invention exhibits a minimum inhibitory concentration ranging from 0.004 to 0.88 pg / mL.

[0027] Moreover, said beta-lactam antibiotic is meropenem with a concentration of 2 g. Avibactam is in a concentration of 500 mg and said chelating agent is essentially ethylene diamine tetraacetic acid (EDTA) in a concentration of 37.5 mg.

[0028] EXAMPLE 1

[0029] For Experimentation Data

[0030] Experimental analysis of minimum inhibitory concentration (MIC)

[0031] Microbial culture

[0032] Escherichia coli (NCIM 2065), Pseudomonas aeruginosa (NCIM 2200), Enterococcus faecalis (MTCC 439) and Staphylococcus aureus (NCIM 5345) were taken.

[0033] *NCIM: National collection of industrial microorganisms

[0034] *MTCC: Microbial type culture collection

[0035] Media and diluent Soybean casein digest agar (SCDA), Mueller hinton agar (MHA) and normal saline with a concentration of 0.9% were taken.

[0036] Accessories

[0037] Calibrated micropipette, sterile micropipette tips of 100 pF and 1.0 mL, sterile cotton swab, sterile disposable petriplates of dimension 15 mm X 100 mm, Bunsen burner, inoculating loop, conical flask, sterile scissors, sterile forceps, sterile disposable gloves, borosilicate glass tube of dimension 15 mm X 180 mm, vortex, 70% of filtered isopropyl alcohol (IP A) and test tube stand.

[0038] Instrument and equipment

[0039] A weighing balance, pH meter, horizontal autoclave, dynamic pass box, biosafety cabinet, Biological oxygen demand (BOD) incubator 37°C, colony counter, refrigerator, micropipette of capacity range 10-1000 pl and vertical autoclave were taken.

[0040] Method for analysis of MIC

[0041] Step 1. Preparation of microbiological media

[0042] The media and diluent were prepared and sterilized. The sterilized molten medium was cooled to 45-50°C, poured in sterile, dry petriplates and was allowed to solidify. The petriplates containing media was avoided from drying in laminar flow and was immediately taken for swabbing.

[0043] Step 2. Preparation of inoculum

[0044] Microorganisms were sub-cultured from working cultures stored at 2-8°C. Once microorganism was sub-cultured, the organism was avoided from passing more than three times. This means that the total passages does not exceed five times. The growth of slant of SCDA or equivalent with the help of sterile normal saline was harvested. The culture suspension was prepared for all the mentioned microbial cultures. The concentration of the microbial inoculum was confirmed by comparing the turbidity of inoculum with the standard 0.5 McFarland. The alternate method for standardizing the inoculum is optical method of 0.08-0.13 OD turbid suspension at 620 nm.

[0045] Step 3. MIC test procedure The media plates of Mueller hinton agar for rapidly growing aerobic organisms were prepared as mentioned above. The inoculum swab was made ready by dipping a sterile non-toxic cotton swab into the standardized inoculum tube and the soaked swab was rotated firmly against the upper inside wall of the tube to remove excess fluid. The swab was avoided from dripping wet. The entire agar surface of Mueller hinton agar plate was inoculated with the swab three times and turning the plate at 60 degree angle between each streaking. The Ezy MIC strip container from was taken cold storage at -20°C. Before opening, the strip was kept at room temperature for 15 minutes. Thereafter, an applicator was taken and the broader sticky side of applicator was gently pressed on the centre of Ezy MIC strip. The applicator along with attached Ezy MIC strip was lifted and the strip was placed at a desired position on agar plate swabbed with test culture. The applicator was gently turned clockwise with fingers so that the applicator was detached from the strip. The pressing of Ezy MIC strip was avoided. The Ezy MIC strip was adsorbed within 60 seconds and firmly adheres to the surface of agar. The care had been taken that once the Ezy MIC strip was in contact with the agar surface, the strip was not moved or repositioned even if the disk was not in the proper location because the drug begins to diffuse immediately upon contact with the agar. After all the strips were in place, the lid of the plates was replaced. The plates were inverted and were placed in an incubator at 37°C for 16-18 hours.

