WO2022106611A1 - Nouvelles compositions de composés de bêta-lactame - Google Patents

Nouvelles compositions de composés de bêta-lactame Download PDF

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Publication number
WO2022106611A1
WO2022106611A1 PCT/EP2021/082287 EP2021082287W WO2022106611A1 WO 2022106611 A1 WO2022106611 A1 WO 2022106611A1 EP 2021082287 W EP2021082287 W EP 2021082287W WO 2022106611 A1 WO2022106611 A1 WO 2022106611A1
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Prior art keywords
acetyl
amino acid
alaninamide
prolinamide
item
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PCT/EP2021/082287
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English (en)
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Sanja Vukoja
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Xellia Pharmaceuticals Aps
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Publication of WO2022106611A1 publication Critical patent/WO2022106611A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to pharmaceutical compositions comprising at least one beta-lactam compound and at least one N-acetyl amino acid amide. Such compositions provide good stability over time.
  • the invention is related to pharmaceutical compositions of betalactam antibiotics and/or beta-lactamase inhibitors and at least one N-acetyl amino acid amide.
  • Beta-lactam antibiotics are antibiotics that contain a beta-lactam ring in their molecular structure. This includes penicillin derivatives (penams), penems, cephalosporins (cephems), monobactams, carbapenems and carbacephems. Most beta-lactam antibiotics work by inhibiting cell wall biosynthesis in the bacterial and are the most widely used group of antibiotics.
  • Beta-lactam antibiotics may include piperacillin, cefazolin, cefepime, aztreonam, ertapenem, ampicillin, ceftazidime, cefoxitin, cefazoline fosamil, oxacillin, amoxicillin, penicillin V, clavunalate potassium, cefadroxil, cephalexin, cefaclor, cefprozil, cefdinir, cefixime, cefpodoxime proxetil.
  • Piperacillin is a semisynthetic broad-spectrum ‘ -lactam antibiotic, which is active against a variety of gram-positive and gram-negative aerobic and anaerobic bacteria.
  • Piperacillin ( Figure 1) comprises a polar side chain that enhances penetration into gram-negative bacteria and reduces susceptibility to cleavage by gram-negative beta-lactamase enzymes. These properties confer activity against the important hospital pathogen Pseudomonas aeruginosa. Thus, piperacillin is sometimes referred to as an "anti -pseudomonal penicillin”.
  • piperacillin When used alone, piperacillin lacks strong activity against the gram-positive pathogens such as Staphylococcus aureus, as the beta-lactam ring is hydrolyzed by the bacteria's beta-lactamase.
  • Beta-lactamases are family of enzymes involved in bacterial resistance to betalactam antibiotics. They act by breaking the beta-lactam ring that allows penicillin- like antibiotics to work. Strategies for combating this form of resistance have included the development of new beta-lactam antibiotics that are more resistant to cleavage and the development of the class of enzyme inhibitors called beta-lactamase inhibitors. Although • -lactamase inhibitors have little antibiotic activity of their own, they prevent degradation of beta-lactam antibiotics by beta-lactamases secreted by resistant microorganisms and thus restore activity of the partner beta-lactam antibiotics.
  • Beta-lactamase inhibitors may or may not have beta-lactam ring.
  • Beta-lactamase inhibitors having beta-lactam ring may include Tazobactam, Sulbactam, Clavulanic acid.
  • Beta-lactamase inhibitors not having beta-lactam ring may include Avibactam; Relebactam, Vaborbactam.
  • Tazobactam is a penicillanic acid sulfone derivative and beta-lactamase inhibitor with antibacterial activity. Tazobactam contains a beta-lactam ring and irreversibly binds to beta-lactamase at or near its active site. This protects other beta-lactam antibiotics from beta-lactamase catalysis. This drug is used in conjunction with betalactamase susceptible penicillins, such as piperacillin, to treat infections caused by beta-lactamase producing organisms.
  • Piperacillin-tazobactam is recommended as part of a three drug regimen for the treatment of hospital-acquired pneumonia suspected as being due to infection by multi-drug resistant pathogens. It is also one of several antibacterials recommended for the treatment of infections known to be caused by anaerobic gram-negative rods.
  • beta-lactams as well as beta-lactam inhibitors are commonly commercially available in a form of lyophilized powder for intravenous infusion which requires reconstitution and subsequent dilution step prior to patient administration.
  • beta-lactams are also available in liquid frozen state, which requires storage in deep freezers and thawing before use. Once, thawed, such beta-lactams are stabile only for a short period of time.
  • product on the market piperacillin/tazobactam frozen solution in the Galaxy bag even in the frozen state i.e. stored at -20°C
  • has a shelf life of 9 months only and upon thawing can be used in period of 24h if stored at 20 to 25 Celsius degree and within 14 days if stored at 2 to 8 Celsius degree upon thawing.
  • compositions of beta-lactams suitable for administration to a subject and which possess long term storage stability both in respect of degradation of beta-lactams and in respect of the formation of individual impurities.
  • composition comprising at least one betalactam compound, its pharmaceutical salts or derivative thereof and at least one N- acetyl amino acid amide. It has been found that the pharmaceutical formulation of beta-lactam compound comprising at least one N-acetyl amino acid amide possess surprisingly enhanced storage stability.
  • beta-lactam compound may include beta-lactam antibiotics and beta-lactamase inhibitors, its pharmaceutical salt or derivative thereof.
  • beta-lactam compound is selected from penams and carbapenems.
  • penams are selected from beta-lactam inhibitors, such as tazobactam, and from extended spectrum of penams, like for instance piperacillin, its pharmaceutical salt or derivative thereof.
  • beta-lactam compound is tazobactam, its pharmaceutical salt or derivative thereof.
  • beta-lactam antibiotic is selected from piperacillin, cefazolin, cefepime, aztreonam, ertapenem, ampicillin, ceftazidime, cefoxitin, cefazoline fosamil, oxacillin, amoxicillin, penicillin V, clavunalate potassium, cefadroxil, cephalexin, cefaclor, cefprozil, cefdinir, cefixime, cefpodoxime proxetil, its salts and derivatives thereof.
  • pharmaceutical formulation of the present disclosure is in liquid form.
  • beta-lactam compound when formulated in formulations according to the present disclosure, degradation product formation is retarded, and accordingly, such formulations exhibit prolonged chemical stability and provide more flexible storage conditions and handling when stored under refrigerated conditions, i.e. at a temperature of from 2°C to 8°C. Furthermore, the pharmaceutical formulation of beta-lactams in accordance with the present disclosure has improved stability under room temperature conditions.
  • a liquid formulation of at least one beta-lactam compound according to the present disclosure is stable at a temperature of from 2°C to 8°C for a certain period of time.
  • a liquid formulation of at least one beta-lactam compound according to the present disclosure is stable under room temperature conditions for a certain period of time.
  • Disclosed formulations may enhance activity and/or efficacy of beta-lactam compound.
  • compositions according to the present disclosure may be used to treat a patient with a microbial infection by administering the pharmaceutical formulation.
  • Liquid formulation of the pharmaceutical formulation in accordance to this disclosure may be optionally diluted before administration.
  • compositions comprising at least one betalactam compound, its pharmaceutical salt or derivative thereof and at least one N- acetyl amino acid amide.
  • N- Acetyl amino acid amide is an amino acid derivative where • -nitrogen of amino acid is N-acetylated and where, instead of carboxylic acid group, amide group is bound to the • carbon atom of the amino acid group.
  • N-acetylated amino acid amide please see Figure 3 below, showing the structure of N-acetyl alaninamide:
  • At least one N-acetyl amino acid amide is also named a “first N-acetyl amino acid amide”.
  • pharmaceutical formulation comprises at least two N-acetyl amino acid amides.
  • N-acetyl amino acid amides are also named a “first N-acetyl amino acid amide” and a “second N-acetyl amino acid amide”.
  • beta-lactam compound a class of antibiotics consisting of antibiotic agents that contain a beta-lactam ring in their molecular structures. This includes penicillin derivatives (penams), cephalosporins (cephems), monobactams, carbapenems, carbacephems as well as beta-lactamase inhibitors.
  • beta-lactam antibiotic is selected from piperacillin, cefazolin, cefepime, aztreonam, ertapenem, ampicillin, ceftazidime, cefoxitin, cefazoline fosamil, oxacillin, amoxicillin, penicillin V, clavunalate potassium, cefadroxil, cephalexin, cefaclor, cefprozil, cefdinir, cefixime, cefpodoxime proxetil, its pharmaceutical salts or derivatives thereof.
  • beta-lactam compound as used herein is also meant a class of betalactamase inhibitors, having or not having beta-lactam ring in their molecular structures.
  • beta-lactamase inhibitor is selected from tazobactam, avibactam, sulbactam, clavulanic acid, vaborbactam, relebactam, its pharmaceutical salt or derivative thereof.
  • Formulations according to the present disclosure showed surprising stability for a reasonable period of time, when stored at a temperature of from 2°C to 8°C, such as, e.g., at a temperature of 2°C , 3 °C or less, 4°C or less, 5 °C or less, 6°C or less, 7°C or less or 8°C or less.
  • room temperature is a room temperature which is from 20 °C to 25 °C.
  • Term “stable” as used herein refers to a pharmaceutical formulation containing beta-lactam compound having sufficient utility as a pharmaceutical product, i.e. that the pharmaceutical formulation exhibits an acceptable purity of beta-lactam compound or an acceptable purity decrease of beta-lactam compound after a certain period of time. Accordingly, in a stable solution or formulation unacceptable amount of degradation of beta-lactam compounds is avoided. Further, in a stable formulation, pharmaceutically desirable appearance such as no visible particles (for example, no visible particles to the naked eye) is retained. Visual inspection may be performed as follows: the vial under inspection is gently swirled and inverted, ensuring that no air bubbles are produced, and inspected for approximately 5 sec with the naked eye.
  • the stability can be determined by measuring of beta-lactam compound remaining in the solution or composition according to the invention after a predetermined time period, preferably expressed as a percentage, for example as a peak-area percentage of a chromatogram (purity). If the formulation initially contains beta-lactam compound in a certain purity, the stability of the formulation will be reflected by a decrease/drop in the chromatographic purity of the beta-lactam compound formulation over time, where a stable formulation would contain the betalactam compound in a specified chromatographic purity after predetermined time period. [042] Stability of the formulation may also be expressed in terms of concentration or absolute amount of beta-lactam compound.
  • Stability may be defined by the amount of beta-lactam compound in the formulation after a certain period of time.
  • Stability may also be defined by the amount of total or individual impurities in the formulation after a certain period of time. Stability may also be defined by increase of total or individual impurities generated after a suitable period of time.
  • the stability can be determined by measuring the amount of each individual impurity in the formulation according to the invention after a predetermined time period, preferably expressed as a percentage, for example as a peak-area percentage of a chromatogram.
  • impurity as used herein is meant a degradation impurity of the active pharmaceutical ingredient in the pharmaceutical formulation.
  • Tazobactam related compound A By the individual impurities related to tazobactam, it is predominantly meant Tazobactam related compound A. Structure of Tazobactam related compound A is shown below as Figure 4.
  • Tazobactam related compound A Piperacillin degrades into the following main degradation impurities: Piperacillin penicilloic acid isomer 1 and 2, Piperacillin penilloic acids, Piperacillin dimer and Piperazinedione-carbonyl D-phenylglycyl-glycine. [051] Structures of these impurities are shown below as Figures 5, 6, 7, 8 and 9.
  • Disclosed formulations also minimize degradation of beta-lactam compound to impurities.
  • Disclosed formulations retain pharmaceutically desirable appearance such as no visible particles.
  • stable is defined as no more than 10% of purity decrease/drop of individual beta-lactam compound in the pharmaceutical formulation, determined by HPLC analysis.
