EDTA INJECTION AND PROCESS FOR MAKING THE SAME

FIELD OF INVENTION

The present invention relates to the field of parenteral preparations. The invention specifically relates to parenteral preparations comprising Ethylenediaminetetraacetic acid (EDTA) and water for injection. The present invention also relates to procedure for manufacturing parenteral preparations comprising Ethylenediaminetetraacetic acid (EDTA) and water for injection.

BACKGROUND OF INVENTION

Ethylenediaminetetraacetic acid (EDTA) was developed by Franz Munz in Germany during the 1930s as an alternative to citric acid. EDTA was approved by the US Food and Drug Administration (FDA) as a food additive in 1947. Since the early 1950s, EDTA has been used in chelation treatment for lead poisoning.

EDTA (CAS No. 60-00-4) is a substituted diamine. The food- and pharmaceutical- grade compound contains not less than 98.0% and not more than 100.5% of C10H16N2O8 (U.S. Pharmacopeial Convention, Inc., 1995). EDTA chemically known as "2-({2- [Bis(carboxymethyl)amino]ethyl}(carboxymethyl)amino) acetic acid" has the structural formula as follows:

EDTA, is a colorless crystalline substance widely used to chelate metal ions. EDTA is a common polydentate ligand. In EDTA, the hydrogen atoms are easily removed in solution to produce anionic EDTA. In its anionic form EDTA has six binding atoms, two nitrogen and four oxygen atoms. EDTA binds to a metal ion at the six binding sites, wrapping itself around the metal ion, forming a very stable complex.

Other names for this ingredient include Edetic Acid (EDTA); Ethylene Diamine Tetra Acetic Acid; N,N'-l,2-Ethanediylbis[N-(Carboxymethyl)Glycine]; Glycine, N,N'-1,2- Ethanediylbis[N-(Carboxymethyl)- (Wenninger and McEwen, 1997); Versenic Acid (Grant, 1972); Edetate (Taylor, 1988); Edathamil (Budavari, 1989; Gennaro, 1990; U.S. Pharmacopeial Convention, Inc. ,1995); Ethylenedinitrilotetraacetic Acid; Ethylenebisiminodiacetic Acid (Lewis, 1993); and 3,6-Diazooctanedioic Acid, 3,6- bis(Carboxymethyl)- [Registry of Toxic Effects of Chemical Substances (RTECS), 1997].

EDTA is marketed in its salt forms such as sodium EDTA or calcium EDTA. EDTA has industrial and medical uses as a chelating agent.

EDTA (ethylenediamine tetraacetic acid) and its salts are substituted diamines. EDTA and their salts include Calcium disodium EDTA, Diammonium EDTA, Dipotassium EDTA, Disodium EDTA, TEA-EDTA, Tetrasodium EDTA, Tripotassium EDTA and Trisodium EDTA.

EDTA injection was approved as Endrate which is a sterile, nonpyrogenic, concentrated solution of edetate disodium in water for injection which as a result of a pH adjustment with sodium hydroxide contains varying amounts of disodium and trisodium salts. After dilution, it is administered by intravenous infusion.

Water for injection which is defined as the water for the preparation of medicines for parenteral administration when water is used as vehicle (water for injections in bulk) and for dissolving or diluting substances or preparations for parenteral administration (sterilized water for injections).

Grey et al. have disclosed in their article titled 'The Effect of Ethylenediaminetetra- acetic Acid on the Cell Walls of Some Gram-Negative Bacteria' published in J. gen. Microbiol, February 1965, 39: 385-399, it was stated that the cell walls of P. aeruginosa and A. faecalis, against which ethylenediaminetetra- acetic acid (EDTA) has a potent bactericidal action, differed from those of the other organisms principally in their sugar components and in their high content of phosphorus. EDTA at alkaline pH selectively solubilized a high proportion of the carbohydrate and phosphorus present, apparently as lipopoly saccharides, in the walls of sensitive organisms.

US 2,130,505 disclose polyamino polycarboxylic acids. The invention specifically relates to the Ethylenediaminetetraacetic acid product which is scarcely soluble in water and may be recrystallized from water.

