US20140228337A1 - Tazobactam Arginine Compositions - Google Patents
Tazobactam Arginine Compositions Download PDFInfo
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- US20140228337A1 US20140228337A1 US14/181,041 US201414181041A US2014228337A1 US 20140228337 A1 US20140228337 A1 US 20140228337A1 US 201414181041 A US201414181041 A US 201414181041A US 2014228337 A1 US2014228337 A1 US 2014228337A1
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- tazobactam
- arginine
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- HZAQEDJRLABGQF-CKXGMKABSA-N C[C@]1(CN2C=CN=N2)C(C(=O)[O-])N2C(=O)CC2S1(=O)=O.NC(=[NH2+])CCCC[C@H]([NH3+])C(=O)[O-] Chemical compound C[C@]1(CN2C=CN=N2)C(C(=O)[O-])N2C(=O)CC2S1(=O)=O.NC(=[NH2+])CCCC[C@H]([NH3+])C(=O)[O-] HZAQEDJRLABGQF-CKXGMKABSA-N 0.000 description 2
- VRSINJNUFSBUSB-SEGLELNBSA-N C[C@]1(CN2C=CN=N2)C(C(=O)O[Y])N2C(=O)CC2S1(=O)=O.NC(=[NH2+])CCCC[C@H]([NH3+])C(=O)[O-].[CH3-] Chemical compound C[C@]1(CN2C=CN=N2)C(C(=O)O[Y])N2C(=O)CC2S1(=O)=O.NC(=[NH2+])CCCC[C@H]([NH3+])C(=O)[O-].[CH3-] VRSINJNUFSBUSB-SEGLELNBSA-N 0.000 description 1
- SHQSVMDWKBRBGB-UHFFFAOYSA-N O=C1CCC1 Chemical compound O=C1CCC1 SHQSVMDWKBRBGB-UHFFFAOYSA-N 0.000 description 1
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- C07D499/897—Compounds with substituents other than a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, directly attached in position 2
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- 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
- A61K31/4164—1,3-Diazoles
- A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
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- 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
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- 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
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- A—HUMAN NECESSITIES
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- 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
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- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
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- A—HUMAN NECESSITIES
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- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic 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; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/04—Preparation
- C07D499/14—Preparation of salts
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic 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; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/86—Heterocyclic 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; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with only atoms other than nitrogen atoms directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- This disclosure relates to solid forms of (2S,3S,5R)-3-((1H-1,2,3-triazol-1-yl)methyl)-3-methyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide (tazobactam), and related compositions and methods.
- the crystal state of a compound may be important when the compound is used for pharmaceutical purposes. Compared with an amorphous solid, the solid physical properties of a crystalline compound may change, which may affect its suitability for pharmaceutical use. For example, a particular crystalline compound may overcome the disadvantage of other solid forms of the compound that readily absorb moisture (e.g., high hygroscopicity). For an ionic drug substance, high hygroscopicity may diminish the drug product's stability profile by a host of mechanisms, as the drug substance may have a propensity to absorb water.
- Water that is absorbed from the environment may lead to degradation products and/or impurities in a drug product or add to the cost of manufacturing the drug product with acceptably low levels of water.
- One compound that can be obtained in amorphous or various crystalline salt forms is (2S,3S,5R)-3-((1H-1,2,3-triazol-1-yl)methyl)-3-methyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide, or tazobactam.
- tazobactam There is a need for solid forms of tazobactam with reduced hygroscopicity for use in drug substance and drug product development.
- Solid forms of tazobactam e.g., arginine salt forms of tazobactam
- compositions comprising these solid forms, are provided herein, in addition to various methods of preparing these compositions.
- certain crystalline tazobactam arginine solid forms are provided herein that have the advantageous characteristic of being less hygroscopic.
- These crystalline tazobactam arginine solid forms can have good thermal stability and light stability in the process of preparation, packing, transportation and storage. Crystalline compounds of tazobactam arginine can also possess other properties that may be beneficial to the preparation of various drug formulations.
- Tazobactam arginine can be a salt consisting of the conjugate base of (2S,3S,5R)-3-((1H-1,2,3-triazol-1-yl)methyl)-3-methyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide (tazobactam) and the conjugate acid of (S)-2-amino-5-guanidinopentanoic acid (L-arginine) in a 1:1 ratio, as represented by the structure below.
- crystalline tazobactam arginine solid form designated herein as “polymorph Ia” or “tazobactam arginine polymorph Ia”), characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2-Theta at angles of 4.8° ⁇ 0.3°, 8.9° ⁇ 0.3°, 11.3° ⁇ 0.3°, 14.9° ⁇ 0.3°, 18.0° ⁇ 0.3°, 19.4° ⁇ 0.3°, 21.3° ⁇ 0.3°, 22.8° ⁇ 0.3°, and 24.3° ⁇ 0.3°.
- the crystalline tazobactam arginine can be further characterized by a differential scanning calorimetry thermogram having a characteristic peak expressed in units of ° C. at a temperature of 209.2 ⁇ 3.
- the crystalline tazobactam arginine is further characterized by a thermogravimetry curve with an onset temperature of 201.9° C. ⁇ 3° C.
- compositions comprising a compound having a beta-lactam chemical sub-structure (e.g., a beta-lactam antibiotic compound) and crystalline tazobactam arginine (e.g., of the polymorph Ia solid form).
- a compound having a beta-lactam chemical sub-structure e.g., a beta-lactam antibiotic compound
- crystalline tazobactam arginine e.g., of the polymorph Ia solid form
- a method for the treatment of bacterial infections in a mammal comprising administering to said mammal a therapeutically effective amount of a crystalline tazobactam arginine compound (e.g., of the polymorph Ia solid form).
- a crystalline tazobactam arginine compound e.g., of the polymorph Ia solid form.
- the crystalline tazobactam arginine can be characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2-Theta at angles of 4.8° ⁇ 0.3°, 8.9° ⁇ 0.3°, 11.3° ⁇ 0.3°, 14.9° ⁇ 0.3°, 18.0° ⁇ 0.3°, 19.4° ⁇ 0.3°, 21.3° ⁇ 0.3°, 22.8° ⁇ 0.3° and 24.3° ⁇ 0.3°.
- a method for the treatment of bacterial infections in a mammal comprising administering to said mammal a therapeutically effective amount of a pharmaceutical composition comprising an beta-lactam compound and a crystalline tazobactam arginine compound (e.g., of the polymorph Ia solid form).
- a pharmaceutical composition comprising an beta-lactam compound and a crystalline tazobactam arginine compound (e.g., of the polymorph Ia solid form).
- the crystalline tazobactam arginine can be characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2-Theta at angles of 4.8° ⁇ 0.3°, 8.9° ⁇ 0.3°, 11.3° ⁇ 0.3°, 14.9° ⁇ 0.3°, 18.0° ⁇ 0.3°, 19.4° ⁇ 0.3°, 21.3° ⁇ 0.3°, 22.8° ⁇ 0.3° and 24.3° ⁇ 0.3°.
- a method for detecting or identifying an agent that inhibits one or more beta-lactamase-producing organisms comprising combining:
- composition comprising one or more beta-lactamase-producing organisms
- crystalline tazobactam arginine wherein the crystalline tazobactam arginine is characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2-Theta at angles of 4.8° ⁇ 0.3°, 8.9° ⁇ 0.3°, 11.3° ⁇ 0.3°, 14.9° ⁇ 0.3°, 18.0° ⁇ 0.3°, 19.4° ⁇ 0.3°, 21.3° ⁇ 0.3°, 22.8° ⁇ 0.3° and 24.3° ⁇ 0.3°; and detecting or measuring a change in the activity of the beta-lactamase-producing organisms, wherein a decrease in the activity of the beta-lactamase-producing organisms indicates that the test agent inhibits the beta-lactamase-producing organisms.
- FIG. 1 depicts the X-ray powder diffraction pattern of polymorph Ia (Example 2).
- FIG. 2 depicts the differential scanning calorimetry (DVS) thermogram of polymorph Ia.
- FIG. 3 depicts the thermogravimetry curve of polymorph Ia.
- FIG. 4 depicts the X-ray powder diffraction pattern of polymorph Ib.
- FIG. 5 depicts the X-ray powder diffraction pattern of tazobactam arginine amorphous.
- FIG. 6 depicts the X-ray power diffraction pattern of polymorph Ia (Example 4).
- FIG. 7 depicts the 1 H-NMR spectrum of polymorph Ia.
- FIG. 8 depicts the DVS graph of tazobactam arginine amorphous (Example 6a).
- FIG. 9 depicts the DVS graph of polymorph Ia (Example 6b).
- FIG. 10 depicts the DVS graph of amorphous tazobactam sodium (Example 6c).
- Tazobactam arginine may occur in an amorphous solid form or in a crystalline solid form.
- Crystalline solid forms of tazobactam arginine may exist in one or more unique polymorph forms, which may additionally comprise one or more equivalents of water or solvent (i.e., hydrates or solvates, respectively).
- Tazobactam arginine is the salt of the conjugate base of tazobactam and the conjugate acid of (S)-2-amino-5-guanidinopentanoic acid (L-arginine) in a 1:1 ratio, as represented by the structure below.
- crystalline tazobactam arginine and hydrates and solvates thereof.
- crystalline tazobactam arginine polymorph Ia also referred to herein as “polymorph Ia” or “tazobactam arginine polymorph Ia”
- crystalline tazobactam arginine polymorph Ib also referred to herein as “polymorph Ib” or “tazobactam arginine polymorph Ib”.
- polymorphism The ability of a substance to exist in more than one crystal form is defined as polymorphism; the different crystal forms of a particular substance are referred to as “polymorphs.”
- polymorphism is affected by the ability of a molecule of a substance to change its conformation or to form different intermolecular or intra-molecular interactions, particularly hydrogen bonds, which is reflected in different atom arrangements in the crystal lattices of different polymorphs.
- morphology which refers to the external shape of the crystal and the planes present, without reference to the internal structure. Crystals can display different morphology based on different conditions, such as, for example, growth rate, stirring, and the presence of impurities.
- the different polymorphs of a substance can possess different energies of the crystal lattice and, thus, in solid state they can show different physical properties such as form, density, melting point, color, stability, solubility, dissolution rate, etc., which can, in turn, affect the stability, dissolution rate and/or bioavailability of a given polymorph and its suitability for use as a pharmaceutical and in pharmaceutical compositions.
- tazobactam arginine Access to different polymorphs of tazobactam arginine is desirable for other reasons as well.
- One such reason is that different polymorphs of a compound (e.g., tazobactam arginine) can incorporate different impurities, or chemical residues, upon crystallization. Certain polymorphs incorporate very little, or no, chemical residues. Accordingly, the formation of certain polymorph forms of a compound may result in purification of the compound.
- Tazobactam arginine polymorph Ia exhibits low hygroscopicity relative to amorphous tazobactam arginine and amorphous tazobactam sodium.