  • a stable composition can be one which has not more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, of purity decrease/drop for individual betalactam compound after a predetermined time period.
  • a stable composition can be one which has not more than 8% of purity decrease/drop for individual beta-lactam compound after a predetermined time period.
  • stable is defined as no more than 5% increase (expressed by peak-area percentage) of each individual impurity formation after a predetermined time period.
  • a stable composition can be one that has not more than 1%, 2%, 3%, 4%, 5%, increase (expressed by peak-area percentage) of individual impurity formation after a predetermined time period.
  • composition of beta-lactam compound described herein is stable over time periods of 7 days (1 week), 14 days (2 weeks), 30 days (1 month), 60 days (2 months), 3 months, 4 months, 180 days (6 months), 9 months, 12 months (1 year), 14 months, 16 months, 18 months, 20 months, 24 months and longer at temperatures of 2-8°C.
  • composition beta-lactam compound described herein is stable over time periods of 7 days (1 week), 14 days (2 weeks), 22 days, 30 days (1 month), 60 days (2 months), 3 months, 6 months and longer at room temperature. [062] In one aspect, composition of beta-lactam compound described herein is stable for at least 4 days at temperature of 30°C.
  • composition of beta-lactam compound described herein is stable for at least 11 days at temperature of 30°C.
  • a stable or stabilized composition can be one that has not more than 5% increase of individual impurity formation over 6 months and longer at temperatures of 2-8°C.
  • a stable or stabilized composition can be one that has not more than 5% increase of individual impurity formation after 12 months and longer at temperatures of 2-8°C.
  • a stable or stabilized composition of tazobactam can be one that has not more than 4% increase of Tazobactam related compound A after 6 months and longer at temperatures of 2-8°C.
  • a stable or stabilized composition can be one wherein purity of betalactam compound present after certain period of time is not less than 90%.
  • a sable or stabilized composition can be one wherein the purity of beta-lactam compound present after 2 months at 2-8 °C is not less than 92%.
  • a sable or stabilized composition can be one wherein the purity of beta-lactam compound present after 4 months at 2-8 °C is not less than 92%.
  • a sable or stabilized composition can be one wherein the purity of beta-lactam compound present after 12 months at 2-8 °C is not less than 92%.
  • the pharmaceutical composition according this disclosure is stable at least 14 days at 25 °C.
  • the pharmaceutical composition according this disclosure is stable at least 22 days at 25 °C.
  • the pharmaceutical composition comprising tazobactam is stable for at least 60 days at 25 °C, as demonstrated by determining the amount of Tazobactam A present in the pharmaceutical composition at 60 days, and wherein the amount of the Tazobactam A present is not more than 10%.
  • compositions described herein can be performed using techniques known in the art, including HPLC.
  • pharmaceutical composition or “pharmaceutically acceptable composition” as used herein, is meant any composition suitable and intended for in vivo use, for example administration to a patient or a subject.
  • patient and “subject” are interchangeable and refer to any human or animal individual who is receiving a composition as described herein.
  • composition As used herein, the terms “pharmaceutical composition”, “pharmaceutically acceptable composition”, “pharmaceutical formulation”, “composition” and “formulation” are used interchangeably.
  • beta-lactam compound is in form of a salt.
  • Beta-lactam compound salt can be selected from calcium, sodium, magnesium or potassium salt.
  • beta-lactam compound salt is sodium salt.
  • pharmaceutical formulation comprises at least piperacillin, its salt and derivative thereof.
  • pharmaceutical formulation comprises at least tazobactam, its salt and derivative thereof.
  • pharmaceutical formulation comprises at least piperacillin sodium.
  • pharmaceutical formulation comprises at least tazobactam sodium.
  • pharmaceutical formulation comprises at least one beta-lactam antibiotic and at least one beta-lactamase inhibitor.
  • pharmaceutical formulation comprises at least piperacillin and at least one beta-lactamase inhibitor.
  • pharmaceutical formulation comprises at least one beta-lactam antibiotic and tazobactam.
  • pharmaceutical formulation comprises piperacillin and tazobactam, its salt and derivative thereof.
  • pharmaceutical formulation comprises at least one beta-lactam antibiotic and at least one beta-lactamase inhibitor, and weight ratio of at least one beta-lactam antibiotic to at least one beta-lactamase inhibitor may be from 1: 1 to 10: 1.
  • pharmaceutical formulation comprises at least one beta-lactam antibiotic and tazobactam, and weight ratio of at least one beta-lactam antibiotic to tazobactam may be from 2: 1 to 8: 1.
  • pharmaceutical formulation comprises piperacillin and at least one beta-lactamase inhibitor, and weight ratio of at least one beta-lactam antibiotic to piperacillin may be from 2: 1 to 8: 1.
  • pharmaceutical formulation comprises piperacillin sodium and tazobactam sodium.
  • weight ratio of piperacillin to tazobactam can be from 4: 1 to 8:1. In an aspect, the weight ratio of piperacillin to tazobactam is 8:1.
  • pharmaceutical formulation is liquid.
  • pharmaceutical formulation may be oral suspension or solution.
  • pharmaceutical formulation comprises water.
  • pharmaceutical formulation may comprise less than 99% w/V of water.
  • pharmaceutical formulation may comprise less than 60% w/V of water.
  • pharmaceutical formulation comprises less than 50% w/V of water.
  • pharmaceutical formulation comprises less than 45% w/V, 40% w/V, 35% w/V, 30% w /V, 25% w /V, 20% w /V, 15% w /V, 10% w /V, 8% w /V, 6% w /V, 4% w /V, 2% w /V, 1% w /V of water.
  • pharmaceutical formulation is semisolid, like ointments, creams, gels, or pastes.
  • the semisolid composition is gel.
  • an N-acetyl amino acid amide may be N- acetyl cysteinamide, N-acetyl glutaminamide, N-acetyl aspartic acid amide, N-acetyl glycinamide, N-acetyl alaninamide, N-acetyl prolinamide, N-acetyl serinamide, N- acetyl threoninamide, N-acetyl valinamide, N-acetyl isoleucinamide, N-acetyl leucinamide, N-acetyl methioninamide, N-acetyl phenylalaninamide, N-acetyl tyrosinamide, N-acetyl asparaginamide, N-acetyl glutamic acid amide, N-acetyl histidinamide, N-acetyl argininamide, N-acetyl citrullinamide,
  • pharmaceutical formulation comprises at least N-Acetyl alaninamide.
  • N-acetyl amino acid amide may be in L configuration, while in some other aspect it may be in D configuration.
  • terms “L configuration” and “D configuration” are referred to stereochemistry of amide group consisting of N- acetylated • -nitrogen in N-Acetyl amino acid amide. If this group in Fisher projection formula is turned right, it is a N-acetyl D-amino acid amide. If it is turned left it is a N-acetyl L-amino acid amide.
  • pharmaceutical formulation comprises at least N-acetyl-L- alaninamide (hereinafter NALAA).
  • pharmaceutical formulation comprises at least N-acetyl-D- alaninamide (hereinafter NADAA).
  • pharmaceutical formulation comprises at least N-acetyl-L- prolinamide (hereinafter NALPA).
  • NALPA N-acetyl-L- prolinamide
  • a concentration of an N-acetyl amino acid amide is from 1 mg/ml to 1500 mg/ml.
  • a concentration of an N-acetyl amino acid amide is from 20 mg/ml to 1000 mg/ml.
  • a concentration of an N-acetyl amino acid amide is 20 mg/ml, 30 mg/ml, 40 mg/ml, 50 mg/ml, 60 mg/ml, 70 mg/ml, 80 mg/ml, 90 mg/ml, 100 mg/ml, 150 mg/ml, 200 mg/ml, 250 mg/ml, 300 mg/ml, 400 mg/ml, 500 mg/ml, 600 mg/ml, 700 mg/ml, 750mg/ml, 800 mg/ml, 900 mg/ml or 1000 mg/ml.
  • a concentration of an N-acetyl amino acid amide is from 300 mg/ml to 750 mg/ml.
  • pharmaceutical formulation comprises two N-acetyl amino acid amides.
  • pharmaceutical formulation comprises N-Acetyl-L-prolinamide and N-Acetyl-L-alaninamide.
  • pharmaceutical formulation comprises N-Acetyl-L-prolinamide and N-Acetyl-D-alaninamide.
  • the first N-acetyl amino acid amide and the second N-acetyl amino acid amide are in molar ratio from 0.2: 1 to 5: 1.
  • the N-acetyl amino acid amide first and the second N-acetyl amino acid amide are in molar ratio of 0.2: 1, 0.3: 1, 0.4:1, 0.5:1, of 1: 1, of 1.5: 1, of 2:1, of 2.5: 1, of 3: 1, of 4:1, of 5:1.
  • the first N-acetyl amino acid amide and the second N-acetyl amino acid amide are in molar ratio of 1 : 1.
  • pharmaceutical formulation comprises two N-acetyl amino acid amides and a concentration of each N-acetyl amino acid amide is 20 mg/ml, 30 mg/ml, 40 mg/ml, 50 mg/ml, 60 mg/ml, 70 mg/ml, 80 mg/ml, 90 mg/ml, 100 mg/ml, 150 mg/ml, 200 mg/ml, 250 mg/ml, 300 mg/ml, 400 mg/ml, 500 mg/ml, 600 mg/ml, 700 mg/ml, 750mg/ml, 800 mg/ml.
  • pharmaceutical formulation comprises two N-acetyl amino acid amides and a concentration of an N-acetyl amino acid amide is 20 mg/ml, 30 mg/ml, 40 mg/ml, 50 mg/ml, 60 mg/ml, 70 mg/ml, 80 mg/ml, 90 mg/ml, 100 mg/ml, 150 mg/ml, 200 mg/ml, 250 mg/ml, 300 mg/ml, 400 mg/ml, 500 mg/ml, 600 mg/ml, 700 mg/ml, 750mg/ml, 800 mg/ml.
  • pharmaceutical formulation comprises two N-acetyl amino acid amides and a concentration of each N-acetyl amino acid amide is from 300 mg/ml to 600 mg/ml.
  • pharmaceutical formulation comprises two N-acetyl amino acid amides and a concentration of each N-acetyl amino acid amide is from 300 to 400 mg/ml.
  • pharmaceutical formulation may comprise at least one additional compound selected from nicotinamide, acetamide, benzamide, amino acids, quaternary ammonium compounds, quaternary phosphonium compounds, organic acids, sugars, urea and derivatives thereof, metal salts, choline chloride, sorbitol, ethyleneglylcol amide, polymers such as PEG, PPG, phenol, glycerol, saccharin, imidazole, its salts or derivatives thereof.
  • additional compound selected from nicotinamide, acetamide, benzamide, amino acids, quaternary ammonium compounds, quaternary phosphonium compounds, organic acids, sugars, urea and derivatives thereof, metal salts, choline chloride, sorbitol, ethyleneglylcol amide, polymers such as PEG, PPG, phenol, glycerol, saccharin, imidazole, its salts or derivatives thereof.
  • At least one N-acetyl amino acid amide and at least one additional compound are in molar ratio from 0.3:1 to 3:1.
  • at least one N-acetyl amino acid amide and at least one additional compound are in molar ratio of 0.3:1, 0.5:1, of 1: 1, of 1.5:1, of 2:1, of 2.5:1, and of 3:1.
  • At least one N-acetyl amino acid amide and at least one additional compound are in molar ratio of 1 : 1.
  • At least two N-acetyl amino acid amides may form a deep eutectic solvent (DES).
  • at least one N-acetyl amino acid amide and at least one additional compound may form a deep eutectic solvent. It is noticed that in case that the deep eutectic solvent has been formed, the pharmaceutical formulation according to the present description is having improved stability over time.