IN 236996 discloses pharmaceutical composition for combating beta lactamase antibiotic resistance using beta-lactamase inhibitor as sterile dry powder for injection using EDTA as chelating agent. This invention also discloses a process for preparing the composition for combating beta lactamase mediated antibiotic resistance using beta-lactmase inhibitors capable of pharmaceutical application. RU 2 397 768 discloses pharmaceutical composition to overcome beta-lactamase mediated antibiotic resistance using beta-lactamase inhibitor, intended for parenteral injection for use as antimicrobial combination with fixed doses using EDTA as an inhibitor of solid particles formation after reconstitution for creating pharmaceutically effective and therapeutically safe composition. This invention also discloses composition is a single dose in a sealed container for parenteral administration after reconstitution volume of aqueous solvent selected from the group consisting of water for injection.

US 6,585,890 discloses a system for producing sterile, pyrogen-free water for injection. This invention relates to process and apparatus for producing sterile water for injection from potable water.

CN 101401786 discloses nelarabine injection containing EDTA or edetate, water for injection along with sodium chloride. This invention also discloses the usage of hydrochloric acid or sodium hydroxide for adjusting the pH to 5.0-7.5.

CN 102462659 discloses a method for preparing sodium phosphate choline injection cell containing citicoline sodium, disodium edetate, sodium hydrogen sulfite for adjusting pH and water for injection.

CN 102973524 discloses a process for preparing esomeprazole sodium freeze-dried powder containing esomeprazole sodium, disodium edetate and / or EDTA, sodium hydroxide for adjusting pH and water for injection.

CN 103263415 discloses Levo pantoprazole sodium composition containing pantoprazole sodium, mannitol, EDTA and water for injection.

CN 103301077 discloses an injectable preparation of esomeprazole sodium composition by lyophilization technique containing esomeprazole sodium, disodium edetate, sodium hydroxide solution and water for injection.

CN 102525893 discloses a preparation process phenylephrine hydrochloride injection containing phenylephrine hydrochloride, sodium chloride, disodium edetate and water for injection.

CN 104146953 discloses a fertile for paroxetine hydrobromide injection containing paroxetine hydrobromide, EDTA or edetate, sodium chloride and water for injection.

All the prior art references shows the use of EDTA along with active ingredient mixture. However, none of the references disclose the use of EDTA injection for parenteral administration without a pH adjusting agent. The present invention attempts composition comprising EDTA and water for injection and procedure for formulating parenteral preparation composition. This parenteral preparation can be used as diluent for preparing drug products for parenteral administration. From the literature it was found that EDTA increases the activity of antibiotics which directs the use of EDTA injection.

OBJECTIVE OF INVENTION

The objective of the present invention is to provide a parenteral composition comprising EDTA.

Another objective of the present invention is to provide the specific procedure for formulating EDTA composition containing EDTA and water for injection, optionally with other excipients.

Another objective of use of present composition to improve the efficacy of antibiotic formulations.

SUMMARY OF INVENTION

Accordingly, the present invention provides an EDTA injection composition suitable for parenteral administration.

Another embodiment of the present invention provides a parenteral composition comprising EDTA and Water for injection for use in parenteral preparations.

Yet another embodiment of the present invention provides a parenteral composition which further contains citric acid.

Yet another embodiment of the present invention provides a parenteral composition which can be used a diluent for injection.

Yet another embodiment of the present invention provides an Injection composition for use in preparing antibiotics intended for parenteral administration, which is prepared by dissolving required quantity of Disodium Edetate (EDTA) in sufficient volume of Water for injection. Then injection solution containing EDTA and water for injection is filtered through 0.22 micron membrane filters. Filtered solution is filled into the type-I glass vials and sealed with aluminum flip-off seals. The vials can be a PP or glass or LDPE, preferably it will be either glass or PP and sizes are in range of 2 mL to 100 mL, preferably 2 mL to 20 mL in capacity. Seals can be aluminium with PP disc, aluminium with plastic cap or plastic twist-off caps or ports etc.

Yet another embodiment of the present invention provides an EDTA injection composition for use along with lyophilized products as a diluent intended for parenteral administration for improving the potency of the drugs.

Still yet another embodiment of the present invention provides a parenteral composition for antibiotics intended for parenteral administration containing EDTA, Water for injection and Citric acid.

Still yet another embodiment of the present invention provides an EDTA injection composition for antibiotics intended for parenteral administration which are used in the treatment of bacterial infections.