[0046] Interpretation

[0047] After the completion of incubation, the MIC was interpreted by observing that where the ellipse was intersecting the MIC scale on the strip. The isolated colonies, micro-colonies and haze appearing in the zone of inhibition were indicative of hetero nature of the culture having resistant subpopulation. In such cases, reading for MIC determination at a point on the scale above which no resistant colonies was observed close to MIC strip within a distance in a range of 1-3 mm. When the growth occurs along the entire strip, the MIC was reported as highest values on the MIC strip. When the inhibition ellipse was below the strip and does not intersect the strip, the MIC was reported as lowest value on the MIC scale.

[0048] Observation Table 1 shows values of the minimum inhibitory concentration obtained for the pharmaceutical drug formulation of meropenem, avibactam and EDTA by taking meropenem / avibactam / EDTA (MAE) MIC strips. Table 2 shows values of the minimum inhibitory concentration obtained for meropenem by taking meropenem Ezy MIC strips. Table 3 shows the comparison of values obtained in Table 1 and Table 2. Table 3 represent the reduction in MIC that is achieved with the pharmaceutical drug formulation of meropenem, avibactam and EDTA.

[0049] Table 1: MIC of the pharmaceutical drug formulation of meropenem, avibactam and EDTA by taking meropenem / avibactam / EDTA (MAE) MIC strips

[0050] Table 2: MIC of meropenem by taking meropenem Ezy MIC strips

[0051] Table 3: Comparison of MIC of meropenem Ezy MIC strips and meropenem / avibactam / EDTA (MAE) MIC strips

[0052] EXAMPLE 2

[0053] Method of preparation of powder injection

[0054] Selection of ingredients or raw materials The active pharmaceutical ingredients (API) includes: meropenem in an amount of 2000 mg (2 gm), avibactam sodium in an amount of 500 mg (0.5 gm) and disodium EDTA in an amount of 37.5 mg.

[0055] Sterilization and depyrogenation of primary packing material

[0056] Before depyrogenation, equipments were cleaned. The glass vials were depyrogenated with the help of depyrogenation tunnel. The flip of seal and rubber plug were sterilized through autoclave.

[0057] Preparation and blending of API

[0058] Before preparation of blending, equipments were cleaned and the systematic process was followed for the assessing the cleanliness and control of the manufacturing environment to ensure product safety and compliance with regulatory standards. The key factors involved were: air quality (particulate and microbial contamination), surface cleanliness (equipment, workbenches, walls and floors), personnel hygiene (gowning and behavior) and water quality taken for API production. The different raw materials were taken in required quantity as per calculation and were transferred to a blender for blending. After blending, the raw material sample was collected by IPQA from the blender and was sent to QC for testing the uniformity content.

[0059] Filling raw material sample into glass vials

[0060] The equipments were cleaned and the surrounding environment was monitored before filling the sample into glass vial. The sterile powder sample was filled aseptically under controlled area (local aseptic processing) into a depyrogenated glass vial. After filling, the filled glass vials were closed with a stopper followed by sealing with the help of a sealing machine.

[0061] Visual inspection of the filled glass vials

[0062] The area and inspection table were cleaned before performing visual inspection. The visual inspection was performed by a qualified visual inspector. The filled and sealed glass vial were inspected visually to check any breakage of a filled glass vial, sealing quality, fill weight, etc.

[0063] Quality control testing

[0064] Sterility testing was done to ensure that no microbial contamination took place. Potency testing was performed to verify the correct drug dosage. Particulate testing was done to check for the absence of visible particles. The reconstitution testing confirmed that the powder sample was dissolved properly and retained potency. Average fill weight testing was done to confirm fill weight as per BMR limit and other test parameter was performed as per the finished product specification.

[0065] Packaging and labelling of the sealed glass vials

[0066] The packing activity was performed as per BPR. The area was cleaned followed by environment monitoring. The labelling of the filled and sealed glass vial was checked as per BPR frequency. All parameters like batch number, manufacturing date, expiry date and other related information was checked, as per BPR frequency. The product was packed as per BPR and the finished product sample was collected and sent to QC for complete analysis. After receiving COA from QC, the batch was released.

[0067] EXAMPLE 3

[0068] Method of Analysis of meropenem, avibactam and EDTA for injection

[0069] Sampling

[0070] The sampling was done during initial filling, after regular interval of one and finally at the end of the filling. Equal quantity of sample was taken during initial filling, after regular interval of one and finally at the end of the filling. The samples were sent to micro lab and during packing, after completion of 20%, 50% and 80% of the process, a composite sample was collected specifically for chemical testing. The sample was placed in a poly bag labelled as “sample for analysis” along with a sample information label.