  • deep eutectic solvent a solvent prepared with a combination of two or more solid substances which have melting point above room temperature, which substances, when mixed in appropriate proportions, give rise to a liquid mixture at room temperature.
  • Solid substances which can be combined in deep eutectic solvent are selected from organic acids, sugars, sugar alcohols, amines, amides and amino acids.
  • water may be added in an amount from 0% w/V to 50 % w/V of water.
  • the first N-acetyl amino acid amide and the second N-acetyl amino acid amide are comprised in the pharmaceutical formulation in the form of deep eutectic solvent.
  • deep eutectic solvent is formed when the first N-acetyl amino acid amide and the second N-acetyl amino acid amide are in molar ratio from 0.3: 1 to 3: 1.
  • deep eutectic solvent is formed when the first N-acetyl amino acid amide and the second N-acetyl amino acid amide are in molar ratio of 0.3: 1, of 0.5:1, of 1:1, of 1.5: 1, of 2: 1, of 2.5: 1, and of 3:1.
  • deep eutectic solvent is formed when the first N-acetyl amino acid amide and the second N-acetyl amino acid amide are in molar ratio of 1: 1.
  • deep eutectic solvent is formed when at least one N-acetyl amino acid amide and at least one additional compound are in molar ratio from 0.3:1 to 3: 1.
  • deep eutectic solvent is formed when at least one N-acetyl amino acid amide and at least one additional compound are in molar ratio of 0.3:1, 0.5:1, of 1:1, of 1.5: 1, of 2:1, of 2.5: 1, and of 3:1.
  • deep eutectic solvent is formed when at least one N-acetyl amino acid amide and at least one additional compound are in molar ratio of 1 : 1.
  • deep eutectic solvents may comprise 50% w/V or less of water.
  • deep eutectic solvents may contain 45% or less, of 40% w/V or less, 35% w/V or less, 30% w/V or less, 25% w/V or less, 20% w/V or less, 15% w/V or less, 10% w/V or less, 5% w/V or less, 2% w/V or less of water.
  • deep eutectic solvent in accordance with this disclosure may comprise from 20% w/V to 50% w/V of water.
  • deep eutectic solvent in accordance with this disclosure may comprise from 20% w/V to 40% w/V of water.
  • deep eutectic solvent in accordance with this disclosure may comprise 40% w/V of water.
  • molar ratio of each of N-acetyl amino acid amides in formulation to total of beta-lactam compounds in the formulation is from 1:1 to 300:1.
  • molar ratio of each of N-acetyl amino acid amides in formulation to total of beta-lactam compounds in the formulation is from 1:1 to 160:1.
  • molar ratio of each of N-acetyl amino acid amides in formulation to total of beta-lactam compounds in the formulation is from 1: 1 to 50:1.
  • molar ratio of each of N-acetyl amino acid amides to total of piperacillin and tazobactam is from 1:1 to 40: 1.
  • molar ratio of each of N-acetyl amino acid amides to total of piperacillin and tazobactam is from 10:1 to 30:1.
  • molar ratio of each of N-acetyl amino acid amides to total of piperacillin and tazobactam is 26: 1.
  • molar ratio of each of N- acetyl amino acid amides in the formulation to piperacillin is from 30: 1 to 60: 1.
  • molar ratio of each of N- acetyl amino acid amides in the formulation to tazobactam is from 100: 1 to 300: 1.
  • pharmaceutical formulation further comprises buffering and/or chelating agents.
  • buffering agents may be selected separately or in combination comprise MES (2-(N-morpholino)ethanesulfonic acid), maleate, malate, phosphate, carbonate, citrate, tartrate, succinate, oxalate, ADA (N-(2- Acetamido)iminodiacetic acid), BIS TRIS (2-[Bis-(2-hydroxy-ethyl)-amino]-2- hydroxymethyl -propane- 1,3-diol), PIPES ( 1 ,4-Piperazinediethanesulfonic acid), ACES (N-(2-Acetamido)-2-aminoethanesulfonic acid), BIS TRIS propane (2-[3-(2- Hydroxy- 1 , 1 -dihydroxymethyl-ethylamino)-propylamino] -2-hydroxymethyl- propane- 1,3-diol), MOPSO (2-Hydroxy-3-morpholino
  • buffers may also act as chelating agents, i.e. citrate buffer, ADA, BIS TRIS; BIS TRIS propane, AMPD; AMP, AMPSO, TABS, ACES, BES, TES, DIPSO; TAPSO, TRIS, TEA, Tricine, Bicine, TAPS, tartaric acid, , succinic acid, oxalic acid, malic acid etc.
  • non-exhaustive list from which chelating agents may be selected separately or in combination comprise Dimethyl methylphosphonate, Diethylenetriamine pentamethylene phosphonic acid, Diethyl allylphosphonate, Diethyl ( 1 -cyanoethyl)phosphonate, Nitrilotri(methylphosphonic acid), N-(2- Hydroxyethyl)iminodiacetic acid, Ethylenediamine-N,N «-disuccinic acid trisodium salt solution, Iminodiacetic acid, Disodium succinate, Sodium gluconate, 15-Crown- 5 ether, 18-Crown-6 ether, DOTA ( 1,4,7, 10-Tetraazacyclododecane- 1,4, 7,10- tetraacetic acid), NOTA (l,4,7-triazacyclononane-l,4,7-triacetic acid) and derivatives thereof.
  • Dimethyl methylphosphonate Diethylenetriamine pentamethylene phosphonic acid, Diethy
  • the buffering agent is citrate buffer.
  • the buffering agent is ADA.
  • the buffering agent is citrate buffer and ADA.
  • the concentration of buffering agent would be from 0.5 mM to 200 mM.
  • the concentration of buffering agent would be from 0.5 mM to 25 mM.
  • the buffer is prepared at pH 5.5 to 8.
  • the buffer is prepared at pH 6 to 6.5.
  • the concentration of chelating agent would be from 0.1 mM to 200 mM.
  • the concentration of chelating agent would be from 10 mM to 25 mM.
  • the compositions may be in form of a ready-to-administer or a ready-to-use composition.
  • ready-to-use includes liquid preconcentrates which require a single step of dilution with a liquid diluent fluid such as water for injection or saline before administration.
  • a “ready-to-administer” composition is synonymous with "ready-to-infuse” or “ready-to-inject” and is not to be read as the term “ready-to-use” composition.
  • a “ready-to-administer” composition is suitable for administration directly to the patient and does not require any dilution steps.
  • ready-to-administer is also distinguished from lyophilized products that require two steps, a first step of reconstitution to form a preconcentrate and then a second step where the preconcentrate is subjected to dilution with a liquid infusion fluid.
  • Suitable fluids for diluting the ready-to-use composition include some which are pharmaceutical; safe and non-toxic for administration to a human, and are compatible for the preparation of a diluted formulation.
  • pharmaceutical formulation can be diluted with water or some diluents for oral use, standard diluents for parenteral use, such as water for injection, 0.9% sodium chloride for injection, Sterile water for injection, Dextrose 5% injection, Bacteriostatic saline/parabens, Bacteriostatic water/parabens, Bacteriostatic saline/benzyl alcohol, Bacteriostatic water/benzyl alcohol, Ringer’s solution or other suitable diluents.
  • standard diluents for parenteral use such as water for injection, 0.9% sodium chloride for injection, Sterile water for injection, Dextrose 5% injection, Bacteriostatic saline/parabens, Bacteriostatic water/parabens, Bacteriostatic saline/benzyl alcohol, Bacteriostatic water/benzyl alcohol, Ringer’s solution or other suitable diluents.
  • the appropriate volume of the liquid formulation of the present invention needed for the required therapeutically effective dose can be aseptically withdrawn and transferred into an infusion bag of 0.9% Sodium Chloride, or of Sterile water for injection or of Bacteriostatic water for injection and administrated to a patient via appropriate route of administration.
  • pharmaceutical formulation is having pH from 4.0 to 8.0.
  • pharmaceutical formulation is having a pH range from 5.5 to 8.
  • Formulations of the present disclosure comprise therapeutically effective amounts of beta-lactam compound, wherein therapeutically effective amounts include concentrations ranging from 0.05 mg/mL to 250 mg/mL 0.5 mg/mL to 250 mg/mL, from 20 mg/mL to 500 mg/mL, from 50 mg/mL to 300 mg/mL, such as concentration of 0.5 mg/mL, 1 mg/mL, 3 mg/mL, 5 mg/mL, 10 mg/mL, 15 mg/mL, 20 mg/mL, 25 mg/mL, 30 mg/mL, 35 mg/mL, 40 mg/mL, 50 mg/mL, 60 mg/mL, 70 mg/mL, 80 mg/mL, 90 mg/mL, 100 mg/mL, 110 mg/mL, 120 mg/mL, 130 mg/mL, 140 mg/mL, 150 mg/mL, 160 mg/mL, 170 mg/mL, 180 mg/mL, 190 mg/mL, 200 mg/mL,
  • concentration of piperacillin in pharmaceutical formulation as described herein is 40 mg/mL.
  • concentration of tazobactam pharmaceutical formulation as described herein is 5 mg/mL.
  • This disclosure also provides method for stabilizing beta-lactam compound in a pharmaceutical composition by mixing beta-lactam compound and at least one N- acetyl amino acid amide.
  • This disclosure also provides process for manufacturing pharmaceutical formulations disclosed herein.
  • the process may comprise the steps of mixing of beta-lactam compound and at least one N-acetyl amino acid amide.
  • This disclosure also provides process for manufacturing any of the disclosed pharmaceutical formulations.
  • the process may comprise the steps of mixing of beta-lactam compound and at least one N-acetyl amino acid amide, and subsequently dissolving composition in a solvent.
  • process for manufacturing pharmaceutical formulations disclosed herein comprises mixing of at least one N-acetyl amino acid amide with a solvent. Prepared solution is then mixed with at least one beta-lactam compound.
  • process for manufacturing pharmaceutical formulations disclosed herein comprises mixing of at least one N-acetyl amino acid amide with a second N-acetyl amino acid amide and/or an additional compound in a solvent. Prepared solution in then mixed with at least one beta-lactam compound. According to the described process, pharmaceutical formulations comprising deep eutectic solvent may be formed.
  • At least one N-acetyl amino acid amide is mixed with the second N-acetyl amino acid amide and/or an additional compound to create a deep eutectic solvent.
  • prepared deep eutectic solvents may comprise up to 50% w/V of water. Heating of mixture can be used until liquid is formed which is then cooled to room temperature. Prepared deep eutectic solvent is then mixed with at least one active pharmaceutical ingredient.
  • pharmaceutical formulation may be manufactured by any process known to the person skilled in the art.
  • solvent means water or any solution in which water is the main solvent (equal or above 50% w/V).
  • Solvents include, but are not limited to solutions comprising at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 98% or 99% w/V water.
  • Solvents can comprise a pharmaceutical organic solvent like ethanol, glycerol, propylene glycol, polyethylene glycols.
  • Solvents can comprise 50% w/V or less of a pharmaceutical organic solvent.
  • pH is the conventional measurement unit of hydrogen ion activity in a solution at room temperature, unless another temperature is specified.
  • pH buffer or “buffer” means a compound or composition used to maintain the pH value or pH range of a formulation within desired parameters over time.
  • pH buffers include aqueous solutions comprising a mixture of a weak acid and its conjugate base (or a weak base and its conjugate acid). The pH of a buffered solution changes very little when a small amount of an acid or base is added to it. A non-exhaustive list of pH buffers are mentioned above.
  • pharmaceutical composition comprises piperacillin sodium and at least one N-acetyl amino acid amide.
  • pharmaceutical composition comprises piperacillin sodium and at least two N-acetyl amino acid amides.