- Low hygroscopicity of a solid compound is desirable for several reasons. For example, compounds that are highly hygroscopic may be chemically unstable, or unsuitable for formulating as a drug product due to changes of the drug form's physical characteristics (e.g., bulk density, dissolution rate, etc.) that can occur if it is stored in settings with varying relative humidity.
- hygroscopicity can impact large-scale manufacturing and handling of a compound. For example, it may be difficult to determine the true weight of a hygroscopic active agent when preparing a pharmaceutical composition comprising that agent.
- the compounds of the invention are identifiable on the basis of characteristic peaks in an X-ray powder diffraction analysis.
- X-ray powder diffraction also referred to as XRPD, is a scientific technique using X-ray, neutron, or electron diffraction on powder, microcrystalline, or other solid materials for structural characterization of the materials.
- polymorph Ia (also referred to herein as “tazobactam arginine polymorph Ia”) and is characterized by an X-ray powder diffraction pattern having one or more characteristic peaks expressed in degrees 2-Theta at angles selected from 8.9° ⁇ 0.3°, 18.0° ⁇ 0.3° and 21.3° ⁇ 0.3°.
- polymorph Ia is characterized by an X-ray powder diffraction pattern having one or more peaks expressed in degrees 2-Theta at angles selected from 4.8° ⁇ 0.3°, 11.3° ⁇ 0.3° and 14.9° ⁇ 0.3°.
- polymorph Ia is characterized by an X-ray powder diffraction pattern having one or more peaks expressed in degrees 2-Theta at angles selected from 19.4° ⁇ 0.3°, 22.8° ⁇ 0.3° and 24.3° ⁇ 0.3°.
- polymorph Ia is characterized by an X-ray powder diffraction pattern having 3-6 peaks expressed in degrees 2-Theta at angles selected from 8.9° ⁇ 0.3°, 18.0° ⁇ 0.3°, 21.3° ⁇ 0.3°, 4.8° ⁇ 0.3°, 11.3° ⁇ 0.3°, 14.9° ⁇ 0.3°, 19.4° ⁇ 0.3°, 22.8° ⁇ 0.3° and 24.3° ⁇ 0.3°.
- polymorph Ia is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-Theta at angles of 8.9° ⁇ 0.3°, 18.0° ⁇ 0.3° and 21.3° ⁇ 0.3°.
- polymorph Ia is characterized by an X-ray powder diffraction pattern having 3-6 peaks expressed in degrees 2-Theta at angles selected from 8.9° ⁇ 0.2°, 18.0° ⁇ 0.2°, 21.3° ⁇ 0.2°, 4.8° ⁇ 0.2°, 11.3° ⁇ 0.2°, 14.9° ⁇ 0.2°, 19.4° ⁇ 0.2°, 22.8° ⁇ 0.2° and 24.3° ⁇ 0.2°.
- polymorph Ia is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-Theta at angles of 8.9° ⁇ 0.2°, 18.0° ⁇ 0.2° and 21.3° ⁇ 0.2°.
- polymorph Ia is characterized by an X-ray powder diffraction pattern having 6-9 peaks expressed in degrees 2-Theta at angles selected from 8.9° ⁇ 0.3°, 18.0° ⁇ 0.3°, 21.3° ⁇ 0.3°, 4.8° ⁇ 0.3°, 11.3° ⁇ 0.3°, 14.9° ⁇ 0.3°, 19.4° ⁇ 0.3°, 22.8° ⁇ 0.3° and 24.3° ⁇ 0.3°.
- polymorph Ia is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-Theta at angles of 4.8° ⁇ 0.3°, 8.9° ⁇ 0.3°, 11.3° ⁇ 0.3°, 14.9° ⁇ 0.3°, 18.0° ⁇ 0.3°, 19.4° ⁇ 0.3°, 21.3° ⁇ 0.3° 22.8° ⁇ 0.3° and 24.3° ⁇ 0.3°.
- polymorph Ia is characterized by an X-ray powder diffraction pattern having 6-9 peaks expressed in degrees 2-Theta at angles selected from 8.9° ⁇ 0.2°, 18.0° ⁇ 0.2°, 21.3° ⁇ 0.2°, 4.8° ⁇ 0.2°, 11.3° ⁇ 0.2°, 14.9° ⁇ 0.2°, 19.4° ⁇ 0.2°, 22.8° ⁇ 0.2° and 24.3° ⁇ 0.2°.
- polymorph Ia is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-Theta at angles of 4.8° ⁇ 0.2°, 8.9° ⁇ 0.2°, 11.3° ⁇ 0.2°, 14.9° ⁇ 0.2°, 18.0° ⁇ 0.2°, 19.4° ⁇ 0.2°, 21.3° ⁇ 0.2° 22.8° ⁇ 0.2° and 24.3° ⁇ 0.2°.
- composition comprising crystalline tazobactam arginine characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2-Theta ⁇ 0.3° at angles of 4.8°, 8.9°, 11.3°, 14.9°, 18.0°, 19.4°, 21.3°, 22.8° and 24.3°.
- composition comprising crystalline tazobactam arginine characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2-Theta ⁇ 0.2° at angles of 4.8°, 8.9°, 11.3°, 14.9°, 18.0°, 19.4°, 21.3°, 22.8° and 24.3°.
- composition comprising crystalline tazobactam arginine characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2-Theta ⁇ 0.1° at angles of 4.8°, 8.9°, 11.3°, 14.9°, 18.0°, 19.4°, 21.3°, 22.8° and 24.3°.
- composition comprising crystalline tazobactam arginine characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2-Theta at angles of about 4.8°, 8.9°, 11.3°, 14.9°, 18.0°, 19.4°, 21.3°, 22.8° and 24.3°.
- polymorph Ia is characterized by an X-ray powder diffraction pattern having peaks substantially in accordance with FIG. 1 .
- polymorph Ia is characterized by an X-ray powder diffraction pattern having peaks substantially in accordance with Table 1.
- polymorph Ia is characterized by a differential scanning calorimetry thermogram having a characteristic peak expressed in units of ° C. at a temperature of 209.2 ⁇ 3.
- polymorph Ia is characterized by a differential scanning calorimetry thermogram substantially in accordance with FIG. 2 .
- polymorph Ia is characterized by a thermogravimetry curve with an onset temperature of 201.8° C. ⁇ 3° C.
- polymorph Ia is characterized by a thermogravimetry curve substantially in accordance with FIG. 3 .
- polymorph Ia may contain impurities.
- impurities include undesired polymorph forms, or residual organic and inorganic molecules such as solvents, water or salts.
- polymorph Ia is substantially free from impurities. In another embodiment, polymorph Ia contains less than 10% by weight total impurities. In another embodiment, polymorph Ia contains less than 5% by weight total impurities. In another embodiment, polymorph Ia contains less than 1% by weight total impurities. In yet another embodiment, polymorph Ia contains less than 0.1% by weight total impurities.
- polymorph Ib is tazobactam arginine trihydrate.
- crystalline tazobactam polymorph Ib is characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2-Theta at angles of 4.4° ⁇ 0.3°, 9.7° ⁇ 0.3°, 17.3° ⁇ 0.3°, 20.2° ⁇ 0.3°, and 22.0° ⁇ 0.3°.
- polymorph Ib is characterized by an X-ray powder diffraction pattern having peaks substantially in accordance with FIG. 4 .
- composition comprising one or more compounds selected from amorphous tazobactam arginine, polymorph Ia and polymorph Ib.
- the composition comprises one or more compounds selected from tazobactam arginine and polymorph Ia.
- polymorph Ia is a crystalline solid substantially free of amorphous tazobactam arginine.
- substantially free of amorphous tazobactam arginine means that the compound contains no significant amount of amorphous tazobactam arginine.
- at least about 95% by weight of crystalline polymorph Ia is present.
- at least about 99% by weight of crystalline polymorph Ia is present.
- polymorph Ia is substantially free from polymorph Ib.
- the term “substantially free of polymorph Ib” means that the compound contains no significant amount of polymorph Ib. In certain embodiments, at least about 95% by weight of crystalline polymorph Ia is present. In still other embodiments of the invention, at least about 99% by weight of crystalline polymorph Ia is present.
- crystalline tazobactam arginine comprising:
- tazobactam acid may first be combined with the solvent, and the resulting mixture then combined with arginine.
- arginine may first be combined with the solvent, and the resulting mixture then combined with tazobactam acid.
- tazobactam acid and arginine may be combined, and the resulting mixture then combined with the solvent.
- the above method is a method of making tazobactam arginine polymorph Ia, said method further comprising: (3) drying the precipitated crystalline tazobactam arginine to afford polymorph Ia.
- the antisolvent is added to the solution of tazobactam arginine. In another embodiment, the solution of tazobactam argine is added to the antisolvent.
- the solvent is selected from the group consisting of water and acetic acid.
- the antisolvent is selected from the group consisting of alcohols, ethers, esters, ketones, nitriles, amides, nitroalkanes, nitroarenes, substituted or unsubstituted aromatic solvents, substituted or unsubstituted aliphatic solvents and mixtures thereof.
- the antisolvent is selected from the group consisting of acetone, acetonitrile, 1-butanol, cyclohexane, dichloromethane, diisopropyl ether, dimethylformamide, dimethylsulfoxide, 1,4-dioxane, ethanol, ethyl acetate, heptanes, methanol, isopropyl acetate, methyl ethyl ketone, methyl isobutyl ketone, N-methyl-2-pyrrolidinone, nitromethane, 2-propanol, tert-butylmethyl ether, tetrahydrofuran, toluene and mixtures thereof.
- the solvent is water.
- the antisolvent is acetone.
- the antisolvent is isopropanol.
- crystalline tazobactam arginine comprising:
- the above method is a method of making tazobactam arginine polymorph Ia, said method further comprising: (3) drying the precipitated crystalline tazobactam arginine to afford polymorph Ia.
- crystalline tazobactam arginine e.g., polymorph Ia
- crystalline tazobactam arginine comprising:
- any one of the above methods is a method of making tazobactam arginine polymorph Ia and the method further comprises: (3) drying the precipitated crystalline tazobactam arginine to afford polymorph Ia.
- crystalline tazobactam arginine comprising:
- Y is a metal atom or ion and X— is a halide ion.
- crystalline tazobactam arginine comprising:
- Y is a metal atom or ion and X— is a halogen ion.
- crystalline tazobactam arginine produced according to the any one of the preceding methods.
- crystalline tazobactam arginine obtainable by any one of the preceding methods.
- the processes and methods described herein may also further comprise adding one or more seed crystals of crystalline tazobactam arginine (e.g., polymorph Ia or polymorph Ib).
- crystalline tazobactam arginine e.g., polymorph Ia or polymorph Ib.
- precipitate refers to the formation of a solid substance from a solution containing the same substance.
- a substance which precipitates from solution may be amorphous or crystalline. Precipitation may occur under a variety of conditions known to those of skill in the art, including the treatment of a solution of a solute (e.g., solute A in solvent B) with an antisolvent (i.e., a solvent that is miscible with solvent B, but does not dissolve solute A).
- solvent/antisolvent pairs include water/acetone and water/isopropanol.