[0071] Total sample and label claim

[0072] The total number of samples taken were 60 vials. Each vial contains: meropenem (sterile) IP equivalent to anhydrous meropenem = 2000 mg; avibactam sodium (sterile) IP = 500 mg; and disodium EDTA (IP) in an amount of 37.5 mg. The samples were stored at a cool and dry place and at a temperature not exceeding 30°C.

[0073] Tests and method of analysis

[0074] Table 4 shows parameters taken for method of analysis.

[0075] Table 4: Parameters for method of analysis

[0076] Description

[0077] A white to off white colored powder sample was filled in a clear and colorless glass vial. An approximately 100 mg of sample was taken in a clean and dry petridish, was spread uniformly, and finally, the color and nature of the sample was observed visually.

[0078] Identification by high performance liquid chromatography (HPLC)

[0079] The principal peak in the chromatogram obtained with test solution corresponded to the peak in chromatogram that was obtained with reference solution.

[0080] Average fill weight: ±2% of targeted fill weight Any adhering labels were removed from a container and the outside of the container was washed and dried. The container was opened and immediately weight of the container and weight of contents of the container was taken. The container was emptied as completely as possible by gentle tapping and rinsed initially with water and then with 95% ethanol and dried at a temperature of 100-105°C for 1 hour, if the nature of the container precluded such treatment to constant weight. The container was then cooled in desiccator and weighed. The difference between the weights represented the weights of the contents. The procedure was repeated with further 19 containers and the average weight was determined by the formula having equation (1).

[0081] Average weight = (Sum of individual content of 20 vials) - 20 . (1)

[0082] Uniformity of fill weight: ± 10% of average fill weight

[0083] The minimum and maximum %age was calculated by formula having equations (2) and (3):

[0084] Minimum %age = ((Minimum individual weight - Average fill weight) x 100) / Average fill weight . (2)

[0085] Maximum %age = ((Maximum individual weight - Average fill weight) x 100) / (A verage fill weight) . (3)

[0086] Related substance

[0087] Chemicals and reagents include triethylamine, phosphoric acid, water and acetonitrile. Solvent mixture was prepared by dissolving 1.0 mT of trimethylamine in 900 mT of water. The pH was adjusted to 5.0 with dilute phosphoric acid and diluted to 1000 mT with water. The test solution was prepared as follows: the weight of the contents of 10 containers was determined. A weighed quantity (about 50 mg of meropenem) of the mixed contents of the 10 containers was dissolved in 10 mT of the solvent mixture and was mixed. The reference solution was prepared as follows: an amount eq. to 50.0 mg of standard was weighed accurately and transferred into a 100 mT volumetric flask. The volume was made up to the mark with the solvent mixture and was sonicated to dissolve. 5 mT of the resulting solution was diluted into a 100 mT volumetric flask, the volume was made up to mark with solvent mixture and was sonicated to dissolve.

[0088] Chromatographic system included a stainless steel column of dimension 25 cm x 4.0 mm that was packed with octadecyl silane and was bonded to porous silica of size 5 pm. The column temperature was 40°C. The mobile phase was prepared by mixing 1.0 mT of trimethylamine and 900 mT of water, adjusting the pH to 5.0 with dilute phosphoric acid, diluting to 1000 mT with water followed by filtration and mixing with 60 volumes of acetonitrile. The flow rate was 1 mT per minute. Spectrophotometer was set at 220 nm and injection volume was 10 pF. The reference solution was injected. The test was not valid unless the tailing factor was not more than 1.5 and the column efficiency was not less than 2500 theoretical plates. Next, the reference solution and test solution was injected. The individual impurity was not more than 0.8% and the sum of all impurities found was not more than 2.0%.

[0089] Bacterial endotoxins

[0090] The bacterial endotoxins were in a range of not more than 0.125 endotoxin unit per mg.

[0091] Sterility

[0092] Media employed was as follows: soybeans casein digest media (30 gm for 1000 mT) and fluid thioglycolate media (29.75 gm for 1000 mT). The apparatus includes a suitable unit consisting of a closed reservoir and a receptacle between which a properly supported membrane of appropriate porosity was placed. For sterility testing, the membrane (cellulose nitrate) of pore size was more than 0.45 micron and diameter of approximately 50 mm.