  • pharmaceutical composition comprises piperacillin sodium and N- Acetyl-L-alaninamide.
  • pharmaceutical composition comprises piperacillin sodium and N- Acetyl-D-alaninamide.
  • pharmaceutical composition comprises piperacillin sodium and N- Acetyl-L-prolinamide.
  • pharmaceutical composition comprises piperacillin sodium, N- Acetyl-L-prolinamide and N-Acetyl-L-alaninamide.
  • pharmaceutical composition comprises piperacillin sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide and N-Acetyl-L- alaninamide.
  • pharmaceutical composition comprises piperacillin sodium, N- Acetyl-L-prolinamide and N-Acetyl-D-alaninamide.
  • pharmaceutical composition comprises piperacillin sodium and deep eutectic solvent formed by N- Acetyl -L-prolinamide and N-Acetyl-D- alaninamide.
  • pharmaceutical composition comprises piperacillin sodium, N- Acetyl-L-prolinamide and N-Acetyl-D-alaninamide, where N-Acetyl-L-prolinamide and N-Acetyl-D-alaninamide are in molar ratio of from 0.3: 1 to 3: 1.
  • pharmaceutical composition comprises piperacillin sodium, N- Acetyl-L-prolinamide and N-Acetyl-D-alaninamide, where N-Acetyl-L-prolinamide and N-Acetyl-D-alaninamide are in molar ratio of 1:1.
  • pharmaceutical composition comprises piperacillin sodium, N- Acetyl-L-prolinamide and N-Acetyl-D-alaninamide, where N-Acetyl-L-prolinamide and N-Acetyl-D-alaninamide are in molar ratio of 1 : 1 and where molar ratio of each said N-acetyl amino acid amides to piperacillin is from 30: 1 to 50:1.
  • pharmaceutical composition comprises piperacillin sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide and N-Acetyl-D- alaninamide, where N-Acetyl-L-prolinamide and N-Acetyl-D-alaninamide are in molar ratio of 1: 1 and where molar ratio of each said N-acetyl amino acid amides to piperacillin is 32:1.
  • pharmaceutical composition comprises piperacillin sodium, N- Acetyl-L-prolinamide and N-Acetyl-L-alaninamide, where N-Acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of from 0.3:1 to 3: 1.
  • pharmaceutical composition comprises piperacillin sodium, N- Acetyl-L-prolinamide and N-Acetyl-L-alaninamide, where N-Acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1:1.
  • pharmaceutical composition comprises piperacillin sodium, N- Acetyl-L-prolinamide and N-Acetyl-L-alaninamide, where N-Acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1: 1 and where molar ratio of each said N-acetyl amino acid amides to piperacillin is from 30: 1 to 50:1.
  • pharmaceutical composition comprises piperacillin sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide and N-Acetyl-L- alaninamide, where N-Acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1: 1 and where molar ratio of each said N-acetyl amino acid amides to piperacillin is 32:1.
  • composition comprises piperacillin sodium, N- Acetyl-L-prolinamide and N-Acetyl-D-alaninamide and water, where N-Acetyl-L- prolinamide and N-Acetyl-D-alaninamide are in molar ratio of 1:1 and where composition comprises water in less than 50% w/V of total composition.
  • composition comprises piperacillin sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide and N-Acetyl-D- alaninamide and water, where N-Acetyl-L-prolinamide and N-Acetyl-D-alaninamide are in molar ratio of 1 : 1 and where composition comprises water in an amount of 40% w/V of total composition.
  • composition comprises piperacillin sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide and N-Acetyl-D- alaninamide and water, where N-Acetyl-L-prolinamide and N-Acetyl-D-alaninamide are in molar ratio of 1:1, where composition comprises water in an amount of 40% w/V of total composition and where molar ratio of each said N-acetyl amino acid amides to piperacillin is from 30: 1 to 50: 1.
  • composition comprises piperacillin sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide, N-Acetyl-D-alaninamide, water and buffering and/or chelating agent, where N-Acetyl-L-prolinamide and N- Acetyl-D-alaninamide are in molar ratio of 1: 1 and where composition comprises water in an amount of 40% w/V of total composition.
  • composition comprises piperacillin sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide and N-Acetyl-D- alaninamide, water and buffering and/or chelating agent, where N-Acetyl-L- prolinamide and N-Acetyl-D-alaninamide are in molar ratio of 1:1, where composition comprises water in an amount of 40% w/V of total composition and where molar ratio of each said N-acetyl amino acid amides to piperacillin is from 30: 1 to 50: 1.
  • composition comprises piperacillin sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide, N-Acetyl-D-alaninamide, water and buffering and/or chelating agent, where N-Acetyl-L-prolinamide and N- Acetyl-D-alaninamide are in molar ratio of 1:1, where composition comprises water in an amount of 40% w/V of total composition and where molar ratio of each said N- acetyl amino acids amide to piperacillin is 32: 1.
  • pharmaceutical composition comprises piperacillin sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide and N-Acetyl-D- alaninamide, water and a citric buffer, where N-Acetyl-L-prolinamide and N-Acetyl- D-alaninamide are in molar ratio of 1 : 1 and where composition comprises water in an amount of 40% w/V of total composition.
  • composition comprises piperacillin sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide, N-Acetyl-D-alaninamide, water and ADA, where N-Acetyl-L-prolinamide and N-Acetyl-D-alaninamide are in molar ratio of 1 : 1 and where composition comprises water in an amount of 40% w/V of total composition.
  • composition comprises piperacillin sodium, N- Acetyl-L-prolinamide and N-Acetyl-L-alaninamide and water, where N-Acetyl-L- prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1: 1 and where composition comprises water in less than 50% of total composition.
  • composition comprises piperacillin sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide and N-Acetyl-L- alaninamide and water, where N-Acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1 : 1 and where composition comprises water in an amount of 40% w/V of total composition.
  • composition comprises piperacillin sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide and N-Acetyl-L- alaninamide and water, where N-Acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1:1, where composition comprises water in an amount of 40% w/V of total composition and where molar ratio of each said N-acetyl amino acid amides to piperacillin is 32: 1.
  • composition comprises piperacillin sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide, N-Acetyl-L-alaninamide, water and buffering and/or chelating agent, where N-Acetyl-L-prolinamide and N- Acetyl-L-alaninamide are in molar ratio of 1:1 and where composition comprises water in an amount of 40% w/V of total composition.
  • composition comprises piperacillin sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide and N-Acetyl-L- alaninamide and water, where N-Acetyl-L-prolinamide and N-acetyl-L-alaninamide are in molar ratio of 1:1, where composition comprises water in an amount of 40% w/V of total composition and where molar ratio of each said N-acetyl amino acid amides to piperacillin is from 30: 1 to 50: 1.
  • composition comprises piperacillin sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide and N-Acetyl-L- alaninamide, water and buffering and/or chelating agent, where N-Acetyl-L- prolinamide and N-acetyl-L-alaninamide are in molar ratio of 1 : 1 , where composition comprises water in an amount of 40% w/V of total composition and where molar ratio of each said N-acetyl amino acid amides to piperacillin is from 30: 1 to 50:1.
  • composition comprises piperacillin sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide, N-Acetyl-L-alaninamide, water and buffering and/or chelating agent, where N-Acetyl-L-prolinamide and N- Acetyl-L-alaninamide are in molar ratio of 1:1, where composition comprises water in an amount of 40% w/V of total composition and where molar ratio of each said N- acetyl amino acid amides to piperacillin is 32:1.
  • composition comprises piperacillin sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide and N-Acetyl-L- alaninamide, water and citric buffer, where N-Acetyl-L-prolinamide and N-Acetyl- L-alaninamide are in molar ratio of 1 : 1 and where composition comprises water in an amount of 40% w/V of total composition.
  • composition comprises piperacillin sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide, N-Acetyl-L-alaninamide, water and ADA, where N-Acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1 : 1 and where composition comprises water in an amount of 40% w/V of total formulation.
  • composition comprises tazobactam sodium and at least one N-acetyl amino acid amide.
  • composition comprises tazobactam sodium and at least two N-acetyl amino acid amides.
  • pharmaceutical composition comprises tazobactam sodium and N- Acetyl-L-alaninamide.
  • pharmaceutical composition comprises tazobactam sodium and N- Acetyl-D-alaninamide.
  • pharmaceutical composition comprises tazobactam sodium and N- Acetyl-L-prolinamide.
  • pharmaceutical composition comprises tazobactam sodium, N- Acetyl-L-prolinamide and N-Acetyl-L-alaninamide.
  • pharmaceutical composition comprises tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide and N-Acetyl-L- alaninamide.
  • pharmaceutical composition comprises tazobactam sodium, N- Acetyl-L-prolinamide and N-Acetyl-D-alaninamide.
  • pharmaceutical composition comprises tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide and N-Acetyl-D- alaninamide.
  • pharmaceutical composition comprises tazobactam sodium, N- Acetyl-L-prolinamide and N-Acetyl-L-alaninamide, where N-Acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of from 0.3:1 to 3: 1.
  • pharmaceutical composition comprises tazobactam sodium, N- Acetyl-L-prolinamide and N-Acetyl-L-alaninamide, where N-Acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1:1.
  • pharmaceutical composition comprises tazobactam sodium, N- Acetyl-L-prolinamide and N-Acetyl-L-alaninamide, where N-Acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1: 1 and where molar ratio of each said N-acetyl amino acid amides to tazobactam is from 150: 1 to 220: 1.
  • pharmaceutical composition comprises tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide and N-Acetyl-L- alaninamide, where N-Acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1: 1 and where molar ratio of each said N-acetyl amino acid amides to tazobactam is 153: 1.
  • pharmaceutical composition comprises tazobactam sodium, N- Acetyl-L-prolinamide and N-Acetyl-D-alaninamide, where N-Acetyl-L-prolinamide and N-Acetyl-D-alaninamide are in molar ratio of from 0.3: 1 to 3: 1.
  • pharmaceutical composition comprises tazobactam sodium, N- Acetyl-L-prolinamide and N-Acetyl-D-alaninamide, where N-Acetyl-L-prolinamide and N-Acetyl-D-alaninamide are in molar ratio of 1:1.
  • pharmaceutical composition comprises tazobactam sodium, N- Acetyl-L-prolinamide and N-Acetyl-D-alaninamide, where N-Acetyl-L-prolinamide and N-Acetyl-D-alaninamide are in molar ratio of 1 : 1 and where molar ratio of each said N-acetyl amino acid amides to tazobactam is from 150: 1 to 220:1.
  • pharmaceutical composition comprises tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide and N-Acetyl-D- alaninamide, where N-Acetyl-L-prolinamide and N-Acetyl-D-alaninamide are in molar ratio of 1: 1 and where molar ratio of each said N-acetyl amino acid amides to tazobactam is 153:1.
  • composition comprises tazobactam sodium, N- Acetyl-L-prolinamide and N-Acetyl-D-alaninamide and water, where N-Acetyl-L- prolinamide and N-Acetyl-D-alaninamide are in molar ratio of 1:1 and where composition comprises water in less than 50% of total composition.
  • composition comprises tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide and N-Acetyl-D- alaninamide and water, where N-Acetyl-L-prolinamide and N-Acetyl-D-alaninamide are in molar ratio of 1 : 1 and where composition comprises water in an amount of 40% w/V of total formulation.
  • composition comprises tazobactam sodium and deep eutectic solvent formed by N- Acetyl -L-prolinamide and N-Acetyl-D- alaninamide and water, where N-Acetyl-L-prolinamide and N-Acetyl-D-alaninamide are in molar ratio of 1:1, where composition comprises water in an amount of 40% w/V of total formulation and where molar ratio of each said N-acetyl amino acid amides to tazobactam is from 150:1 to 220:1.