Still yet another embodiment of the present invention provides antibiotic composition supplied with Disodium Edetate (EDTA) and water for injection composition kit comprising: a) Sterile APIs or Combination of two or more sterile API's filled in a cleaned and depyrogenated type-I glass vials, purge the filled vials with pre filtered nitrogen gas in head space at very low pressure to avoid flashing of powder, and b) Disodium Edetate (EDTA) and water for injection diluent which is supplied in a type-I glass vials and seal with aluminum flip-off seals.

Still yet another embodiment of the present invention provides a composition of Ceftriaxone sodium and Sulbactam Sodium supplied with Disodium Edetate (EDTA) and water for injection composition kit comprising:

a) Mixture of both sterile Ceftriaxone sodium and sterile Sulbactam Sodium is filled in a cleaned and depyrogenated type-I glass vials, purge the filled vials with pre filtered nitrogen gas in head space at very low pressure to avoid flashing of powder, and

b) Disodium Edetate (EDTA) and water for injection composition which is supplied in a type-I glass vials and seal with aluminum flip-off seals.

Still yet another embodiment of the present invention provides a composition of Cefoperazone sodium and Sulbactam Sodium supplied with Disodium Edetate (EDTA) and water for injection composition kit comprising:

a) Mixture of sterile Cefoperazone sodium and sterile Sulbactam Sodium is filled in a cleaned and depyrogenated type-I glass vials, purge the filled vials with pre filtered nitrogen gas in head space at very low pressure to avoid flashing of powder, and

b) Disodium Edetate (EDTA) and water for injection composition which is supplied in a type-I glass vials and seal with aluminum flip-off seals.

Still yet another embodiment of the present invention provides a composition of Cefepime Hydrochloride monohydrate and Sulbactam Sodium supplied with Disodium Edetate (EDTA) and water for injection composition kit comprising:

a) Mixture of sterile Cefepime Hydrochloride monohydrate and sterile Sulbactam Sodium is filled in a cleaned and depyrogenated type-I glass vials, purge the filled vials with pre filtered nitrogen gas in head space at very low pressure to avoid flashing of powder, and

b) Disodium Edetate (EDTA) and water for injection composition which is supplied in a type-I glass vials and seal with aluminum flip-off seals.

Still yet another embodiment of the present invention provides a composition of Cefpirome Sulfate and Sulbactam Sodium supplied with Disodium Edetate (EDTA) and water for injection composition kit comprising:

a) Mixture of sterile Cefpirome Sulfate and sterile Sulbactam Sodium) is filled in a cleaned and depyrogenated type-I glass vials, purge the filled vials with pre filtered nitrogen gas in head space at very low pressure to avoid flashing of powder, and

b) Disodium Edetate (EDTA) and water for injection composition which is supplied in a type-I glass vials and seal with aluminum flip-off seals.

Still yet another embodiment of the present invention provides composition of Ceftazidime Sodium and Sulbactam Sodium supplied with Disodium Edetate (EDTA) and water for injection composition kit comprising:

a) Mixture of sterile Ceftazidime Sodium and sterile Sulbactam Sodium is filled in a cleaned and depyrogenated type-I glass vials, purge the filled vials with pre filtered nitrogen gas in head space at very low pressure to avoid flashing of powder, and

b) Disodium Edetate (EDTA) and water for injection composition which is supplied in a type-I glass vials and seal with aluminum flip-off seals. Still yet another embodiment of the present invention provides composition of Ceftalozone Sulfate and Sulbactam Sodium supplied with Disodium Edetate (EDTA) and water for injection composition kit comprising:

a) Mixture of sterile Ceftalozone Sulfate and sterile Sulbactam Sodium is filled in a cleaned and depyrogenated type-I glass vials, purge the filled vials with pre filtered nitrogen gas in head space at very low pressure to avoid flashing of powder, and

b) Disodium Edetate (EDTA) and water for injection composition which is supplied in a type-I glass vials and seal with aluminum flip-off seals.

Still yet another embodiment of the present invention provides composition of Cefotaxime Sodium and Sulbactam Sodium supplied with Disodium Edetate (EDTA) and water for injection composition, kit comprising:

a) Mixture of sterile Cefotaxime Sodium and sterile Sulbactam Sodium is filled in a cleaned and depyrogenated type-I glass vials, purge the filled vials with pre filtered nitrogen gas in head space at very low pressure to avoid flashing of powder, and

b) Disodium Edetate (EDTA) and water for injection composition which is supplied in a type-I glass vials and seal with aluminum flip-off seals.