- a pharmaceutical composition comprising tazobactam arginine polymorph Ia.
- a pharmaceutical composition comprising crystalline tazobactam arginine, hydrates or solvates thereof, and one or more beta-lactam compounds, and a pharmaceutically acceptable carrier or diluent.
- the pharmaceutical composition is useful for treating a bacterial infection.
- the bacterial infection can result from either gram-negative or gram-positive organisms.
- the crystalline tazobactam arginine is polymorph Ia. Polymorph Ia is characterized as described above.
- a pharmaceutical composition prepared by a method comprising the step of combining crystalline tazobactam arginine, or hydrates or solvates thereof, and a beta-lactam compound.
- the crystalline tazobactam arginine is polymorph Ia. Polymorph Ia is characterized as described above.
- beta-lactam compound is a compound possessing one or more beta-lactam moieties, i.e.,
- the pharmaceutical composition comprises polymorph Ia and (2S,5R,6R)-3,3-dimethyl-7-oxo-6-(2-phenylacetamido)-4-thia-1-zabicyclo[3.2.0]heptane-2-carboxylic acid or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof, and a pharmaceutically acceptable carrier or diluent.
- the pharmaceutical composition comprises polymorph Ia and (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-( ⁇ 2 -[(iminomethyl)amino]ethyl ⁇ thio)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof, and a pharmaceutically acceptable carrier or diluent.
- the pharmaceutical composition comprises polymorph Ia and (5R,6S)-6-((R)-1-hydroxyethyl)-7-oxo-3((R)-tetrahydrofuran-2-yl)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof, and a pharmaceutically acceptable carrier or diluent.
- the pharmaceutical composition comprises polymorph Ia and (2S,5R,6R)-6- ⁇ [3-(2-chlorophenyl)-5-methyl-oxazole-4-carbonyl]amino ⁇ -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof, and a pharmaceutically acceptable carrier or diluent.
- the pharmaceutical composition comprises polymorph Ia and (6R,7R,Z)-3-(acetoxymethyl)-7-(2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof, and a pharmaceutically acceptable carrier or diluent.
- the pharmaceutical composition comprises polymorph Ia and (6R,7R,Z)-7-(2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)-3-((1-methylpyrrolidinium-1-yl)methyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate, or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof, and a pharmaceutically acceptable carrier or diluent.
- the pharmaceutical composition comprises polymorph Ia and (2S,5R,6R)-6- ⁇ [(2R)-2-amino-2-(4-hydroxyphenyl)-acetyl]amino ⁇ -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof, and a pharmaceutically acceptable carrier or diluent.
- the pharmaceutical composition comprises polymorph Ia and 3-[5-(dimethylcarbamoyl) pyrrolidin-2-yl]sulfanyl-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof, and a pharmaceutically acceptable carrier or diluent.
- compositions comprising compounds of the invention can be identified by comparison of the compositions' X-ray powder diffraction patterns to an X-ray powder diffraction pattern of a compound of the invention. It will be appreciated that pharmaceutical compositions comprising a compound of the invention may exhibit non-identical X-ray powder diffraction patterns as compared to an X-ray powder diffraction pattern of a pure compound of the invention.
- composition includes preparations suitable for administration to mammals, e.g., humans.
- the compounds of the present invention are administered as pharmaceuticals to mammals, e.g., humans, they can be given per se or as a pharmaceutical composition containing, for example, 0.1% to 99.9% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
- compositions described herein can be formulated to have any concentration desired (i.e., any concentration of crystalline tazobactam arginine, or a hydrate or solvate thereof, and any concentration of a beta-lactam compound).
- the composition is formulated such that it comprises at least a therapeutically effective amount of both compounds (i.e., a therapeutically effective amount of the combination of crystalline tazobactam arginine, or a hydrate or solvate thereof, and the beta-lactam compound).
- the composition is formulated such that it would not cause one or more unwanted side effects.
- the compounds of the invention can be combined with a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques.
- pharmaceutically acceptable carrier may include any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
- Gennaro (Mack Publishing Co., Easton, Pa., 1990) discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this invention.
- materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatine; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil, sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen free water; isotonic saline (“normal saline”); Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible
- compositions include those suitable for oral, sublingual, nasal rectal, vaginal, topical, buccal and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route will depend on the nature and severity of the condition being treated.
- the compositions may be conveniently presented in unit dosage form, and prepared by any of the methods well known in the art of pharmacy.
- the pharmaceutical composition is formulated for oral administration in the form of a pill, capsule, lozenge or tablet.
- the pharmaceutical composition is in the form of a suspension.
- compositions disclosed herein can be prepared via lyophilization.
- lyophilization is a process of drying in which water is sublimed from a frozen solution of one or more solutes. Specific methods of lyophilization are described in Remington's Pharmaceutical Sciences, Chapter 84, page 1565, Eighteenth Edition, A. R. Gennaro, (Mack Publishing Co., Easton, Pa., 1990).
- compositions comprising crystalline tazobactam arginine (e.g., polymorph Ia) and one or more beta-lactam compounds are formulated for parenteral administration.
- pharmaceutical compositions comprising tazobactam arginine and one or more beta-lactam compounds are formulated for oral administration.
- Tazobactam arginine inhibits or decreases the activity of beta-lactamases (e.g., bacterial beta-lactamases), and can be combined with beta-lactam compounds (e.g., antibiotics), thereby broadening the spectrum of the beta-lactam compound and increasing the beta-lactam compound's efficacy against organisms that produce beta-lactamase.
- beta-lactamases e.g., bacterial beta-lactamases
- beta-lactam compounds e.g., antibiotics
- a method for the treatment of bacterial infections in a mammal comprising administering to said mammal a therapeutically effective amount of a pharmaceutical composition comprising tazobactam arginine polymorph Ia.
- the pharmaceutical composition comprises polymorph Ia and (2S,5R,6R)-3,3-dimethyl-7-oxo-6-(2-phenylacetamido)-4-thia-1-zabicyclo[3.2.0]heptane-2-carboxylic acid, or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof.
- the pharmaceutical composition comprises polymorph Ia and (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-( ⁇ 2-[(iminomethyl)amino]ethyl ⁇ thio)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof.
- the pharmaceutical composition comprises polymorph Ia and (6R,7R,Z)-3-(acetoxymethyl)-7-(2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof.
- the pharmaceutical composition comprises polymorph Ia and (6R,7R)-7- ⁇ [(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino ⁇ -3- ⁇ [(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-1,2,4-triazin-3-yl)thio]methyl ⁇ -8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof.
- the bacterial infection is caused by bacteria that are susceptible to the composition comprising polymorph Ia and (2S,5R,6R)-6-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-phenylacetamidol-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof.
- ESBL extended-spectrum beta-lactamase-producing organisms selected from the group consisting of Enterobacteriaceae spp.: Escherichia coli, Klebsiella spp. (including K. pneumoniae and K. oxytoca ), Proteus mirabilis, Proteus vulgaris, Enterobacter spp., Serratia spp., Citrobacter spp., Pseudomonas spp., Acinetobacter spp.) and Bacteroides spp.;
- CSBL conventional-spectrum beta-lactamase
- Appendicitis (complicated by rupture or abscess) and peritonitis caused by piperacillin-resistant beta-lactamase producing strains of Escherichia coli or the following members of the Bacteroides fragilis group: B. fragilis, B. ovatus, B. thetaiotaomicron , or B. vulgates;
- Nosocomial pneumonia caused by piperacillin-resistant, beta-lactamase producing strains of Staphylococcus aureus and by Acinetobacter baumanii, Haemophilus influenzae, Klebsiella pneumoniae , and Pseudomonas aeruginosa.
- tazobactam arginine and hydrates and solvates thereof, for use in a method of treating bacterial infection.
- a combination of tazobactam arginine and one or more beta-lactam compounds is used in said method.
- composition comprising one or more beta-lactamase-producing organisms
- activity refers to the ability of the beta-lactamase-producing organism to reproduce and/or infect another organism, or “activity” refers to the presence of an indicator of the ability of the beta-lactamase-producing organism to reproduce and/or infect another organism.
- Methods for detecting and/or measuring changes in the activity of beta-lactamase-producing organisms are known to those of skill in the art.
- compositions of the subject invention may be assessed by standard testing procedures.
- Non-limiting examples of such a procedure include the Kirby-Bauer method, the Stokes test, the E-test, broth dilution and agar dilution for determination of minimum inhibitory concentration (MIC), as described in “Approved Standard. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically,” 3.sup.rd ed., published 1993 by the National Committee for Clinical Laboratory standards, Villanova, Pa., USA.
- the methods described herein are performed using automation (e.g., Siemens' MicroScan Systems).
- the beta-lactamase inhibitor is tazobactam arginine.
- the beta-lactamase inhibitor is tazobactam arginine polymorph Ia.
- test agent can be selected from the group consisting of penicillins, cephalosporins, carbapenems, and combinations thereof.
- the test agent is selected from the compounds listed in Table 2, and pharmaceutically acceptable isomers, salts, esters, hydrates, solvates, or combinations thereof.
- beta-lactamase-producing organisms are selected from the group comprising:
- ESBL extended-spectrum beta-lactamase-producing organisms selected from the group consisting of Enterobacteriaceae spp.: Escherichia coli, Klebsiella spp. (including K. pneumoniae and K. oxytoca ), Proteus mirabilis, Proteus vulgaris, Enterobacter spp., Serratia spp., Citrobacter spp.) and Bacteroides spp.;
- CSBL conventional-spectrum beta-lactamase
- Inducible-AmpC-type beta-lactamases such as Citrobacter spp., Serratia spp., Morganella morganii, Proteus vulgaris , and Enterobacter cloacae.
- Tazobactam arginine amorphous (1.00 g) was dissolved in 10.0 mL of deionized water. 30 mL of acetone was added to the aqueous solution by drop-wise addition. The mixture was allowed to sit overnight at ambient temperature, resulting in white fine needles. After filtration and vacuum drying for 4 hours, tazobactam arginine polymorph Ia (516 mg) was obtained. The XRPD spectrum of the tazobactam arginine polymorph Ia is depicted in FIG. 1 .
- the 1 H-NMR spectrum ( FIG. 7 ) of polymorph Ia indicates a stoichiometry of 1:1 tazobactam acid:arginine.
- the solvent solubility screen was carried out using a solvent addition technique. For each of 25 solvent systems, the following procedure was used: (1) about 20 mg of crystalline tazobactam arginine was placed into a vial; (2) solvent was added to the vial in 5 volume aliquots (100 ⁇ L) until complete dissolution, or 100 volumes, had been added; (3) between additions, the sample was heated to about 50° C. in order to determine the approximate solubility at an elevated temperature; (4) if 100 volumes was reached and complete dissolution was not observed, solubility was calculated to be below that point. Results of the solvent solubility screen are shown in Table 3.