  • composition comprises tazobactam sodium and deep eutectic solvent formed by N- Acetyl -L-prolinamide and N-Acetyl-D- alaninamide and water, where N-Acetyl-L-prolinamide and N-Acetyl-D-alaninamide are in molar ratio of 1:1, where composition comprises water in an amount of 40% w/V of total formulation and where molar ratio of each said N-acetyl amino acid amides to tazobactam is from 153:1.
  • composition comprises tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide, N-Acetyl-D-alaninamide, water and buffering and/or chelating agent, where N-Acetyl-L-prolinamide and N- Acetyl-D-alaninamide are in molar ratio of 1: 1 and where composition comprises water in an amount of 40% w/V of total formulation.
  • composition comprises tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide, N-Acetyl-D-alaninamide, water and buffering and/or chelating agent, where N-Acetyl-L-prolinamide and N- Acetyl-D-alaninamide are in molar ratio of 1: 1, where composition comprises water in an amount of 40% w/V of total formulation and where molar ratio of each said N- acetyl amino acid amides to tazobactam is from 150: 1 to 220:1.
  • composition comprises tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide, N-Acetyl-D-alaninamide, water and buffering and/or chelating agent, where N-Acetyl-L-prolinamide and N- Acetyl-D-alaninamide are in molar ratio of 1: 1, where composition comprises water in an amount of 40% w/V of total formulation and where molar ratio of each said N- acetyl amino acid amides to tazobactam is from 153: 1.
  • composition comprises tazobactam sodium and deep eutectic solvent formed by N- Acetyl -L-prolinamide and N-Acetyl-D- alaninamide, water and citric buffer, where N-Acetyl-L-prolinamide and N-Acetyl- D-alaninamide are in molar ratio of 1 : 1 and where composition comprises water in an amount of 40% w/V of total formulation.
  • composition comprises tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide, N-Acetyl-D-alaninamide, water and ADA, where N-Acetyl-L-prolinamide and N-Acetyl-D-alaninamide are in molar ratio of 1: 1 and where composition comprises water in an amount of 40% w/V of total formulation.
  • pharmaceutical composition comprises tazobactam sodium, N- Acetyl-L-prolinamide and N-Acetyl-L-alaninamide and water, where N-Acetyl-L- prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1:1 and where water is comprised in less than 50% of total volume of the formulation.
  • composition comprises tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide and N-Acetyl-L- alaninamide and water, where N-Acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1 : 1 and where composition comprises water in an amount of 40% w/V of total formulation.
  • composition comprises tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide and N-Acetyl-L- alaninamide and water, where N-Acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1: 1, where composition comprises water in an amount of 40% w/V of total formulation and where molar ratio of each said N-acetyl amino acid amides to tazobactam is from 150:1 to 220:1.
  • composition comprises tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide and N-Acetyl-L- alaninamide and water, where N-Acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1: 1, where composition comprises water in an amount of 40% w/V of total formulation and where molar ratio of each said N-acetyl amino acid amides to tazobactam is from 153:1.
  • composition comprises tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide, N-Acetyl-L-alaninamide, water and buffering and/or chelating agent, where N-Acetyl-L-prolinamide and N- Acetyl-L-alaninamide are in molar ratio of 1 : 1 and were composition comprises water in an amount of 40% w/V of total formulation.
  • composition comprises tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide, N-Acetyl-L-alaninamide, water and buffering and/or chelating agent, where N-Acetyl-L-prolinamide and N- Acetyl-L-alaninamide are in molar ratio of 1: 1, where composition comprises water in an amount of 40% w/V of total formulation and where molar ratio of each said N- acetyl amino acid amides to tazobactam is from 150: 1 to 220:1.
  • composition comprises tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide, N-Acetyl-L-alaninamide, water and buffering and/or chelating agent, where N-Acetyl-L-prolinamide and N- Acetyl-L-alaninamide are in molar ratio of 1: 1, where composition comprises water in an amount of 40% w/V of total formulation and where molar ratio of each said N- acetyl amino acid amides to tazobactam is from 153: 1.
  • composition comprises tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide and N-Acetyl-L- alaninamide, water and citric buffer, where N-Acetyl-L-prolinamide and N-Acetyl- L-alaninamide are in molar ratio of 1: 1 and were composition comprises water in an amount of 40% w/V of total formulation.
  • composition comprises tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide, N-Acetyl-L-alaninamide, water and ADA, where N-Acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1: 1 and were composition comprises water in an amount of 40% w/V of total formulation.
  • pharmaceutical composition comprises piperacillin sodium, tazobactam sodium and at least one N- acetyl amino acid amide.
  • pharmaceutical composition comprises piperacillin sodium, tazobactam sodium and at least two N-acetyl amino acid amides.
  • pharmaceutical composition comprises piperacillin sodium, tazobactam sodium and at least two N-acetyl amino acid amides, where molar ratio of each N-acetyl amino acid amide to total of piperacillin and tazobactam is from 10:1 to 30: 1.
  • pharmaceutical composition comprises piperacillin sodium, tazobactam sodium and N-Acetyl-L-alaninamide.
  • pharmaceutical composition comprises piperacillin sodium, tazobactam sodium and N-Acetyl-D-alaninamide.
  • pharmaceutical composition comprises piperacillin sodium, tazobactam sodium and N-Acetyl-L-prolinamide.
  • pharmaceutical composition comprises piperacillin sodium, tazobactam sodium, N-Acetyl-L-prolinamide and N-Acetyl-L-alaninamide.
  • pharmaceutical composition comprises piperacillin sodium, tazobactam sodium, N-Acetyl-L-prolinamide and N-Acetyl-D-alaninamide.
  • pharmaceutical composition comprises piperacillin sodium, tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide and N-Acetyl-L-alaninamide.
  • pharmaceutical composition comprises piperacillin sodium, tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide and N-Acetyl-D-alaninamide.
  • pharmaceutical composition comprises piperacillin sodium, tazobactam sodium, N-Acetyl-L-prolinamide and N-Acetyl-D-alaninamide, where N-Acetyl-L-prolinamide and N-Acetyl-D-alaninamide are in molar ratio of from 0.3:1 to 3:1.
  • pharmaceutical composition comprises piperacillin sodium, tazobactam sodium, N-Acetyl-L-prolinamide and N-Acetyl-D-alaninamide, where N-Acetyl-L-prolinamide and N-Acetyl-D-alaninamide are in molar ratio of 1: 1.
  • pharmaceutical composition comprises piperacillin sodium, tazobactam sodium, N-Acetyl-L-prolinamide and N-Acetyl-D-alaninamide, where N-Acetyl-L-prolinamide and N-Acetyl-D-alaninamide are in molar ratio of 1:1 and where molar ratio of each N-acetyl amino acid amide to total of piperacillin and tazobactam is 26:1.
  • pharmaceutical composition comprises piperacillin sodium, tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide and N-Acetyl-D-alaninamide, where N-Acetyl-L-prolinamide and N-Acetyl-D- alaninamide are in molar ratio of 1: 1 and where molar ratio of each N-acetyl amino acid amide to total of piperacillin and tazobactam is 26:1.
  • pharmaceutical composition comprises piperacillin sodium, tazobactam sodium, N-Acetyl-L-prolinamide and N-Acetyl-L-alaninamide, where N- Acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of from 0.3:1 to 3 : 1.
  • pharmaceutical composition comprises piperacillin sodium, tazobactam sodium, N-Acetyl-L-prolinamide and N-Acetyl-L-alaninamide, where N- Acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1:1.
  • pharmaceutical composition comprises piperacillin sodium, tazobactam sodium, N-Acetyl-L-prolinamide and N-Acetyl-L-alaninamide, where N- Acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1:1 and where molar ratio of each N-acetyl amino acid amide to total of piperacillin and tazobactam is 26:1.
  • pharmaceutical composition comprises piperacillin sodium, tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide and N-Acetyl-L-alaninamide, where N-Acetyl-L-prolinamide and N-Acetyl-L- alaninamide are in molar ratio of 1: 1 and where molar ratio of each N-acetyl amino acid amide to total of piperacillin and tazobactam is 26:1.
  • composition comprises piperacillin sodium and tazobactam sodium and N-Acetyl-L-prolinamide and N-Acetyl-D-alaninamide and water, where N-Acetyl-L-prolinamide and N-Acetyl-D-alaninamide are in molar ratio of 1 : 1 and where composition comprises water in less than 50% of total volume of the formulation.
  • composition comprises piperacillin sodium and tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide and N-Acetyl-D-alaninamide and water, where N-Acetyl-L-prolinamide and N-Acetyl- D-alaninamide are in molar ratio of 1 : 1 and where composition comprises water in an amount of 40% w/V of total formulation.
  • composition comprises piperacillin sodium and tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide and N-Acetyl-D-alaninamide and water, where N-Acetyl-L-prolinamide and N-Acetyl- D-alaninamide are in molar ratio of 1: 1, composition comprises water in an amount of 40% w/V of total formulation and where molar ratio of each N-acetyl amino acid amide to total of piperacillin and tazobactam is 26: 1.
  • composition comprises piperacillin sodium and tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide, N- Acetyl-D-alaninamide, water and buffering and/or chelating agent, where N-Acetyl- L-prolinamide and N-Acetyl-D-alaninamide are in molar ratio of 1:1 and were composition comprises water in an amount of 40% w/V of total formulation.
  • composition comprises piperacillin sodium and tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide, N- Acetyl-D-alaninamide, water and buffering and/or chelating agent, where N-Acetyl- L-prolinamide and N-Acetyl-D-alaninamide are in molar ratio of 1: 1, composition comprises water in an amount of 40% w/V of total formulation and where molar ratio of each N-acetyl amino acid amide to total of piperacillin and tazobactam is 26:1.
  • composition comprises piperacillin sodium and tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide and N-Acetyl-D-alaninamide, water and citric buffer, where N-Acetyl-L-prolinamide and N-Acetyl-D-alaninamide are in molar ratio of 1:1 and were composition comprises water in an amount of 40% w/V of total formulation.
  • pharmaceutical composition comprises piperacillin sodium and tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide and N-Acetyl-D-alaninamide, water and citric buffer, where piperacillin and tazobactam are comprised in weight ratio 8:1, where N-Acetyl-L-prolinamide and N-Acetyl-D- alaninamide are in molar ratio of 1 : 1 and were composition comprises water in an amount of 40% w/V of total formulation.
  • composition comprises piperacillin sodium and tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide, N- Acetyl-D-alaninamide, water and ADA, where N-Acetyl-L-prolinamide and N- Acetyl-D-alaninamide are in molar ratio of 1: 1 and where composition comprises water in an amount of 40% w/V of total formulation.
  • pharmaceutical composition comprises piperacillin sodium and tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide and N-Acetyl-D-alaninamide, water and ADA, where piperacillin and tazobactam are comprised in weight ratio 8:1, where N-Acetyl-L-prolinamide and N-Acetyl-D- alaninamide are in molar ratio of 1 : 1 and were composition comprises water in an amount of 40% w/V of total formulation.
  • composition comprises piperacillin sodium and tazobactam sodium and N-Acetyl-L-prolinamide and N-Acetyl-L-alaninamide and water, where N-Acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1 : 1 and where composition comprises water in less than 50% of total volume of the formulation.
  • pharmaceutical composition comprises piperacillin sodium and tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide and N-Acetyl-L-alaninamide and water, where N-Acetyl-L-prolinamide and N-Acetyl-L- alaninamide are in molar ratio of 1 : 1 and where composition comprises water in an amount of 40% w/V of total formulation.