Still yet another embodiment of the present invention provides composition of Cefoperazone Sodium and Tazobactam Sodium supplied with Disodium Edetate (EDTA) and water for injection composition kit comprising:

a) Mixture of. sterile Cefoperazone Sodium and sterile Tazobactam Sodium is filled in a cleaned and depyrogenated type-I glass vials, purge the filled vials with pre filtered nitrogen gas in head space at very low pressure to avoid flashing of powder, and

b) Disodium Edetate (EDTA) and water for injection composition which is supplied in a type-I glass vials and seal with aluminum flip-off seals.

Still yet another embodiment of the present invention provides composition of Cefepime Hydrochloride monohydrate and Tazobactam Sodium supplied with Disodium Edetate (EDTA) and water for injection composition kit comprising:

a) Mixture of sterile Cefepime Hydrochloride monohydrate and sterile Tazobactam Sodium is filled in a cleaned and depyrogenated type-I glass vials, purge the filled vials with pre filtered nitrogen gas in head space at very low pressure to avoid flashing of powder, and

b) Disodium Edetate (EDTA) and water for injection composition which is supplied in a type-I glass vials and seal with aluminum flip-off seals.

Still yet another embodiment of the present invention provides composition of Cefpirome Sulfate and Tazobactam Sodium supplied with Disodium Edetate (EDTA) and water for injection composition kit comprising:

a) Mixture of sterile Cefpirome Sulfate and sterile Tazobactam Sodium is filled in a cleaned and depyrogenated type-I glass vials, purge the filled vials with pre filtered nitrogen gas in head space at very low pressure to avoid flashing of powder, and

b) Disodium Edetate (EDTA) and water for injection composition which is supplied in a type-I glass vials and seal with aluminum flip-off seals.

Still yet another embodiment of the present invention provides composition of Ceftazidime Sodium and Tazobactam Sodium supplied with Disodium Edetate (EDTA) and water for injection composition kit comprising:

a) Mixture of sterile Ceftazidime Sodium and sterile Tazobactam Sodium is filled in a cleaned and depyrogenated type-I glass vials, purge the filled vials with pre filtered nitrogen gas in head space at very low pressure to avoid flashing of powder, and

b) Disodium Edetate (EDTA) and water for injection composition which is supplied in a type-I glass vials and seal with aluminum flip-off seals.

Still yet another embodiment of the present invention provides composition of Ceftalozone Sulfate and Tazobactam Sodium supplied with Disodium Edetate (EDTA) and water for injection composition kit comprising:

a) Mixture of sterile Ceftalozone Sulfate and sterile Tazobactam Sodium is filled in a cleaned and depyrogenated type-I glass vials, purge the filled vials with pre filtered nitrogen gas in head space at very low pressure to avoid flashing of powder, and

b) Disodium Edetate (EDTA) and water for injection composition which is supplied in a type-I glass vials and seal with aluminum flip-off seals. Still yet another embodiment of the present invention provides composition of Piperacillin Sodium and Tazobactam Sodium supplied with Disodium Edetate (EDTA) and water for injection composition kit comprising:

a) Mixture of sterile Piperacillin Sodium and sterile Tazobactam Sodium is filled in a cleaned and depyrogenated type-I glass vials, purge the filled vials with pre filtered nitrogen gas in head space at very low pressure to avoid flashing of powder, and

b) Disodium Edetate (EDTA) and water for injection composition which is supplied in a type-I glass vials and seal with aluminum flip-off seals.

Still yet another embodiment of the present invention provides composition of

Ceftazidime Sodium and Avibactam Sodium supplied with Disodium Edetate (EDTA) and water for injection composition kit comprising:

a) Mixture of sterile Ceftazidime Sodium and sterile Avibactam Sodium is filled in a cleaned and depyrogenated type-I glass vials, purge the filled vials with pre filtered nitrogen gas in head space at very low pressure to avoid flashing of powder, and

b) Disodium Edetate (EDTA) and water for injection composition which is supplied in a type-I glass vials and seal with aluminum flip-off seals.