[0093] Membrane filtration method

[0094] 1 mF of stock solution of organism (S. aureus, B. subtilis and C. albicane) was inoculated into 99 mL sterile normal saline solution. The obtained solution was then filtered through 0.45 micron cellulose nitrate filter paper and the filtrate was collected into sterile flask, the filter paper was cut into two pieces and the filter paper was inoculated into tubes of thioglycolate and soybean casein digest medium. The same procedure was repeated for each of the organisms. The tubes were inoculated for 14 days and were observed daily and no growth was observed in filtrate up to 14 days.

[0095] Particulate matter

[0096] The particulate matter was analyzed by liquid particle counter. The sample was observed visually for checking the visible particulate matter and the constituted solution was essentially free from particle of foreign matter. For the sub visible particulate matter, it was observed that the particles of size >10 pm were present in a range of not more than 6000 particles per vial and particles of size >25 pm were present in a range of not more than 600 particle per vial. Blank preparation and analysis

[0097] (1) Before analyzing a test sample, a blank test for system was suitably done.

[0098] (2) Glassware was thoroughly cleaned with non-ionic detergent and was made free from any residue of water.

[0099] (3) The filtered purified water not more than 500 mL was taken for blank test.

[0100] (4) The sample was degassed sonicating for about 30 seconds.

[0101] (5) The sample was analyzed against the white and black background for black particle, white particle, fibre particle and any other visible particle.

[0102] If any type of visible particles were present in the preparation, then the preparation was discarded and points (2 to 4) were repeated until a sample free from any visible particle was obtained. For testing of sub visible particle, the sample was put on the liquid particle counter’s stage. The sample syringe was put into the sample and put a magnetic stirrer into the sample. A bottle was taken for collection of waste and the waste generation syringe was put into the waste collection bottle.

[0103] Test preparation and analysis

[0104] After the blank analysis, again the system was flushed with water and proceeded for test sample analysis. The samples were put on the laminar air flow workbench provided for liquid particle count; the stickers and labels were removed by dipping into warm water. Each sample vial was reverted for approximately 20 times followed by addition of sterilized water of injection as directed in the labeling and each sample was analyzed against the white and black background for black particle, white particle, fiber particle and any other visible particle. After visual inspection, the outer surface of container opening was cleaned by a jet of particle free water and by avoiding any contamination of the content, the closure of the container was removed. Then, the test sample was analyzed as per described in the section blank preparation and analysis.

[0105] Test sample quantity and preparation

[0106] The content of 10 units was combined in a clean container. The sample was degassed by sonicating for about 30 seconds.

[0107] Constituted solution Completeness of solution: The solid was dissolved completely, leaving no visible residue as undissolved matter.

[0108] Clarity of solution: The constituted solution was as clear as the solution of the diluents and sterile water for injection contained in a similar vessel and examined similarly.

[0109] 5 sample vials and 1 blank vial were taken. Sterile water for injection was added as directed in the labelling and was filtered through 0.2 pm filter. The solution was mixed well and the sample was completely dissolved. The air bubbles were removed with the help of sonicator. Now, the sample vial with the blank was allowed to stand and was observed against black and white background to check the presence of any undissolved matter. The solution was as clear as the blank vial containing sterile water for injections in the sample vial and in visible particulate matter.

[0110] Assay of meropenem and avibactam determined by liquid chromatography

[0111] The chemicals employed were potassium dihydrogen orthophosphate, orthophosphoric acid, water and acetonitrile. A phosphate buffer (pH = 4.0) was prepared as follows: 2.75 gm of potassium dihydrogen orthophosphate was dissolved in 500 mT of water and further was diluted to 1000 mT with water. The pH was adjusted to 4.0T0.05 by dilute orthophosphoric acid. Mobile phase was prepared by mixing 900 mT of a phosphate buffer having pH=4.0 and 100 mT of acetonitrile. The standard solution was prepared as follows: an amount equivalent to 100 mg of meropenem working standard and equivalent to 50 mg of avibactam sodium working standard in 50 mT volumetric flask was taken and diluted up to mark with mobile phase. Further, 5.0 mF of the prepared solution in 50 mL volumetric flask was taken and diluted up to mark with mobile phase. The sample solution was prepared as follows: about 190 mg of sample was weighed into a 50 mL volumetric flask and diluted up to mark with mobile phase. Further, 5.0 mL of the prepared solution was taken in 50 mL volumetric flask and diluted up to mark with mobile phase.