  • composition comprises piperacillin sodium and tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide and N-Acetyl-L-alaninamide and water, where N-Acetyl-L-prolinamide and N-Acetyl-L- alaninamide are in molar ratio of 1:1, composition comprises water in an amount of 40% w/V of total formulation and where molar ratio of each N-acetyl amino acid amide to total of piperacillin and tazobactam is 26: 1.
  • composition comprises piperacillin sodium and tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide, N- Acetyl-L-alaninamide, water and buffering and/or chelating agent, where N-AcetyL L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1:1 and where composition comprises water in an amount of 40% w/V of total formulation.
  • composition comprises piperacillin sodium and tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide, N- Acetyl-L-alaninamide, water and buffering and/or chelating agent, where N-Acetyl- L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1: 1, composition comprises water in an amount of 40% w/V of total formulation and where molar ratio of each N-acetyl amino acid amide to total of piperacillin and tazobactam is 26:1.
  • composition comprises piperacillin sodium and tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide and N-Acetyl-L-alaninamide, water and citric buffer, where N-Acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1 : 1 and where composition comprises water in an amount of 40% w/V of total formulation.
  • composition comprises piperacillin sodium and tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide and N-Acetyl-L-alaninamide, water and citric buffer, where piperacillin and tazobactam are comprised in weight ratio 8:1, where N-Acetyl-L-prolinamide and N-Acetyl-L- alaninamide are in molar ratio of 1 : 1 and where composition comprises water in an amount of 40% w/V of total formulation.
  • composition comprises piperacillin sodium and tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide and N-Acetyl-L-alaninamide, water and citric buffer, where piperacillin and tazobactam are comprised in weight ratio 8:1, where N-Acetyl-L-prolinamide and N-Acetyl-L- alaninamide are in molar ratio of 1:1, where composition comprises water in an amount of 40% w/V of total formulation and where molar ratio of each N-acetyl amino acid amide to total of piperacillin and tazobactam is 26: 1.
  • composition comprises piperacillin sodium and tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide, N- Acetyl-L-alaninamide, water and ADA, where N-Acetyl-L-prolinamide and N- Acetyl-L-alaninamide are in molar ratio of 1:1 and where composition comprises water in an amount of 40% w/V of total formulation.
  • pharmaceutical composition comprises piperacillin sodium and tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide, N- Acetyl-L-alaninamide, water and ADA, where piperacillin and tazobactam are comprised in weight ratio 8: 1, where N-Acetyl-L-prolinamide and N-Acetyl-L- alaninamide are in molar ratio of 1 : 1 and where composition comprises water in an amount of 40% w/V of total formulation.
  • composition comprises piperacillin sodium and tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide, N- Acetyl-L-alaninamide, water and ADA, where piperacillin and tazobactam are comprised in weight ratio 8:1, where N-Acetyl-L-prolinamide and N-AcetyLL- alaninamide are in molar ratio of 1:1, where composition comprises water in an amount of 40% w/V of total formulation and where molar ratio of each N-acetyl amino acid amide to total of piperacillin and tazobactam is 26: 1.
  • the disclosure also relates to the packaging any of the above pharmaceutical formulations.
  • the liquid pharmaceutical formulation may be packaged in a bag ready to be administered to a patient. Further, the formulation may be packaged in dual chamber bag or syringe.
  • liquid pharmaceutical formulation may be packaged in a vial or ampoule for dilution prior to administration a patient.
  • pharmaceutical formulation may be packaged for oral administration in form of oral suspension or oral solution.
  • pharmaceutical formulation may be packaged for topical administration in form of gel.
  • the pharmaceutical formulation may be used in the treatment of microbial infections caused by Gram positive bacteria, and in some cases for treatment of microbial infections caused by Gram negative bacteria.
  • the formulation comprises piperacillin and tazobactam and may be used in treatment of for the treatment of appendicitis (complicated by rupture or abscess) and peritonitis caused by piperacillin-resistant, beta-lactamase producing isolates of Escherichia coli or the following members of the Bacteroides fragilis group: B. fragilis, B. ovatus, B. thetaiotaomicron, or B.
  • nosocomial pneumonia caused by piperacillin-resistant, beta-lactamase producing isolates of Staphylococcus aureus and by piperacillin/tazobactam- susceptible Acinetobacter baumannii, Haemophilus influenzae, Klebsiella pneumoniae, and Pseudomonas aeruginosa, uncomplicated and complicated skin and skin structure infections, including cellulitis, cutaneous abscesses and ischemic/diabetic foot infections caused by piperacillin-resistant, beta-lactamase producing isolates of Staphylococcus aureus, postpartum endometritis or pelvic inflammatory disease caused by piperacillin-resistant, beta-lactamase producing isolates of Escherichia coli, and community-acquired pneumonia (moderate severity only) caused by piperacillin-resistant, beta-lactamase producing isolates of Haemophilus influenzae.
  • piperacillin or piperacillin/tazobactam are used for treating against variety of gram-positive and gram-negative aerobic and anaerobic bacteria.
  • the use of pharmaceutical formulation of piperacillin in accordance with the present invention is for treating the gram-positive pathogens such as Staphylococcus aureus, or intra - abdominal infections, skin and skin structure infections, female pelvic infections, community - acquired pneumonia, nosocomial pneumonia.
  • compositions as disclosed herein may be used for prevention of biofilm as well as for treating already formed biofilms.
  • compositions described herein are intended to be administered via injection, for example subcutaneously, intracutaneously, intravenously, intramuscularly, intraarticularly, intrasynovially, intrasternally, intrathecally, intralesionally, intracranially or via infusion.
  • formulations described herein may be administered orally, topically.
  • formulation described herein are used topically.
  • formulation described herein may be used topically for treatment of skin and soft tissue infections caused by Staphylococcus aureus.
  • formulation described herein may be used topically for treatment of skin infections caused by Methicillin-resistant Staphylococcus aureus (MRSA), Methicillin-susceptible Staphylococcus aureus (MSSA).
  • MRSA Methicillin-resistant Staphylococcus aureus
  • MSSA Methicillin-susceptible Staphylococcus aureus
  • molar ratios and concentrations of ingredients comprised in the pharmaceutical formulation and solvents are defined by the amount of said ingredients used for production of said pharmaceutical formulation.
  • compositions described herein may further comprise one or more pharmaceutical excipients such as antioxidants, surfactants, complexing agents, preservatives, bulking agents, vehicles, solubilizers, thickening agents, binders, and combinations thereof.
  • pharmaceutical excipients such as antioxidants, surfactants, complexing agents, preservatives, bulking agents, vehicles, solubilizers, thickening agents, binders, and combinations thereof.
  • API Active pharmaceutical ingredient
  • Beta-lactam compound formulations without N-acetyl amino cid amides are shown for comparative purposes.
  • containers were taken from stability chambers at various time points, such as 4 days, 7 days, 8 days, 11 days, 14 days, 22 days, 1 month, 2 months, 3 months, 4 months etc. and analyzed by HPLC.
  • the impurities for active compounds and amount of total impurities were determined by HPLC analysis, equipped with an ultraviolet (UV) detector. All samples were analyzed using a reverse-phase Cl 8 column and by measuring the absorbance (area under the curve) at a wavelength of 220 nm.
  • the HPLC conditions used were those disclosed in the Official Monographs/Piperacillin, USP 40, pages 5731-5734, Piperacillin and Tazobactam for Injection, Impurities, procedure 3 and 4 with some modifications (disclosed below).
  • Injection volume 20 pL/2pL (depending on the sample dilution)
  • Buffer 27.6 g/L of monobasic sodium phosphate dihydrate
  • Solution A 0.4 M aqueous tetrabutylammonium hydroxide
  • Solution B Methanol, Solution A, Buffer, and water (275:3:100:622). Adjust with phosphoric acid to a pH of 5.5 ⁇ 0.05.
  • Solution C Methanol, Solution A, Buffer, and water (615:3:100:282). Adjust with phosphoric acid to a pH of 5.5 ⁇ 0.05.
  • Sample solution preparation for formulation comprising deep eutectic solvent ImL of the formulation is dissolved in mobile phase A and diluted to 10.0 mL with mobile phase A.
  • Buffer 4.46 g/L of potassium phosphate monobasic
  • Solution B Acetonitrile and Solution A (550:450). Adjust with IM potassium hydroxide to a pH of 6.0 ⁇ 0.05.
  • Sample solution ImL of the formulation dissolved in buffer and diluted to 10.0 mL with buffer.
  • Atot total sample peak area (for each active component separately, area of the main peak + areas of all impurities related to this active compound)
  • Ai peak area of an individual peak
  • Atot total sample peak area (for each active component separately, area of the main peak + areas of all impurities related to this active compound)
  • APIs are added in a form of sodium salts (Piperacillin sodium equivalent to concentration of Piperacillin stated in the tables; Tazobactam sodium equivalent to concentration of Tazobactam stated in the tables).
  • Liquid pharmaceutical compositions of piperacillin sodium and N-acetyl amino acid amides were prepared in predetermined concentrations and in certain compositions (as shown below). N-acetyl amino acid amides were mixed with water and optionally with a buffer. After that, piperacillin sodium is mixed with liquid containing N-acetylated amino acid amides in the 10 molar ratios specified in Table 1 below, until the substances were dissolved. Water was added to make the solution up to the prescribed volume and stirred to give homogenous solution with the concentration of 40 mg/ml of piperacillin.
  • Tables la and lb are showing stability data of Piperacillin sodium formulations prepared by above described process.
  • Liquid pharmaceutical compositions of tazobactam sodium and N-acetyl amino acid amides were prepared in predetermined concentrations and in certain compositions (as shown below).
  • N-acetyl amino acid amides are mixed with water and optionally with a buffer.
  • tazobactam sodium is mixed with liquid containing N-acetylated amino acid amides in the molar
  • Table 2 is showing stability data of Tazobactam sodium formulation formulations prepared by above described process.
  • Liquid pharmaceutical compositions of piperacillin sodium, tazobactam sodium and N-acetyl amino acid amides were 5 prepared in certain compositions (as shown below). N-acetyl amino acid amides are mixed with water and optionally with a buffer. After that, tazobactam sodium and piperacillin sodium were mixed with liquid containing N-acetylated amino acid amide in the molar ratios specified in Table 3 below, until the substances were dissolved. Water was added to make the solution up to the prescribed volume and stirred to give homogenous solution with the concentration of 40 mg/ml of piperacillin and 5 mg/ml of tazobactam.
  • Tables 3a and 3b are showing stability data of Piperacillin sodium and Tazobactam sodium formulations prepared by above described process. Molar ratio of two N-acetyl amino acid amides is 1:1.
  • Liquid pharmaceutical compositions of piperacillin sodium and N-acetyl amino acid amides were prepared in certain compositions (as shown below). N-acetyl amino acid amides and water/buffers were mixed in a bottle. Bottle was closed and 5 mixing continued in oil bath heated to 60-70°C until liquid was formed. Formed liquid is then cooled to room temperature in order to prepare deep eutectic solvents. Part of volume of DES was mixed with piperacillin sodium until the substance was dissolved. After that, DES was added to make the solution up to the prescribed volume and stirred to give homogenous solution with the concentration of 40 mg/ml of piperacillin.
  • Tables 4a and 4b are showing stability data of Piperacillin sodium DES formulations prepared by above described process. Molar ratio of two N-acetyl amino acid amides is 1: 1. Buffers prepared in pH range of 6 - 6.5.