Still yet another embodiment of the present invention provides composition of Piperacillin and Tazobactam supplied with Disodium Edetate (EDTA) and water for injection composition kit comprising:

a) Mixture of sterile Piperacillin and Tazobactam is filled in a cleaned and depyrogenated type-I glass vials, purge the filled vials with pre filtered nitrogen gas in head space at very low pressure to avoid flashing of powder, and b) Disodium Edetate (EDTA), citric acid and water for injection as diluent which is supplied in a type-I glass vials and seal with aluminum flip-off seals.

DETAILED DESCRIPTION OF THE INVENTION

Another embodiment of the present invention provides an EDTA injection composition containing EDTA and Water for injection for parenteral preparations.

Another embodiment of the present invention provides an EDTA injection composition for antibiotics intended for parenteral administration, which is prepared by dissolving required quantity of Disodium Edetate (EDTA) in quantity sufficient volume of Water for injection. Then diluent solution containing EDTA and water for injection is filtered through 0.22 micron PVDF membrane filters. Filtered solution is filled into the type-I glass vials and seal with aluminum flip-off seals. The vials can be a PP or glass or LDPE, preferably it will be either glass or PP and sizes are in range of 2mL to 100 mL, preferably 2 mL to 20 mL in capacity. Seals can be aluminium with PP disc, aluminium with plastic cap or plastic twist-off caps or ports etc.

EDTA (ethylenediamine tetraacetic acid) and its salts are substituted diamines. EDTA and their salts include Calcium disodium EDTA, Diammonium EDTA, Dipotassium EDTA, Disodium EDTA, TEA-EDTA, Tetrasodium EDTA, Tripotassium EDTA and Trisodium EDTA.

Water for Injections is a clear, colourless, particle-free, odourless and tasteless liquid. It is sterile, with a pH of 5.0-7.0 and contains no anti-microbial agents .Water for injection is indicated to serve as a vehicle for dilution and reconstitution of suitable medicinal products for parenteral administration.

The diluent of the present inventionwherein the aqueous vehicle includes Water for

Injection (WFI) (USP), Bacteriostatic Water for Injection (BWFI) and Sterile Water for Injection (SWFI) (USP).

The diluent of the present invention can be used alone or in mixture with any other diluents such as Normal saline (0.9% Sodium Chloride), Dextran 6% in saline, 0.167M Sodium lactate, Lactated Ringer's solution, 5% Dextrose, 5% Dextrose in 0.45% saline, all combinations of dextrose injection and sodium chloride injection ( USP), containing up to 2.5% dextrose (USP), and 0.45% sodium chloride (USP), 5% Dextrose in 0.9% saline, sterile water for injection, M/6 Sodium Lactate Injection, 10% invert sugar and all combinations of dextrose injection and sodium chloride injection (USP), containing up to 2.5% dextrose (USP), and 0.45% sodium chloride ( USP), 10% Dextrose Injection (USP), Bacteriostatic Water for Injection [Benzyl Alcohol or Parabens], Bacteriostatic saline [Benzyl Alcohol or Parabens], Normosol ^® M and 5% Dextrose Injection, Normosol ^® R and 1% Lidocaine Hydrochloride etc.,

The EDTA injection of the present invention is used for reconstitution of any parenteral product before administration. Reconstitution before administration offers a good stability compared to a ready for injection product.