[0112] The chromatographic system included a Cl 8 column with a dimension of 250 mm x 4.6 mm packed with octadecylsilane bonded to porous silica of size 5 pm. The flow rate was 1.0 mL per minute and detection was achieved at a wavelength of 230 nm. The injection volume was 10 pL. The column temperature was 25°C.

[0113] Assay: EDTA The reagents and chemicals were 2 M hydrochloric acid (HC1), 0.1 M lead nitrate, hexamine, xylenol orange triturate. The solution of HC1 was taken by diluting 17.0 mT of HC1 with 100 mT of purified water.

[0114] An amount equivalent to 0.35 gm of EDTA (13 gm of test powder) was dissolved in sufficient water to produce 300 mT and sonicated for 10-15 minutes in sonicator, added 2 gm of hexamine and 2 mT of 2M HC1. Titrated with 0.1 M lead nitrate using 50 mg of xylenol orange triturate as indicator. A blank titration was performed. 1 mT of 0.1 M lead nitrate was equivalent to 0.03362 gm of Ci0Hi4N2Na2O8.2H2O. The calculation was done by the formula having equation (4):

[0115] %age or concentration of analyte= (Volume x Factor x Normality x Avg. wt.) / (0.1 M x sample wt.) . (4)

[0116] Where, the product of Volume, Factor and Normality gave the number of equivalents (or moles, after adjusting for stoichiometry) of titrant used in the reaction. Multiplication by average weight converted the equivalents into a mass (or a comparable measure) of the analyte. The obtained product divided by 0.1 M (the normalization constant) and sample weight adjusted the calculated mass relative to both the standardized titrant concentration and the amount of sample taken. The final result was often expressed as a percentage or concentration of the analyte in the sample and essentially, depicted that how much of the substance was present based on how much titrant was required for complete reaction.

[0117] Therefore, the present invention provides a pharmaceutical drug formulation of a betalactam antibiotic and an inhibiting agent in a ratio of 4:1 and a chelating agent in an amount of 3 mg / mE with reduced minimum inhibitory concentration that is effective against bacterial infections.

[0118] Many modifications and other embodiments of the invention set forth herein will readily occur to one skilled in the art to which the invention pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the invention is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

Claims

CLAIMSWe claim:

1. A pharmaceutical drug formulation comprising of: a beta-lactam antibiotic; an inhibiting agent in a desired ratio; and a chelating agent in a predefined concentration; wherein, said beta-lactam antibiotic is a carbapenem antibiotic; said inhibiting agent is avibactam; said chelating agent is ethylene diamine tetraacetic acid (EDTA), diethylene triamine pentaacetic acid (DTP A) or hydroxyethyl ethylene diamine tetraacetic acid (HEDTA); and said desired ratio of said beta-lactam antibiotic and said inhibiting agent is 4: 1 and the predefined concentration of said chelating agent is 3 mg / mL.

2. The pharmaceutical drug formulation as claimed in claim 1, wherein said pharmaceutical drug formulation is in the form of a tablet, a capsule, an injection, a suspension, a gel or a cream.

3. The pharmaceutical drug formulation as claimed in claim 1, wherein said pharmaceutical drug formulation exhibits a minimum inhibitory concentration ranging from 0.004 to 0.88 pg / mL.

4. The pharmaceutical drug formulation as claimed in claim 1, wherein said betalactam antibiotic is meropenem.

5. The pharmaceutical drug formulation as claimed in claim 1, wherein meropenem is in a concentration of 2 g.

6. The pharmaceutical drug formulation as claimed in claim 1, wherein avibactam is in a concentration of 500 mg.

7. The pharmaceutical drug formulation as claimed in claim 1 , wherein said chelating agent is essentially ethylene diamine tetraacetic acid (EDTA).

8. The pharmaceutical drug formulation as claimed in claim 1, wherein ethylene diamine tetraacetic acid (EDTA) is in a concentration of 37.5 mg.

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