- Beta-lactam compounds No. IUPAC Name CAS No. 1 (2S,5R,6R)-6-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2- 61477-96-1 phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-l-azabicyclo[3.2.0]heptane- 2-carboxylic acid 2 (2S,5R,6R)-3,3-dimethyl-7-oxo-6- (2-phenylacetamido)-4-thia-1- 61-33-6 zabicyclo[3.2.0]heptane-2-carboxylic acid 3 (5R,6S)-6- [(1R)-1-hydroxyethyl]-3- ( ⁇ 2-[(iminomethyl)amino]ethyl ⁇ thio)- 74431-23-5 7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2
- Solvent solubility screen results Solvent Solubility @ 22° C. (mg/ml) Solubility @ 50° C. (mg/ml) Acetic acid >100 mg/ml >200 mg/ml Acetone ⁇ 10 mg/ml ⁇ 10 mg/ml Acetonitrile ⁇ 10 mg/ml ⁇ 10 mg/ml 1-butanol ⁇ 10 mg/ml ⁇ 10 mg/ml Cyclohexane ⁇ 10 mg/ml ⁇ 10 mg/ml Dichloromethane ⁇ 10 mg/ml ⁇ 10 mg/ml Diisopropyl ether ⁇ 10 mg/ml ⁇ 10 mg/ml Dimethylformamide ⁇ 10 mg/ml ⁇ 10 mg/ml Dimethylsulfoxide ⁇ 10 mg/ml ca.
Abstract
Description
- This application is a continuation of U.S. patent application Ser. No. 13/828,534, filed on Mar. 14, 2013, which was a continuation of U.S. patent application Ser. No. 13/628,742, filed on Sep. 27, 2012. The entire contents of these applications are incorporated herein by reference.
- This disclosure relates to solid forms of (2S,3S,5R)-3-((1H-1,2,3-triazol-1-yl)methyl)-3-methyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-
carboxylic acid 4,4-dioxide (tazobactam), and related compositions and methods. - The crystal state of a compound may be important when the compound is used for pharmaceutical purposes. Compared with an amorphous solid, the solid physical properties of a crystalline compound may change, which may affect its suitability for pharmaceutical use. For example, a particular crystalline compound may overcome the disadvantage of other solid forms of the compound that readily absorb moisture (e.g., high hygroscopicity). For an ionic drug substance, high hygroscopicity may diminish the drug product's stability profile by a host of mechanisms, as the drug substance may have a propensity to absorb water. Water that is absorbed from the environment (packaging materials, exposure to air, or in the case of formulated products, from other materials), may lead to degradation products and/or impurities in a drug product or add to the cost of manufacturing the drug product with acceptably low levels of water.
- One compound that can be obtained in amorphous or various crystalline salt forms is (2S,3S,5R)-3-((1H-1,2,3-triazol-1-yl)methyl)-3-methyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-
carboxylic acid 4,4-dioxide, or tazobactam. There is a need for solid forms of tazobactam with reduced hygroscopicity for use in drug substance and drug product development. - Solid forms of tazobactam (e.g., arginine salt forms of tazobactam) and compositions comprising these solid forms, are provided herein, in addition to various methods of preparing these compositions. Compared with previous crystalline forms of tazobactam, certain crystalline tazobactam arginine solid forms are provided herein that have the advantageous characteristic of being less hygroscopic. These crystalline tazobactam arginine solid forms can have good thermal stability and light stability in the process of preparation, packing, transportation and storage. Crystalline compounds of tazobactam arginine can also possess other properties that may be beneficial to the preparation of various drug formulations.
- Crystalline tazobactam arginine, and hydrates and solvates thereof, can be obtained in various solid forms. Tazobactam arginine can be a salt consisting of the conjugate base of (2S,3S,5R)-3-((1H-1,2,3-triazol-1-yl)methyl)-3-methyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-
carboxylic acid 4,4-dioxide (tazobactam) and the conjugate acid of (S)-2-amino-5-guanidinopentanoic acid (L-arginine) in a 1:1 ratio, as represented by the structure below. - In one aspect, provided herein is a particularly preferred crystalline tazobactam arginine solid form (designated herein as “polymorph Ia” or “tazobactam arginine polymorph Ia”), characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2-Theta at angles of 4.8°±0.3°, 8.9°±0.3°, 11.3°±0.3°, 14.9°±0.3°, 18.0°±0.3°, 19.4°±0.3°, 21.3°±0.3°, 22.8°±0.3°, and 24.3°±0.3°. The crystalline tazobactam arginine can be further characterized by a differential scanning calorimetry thermogram having a characteristic peak expressed in units of ° C. at a temperature of 209.2±3. In another embodiment, the crystalline tazobactam arginine is further characterized by a thermogravimetry curve with an onset temperature of 201.9° C.±3° C.
- Also provided are pharmaceutical compositions comprising a compound having a beta-lactam chemical sub-structure (e.g., a beta-lactam antibiotic compound) and crystalline tazobactam arginine (e.g., of the polymorph Ia solid form).
- In another aspect, provided herein is a method for the treatment of bacterial infections in a mammal, comprising administering to said mammal a therapeutically effective amount of a crystalline tazobactam arginine compound (e.g., of the polymorph Ia solid form). The crystalline tazobactam arginine can be characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2-Theta at angles of 4.8°±0.3°, 8.9°±0.3°, 11.3°±0.3°, 14.9°±0.3°, 18.0°±0.3°, 19.4°±0.3°, 21.3°±0.3°, 22.8°±0.3° and 24.3°±0.3°.
- In another aspect, provided herein is a method for the treatment of bacterial infections in a mammal, comprising administering to said mammal a therapeutically effective amount of a pharmaceutical composition comprising an beta-lactam compound and a crystalline tazobactam arginine compound (e.g., of the polymorph Ia solid form). The crystalline tazobactam arginine can be characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2-Theta at angles of 4.8°±0.3°, 8.9°±0.3°, 11.3°±0.3°, 14.9°±0.3°, 18.0°±0.3°, 19.4°±0.3°, 21.3°±0.3°, 22.8°±0.3° and 24.3°±0.3°.
- In another aspect, provided herein is a method for detecting or identifying an agent that inhibits one or more beta-lactamase-producing organisms, said method comprising combining:
- (a) a test agent;
- (b) a composition comprising one or more beta-lactamase-producing organisms; and
- (c) crystalline tazobactam arginine, wherein the crystalline tazobactam arginine is characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2-Theta at angles of 4.8°±0.3°, 8.9°±0.3°, 11.3°±0.3°, 14.9°±0.3°, 18.0°±0.3°, 19.4°±0.3°, 21.3°±0.3°, 22.8°±0.3° and 24.3°±0.3°; and detecting or measuring a change in the activity of the beta-lactamase-producing organisms, wherein a decrease in the activity of the beta-lactamase-producing organisms indicates that the test agent inhibits the beta-lactamase-producing organisms.
-
FIG. 1 depicts the X-ray powder diffraction pattern of polymorph Ia (Example 2). -
FIG. 2 depicts the differential scanning calorimetry (DVS) thermogram of polymorph Ia. -
FIG. 3 depicts the thermogravimetry curve of polymorph Ia. -
FIG. 4 depicts the X-ray powder diffraction pattern of polymorph Ib. -
FIG. 5 depicts the X-ray powder diffraction pattern of tazobactam arginine amorphous. -
FIG. 6 depicts the X-ray power diffraction pattern of polymorph Ia (Example 4). -
FIG. 7 depicts the 1H-NMR spectrum of polymorph Ia. -
FIG. 8 depicts the DVS graph of tazobactam arginine amorphous (Example 6a). -
FIG. 9 depicts the DVS graph of polymorph Ia (Example 6b). -
FIG. 10 depicts the DVS graph of amorphous tazobactam sodium (Example 6c). - Tazobactam arginine may occur in an amorphous solid form or in a crystalline solid form. Crystalline solid forms of tazobactam arginine may exist in one or more unique polymorph forms, which may additionally comprise one or more equivalents of water or solvent (i.e., hydrates or solvates, respectively).
- Tazobactam arginine is the salt of the conjugate base of tazobactam and the conjugate acid of (S)-2-amino-5-guanidinopentanoic acid (L-arginine) in a 1:1 ratio, as represented by the structure below.
- Accordingly, provided herein is crystalline tazobactam arginine, and hydrates and solvates thereof. In particular, provided herein is crystalline tazobactam arginine polymorph Ia, also referred to herein as “polymorph Ia” or “tazobactam arginine polymorph Ia”, and crystalline tazobactam arginine polymorph Ib, also referred to herein as “polymorph Ib” or “tazobactam arginine polymorph Ib”.
- The ability of a substance to exist in more than one crystal form is defined as polymorphism; the different crystal forms of a particular substance are referred to as “polymorphs.” In general, polymorphism is affected by the ability of a molecule of a substance to change its conformation or to form different intermolecular or intra-molecular interactions, particularly hydrogen bonds, which is reflected in different atom arrangements in the crystal lattices of different polymorphs. In contrast, the overall external form of a substance is known as “morphology,” which refers to the external shape of the crystal and the planes present, without reference to the internal structure. Crystals can display different morphology based on different conditions, such as, for example, growth rate, stirring, and the presence of impurities.
- The different polymorphs of a substance can possess different energies of the crystal lattice and, thus, in solid state they can show different physical properties such as form, density, melting point, color, stability, solubility, dissolution rate, etc., which can, in turn, affect the stability, dissolution rate and/or bioavailability of a given polymorph and its suitability for use as a pharmaceutical and in pharmaceutical compositions.
- Access to different polymorphs of tazobactam arginine is desirable for other reasons as well. One such reason is that different polymorphs of a compound (e.g., tazobactam arginine) can incorporate different impurities, or chemical residues, upon crystallization. Certain polymorphs incorporate very little, or no, chemical residues. Accordingly, the formation of certain polymorph forms of a compound may result in purification of the compound.
- Tazobactam arginine polymorph Ia exhibits low hygroscopicity relative to amorphous tazobactam arginine and amorphous tazobactam sodium. Low hygroscopicity of a solid compound is desirable for several reasons. For example, compounds that are highly hygroscopic may be chemically unstable, or unsuitable for formulating as a drug product due to changes of the drug form's physical characteristics (e.g., bulk density, dissolution rate, etc.) that can occur if it is stored in settings with varying relative humidity. Also, hygroscopicity can impact large-scale manufacturing and handling of a compound. For example, it may be difficult to determine the true weight of a hygroscopic active agent when preparing a pharmaceutical composition comprising that agent.
- In certain embodiments, the compounds of the invention are identifiable on the basis of characteristic peaks in an X-ray powder diffraction analysis. X-ray powder diffraction, also referred to as XRPD, is a scientific technique using X-ray, neutron, or electron diffraction on powder, microcrystalline, or other solid materials for structural characterization of the materials.