  • Liquid pharmaceutical compositions of tazobactam sodium and N-acetyl amino acid amides were prepared in certain compositions (as shown below). N-acetyl amino acid amides and water/buffers were mixed in a bottle. Bottle was closed and mixing continued in oil bath heated to 60-70°C until liquid was formed. Formed liquid is then cooled to room temperature in order to prepare deep eutectic solvents. Part of volume of DES was mixed with tazobactam sodium until the substance was
  • Table 5 is showing stability data of Tazobactam sodium DES formulations prepared by above described process. Molar ratio of two N-acetyl amino acid amides is 1:1. Buffers prepared in pH range of 6 - 6.5.
  • Liquid pharmaceutical compositions of piperacillin sodium, tazobactam sodium and N-acetyl amino acid amides were prepared in certain compositions (as shown below). N-acetyl amino acid amides and water/buffers were mixed in a bottle. Bottle was closed and mixing continued in oil bath heated to 50-70°C until liquid was formed. Formed liquid is then cooled to room temperature in order to prepare deep eutectic solvents. Part of volume of DES was mixed with tazobactam sodium 5 and piperacillin sodium until the substances were dissolved. After that, DES was added to make the solution up to the prescribed volume and stirred to give homogenous solution with the concentration of 40 mg/ml of piperacillin and 5 mg/ml of tazobactam.
  • Tables 6a and 6b are showing stability data of Piperacillin sodium and Tazobactam sodium DES formulations prepared by above
  • Liquid pharmaceutical compositions of piperacillin sodium, tazobactam sodium and N-acetyl amino acid amides were prepared in certain compositions (as shown below). N-acetyl amino acid amides and water/buffers were mixed in a bottle.
  • Tables 7a and 7b are showing stability data of Piperacillin sodium and Tazobactam sodium formulation - diluted stream.
  • Item 1 A pharmaceutical formulation comprising at least one beta-lactam compound, its salt or derivative thereof and at least one N-acetyl amino acid amide.
  • At least one betalactam compound may include beta-lactam antibiotics and beta lactamase-inhibitors, its pharmaceutical salt or derivative thereof.
  • beta-lactam antibiotics may include piperacillin, cefazolin, cefepime, aztreonam, ertapenem, ampicillin, ceftazidime, cefoxitin, cefazoline fosamil, oxacillin, amoxicillin, penicillin V, clavunalate potassium, cefadroxil, cephalexin, cefaclor, cefprozil, cefdinir, cefixime, cefpodoxime proxetil, its salt and derivative thereof.
  • Item 4 The pharmaceutical formulation according to item 3, wherein beta-lactam antibiotic is piperacillin, its pharmaceutical salt or derivative thereof.
  • beta-lactamase inhibitors may include tazobactam, avibactam, sulbactam, clavulanic acid, vaborbactam, relebacatm, its pharmaceutical salt or derivative thereof.
  • Item 6 The pharmaceutical formulation according to item 5, wherein beta-lactamase inhibitor is tazobactam, its pharmaceutical salt or derivative thereof.
  • Item 7 The pharmaceutical formulation according to item 2, wherein the formulation comprises at least one beta-lactam antibiotic and at least one beta-lactamase inhibitor.
  • Item 8 The pharmaceutical formulation according to item 7, wherein the formulation comprises at least piperacillin and at least one beta-lactamase inhibitor.
  • Item 9 The pharmaceutical formulation according to item 7, wherein the formulation comprises at least one beta-lactam antibiotic and tazobactam.
  • Item 10 The pharmaceutical formulation according to item 7, wherein the formulation comprises piperacillin and tazobactam, its pharmaceutical salt or derivative thereof.
  • Item 11 The pharmaceutical formulation according to item 1 , wherein beta-lactam compound is in form of a salt, where salt may include calcium, sodium, magnesium or potassium salt.
  • Item 12 The pharmaceutical formulation according to item 11, wherein beta-lactam compound is in form of sodium salt.
  • Item 13 The pharmaceutical formulation according to item 12, wherein beta-lactam compound is piperacillin and where piperacillin is in form of sodium salt.
  • Item 14 The pharmaceutical formulation according to item 12, wherein beta-lactam compound is tazobactam and where tazobactam is in form of sodium salt.
  • Item 15 The pharmaceutical formulation according to item 7, wherein weight ratio of at least one beta-lactam antibiotic to at least one beta-lactamase inhibitor may be from 1: 1 to 10: 1.
  • Item 16 The pharmaceutical formulation according to item 9, wherein weight ratio of at least one beta-lactam antibiotic to tazobactam may be from 2: 1 to 8: 1.
  • Item 18 The pharmaceutical formulation according to item 10, wherein weight ratio of piperacillin to tazobactam can be from 4: 1 to 8: 1.
  • Item 19 The pharmaceutical formulation according to item 10, wherein weight ratio of piperacillin to tazobactam is 8:1.
  • N-acetyl amino acid amide may be N-acetyl cysteinamide, N-acetyl glutaminamide, N-acetyl aspartic acid amide, N-acetyl glycinamide, N-acetyl alaninamide, N-acetyl prolinamide, N-acetyl serinamide, N-acetyl threoninamide, N-acetyl valinamide, N-acetyl isoleucinamide, N- acetyl leucinamide, N-acetyl methioninamide, N-acetyl phenylalaninamide, N-acetyl tyrosinamide, N-acetyl asparaginamide, N-acetyl glutamic acid amide, N-acetyl histidinamide, N-acetyl argininamide, N-acetyl citrullinamide,
  • N-acetyl amino acid amide may be in L configuration, while in some other aspect N-acetyl amino acid amide may be in D configuration.
  • Item 22 The pharmaceutical formulation according to item 21, wherein formulation comprises at least N-Acetyl-L-alaninamide (hereinafter NALAA).
  • NALAA N-Acetyl-L-alaninamide
  • NADAA N-acetyl-D-alaninamide
  • NALPA N-acetyl-L-prolinamide
  • Item 25 The pharmaceutical formulation according to item 1, wherein a concentration of an N-acetyl amino acid amide is from 1 mg/ml to 1500 mg/ml.
  • Item 26 The pharmaceutical formulation according to item 25, wherein concentration of an N-acetyl amino acid amide is from 20 mg/ml to 1000 mg/ml.
  • Item 27 The pharmaceutical formulation according to item 25, wherein concentration of each N-acetyl amino acid amide is 20 mg/ml, 30 mg/ml, 40 mg/ml, 50 mg/ml, 60 mg/ml, 70 mg/ml, 80 mg/ml, 90 mg/ml, 100 mg/ml, 150 mg/ml, 200 mg/ml, 250 mg/ml, 300 mg/ml, 400 mg/ml, 500 mg/ml, 600 mg/ml, 700 mg/ml, 750 mg/ml, 800 mg/ml.
  • Item 28 The pharmaceutical formulation according to item 25, wherein concentration of an N-acetyl amino acid amide is from 300 mg/ml to 750 mg/ml.
  • Item 29 The pharmaceutical formulation according to item 1, wherein formulation comprises at least two N-acetyl amino acid amides, i.e. a first and a second N-acetyl amino acid amide.
  • Item 30 The pharmaceutical formulation according to item 29, wherein pharmaceutically acceptable formulation comprises N-Acetyl-L-prolinamide and N- Acetyl-L-alaninamide.
  • Item 31 The pharmaceutical formulation according to item 29, wherein pharmaceutically acceptable formulation comprises N-Acetyl-L-prolinamide and N- Acetyl-D-alaninamide.
  • Item 32 The pharmaceutical formulation according to item 29, wherein concentration of each amide is from 300 mg/ml to 600 mg/ml.
  • Item 33 The pharmaceutical formulation according to item 29, wherein concentration of each amide is from 300 to 400 mg/ml.
  • Item 34 The pharmaceutical formulation according to item 29, wherein the first N-acetyl amino acid amide and the second N-acetyl amino acid amide are in molar ratio from 0.2: 1 to 5:1.
  • Item 35 The pharmaceutical formulation according to item 29, wherein the first N-acetyl amino acid amide and the second N-acetyl amino acid amide are in molar ratio of 0.2: 1, 0.3:1, 0.4:1, 0.5:1, of 1:1, of 1.5:1, of 2:1, of 2.5: 1, of 3:1, of 4:1, of 5:1.
  • Item 36 The pharmaceutical formulation according to item 29, wherein, the first N- acetyl amino acid amide and the second N-acetyl amino acid amide are in molar ratio of 1: 1.
  • Item 37 The pharmaceutical formulation according to item 29, wherein the first N-acetyl amino acid amide and the second N-acetyl amino acid amide are comprised in the pharmaceutically acceptable formulation in the form of deep eutectic solvent.
  • Item 38 The pharmaceutical formulation according to item 37, wherein the first N- acetylated amino acid amide and the second N-acetylated amino acid amide are in molar ratio from 0.3:1 to 3 : 1.
  • Item 39 The pharmaceutical formulation according to item 37, wherein the first N- acetylated amino acid amide and the second N-acetylated amino acid amide are in molar ratio of 0.3:1, of 0.5:1, of 1:1, of 1.5: 1, of 2:1, of 2.5: 1, and of 3:1.
  • Item 40 The pharmaceutical formulation according to item 37, wherein the first N- acetylated amino acid amide and the second N-acetylated amino acid amide are in molar ratio of 1 : 1.
  • Item 41 The pharmaceutical formulation according to item 1, wherein formulation comprises additional compounds selected from nicotinamide, acetamide, benzamide, amino acids, quaternary ammonium compounds, quaternary phosphonium compounds, organic acids, sugars, urea and derivatives thereof, metal salts, choline chloride, sorbitol, ethyleneglylcol amide, polymers such as PEG, PPG, phenol, glycerol, saccharin, imidazole, its salts or derivatives thereof.
  • additional compounds selected from nicotinamide, acetamide, benzamide, amino acids, quaternary ammonium compounds, quaternary phosphonium compounds, organic acids, sugars, urea and derivatives thereof, metal salts, choline chloride, sorbitol, ethyleneglylcol amide, polymers such as PEG, PPG, phenol, glycerol, saccharin, imidazole, its salts or derivatives thereof.
  • Item 42 The pharmaceutical formulation according to item 41, wherein at least one N- acetylated amino acid amide and at least one additional compound are in molar ratio from 0.3:1 to 3:1.
  • Item 43 The pharmaceutical formulation according to item 41, wherein at least one N- acetylated amino acid amide and at least one additional compound are in molar ratio of 0.3: 1, 0.5:1, of 1:1, of 1.5:1, of 2:1, of 2.5: 1, and of 3:1.
  • Item 43 The pharmaceutical formulation according to item 41, wherein at least one N- acetylated amino acid amide and at least one additional compound are in molar ratio of 1: 1.
  • Item 44 The pharmaceutical formulation according to item 41 , wherein the first N-acetyl amino acid amide and at least one additional compound are comprised in the pharmaceutical formulation in the form of deep eutectic solvent.
  • Item 45 The pharmaceutical formulation according to item 44, wherein deep eutectic solvent is formed when the first N-acetyl amino acid amide and at least one additional compound are in molar ratio from 0.3: 1 to 3: 1.
  • Item 46 The pharmaceutical formulation according to item 44, wherein deep eutectic solvent is formed when the first N-acetyl amino acid amide and at least one additional compound are in molar ratio of 0.3: 1, of 0.5: 1, of 1: 1, of 1.5:1, of 2:1, of 2.5: 1, and of 3: 1.
  • Item 47 The pharmaceutical formulation according to item 44, wherein deep eutectic solvent is formed when the first N-acetyl amino acid amide and at least one additional compound are in molar ratio of 1 : 1.
  • Item 48 The pharmaceutical formulation according to item 37 and 44, wherein deep eutectic solvents may comprise 50% w/V or less of water.