Parenteral product as used herein refers to any pharmaceutical product used for the treatment of a disease. The product can be selected from antibiotics, antiseptics, anti-infective agents, antimicrobial agents, antibacterial agents, antifungal agents, antiviral agents, antiprotozoal agents, sporicidal agents, antiparasitic agents, peripheral neuropathy agents, neuropathic agents, analgesic agents, anti-inflammatory agents, anti-allergic agents, anti- hypertension agents, mitomycin-type antibiotics, polyene antifungal agents, antiperspirant agents, decongestants, anti-kinetosis agents, central nervous system agents, wound healing agents, anti-VEGF agents, anti-tumor agents, escharotic agents, anti-psoriasis agents, antidiabetic agents, anti-arthritis agents, anti-itching agents, antipruritic agents, anesthetic agents, anti-malarial agents, dermatological agents, anti-arrhythmic agents, anticonvulsants, antiemetic agents, anti-rheumatoid agents, anti- androgenic agents, anthracyclines, anti- smoking agents, anti-acne agents, anticholinergic agents, anti-aging agents, antihistamines, anti-parasitic agents, hemostatic agents, vasoconstrictors, vasodilators, anticlotting agents, cardiovascular agents, angina agents, erectile dysfunction agents, sex hormones, growth hormones, immunomodulators, tumor necrosis factor alpha, anti-cancer agents, antineoplastic agents, anti-depressant agents, antitussive agents, anti-neoplastic agents, narcotic antagonistics, anti-hypercholesterolaemia agents, apoptosis-inducing agents, birth control agents, sunless tanning agents, emollients, alpha-hydroxyl acids, matrix metalloproteinases, topical retinoids, hormones, tumor- specific antibodies, antisense oligonucleotides, small interfering RNA (siRNA), anti-VEGF RNA aptamer, nucleic acids, DNA, vitamins, essential oils, silver salts, zinc salts, salicylic acid, benzoyl peroxide, 5-fluorouracil, nicotinic acid, nitroglycerin, clonidine, estradiol, testosterone, nicotine, motion sickness agents, scopolamine, fentanyl, diclofenac, buprenorphine, bupivacaine, ketoprofen, opiods, cannabinoids, enzymes, enzyme inhibitors, oligopeptides, cyclopeptides, polypeptides, proteins, prodrugs, protease inhibitors, cytokines, hyaluronic acid, chondroitin sulfate, dermatan sulfate, parasympatholytic agents, chelating agents, hair growth agents, lipids, glycolipids, glycoproteins, endocrine hormones, growth hormones, growth factors, heat shock proteins, immunological response modifiers, saccharides, polysaccharides, insulin and insulin derivatives, steroids, corticosteroids, and non-steroidal anti-inflammatory drugs or similar materials, in either their salt form or their neutral form, either being inherently hydrophilic or encapsulated within a hydrophilic microparticle or nanoparticle. Such biologically-active agents could be in either of the (R)-, (R,S)-, or (S)-configuration, or a combination thereof.

Antibiotics of the present invention includePenicillins, Cephalosporins, Monobactams, Carbapenems, Macrolide Antibiotics, Lincosamides, Streptogramins, Aminoglycoside Antibiotics, Quinolone Antibiotics, Sulfonamides, Tetracycline Antibiotics and Other Antibiotics or combinations thereof.

Penicillins include Amoxicillin, Ampicillin, Bacampicillin, Carbenicillin, Cloxacillin, DicloxaciUin, FlucloxaciUin, Mezlocillin, Nafcillin, Oxacillin, Penicillin G, Penicillin V, Piperacillin, Pivampicillin, Pivmecillinam, Ticarcillin etc or combination thereof.

Cephalosporins include first generation, second generation, third generation, fourth generation, fifth generation, not classified and combinations.

First generation cephalosporins include Cefacetrile (cephacetrile), Cefadroxil (cefadroxyl), Cefalexin (cephalexin), Cefaloglycin (cephaloglycin), Cefalonium (cephalonium), Cefaloridine (cephaloradine), Cefalotin (cephalothin), Cefapirin (cephapirin), Cefatrizine, Cefazaflur, Cefazedone, Cefazolin (cephazolin), Cefradine (cephradine), Cefroxadine, Ceftezole etc.

Second generation cephalosporins include Cefaclor, Cefamandole, Cefmetazole, Cefonicid, Cefotetan, Cefoxitin, Cefprozil (cefproxil), Cefuroxime, Cefuzonam etc.

Third generation cephalosporins include Cefcapene, Cefdaloxime, Cefdinir, Cefditoren, Cefetamet, Cefixime, Cefmenoxime, Cefodizime, Cefotaxime, Cefpimizole, Cefpodoxime, Cefteram, Ceftibuten, Ceftiofur, Ceftiolene, Ceftizoxime, Ceftriaxone, Cefoperazone, Ceftazidime etc.

Fourth generation cephalosporins includeCefclidine, Cefepime, Cefluprenam, Cefoselis, Cefozopran, Cefpirome, Cefquinome etc.

Fifth generation cephalosporins include Ceftobiprole, Ceftaroline etc.

Other cephalosporins include Cefaclomezine, Cefaloram, Cefaparole, Cefcanel, Cefedrolor, Cefempidone, Cefetrizole, Cefivitril, Cefmatilen, Cefmepidium, Cefovecin, Cefoxazole, Cefrotil, Cefsumide, Cefuracetime, Ceftioxide etc.

Combinations include Ceftazidime/ Avibactam.

Monobactams include Aztreonam etc.