- One embodiment of crystalline tazobactam arginine is referred to as polymorph Ia (also referred to herein as “tazobactam arginine polymorph Ia”) and is characterized by an X-ray powder diffraction pattern having one or more characteristic peaks expressed in degrees 2-Theta at angles selected from 8.9°±0.3°, 18.0°±0.3° and 21.3°±0.3°. In another embodiment, polymorph Ia is characterized by an X-ray powder diffraction pattern having one or more peaks expressed in degrees 2-Theta at angles selected from 4.8°±0.3°, 11.3°±0.3° and 14.9°±0.3°. In still another embodiment, polymorph Ia is characterized by an X-ray powder diffraction pattern having one or more peaks expressed in degrees 2-Theta at angles selected from 19.4°±0.3°, 22.8°±0.3° and 24.3°±0.3°.
- In another embodiment, polymorph Ia is characterized by an X-ray powder diffraction pattern having 3-6 peaks expressed in degrees 2-Theta at angles selected from 8.9°±0.3°, 18.0°±0.3°, 21.3°±0.3°, 4.8°±0.3°, 11.3°±0.3°, 14.9°±0.3°, 19.4°±0.3°, 22.8°±0.3° and 24.3°±0.3°. In a particular embodiment, polymorph Ia is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-Theta at angles of 8.9°±0.3°, 18.0°±0.3° and 21.3°±0.3°.
- In yet another embodiment, polymorph Ia is characterized by an X-ray powder diffraction pattern having 3-6 peaks expressed in degrees 2-Theta at angles selected from 8.9°±0.2°, 18.0°±0.2°, 21.3°±0.2°, 4.8°±0.2°, 11.3°±0.2°, 14.9°±0.2°, 19.4°±0.2°, 22.8°±0.2° and 24.3°±0.2°. In a particular embodiment, polymorph Ia is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-Theta at angles of 8.9°±0.2°, 18.0°±0.2° and 21.3°±0.2°.
- In still another embodiment, polymorph Ia is characterized by an X-ray powder diffraction pattern having 6-9 peaks expressed in degrees 2-Theta at angles selected from 8.9°±0.3°, 18.0°±0.3°, 21.3°±0.3°, 4.8°±0.3°, 11.3°±0.3°, 14.9°±0.3°, 19.4°±0.3°, 22.8°±0.3° and 24.3°±0.3°. In a particular embodiment, polymorph Ia is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-Theta at angles of 4.8°±0.3°, 8.9°±0.3°, 11.3°±0.3°, 14.9°±0.3°, 18.0°±0.3°, 19.4°±0.3°, 21.3°±0.3° 22.8°±0.3° and 24.3°±0.3°.
- In still another embodiment, polymorph Ia is characterized by an X-ray powder diffraction pattern having 6-9 peaks expressed in degrees 2-Theta at angles selected from 8.9°±0.2°, 18.0°±0.2°, 21.3°±0.2°, 4.8°±0.2°, 11.3°±0.2°, 14.9°±0.2°, 19.4°±0.2°, 22.8°±0.2° and 24.3°±0.2°. In a particular embodiment, polymorph Ia is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-Theta at angles of 4.8°±0.2°, 8.9°±0.2°, 11.3°±0.2°, 14.9°±0.2°, 18.0°±0.2°, 19.4°±0.2°, 21.3°±0.2° 22.8°±0.2° and 24.3°±0.2°.
- In still another embodiment, provided herein is a composition comprising crystalline tazobactam arginine characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2-Theta±0.3° at angles of 4.8°, 8.9°, 11.3°, 14.9°, 18.0°, 19.4°, 21.3°, 22.8° and 24.3°.
- In still another embodiment, provided herein is a composition comprising crystalline tazobactam arginine characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2-Theta±0.2° at angles of 4.8°, 8.9°, 11.3°, 14.9°, 18.0°, 19.4°, 21.3°, 22.8° and 24.3°.
- In still another embodiment, provided herein is a composition comprising crystalline tazobactam arginine characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2-Theta±0.1° at angles of 4.8°, 8.9°, 11.3°, 14.9°, 18.0°, 19.4°, 21.3°, 22.8° and 24.3°.
- In still another embodiment, provided herein is a composition comprising crystalline tazobactam arginine characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2-Theta at angles of about 4.8°, 8.9°, 11.3°, 14.9°, 18.0°, 19.4°, 21.3°, 22.8° and 24.3°.
- In one embodiment, polymorph Ia is characterized by an X-ray powder diffraction pattern having peaks substantially in accordance with
FIG. 1 . In another embodiment, polymorph Ia is characterized by an X-ray powder diffraction pattern having peaks substantially in accordance with Table 1. - The compounds of the invention may also be defined by their differential scanning calorimetry (DSC) thermograms. In one embodiment, polymorph Ia is characterized by a differential scanning calorimetry thermogram having a characteristic peak expressed in units of ° C. at a temperature of 209.2±3. In a particular embodiment, polymorph Ia is characterized by a differential scanning calorimetry thermogram substantially in accordance with
FIG. 2 . - The compounds of the invention can be also be defined by their thermogravimetry (TG) signals. In one embodiment, polymorph Ia is characterized by a thermogravimetry curve with an onset temperature of 201.8° C.±3° C. In a particular embodiment, polymorph Ia is characterized by a thermogravimetry curve substantially in accordance with
FIG. 3 . - In certain embodiments, polymorph Ia may contain impurities. Non-limiting examples of impurities include undesired polymorph forms, or residual organic and inorganic molecules such as solvents, water or salts.
- In another embodiment, polymorph Ia is substantially free from impurities. In another embodiment, polymorph Ia contains less than 10% by weight total impurities. In another embodiment, polymorph Ia contains less than 5% by weight total impurities. In another embodiment, polymorph Ia contains less than 1% by weight total impurities. In yet another embodiment, polymorph Ia contains less than 0.1% by weight total impurities.
- In another aspect, provided herein is crystalline tazobactam arginine polymorph Ib. In one embodiment, polymorph Ib is tazobactam arginine trihydrate. In another embodiment, crystalline tazobactam polymorph Ib is characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2-Theta at angles of 4.4°±0.3°, 9.7°±0.3°, 17.3°±0.3°, 20.2°±0.3°, and 22.0°±0.3°. In a particular embodiment, polymorph Ib is characterized by an X-ray powder diffraction pattern having peaks substantially in accordance with
FIG. 4 . - In another aspect, provided herein is a composition comprising one or more compounds selected from amorphous tazobactam arginine, polymorph Ia and polymorph Ib. In one embodiment, the composition comprises one or more compounds selected from tazobactam arginine and polymorph Ia.
- In certain embodiments, polymorph Ia is a crystalline solid substantially free of amorphous tazobactam arginine. As used herein, the term “substantially free of amorphous tazobactam arginine” means that the compound contains no significant amount of amorphous tazobactam arginine. In certain embodiments, at least about 95% by weight of crystalline polymorph Ia is present. In still other embodiments of the invention, at least about 99% by weight of crystalline polymorph Ia is present.
- In another embodiment, polymorph Ia is substantially free from polymorph Ib. As used herein, the term “substantially free of polymorph Ib “means that the compound contains no significant amount of polymorph Ib. In certain embodiments, at least about 95% by weight of crystalline polymorph Ia is present. In still other embodiments of the invention, at least about 99% by weight of crystalline polymorph Ia is present.
- Provided herein is a method of making crystalline tazobactam arginine comprising:
- (1) combining tazobactam acid, arginine and a solvent, such that a solution of tazobactam arginine is formed; and
- (2) combining an antisolvent with the solution, wherein the antisolvent is miscible with the solvent and wherein tazobactam arginine is partially or completely insoluble in the antisolvent, such that crystalline tazobactam arginine precipitates from the solution.
- In step (1), tazobactam acid may first be combined with the solvent, and the resulting mixture then combined with arginine. Alternatively, arginine may first be combined with the solvent, and the resulting mixture then combined with tazobactam acid. Alternatively, tazobactam acid and arginine may be combined, and the resulting mixture then combined with the solvent.
- In one embodiment, the above method is a method of making tazobactam arginine polymorph Ia, said method further comprising: (3) drying the precipitated crystalline tazobactam arginine to afford polymorph Ia.
- In one embodiment, the antisolvent is added to the solution of tazobactam arginine. In another embodiment, the solution of tazobactam argine is added to the antisolvent. In certain embodiments, the solvent is selected from the group consisting of water and acetic acid. In certain embodiments, the antisolvent is selected from the group consisting of alcohols, ethers, esters, ketones, nitriles, amides, nitroalkanes, nitroarenes, substituted or unsubstituted aromatic solvents, substituted or unsubstituted aliphatic solvents and mixtures thereof. In certain embodiments, the antisolvent is selected from the group consisting of acetone, acetonitrile, 1-butanol, cyclohexane, dichloromethane, diisopropyl ether, dimethylformamide, dimethylsulfoxide, 1,4-dioxane, ethanol, ethyl acetate, heptanes, methanol, isopropyl acetate, methyl ethyl ketone, methyl isobutyl ketone, N-methyl-2-pyrrolidinone, nitromethane, 2-propanol, tert-butylmethyl ether, tetrahydrofuran, toluene and mixtures thereof. Experiments determining solubility of crystalline tazobactam arginine in a variety of solvents are described in Experiment 6, and results are summarized in Table 3. In a preferred embodiment, the solvent is water. In another preferred embodiment, the antisolvent is acetone. In yet another preferred embodiment, the antisolvent is isopropanol.
- Accordingly, provided herein is a method of making crystalline tazobactam arginine comprising:
- (1) combining tazobactam acid, arginine and water, such that an aqueous solution of tazobactam arginine is formed; and
- (2) combining acetone with the aqueous solution, such that crystalline tazobactam arginine precipitates from the solution.
- In one embodiment, the above method is a method of making tazobactam arginine polymorph Ia, said method further comprising: (3) drying the precipitated crystalline tazobactam arginine to afford polymorph Ia.
- In another aspect, provided herein is a method of making crystalline tazobactam arginine (e.g., polymorph Ia) comprising:
- (1) combining tazobactam arginine and a solvent, such that a solution of tazobactam arginine is formed; and
- (2) combining an antisolvent with the solution, wherein the antisolvent is miscible with the solvent and wherein tazobactam arginine is partially or completely insoluble in the antisolvent, such that crystalline tazobactam arginine precipitates from the solution.
- In another aspect, provided herein is a method of making crystalline tazobactam arginine comprising:
- (1) combining tazobactam acid, arginine and a solvent/antisolvent mixture, such that a solution of tazobactam arginine is formed; and
- (2) combining an antisolvent with the solution, wherein the antisolvent is miscible with the solvent and wherein tazobactam arginine is partially or completely insoluble in the antisolvent, such that crystalline tazobactam arginine precipitates from the solution.
- In certain embodiments, any one of the above methods is a method of making tazobactam arginine polymorph Ia and the method further comprises: (3) drying the precipitated crystalline tazobactam arginine to afford polymorph Ia.
- In another aspect, provided herein is a method of making crystalline tazobactam arginine comprising:
- (1) combining a compound according to formula (I), a compound according to formula (II), and a solvent, such that a solution comprising tazobactam arginine is formed, and such that crystalline tazobactam arginine precipitates from the solution.
- In one embodiment, Y is a metal atom or ion and X— is a halide ion.