  • Item 49 The pharmaceutical formulation according to item 48, wherein deep eutectic solvents may contain 45% or less, of 40% w/V or less, 35% w/V or less, 30% w/V or less, 25% w/V or less, 20% w/V or less, 15% w/V or less, 10% w/V or less, 5% w/V or less, 2% w/V or less of water.
  • Item 50 The pharmaceutical formulation according to item 48, wherein deep eutectic solvent in accordance with this disclosure may comprise from 20% w/V to 50% w/V of water.
  • Item 51 The pharmaceutical formulation according to item 1 , wherein pharmaceutical formulation further comprises buffering and/or chelating agents.
  • Item 52 The pharmaceutical formulation according to item 51, wherein the buffering agent is citrate buffer.
  • Item 53 The pharmaceutical formulation according to item 51, wherein the buffering agent is ADA.
  • Item 54 The pharmaceutical formulation according to item 51, wherein the buffering agent is citrate buffer and ADA.
  • Item 55 The pharmaceutical formulation according to item 51, wherein the concentration of buffering and/or chelating agents would be from ImM to 200 mM.
  • Item 56 The pharmaceutical formulation according to item 51, wherein the concentration of buffering and/or chelating agent would be from lOmM to 60 mM.
  • Item 57 The pharmaceutical formulation according to item 51, wherein the buffering agent is prepared at pH 6 to 6.5.
  • Item 58 The pharmaceutical formulation according to item 1, wherein pharmaceutical formulation is liquid.
  • Item 59 The pharmaceutical formulation according to item 1, wherein pharmaceutical formulation may be oral suspension or solution.
  • Item 60 The pharmaceutical formulation according to item 1 , wherein pharmaceutical formulation comprises water.
  • Item 61 The pharmaceutical formulation according to item 60, wherein water is comprised in concentration of less than 50% w/V.
  • Item 62 The pharmaceutical formulation according to item 60, wherein pharmaceutical formulation comprises less than 45% w/V, 40% w/V, 35% w/V, 30% w /V, 25% w /V, 20% w /V, 15% w /V, 10% w /V, 8% w /V, 6% w /V, 4% w /V, 2% w /V, 1% w /V of water.
  • Item 63 The pharmaceutical formulation according to item 61, wherein formulations can be further diluted.
  • Item 64 The pharmaceutical formulation according to item 1, wherein pharmaceutical formulation is semisolid, like ointments, creams, gels, or pastes.
  • Item 65 The pharmaceutical formulation according to item 64, wherein the semisolid composition is gel.
  • Item 66 The pharmaceutical formulation according to item 1, wherein pharmaceutical formulation is intended to be administered via injection, for example subcutaneously, intracutaneously, intravenously, intramuscularly, intraarticularly, intrasynovially, intrasternally, intrathecally, intralesionally, intracranially or via infusion.
  • Item 67 The pharmaceutical formulation according to item 1, wherein pharmaceutical formulation is administered orally, topically.
  • Item 68 The pharmaceutical formulation according to item 1, wherein pharmaceutical composition comprises piperacillin sodium and at least one N-acetyl amino acid amide.
  • Item 69 The pharmaceutical formulation according to item 4, wherein pharmaceutical composition comprises piperacillin sodium and at least two N-acetyl amino acid amides.
  • Item 70 The pharmaceutical formulation according to item 20, wherein pharmaceutical composition comprises piperacillin sodium and N-Acetyl-L-alaninamide.
  • Item 71 The pharmaceutical formulation according to item 20, wherein pharmaceutical composition comprises piperacillin sodium and N-Acetyl-D-alaninamide.
  • Item 72 The pharmaceutical formulation according to item 20, wherein pharmaceutical composition comprises piperacillin sodium and N-Acetyl-L-prolinamide.
  • Item 73 The pharmaceutical formulation according to item 29, wherein pharmaceutical composition comprises piperacillin sodium, N-Acetyl-L-prolinamide and N-Acetyl-L- alaninamide.
  • Item 74 The pharmaceutical formulation according to item 37, wherein pharmaceutical composition comprises piperacillin sodium and a deep eutectic solvent formed by N- Acetyl-L-prolinamide and N-Acetyl-L-alaninamide.
  • Item 75 The pharmaceutical formulation according to item 29, wherein pharmaceutical composition comprises piperacillin sodium, N-Acetyl-L-prolinamide and N-Acetyl-D- alaninamide.
  • Item 76 The pharmaceutical formulation according to item 37, wherein pharmaceutical composition comprises piperacillin sodium and a deep eutectic solvent formed by N- Acetyl-L-prolinamide and N-Acetyl-D-alaninamide.
  • Item 77 The pharmaceutical formulation according to item 1, wherein pharmaceutical composition comprises tazobactam sodium and at least one N-acetyl amino acid amide.
  • Item 78 The pharmaceutical formulation according to item 29, wherein pharmaceutical composition comprises tazobactam sodium and at least two N-acetyl amino acid amides.
  • Item 79. The pharmaceutical formulation according to item 20, wherein pharmaceutical composition comprises tazobactam sodium and N-Acetyl-L-alaninamide.
  • Item 80 The pharmaceutical formulation according to item 20, wherein pharmaceutical composition comprises tazobactam sodium and N-Acetyl-D-alaninamide.
  • Item 81 The pharmaceutical formulation according to item 20, wherein pharmaceutical composition comprises tazobactam sodium and N-Acetyl-L-prolinamide.
  • Item 82 The pharmaceutical formulation according to item 29, wherein pharmaceutical composition comprises tazobactam sodium, N-Acetyl-L-prolinamide and N-Acetyl-L- alaninamide.
  • Item 83 The pharmaceutical formulation according to item 29, wherein pharmaceutical composition comprises tazobactam sodium, N-Acetyl-L-prolinamide and N-Acetyl-L- alaninamide.
  • Item 84 The pharmaceutical formulation according to item 37, wherein pharmaceutical composition comprises tazobactam sodium and deep eutectic solvent formed by N- Acetyl-L-prolinamide and N-Acetyl-L-alaninamide.
  • Item 85 The pharmaceutical formulation according to item 29, wherein pharmaceutical composition comprises tazobactam sodium, N-Acetyl-L-prolinamide and N-AcetyLD- alaninamide.
  • Item 86 The pharmaceutical formulation according to item 37, wherein, pharmaceutical composition comprises tazobactam sodium and deep eutectic solvent formed by N- Acetyl-L-prolinamide and N-Acetyl-D-alaninamide.
  • Item 87 The pharmaceutical formulation according to item 10, wherein pharmaceutical composition comprises piperacillin sodium, tazobactam sodium and at least one N-acetyl amino acid amide.
  • Item 88 The pharmaceutical formulation according to item 29, wherein, pharmaceutical composition comprises piperacillin sodium, tazobactam sodium and at least two N- acetyl amino acid amides.
  • Item 89 The pharmaceutical formulation according to item 20, wherein pharmaceutical composition comprises piperacillin sodium, tazobactam sodium and N-AcetyLL- alaninamide.
  • Item 90 The pharmaceutical formulation according to item 20, wherein pharmaceutical composition comprises piperacillin sodium, tazobactam sodium and N-Acetyl-D- alaninamide.
  • Item 91 The pharmaceutical formulation according to item 20, wherein pharmaceutical composition comprises piperacillin sodium, tazobactam sodium and N-Acetyl-L- prolinamide.
  • Item 92 The pharmaceutical formulation according to item 29, wherein pharmaceutical composition comprises piperacillin sodium, tazobactam sodium, N-Acetyl-L- prolinamide and N-Acetyl-L-alaninamide.
  • Item 93 The pharmaceutical formulation according to item 29, wherein pharmaceutical composition comprises piperacillin sodium, tazobactam sodium, N-Acetyl-L- prolinamide and N-Acetyl-D-alaninamide.
  • Item 94 The pharmaceutical formulation according to item 37, wherein pharmaceutical composition comprises piperacillin sodium, tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide and N-Acetyl-L-alaninamide.
  • Item 95 The pharmaceutical formulation according to item 37, wherein pharmaceutical composition comprises piperacillin sodium, tazobactam sodium and deep eutectic solvent formed by N-Acetyl-L-prolinamide and N-Acetyl-D-alaninamide.
  • Item 96 The pharmaceutical formulation according to item 37, wherein molar ratio of each of N-acetyl amino acid amides in formulation to total of beta-lactam compounds in the formulation is from 1:1 to 300:1.
  • Item 97 The pharmaceutical formulation according to item 96, wherein formulation comprises piperacillin and tazobactam, molar ratio of each of N-acetyl amino acid amides to total of piperacillin and tazobactam is from 10:1 to 30:1.
  • Item 98 The pharmaceutical formulation according to item 96, wherein formulation comprises piperacillin, molar ratio of each of N-acetyl amino acid amides in the formulation to piperacillin is from 30: 1 to 60:1.
  • Item 99 The pharmaceutical formulation according to item 96, wherein formulation comprises tazobactam, molar ratio of each of N-acetyl amino acid amides in the formulation to tazobactam is from 100: 1 to 300:1.
  • Item 100 The pharmaceutical formulation according to item 25, wherein concentration of an N-acetyl amino acid amide is 20 mg/ml, 30 mg/ml, 40 mg/ml, 50 mg/ml, 60 mg/ml, 70 mg/ml, 80 mg/ml, 90 mg/ml, 100 mg/ml, 150 mg/ml, 200 mg/ml, 250 mg/ml, 300 mg/ml, 400 mg/ml, 500 mg/ml, 600 mg/ml, 700 mg/ml, 750 mg/ml, 800 mg/ml.

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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Engineering & Computer Science (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des compositions pharmaceutiques comprenant au moins un composé de beta-lactame et au moins un amide d'acide aminé N-acétyle. De telles compositions offrent une bonne stabilité dans le temps. L'invention concerne également une méthode de traitement d'infections bactériennes chez un sujet par l'administration de l'une quelconque des compositions décrites ici, ainsi qu'un procédé de stabilisation d'un composé de beta-lactame dans une composition pharmaceutique par mélange d'un composé de beta-lactame et d'au moins un amide d'acide aminé N-acétyle.
PCT/EP2021/082287 2020-11-20 2021-11-19 Nouvelles compositions de composés de bêta-lactame WO2022106611A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5944354A (ja) * 1982-09-03 1984-03-12 Tanabe Seiyaku Co Ltd 光学活性ｎ−アセチル−メチオニンアミドのラセミ化法
US20060084639A1 (en) * 2004-10-14 2006-04-20 Wyeth Compositions containing piperacillin and tazobactam useful for injection
CN102898438A (zh) * 2012-09-14 2013-01-30 北京新天宇科技开发有限公司 哌拉西林钠与舒巴坦钠共晶及其制备方法、以及包含该共晶的药物组合物及其应用
EP2896625A1 (fr) * 2012-09-14 2015-07-22 Beijing Xintianyu Technology Development Co., Ltd. Co-cristal de pipéracilline sodium et de sulbactam sodium et son procédé de préparation, et compositions pharmaceutiques le contenant et leurs utilisations

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5944354A (ja) * 1982-09-03 1984-03-12 Tanabe Seiyaku Co Ltd 光学活性ｎ−アセチル−メチオニンアミドのラセミ化法
US20060084639A1 (en) * 2004-10-14 2006-04-20 Wyeth Compositions containing piperacillin and tazobactam useful for injection
CN102898438A (zh) * 2012-09-14 2013-01-30 北京新天宇科技开发有限公司 哌拉西林钠与舒巴坦钠共晶及其制备方法、以及包含该共晶的药物组合物及其应用
EP2896625A1 (fr) * 2012-09-14 2015-07-22 Beijing Xintianyu Technology Development Co., Ltd. Co-cristal de pipéracilline sodium et de sulbactam sodium et son procédé de préparation, et compositions pharmaceutiques le contenant et leurs utilisations

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