Carbapenems include Imipenem, Imipenem/cilastatin, Doripenem, Meropenem, Ertapenem, Faropenem etc.

Macrolide Antibiotics includes Azithromycin, Erythromycin, Clarithromycin, Dirithromycin, Roxithromycin, Ketolides (eg: Telithromycin) etc.

Lincosamides include Clindamycin, Lincomycin etc.

Streptogramins include Pristinamycin, Quinupristin/dalfopristin etc. Aminoglycoside Antibiotics includes Amikacin, Gentamicin, Kanamycin, Neomycin, Netilmicin, Paromomycin, Streptomycin, Tobramycin etc.

Quinolone Antibiotics include first generation, second generation, third generation, fourth generation.

First generation quinolone antibiotics include Flumequine, Nalidixic acid, Oxolinic acid, Piromidic acid, Pipemidic acid, Rosoxacin etc.

Second generation quinolone antibiotics include Ciprofloxacin, Enoxacin, Lomefloxacin, Nadifloxacin, Norfloxacin, Ofloxacin, Pefloxacin, Rufloxacin etc.

Third generation quinolone antibiotics include Balofloxacin, Gatifloxacin, Grepafloxacin, Levofloxacin, Moxifloxacin, Pazufloxacin, Sparfloxacin, Temafloxacin, Tosufloxacin etc. Fourth generation quinolone antibiotics include Besifloxacin, Clinafloxacin, Gemifloxacin, Sitafloxacin, Trovafloxacin, Prulifloxacin etc.

Sulfonamides include Sulfamethizole, Sulfamethoxazole, Sulfisoxazole, Trimethoprim-Sulfamethoxazole etc.

Tetracycline Antibiotics include Demeclocycline, Doxycycline, Minocycline,

Oxytetracycline, Tetracycline, Glycylcyclines (eg: Tigecycline) etc.

Other Antibiotics include Chloramphenicol, Metronidazole, Tinidazole, Nitrofurantoin, Glycopeptides (eg: Vancomycin, Teicoplanin), Lipoglycopeptides (eg: Telavancin), Oxazolidinones (Linezolid, Cycloserine 2), Rifamycins (eg: Rifampin, Rifabutin, Rifapentine, Rifalazil), Polypeptides (eg: Bacitracin, Polymyxin B), Tuberactinomycins (eg: Viomycin, Capreomycin) etc.

The following examples describe the nature of the invention and are given only for the purpose of illustrating the present invention in more detail and are not limitative.

EXAMPLES

Example 1;

Example 2:

Example 6: S.No. Ingredients %w/w

1. Disodium EDTA 0.1 - 2 mg

2. Citric acid q.s. to adjust osmolality

3. Water for injection (WFI) 2-20 ml

Example 7:

S.No. Ingredients %w/w

Drug Product

1. Ceftriaxone Sodium eq. to Ceftriaxone 0.125- 2 g

2. Sulbactam Sodium eq. to Sulbactam 0.0625-lg

Diluent

3. Disodium EDTA 0.1 - 2 mg

4. Water for injection (WFI) 2-20 ml

Example 8:

S.No. Ingredients %w/w

Drug Product

1. Ceftolozane Sulfate eq. to Ceftolozane i g

2. Tazobactam Sodium eq. to Tazobactam 0.5 g

Diluent

3. Disodium EDTA 0.1 - 2 mg

4. Water for injection (WFI) 2-20 ml

Example 9:

S.No. Ingredients %w/w

Drug Product

1. Ceftriaxone Sodium eq. to Ceftriaxone 0.5- 2.0 g

2. Tazobactam Sodium eq. to Tazobactam 0.0625- 0.5 g

Diluent

3. Disodium EDTA 0.1 - 2 mg 4. Water for injection (WFI) 2-20 ml

Example 10:

S.No. Ingredients %w/w

Drug Product

1. Cefoperazone Sodium eq. to Cefoperazone 0.5- 1 g

2. Sulbactam Sodium eq. to Sulbactam 0.5 g - lg

Diluent

3. Disodium EDTA 0.1 - 2 mg

4. Water for injection (WFI) 2-20 ml

Example 11:

S.No. Ingredients %w/w

Drug Product

1. Cefoperazone Sodium eq. to Cefoperazone 0.5- 2 g

2. Sulbactam Sodium eq. to Sulbactam 0.250 g - l.Og

Diluent

3. Disodium EDTA 0.1 - 2 mg

4. Water for injection (WFI) 2-20 ml

Example 12:

S.No. Ingredients %w/w

Drug Product

1. Piperacillin Sodium eq. to Piperacillin 2.0- 4.0 g

2. Tazobactam Sodium eq. to Tazobactam 0.250 g - 0.5g

Diluent

3. Disodium EDTA 0.5-1.0 mg

4. Citric acid q.s. to adjust Osmolarity

4. Water for injection (WFI) 10-20 ml

Example 13: S.No. Ingredients %w/w

Drug Product

1. Cefotaxime Sodium eq. to Cefotaxime 0.250- 2 g

2. Sulbactam Sodium eq. to Sulbactam 0.125-lg

Diluent

3. Disodium EDTA 0.1 - 2 mg

4. Water for injection (WFI) 2-20 ml

Example 14:

S.No. Ingredients %w/w

Drug Product

1. Cefepime Hydrochloride monohydrate eq. to Cefepime 0.250- 1 g

2. Sulbactam Sodium eq. to Sulbactam 0.125-0.5g

Diluent

3. Disodium EDTA 0.1 - 2 mg

4. Water for injection (WFI) 2-20 ml

Example 15:

S.No. Ingredients %w/w

Drug Product

1. Ceftazidime Sodium eq. to Ceftazidime lg -2 g

2. Avibactam Sodium eq. to Avibactam 0.250-0.5g

Diluent

3. Disodium EDTA 0.1 - 2 mg

4. Water for injection (WFI) 2-20 ml

Brief Manufacturing Process:

Drug Product: for some combinations sterile mixture is available and for others where it's not available in a mixture, below procedure to be followed.

1) Weighed quantity of sterile materials of first active and second active was transferred to blender and blended for 15 minutes, 2) Above blend was shifted through #30.0 mesh and again mixed for 15 minutes in a blender,

3) Cleaned, dried and depyrogenated vials were purged with nitrogen gas before filling of above powder mixture,

4) Above Premix was filled at the target fill weight into a Cleaned, dried and depyrogenated clear 10 mL or 20 mL or 50 mL or 100 mL/20 mm clear moulded type-I glass vial with pre-filtered Nitrogen gas purged in the head space of vial at a very low pressure to avoid flashing/dusting of powder, and

5) Filled vials were stoppered with 20 mm bromobutyl rubber stoppers and sealed with 20mm aluminium flip-off seal.

Diluent: Add and dissolve required qty of Disodium Edetate (EDTA) in q.s. volume of WFI. Filter the above solution through 0.22 micron membrane filters, fill the filtered solution into type-I glass vials and seal with aluminum flip-off seals.

The composition as described in the present invention can be used as diluent for reconstitution of the parenteral product before administration thereby offering stability to the product. Further, the EDTA is not mixed with the API's thereby avoiding the interaction of EDTA with the API and other excipients if any in the parenteral product. By adding EDTA to the diluent instead of to the API and reconstituted before the administration the efficacy of the product is retained.

Further, the diluent is supplied separately thus the diluent can be used for reconstituting any parenteral product instead of adding EDTA to every drug product.

Formulations of Disodium Edetate injection as prepared in Examples of the present invention are filled into vials and are subjected to stability as per ICH guideline. The data is summarised in the tables given below:

Table 1;

Stability data of Disodium Edetate injection prepared as per example 1 (20mL fill in 20 mL molded vial and bromobutyl rubber stoppers)

pH 5.0-7.5 7.05 6.68 6.65

Clarity of Solution should Clear solution Clear solution Clear solution solution be clear

Color of Clear colorless colorless colorless colorless solution solution solution solution solution

Assay 90- 110% 102.3 100.7 100.5

Table 2:

Stability data of Disodium Edetate injection prepared as per example 1 (5 mL fill in 5 mL tubular vial and bromobutyl rubber stoppers)

Table 4:

Table 5:

Table 6: Months 3 Months 3 Months pH 5.0-7.5 7.03 7.05 7.14

Clarity of Solution should Clear colorless Clear colourless Clear colorless solution be clear solution solution solution

Color of Clear colorless Clear colorless Clear colourless Clear colorless solution solution solution solution solution

Assay 90-110% 93.6 98.1 102

It is evident from Tables 1-6 that all formulations, according to the invention, are stable after 3 months at 40°C and 75% RH.