- In still another aspect, provided herein is a method of making crystalline tazobactam arginine comprising:
- (1) combining a compound according for formula (I), a compound according to formula (II), and a solvent, such that a solution comprising tazobactam arginine is formed; and
- (2) combining an antisolvent with the solution, wherein the antisolvent is miscible with the solvent and wherein tazobactam arginine is partially or completely insoluble in the antisolvent, such that crystalline tazobactam arginine precipitates from the solution. In one embodiment, Y is a metal atom or ion and X— is a halogen ion.
- In another aspect, provided herein is crystalline tazobactam arginine produced according to the any one of the preceding methods. In another aspect, provided herein is crystalline tazobactam arginine obtainable by any one of the preceding methods.
- The processes and methods described herein may also further comprise adding one or more seed crystals of crystalline tazobactam arginine (e.g., polymorph Ia or polymorph Ib).
- As used herein, the verb “precipitate” refers to the formation of a solid substance from a solution containing the same substance. A substance which precipitates from solution may be amorphous or crystalline. Precipitation may occur under a variety of conditions known to those of skill in the art, including the treatment of a solution of a solute (e.g., solute A in solvent B) with an antisolvent (i.e., a solvent that is miscible with solvent B, but does not dissolve solute A). Non-limiting examples of solvent/antisolvent pairs include water/acetone and water/isopropanol.
- In one aspect, provided herein is a pharmaceutical composition comprising tazobactam arginine polymorph Ia.
- In another aspect, provided herein is a pharmaceutical composition comprising crystalline tazobactam arginine, hydrates or solvates thereof, and one or more beta-lactam compounds, and a pharmaceutically acceptable carrier or diluent. In one embodiment, the pharmaceutical composition is useful for treating a bacterial infection. The bacterial infection can result from either gram-negative or gram-positive organisms. In one embodiment, the crystalline tazobactam arginine is polymorph Ia. Polymorph Ia is characterized as described above.
- In yet another aspect, provided herein is a pharmaceutical composition prepared by a method comprising the step of combining crystalline tazobactam arginine, or hydrates or solvates thereof, and a beta-lactam compound. In one embodiment, the crystalline tazobactam arginine is polymorph Ia. Polymorph Ia is characterized as described above.
- A “beta-lactam compound” is a compound possessing one or more beta-lactam moieties, i.e.,
- substituted one or more times as valency permits. In certain non-limiting embodiments the beta-lactam compounds described herein can be selected from the group consisting of penicillins, cephalosporins, carbapenems, and combinations thereof. In certain embodiments, said one or more beta-lactam compounds are selected from the compounds listed in Table 2, and pharmaceutically acceptable isomers, salts, esters, hydrates, solvates, or combinations thereof.
- The following compounds are listed in Table 2:
-
- (2S,5R,6R)-6-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid;
- (2S,5R,6R)-3,3-dimethyl-7-oxo-6-(2-phenylacetamido)-4-thia-1-zabicyclo[3.2.0]heptane-2-carboxylic acid;
- (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-({2-[(iminomethyl)amino]ethyl}thio)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;
- (5R,6S)-6-((R)-1-hydroxyethyl)-7-oxo-3-((R)-tetrahydrofuran-2-yl)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;
- (2S,5R,6R)-6-{[3-(2-chlorophenyl)-5-methyl-oxazole-4-carbonyl]amino}-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid;
- (6R,7R,Z)-7-(2-(2-aminothiazol-4-yl)-2-(2-carboxypropan-2-yloxyimino)acetamido)-8-oxo-3-(pyridinium-1-ylmethyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate;
- 6R,7R,Z)-3-(acetoxymethyl)-7-(2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
- (6R,7R)-7-[(2Z)-2-ethoxyimino-2-[5-(phosphonoamino)-1,2,4-thiadiazol-3-yl]acetyl]amino]-3-[4-(1-methylpyridin-1-ium-4-yl)-1,3-thiazol-2-yl]sulfanyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate;
- (6R,7R,Z)-7-(2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)-3-((1-methylpyrrolidinium-1-yl)methyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate;
- (6R,7R)-3-{[(aminocarbonyl)oxy]methyl}-7-{[(2Z)-2-(2-furyl)-2-(methoxyimino) acetyl]amino}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
- (6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-{[(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-1,2,4-triazin-3-yl)thio]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
- (2S,5R,6R)-6-{[(2R)-2-amino-2-(4-hydroxyphenyl)-acetyl]amino}-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid;
- 3-[5-(dimethylcarbamoyl)pyrrolidin-2-yl]sulfanyl-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
- In a particular embodiment, the pharmaceutical composition comprises polymorph Ia and (2S,5R,6R)-3,3-dimethyl-7-oxo-6-(2-phenylacetamido)-4-thia-1-zabicyclo[3.2.0]heptane-2-carboxylic acid or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof, and a pharmaceutically acceptable carrier or diluent.
- In another particular embodiment, the pharmaceutical composition comprises polymorph Ia and (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-({2-[(iminomethyl)amino]ethyl}thio)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof, and a pharmaceutically acceptable carrier or diluent.
- In another particular embodiment, the pharmaceutical composition comprises polymorph Ia and (5R,6S)-6-((R)-1-hydroxyethyl)-7-oxo-3((R)-tetrahydrofuran-2-yl)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof, and a pharmaceutically acceptable carrier or diluent.
- In another particular embodiment, the pharmaceutical composition comprises polymorph Ia and (2S,5R,6R)-6-{[3-(2-chlorophenyl)-5-methyl-oxazole-4-carbonyl]amino}-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof, and a pharmaceutically acceptable carrier or diluent.
- In another particular embodiment, the pharmaceutical composition comprises polymorph Ia and (6R,7R,Z)-7-(2-(2-aminothiazol-4-yl)-2-(2-carboxypropan-2-yloxyimino)acetamido)-8-oxo-3-(pyridinium-1-ylmethyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof, and a pharmaceutically acceptable carrier or diluent.
- In another particular embodiment, the pharmaceutical composition comprises polymorph Ia and (6R,7R,Z)-3-(acetoxymethyl)-7-(2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof, and a pharmaceutically acceptable carrier or diluent.
- In another particular embodiment, the pharmaceutical composition comprises polymorph Ia and (6R,7R)-7-[(2Z)-2-ethoxyimino-2-[5-(phosphonoamino)-1,2,4-thiadiazol-3-yl]acetyl]amino]-3-[4-(1-methylpyridin-1-ium-4-yl)-1,3-thiazol-2-yl]sulfanyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof, and a pharmaceutically acceptable carrier or diluent.
- In another particular embodiment, the pharmaceutical composition comprises polymorph Ia and (6R,7R,Z)-7-(2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)-3-((1-methylpyrrolidinium-1-yl)methyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate, or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof, and a pharmaceutically acceptable carrier or diluent.
- In another particular embodiment, the pharmaceutical composition comprises polymorph Ia and (6R,7R)-3-{[(aminocarbonyl)oxy]methyl}-7-{[(2Z)-2-(2-furyl)-2-(methoxyimino) acetyl]amino}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof, and a pharmaceutically acceptable carrier or diluent.
- In another particular embodiment, the pharmaceutical composition comprises polymorph Ia and (6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-{[(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-1,2,4-triazin-3-yl)thio]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof, and a pharmaceutically acceptable carrier or diluent.
- In another particular embodiment, the pharmaceutical composition comprises polymorph Ia and (2S,5R,6R)-6-{[(2R)-2-amino-2-(4-hydroxyphenyl)-acetyl]amino}-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof, and a pharmaceutically acceptable carrier or diluent.
- In another particular embodiment, the pharmaceutical composition comprises polymorph Ia and (2S,5R,6R)-6-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-phenylacetamido}-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof, and a pharmaceutically acceptable carrier or diluent.
- In another particular embodiment, the pharmaceutical composition comprises polymorph Ia and 3-[5-(dimethylcarbamoyl) pyrrolidin-2-yl]sulfanyl-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof, and a pharmaceutically acceptable carrier or diluent.
- Pharmaceutical compositions comprising compounds of the invention can be identified by comparison of the compositions' X-ray powder diffraction patterns to an X-ray powder diffraction pattern of a compound of the invention. It will be appreciated that pharmaceutical compositions comprising a compound of the invention may exhibit non-identical X-ray powder diffraction patterns as compared to an X-ray powder diffraction pattern of a pure compound of the invention.
- The term “pharmaceutical composition” includes preparations suitable for administration to mammals, e.g., humans. When the compounds of the present invention are administered as pharmaceuticals to mammals, e.g., humans, they can be given per se or as a pharmaceutical composition containing, for example, 0.1% to 99.9% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
- The pharmaceutical compositions described herein can be formulated to have any concentration desired (i.e., any concentration of crystalline tazobactam arginine, or a hydrate or solvate thereof, and any concentration of a beta-lactam compound). In some embodiments, the composition is formulated such that it comprises at least a therapeutically effective amount of both compounds (i.e., a therapeutically effective amount of the combination of crystalline tazobactam arginine, or a hydrate or solvate thereof, and the beta-lactam compound). In some embodiments, the composition is formulated such that it would not cause one or more unwanted side effects.
- The compounds of the invention (i.e., polymorphs, hydrates and solvates of tazobactam arginine) can be combined with a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques. As used herein, “pharmaceutically acceptable carrier” may include any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Eighteenth Edition, A. R. Gennaro (Mack Publishing Co., Easton, Pa., 1990) discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatine; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil, sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen free water; isotonic saline (“normal saline”); Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, trehalose, or reducing or non-reducing sugars, 5% dextrose (D5W), preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
- Furthermore, the carrier may take a wide variety of forms depending on the form of the preparation desired for administration, e.g. oral, nasal, rectal, vaginal, parenteral (including intravenous injections or infusions). In preparing compositions for oral dosage form any of the usual pharmaceutical media may be employed. Usual pharmaceutical media include, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as for example, suspensions, solutions, emulsions and elixirs); aerosols; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like, in the case of oral solid preparations (such as for example, powders, capsules, and tablets).
- Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
- Pharmaceutical compositions include those suitable for oral, sublingual, nasal rectal, vaginal, topical, buccal and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route will depend on the nature and severity of the condition being treated. The compositions may be conveniently presented in unit dosage form, and prepared by any of the methods well known in the art of pharmacy. In certain embodiments, the pharmaceutical composition is formulated for oral administration in the form of a pill, capsule, lozenge or tablet. In other embodiments, the pharmaceutical composition is in the form of a suspension.
- The pharmaceutical compositions disclosed herein can be prepared via lyophilization. As is known to those skilled in the art, lyophilization is a process of drying in which water is sublimed from a frozen solution of one or more solutes. Specific methods of lyophilization are described in Remington's Pharmaceutical Sciences, Chapter 84, page 1565, Eighteenth Edition, A. R. Gennaro, (Mack Publishing Co., Easton, Pa., 1990).
- In a preferred embodiment, pharmaceutical compositions comprising crystalline tazobactam arginine (e.g., polymorph Ia) and one or more beta-lactam compounds are formulated for parenteral administration. In another preferred embodiment, pharmaceutical compositions comprising tazobactam arginine and one or more beta-lactam compounds are formulated for oral administration.
- Tazobactam arginine inhibits or decreases the activity of beta-lactamases (e.g., bacterial beta-lactamases), and can be combined with beta-lactam compounds (e.g., antibiotics), thereby broadening the spectrum of the beta-lactam compound and increasing the beta-lactam compound's efficacy against organisms that produce beta-lactamase. A compound or a composition possesses efficacy against an organism if it kills or weakens the organism, or inhibits or prevents reproduction the organism.
- In one aspect, provided herein is a method for the treatment of bacterial infections in a mammal, comprising administering to said mammal a therapeutically effective amount of tazobactam arginine polymorph Ia.
- In another aspect, provided herein is a method for the treatment of bacterial infections in a mammal, comprising administering to said mammal a therapeutically effective amount of a pharmaceutical composition comprising tazobactam arginine polymorph Ia.
- In yet another aspect, provided herein is a method for the treatment of bacterial infections in a mammal, comprising administering to said mammal a therapeutically effective amount of a pharmaceutical composition comprising crystalline tazobactam arginine and one or more beta-lactam compounds, or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof. In one embodiment, the mammal is human. In another embodiment, tazobactam arginine is polymorph Ia. In yet another embodiment, said one or more beta-lactam compounds are selected from the group consisting of penicillins, cephalosporins, carbapenems, and combinations thereof. In certain embodiments, the beta-lactam compound is selected from the compounds listed in Table 2, and pharmaceutically acceptable isomers, salts, esters, hydrates, solvates, or combinations thereof.
- The following compounds are listed in Table 2: (2S,5R,6R)-6-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid; (2S,5R,6R)-3,3-dimethyl-7-oxo-6-(2-phenylacetamido)-4-thia-1-zabicyclo[3.2.0]heptane-2-carboxylic acid; (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-({2-[(iminomethyl)amino]ethyl}thio)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid; (5R,6S)-6-((R)-1-hydroxyethyl)-7-oxo-3-((R)-tetrahydrofuran-2-yl)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid; (2S,5R,6R)-6-{[3-(2-chlorophenyl)-5-methyl-oxazole-4-carbonyl]amino}-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid; (6R,7R,Z)-7-(2-(2-aminothiazol-4-yl)-2-(2-carboxypropan-2-yloxyimino)acetamido)-8-oxo-3-(pyridinium-1-ylmethyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate; (6R,7R,Z)-3-(acetoxymethyl)-7-(2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; (6R,7R)-7-[(2Z)-2-ethoxyimino-2-[5-(phosphonoamino)-1,2,4-thiadiazol-3-yl]acetyl]amino]-3-[4-(1-methylpyridin-1-ium-4-yl)-1,3-thiazol-2-yl]sulfanyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate; (6R,7R,Z)-7-(2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)-3-((1-methylpyrrolidinium-1-yl)methyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate; (6R,7R)-3-{[(aminocarbonyl)oxy]methyl}-7-{[(2Z)-2-(2-furyl)-2-(methoxyimino) acetyl]amino}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; (6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-{[(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-b 1,2,4-triazin-3-yl)thio]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; (2S,5R,6R)-6-{[(2R)-2-amino-2-(4-hydroxyphenyl)-acetyl]amino}-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid; 3-[5-(dimethylcarbamoyl)pyrrolidin-2-yl]sulfanyl-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
- In a particular embodiment of the method, the pharmaceutical composition comprises polymorph Ia and (2S,5R,6R)-3,3-dimethyl-7-oxo-6-(2-phenylacetamido)-4-thia-1-zabicyclo[3.2.0]heptane-2-carboxylic acid, or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof.
- In another particular embodiment of the method, the pharmaceutical composition comprises polymorph Ia and (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-({2-[(iminomethyl)amino]ethyl}thio)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof.
- In another particular embodiment of the method, the pharmaceutical composition comprises polymorph Ia and (5R,6S)-6-((R)-1-hydroxyethyl)-7-oxo-3-((R)-tetrahydrofuran-2-yl)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof.
- In another particular embodiment of the method, the pharmaceutical composition comprises polymorph Ia and (2S,5R,6R)-6-{[3-(2-chlorophenyl)-5-methyl-oxazole-4-carbonyl]amino}-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof.
- In another particular embodiment of the method, the pharmaceutical composition comprises polymorph Ia and (6R,7R,Z)-7-(2-(2-aminothiazol-4-yl)-2-(2-carboxypropan-2-yloxyimino)acetamido)-8-oxo-3-(pyridinium-1-ylmethyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate, or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof.
- In another particular embodiment of the method, the pharmaceutical composition comprises polymorph Ia and (6R,7R,Z)-3-(acetoxymethyl)-7-(2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof.
- In another particular embodiment of the method, the pharmaceutical composition comprises polymorph Ia and (6R,7R)-7-R2Z)-2-ethoxyimino-2-[5-(phosphonoamino)-1,2,4-thiadiazol-3-yl]acetyl]amino]-3-[4-(1-methylpyridin-1-ium-4-yl)-1,3-thiazol-2-yl]sulfanyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof.
- In another particular embodiment of the method, the pharmaceutical composition comprises polymorph Ia and (6R,7R,Z)-7-(2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)-3-((1-methylpyrrolidinium-1-yl)methyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate, or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof.
- In another particular embodiment of the method, the pharmaceutical composition comprises polymorph Ia and (6R,7R)-3-{[(aminocarbonyl)oxy]methyl}-7-{[(2Z)-2-(2-furyl)-2-(methoxyimino) acetyl]amino}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof.
- In another particular embodiment of the method, the pharmaceutical composition comprises polymorph Ia and (6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-{[(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-1,2,4-triazin-3-yl)thio]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof.
- In another particular embodiment of the method, the pharmaceutical composition comprises polymorph Ia and (2S,5R,6R)-6-{[(2R)-2-amino-2-(4-hydroxyphenyl)-acetyl]amino}-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof.
- In another particular embodiment of the method, the pharmaceutical composition comprises polymorph Ia and 3-[5-(dimethylcarbamoyl)pyrrolidin-2-yl]sulfanyl-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof.
- In another particular embodiment of the method, the pharmaceutical composition comprises polymorph Ia and (2S,5R,6R)-6-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof. In another particular embodiment, the bacterial infection is caused by bacteria that are susceptible to the composition comprising polymorph Ia and (2S,5R,6R)-6-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-phenylacetamidol-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, or combination thereof.
- In another aspect, provided herein is a method for the treatment of bacterial infections in a mammal, comprising administering to said mammal a therapeutically effective amount of a pharmaceutical composition comprising an antibiotic and a crystalline tazobactam arginine compound (e.g., of the polymorph Ia solid form). The crystalline tazobactam arginine can be characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2-Theta at angles of 4.8°±0.3°, 8.9°±0.3°, 11.3°±0.3°, 14.9°±0.3°, 18.0°±0.3°, 19.4°±0.3°, 21.3°±0.3°, 22.8°±0.3° and 24.3°±0.3°.
- Non-limiting examples of bacterial infections that can be treated by the methods of the invention include infections caused by: aerobic and facultative gram-positive microorganisms (e.g., Staphylococcus aureus, Enterococcus faecalis, Staphylococcus epidermidis, Streptococcus agalactiae, Streptococcus pneumonia, Streptococcus pyogenes, Viridans group streptococci), aerobic and facultative gram-negative microorganisms (e.g., Acinetobacter baumanii, Escherichia coli, Haemophilus influenza, Klebsiella pneumonia, Pseudomonas aeruginosa, Citrobacter koseri, Moraxella catarrhalis, Morganella morganii, Neisseria gonorrhoeae, Proteus mirabilis, Proteus vulgaris, Serratia marcescens, Providencia stuartii, Providencia rettgeri, Salmonella enterica), gram-positive anaerobes (Clostridium perfringens), and gram-negative anaerobes (e.g., Bacteroides fragilis group (e.g., B. fragilis, B. ovatus, B. thetaiotaomicron, and B. vulgates), Bacteroides distasonis, Prevotella melaninogenica).
- In certain embodiments of the methods described herein, bacterial infection resulting from beta-lactamase-producing organisms are treated or controlled. Non-limiting examples of beta-lactamase-producing organisms include:
- (1) ESBL (extended-spectrum beta-lactamase)-producing organisms selected from the group consisting of Enterobacteriaceae spp.: Escherichia coli, Klebsiella spp. (including K. pneumoniae and K. oxytoca), Proteus mirabilis, Proteus vulgaris, Enterobacter spp., Serratia spp., Citrobacter spp., Pseudomonas spp., Acinetobacter spp.) and Bacteroides spp.;
- (2) CSBL (conventional-spectrum beta-lactamase)-producing organisms, known to those of skill in the art; and
- (3) Inducible-AmpC-type beta-lactamases, such as Citrobacter spp., Serratia spp., Morganella morganii, Proteus vulgaris, and Enterobacter cloacae.
- In certain embodiments of the methods described herein, bacterial infection is associated with one or more of the following conditions:
- Appendicitis (complicated by rupture or abscess) and peritonitis caused by piperacillin-resistant beta-lactamase producing strains of Escherichia coli or the following members of the Bacteroides fragilis group: B. fragilis, B. ovatus, B. thetaiotaomicron, or B. vulgates;
- Uncomplicated and complicated skin and skin structure infections, including cellulitis, cutaneous abscesses, and ischemic/diabetic foot infections caused by piperacillin-resistant, beta-lactamase producing strains of Staphylococcus aureus;
- Postpartum endometritis or pelvic inflammatory disease caused by piperacillin-resistant, beta-lactamase producing strains of Escherichia coli;
- Community-acquired pneumonia (moderate severity only) caused by piperacillin-resistant, beta-lactamase producing strains of Haemophilus influenza;
- Nosocomial pneumonia (moderate to severe) caused by piperacillin-resistant, beta-lactamase producing strains of Staphylococcus aureus and by Acinetobacter baumanii, Haemophilus influenzae, Klebsiella pneumoniae, and Pseudomonas aeruginosa.
- Complicated intra-abdominal infections; Complicated urinary tract infections (cUTIs); Acute Pyelonephritis; Systemic Inflammatory Response Syndrome (SIRS).
- Also provided herein is the use of a crystalline tazobactam arginine, and hydrates and solvates thereof, in combination with one or more beta-lactam compounds, for the manufacture of a medicament for the treatment of bacterial infection. The bacterial infection can result from either gram-negative or gram-positive organisms. In one embodiment, the crystalline tazobactam arginine is polymorph Ia. Polymorph Ia is characterized as described above. Said one or more beta-lactam compounds can be selected from the group consisting of penicillins, cephalosporins, carbapenems, and combinations thereof. In certain embodiments, said one or more beta-lactam compounds are selected from the compounds listed in Table 2, and pharmaceutically acceptable isomers, salts, esters, hydrates, solvates, or combinations thereof.
- Also provided herein is tazobactam arginine, and hydrates and solvates thereof, for use in a method of treating bacterial infection. In some embodiments, a combination of tazobactam arginine and one or more beta-lactam compounds is used in said method.
- As used herein, “treating”, “treat” or “treatment” describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a pharmaceutical composition of the present invention to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder. The term “treat” can also include treatment of a cell in vitro or an animal model.
- By a “therapeutically effective amount” of a compound of the invention is meant a sufficient amount of the compound to treat the disorder (e.g., bacterial infection). The specific therapeutically effective amount that is required for the treatment of any particular patient or organism (e.g., a mammal) will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound or composition employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts (see, for example, Goodman and Gilman's, “The Pharmacological Basis of Therapeutics”, Tenth Edition, A. Gilman, J. Hardman and L. Limbird, eds., McGraw-Hill Press, 155-173, 2001, which is incorporated herein by reference in its entirety). The therapeutically effective amount for a given situation can be readily determined by routine experimentation and is within the skill and judgment of the ordinary clinician.
- Provided herein is a method for detecting or identifying an agent that will inhibit one or more beta-lactamase-producing organisms, said method comprising combining:
- (a) a test agent;
- (b) a composition comprising one or more beta-lactamase-producing organisms; and
- (c) a beta-lactamase inhibitor; and
- detecting or measuring a change in the activity of the beta-lactamase-producing organisms, wherein a decrease in the activity of the beta-lactamase-producing organisms indicates that the test agent inhibits the beta-lactamase-producing organisms.
- As used in the above method, “activity” refers to the ability of the beta-lactamase-producing organism to reproduce and/or infect another organism, or “activity” refers to the presence of an indicator of the ability of the beta-lactamase-producing organism to reproduce and/or infect another organism. Methods for detecting and/or measuring changes in the activity of beta-lactamase-producing organisms are known to those of skill in the art.
- In another aspect, provided herein is a method of determining the susceptibility of a beta-lactamase-producing organism to a composition comprising a beta-lactam compound and a beta-lactamase inhibitor. The in vitro activity of compositions of the subject invention may be assessed by standard testing procedures. Non-limiting examples of such a procedure include the Kirby-Bauer method, the Stokes test, the E-test, broth dilution and agar dilution for determination of minimum inhibitory concentration (MIC), as described in “Approved Standard. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically,” 3.sup.rd ed., published 1993 by the National Committee for Clinical Laboratory standards, Villanova, Pa., USA. In certain embodiments, the methods described herein are performed using automation (e.g., Siemens' MicroScan Systems).
- In one embodiment of the above methods, the beta-lactamase inhibitor is tazobactam arginine. In a preferred embodiment, the beta-lactamase inhibitor is tazobactam arginine polymorph Ia.
- The test agent can be selected from the group consisting of penicillins, cephalosporins, carbapenems, and combinations thereof. In some embodiments, the test agent is selected from the compounds listed in Table 2, and pharmaceutically acceptable isomers, salts, esters, hydrates, solvates, or combinations thereof.
- In certain embodiments of the methods described herein, beta-lactamase-producing organisms are selected from the group comprising:
- (1) ESBL (extended-spectrum beta-lactamase)-producing organisms selected from the group consisting of Enterobacteriaceae spp.: Escherichia coli, Klebsiella spp. (including K. pneumoniae and K. oxytoca), Proteus mirabilis, Proteus vulgaris, Enterobacter spp., Serratia spp., Citrobacter spp.) and Bacteroides spp.;
- (2) CSBL (conventional-spectrum beta-lactamase)-producing organisms, known to those of skill in the art; and
- (3) Inducible-AmpC-type beta-lactamases, such as Citrobacter spp., Serratia spp., Morganella morganii, Proteus vulgaris, and Enterobacter cloacae.
- L-arginine (2.9 g) was dissolved in 100 mL of deionized water and 5.0 g of tazobactam acid was then added, resulting a homogenous solution. The solution was lyophilized overnight to yield tazobactam arginine amorphous as an off-white solid (8.0 g). The XRPD spectrum of the tazobactam arginine amorphous is depicted in
FIG. 5 . - Tazobactam arginine amorphous (1.00 g) was dissolved in 10.0 mL of deionized water. 30 mL of acetone was added to the aqueous solution by drop-wise addition. The mixture was allowed to sit overnight at ambient temperature, resulting in white fine needles. After filtration and vacuum drying for 4 hours, tazobactam arginine polymorph Ia (516 mg) was obtained. The XRPD spectrum of the tazobactam arginine polymorph Ia is depicted in
FIG. 1 . - L-arginine (1.16 g) was charged to the reactor and dissolved in a mixture of deionized water-acetone (1:1, v/v, 40 mL) by mechanically stirring at 300 rpm, 30° C. over 5 min. Tazobactam acid (2.00 g) was then added to the above solution over 2 min with the observed pH change from 10.5±0.5 to 5.9±0.5. After adding 34.5 mL of acetone over 30 min at 30° C., crystallization started, then the suspension was cooled down to 15° C. at 0.1° C./min and kept stirring at 15° C. for additional 1.5 hr. White fine needle crystals were filtered out and vacuum dried for 2 hours at 35° C. to obtain 2.59 g (82% yield) of tazobactam arginine polymorph Ia.
-
- 1) 20 g of tazobactam acid and 1 equivalent of L-arginine was placed into a jacketed, glass, 1 liter laboratory reactor with an overhead stirrer.
- 2) 5 volumes (relative to tazobactam acid weight) of ambient temperature (ca. 22° C.) water was added to the reactor and stirred at 480 rpm. The reactor temperature was maintained between 23-27° C. with a target temperature of 25° C. The reaction was stirred for 10-15 minutes in order to obtain complete dissolution. Stirring at 480 rpm was maintained throughout the reaction.
- 3) 0.75 vol. ambient temperature deionised water was added to the reactor. This step was included to account for the sterile filtration and washing step required in the process.
- 4) 8 volumes (160 ml) of acetone was added over 10 minutes.
- 5) The reaction mixture was aged for 15 minutes, at which point precipitation of tazobactam arginine begins.
- 6) A controlled cool was started from 25° C. down to 10° C. over 1.5 hours at a rate of 10° C./hour.
- 7) After reaching 10° C., 18 volumes of acetone was added over two hours (i.e., total acetone added throughout reaction was 26 volumes).
- 8) After the acetone addition, the reaction mixture was allowed to age for 1 hour.
- 9) The reaction mixture was filtered and washed with 5 volumes of cold acetone (ca. 4° C.).
- 10) The resulting solid was dried at ambient (ca. 22° C.) under vacuum and nitrogen bleed for 24 hours with regular mixing of the solid, to furnish polymorph Ia in 90% yield. The XRPD spectrum of the tazobactam arginine polymorph Ia is depicted in
FIG. 6 . - The 1H-NMR spectrum (
FIG. 7 ) of polymorph Ia indicates a stoichiometry of 1:1 tazobactam acid:arginine. -
- 1) 20 g of tazobactam acid and 1 equivalent of L-arginine was placed into a 1 liter reactor.
- 2) 5 volumes (ca. 100 ml) of water (relative to tazobactam acid weight) was added to the reactor and stirred at 300 rpm (25° C.) for 10-15 minutes in order to obtain complete dissolution.
- 3) A further 0.75 vol water was then added to account for washing in sterile filtration step.
- 4) 6 volumes (120 ml) of ispopropanol was added over ca. 15 minutes in order to initiate precipitation.
- 5) The suspension was then aged for 15 minutes before cooling down to 10° C. over 1.5 hours at a rate of 10° C./hour.
- 6) After reaching 10° C., isopropanol addition was started at a rate of 185 ml/hour, adding a further 16 volumes (i.e., total isopropanol added throughout reaction was 24 volumes).
- 7) The reaction was then allowed to age for 1 hour.
- 8) The suspension was filtered and washed with 5 volumes of cold isopropanol (ca. 4° C.).
- 9) The resulting solid was then dried at ambient under vacuum and nitrogen bleed for 24 hours with regular mixing of the solids to yield tazobactam arginine crystalline polymorph Ia.
- Analysis by DVS was performed on a VTI SGA-100 water vapor sorption analyser using approximately 18-23 mg of each sample. Each sample was pre-dried at 60° C. for a maximum of 1 hour and then analyzed at 25° C. in 10% relative humidity (RH) steps from 5-95% (adsorption) and then 90-10% RH (desorption). The sample was equilibrated to each humidity level for a maximum of 3 hours or until constant weight was attained. Equilibrium criteria were set at less than 0.0050% weight change within 5 minutes.
- (6a) Tazobactam arginine amorphous exhibited approximately 10.7% weight increase at 95% relative humidity (RH). See
FIG. 8 . - (6 b) Tazobactam arginine polymorph Ia exhibited approximately 0.2% weight increase at 95% RH. See
FIG. 9 . - (6 c) Amorphous tazobactam sodium exhibited approximately 80% weight increase at 95% RH. See
FIG. 10 . - The solvent solubility screen was carried out using a solvent addition technique. For each of 25 solvent systems, the following procedure was used: (1) about 20 mg of crystalline tazobactam arginine was placed into a vial; (2) solvent was added to the vial in 5 volume aliquots (100 μL) until complete dissolution, or 100 volumes, had been added; (3) between additions, the sample was heated to about 50° C. in order to determine the approximate solubility at an elevated temperature; (4) if 100 volumes was reached and complete dissolution was not observed, solubility was calculated to be below that point. Results of the solvent solubility screen are shown in Table 3.
-
- I. X-Ray Powder Diffraction (XRPD) experiments were performed using a Bruker D8 Advance X-ray powder diffractometer utilizing a zero return silicon plate. A suitable amount of sample was placed directly on the sample holder, pressed flat to smooth, and analyzed from 3°-40° 2θ using Bragg-Brentano optics. A step size of 0.01° and a step time of 0.3 sec/step were utilized. Analysis was started immediately following sample preparation.
- II. Differential Scanning calorimetry (DSC) experiments were performed on a TA Instruments Q100 instrument. A temperature range of 40° C. to 300° C. with a ramp rate of 10° C./minute was utilized. Approximately 1.0 mg of sample was weighed into a tared aluminum sample pan and sealed hermetically. A small hole was pushed into the cover of the sample pan to allow for pressure release.
- III. Thermo Gravimetric Analysis (TGA) experiments were performed on a
TA Instruments 5000 instrument from 20 to 300° C. with a heating rate of 10° C./minute for all samples. -
-
TABLE 1 XRPD Scanning Data of Tazobactam Arginine Polymorph Ia (Figure 1) Chord Mid. D (Obs. Intensity % Max Int. Intensity I. Breadth 2-Theta ° Angstrom % Cps Count 2-Theta ° 4.818 18.27951 33.5 130 7043 0.166 8.978 9.83463 100.0 364 21035 0.174 9.916 8.90757 8.7 32.3 1832 0.168 11.301 7.81865 27.8 104 5844 0.167 14.521 6.09321 20.2 75.5 4251 0.108 14.902 5.93864 27.8 102 5850 0.162 15.93 5.56039 1.9 7.2 394 0.148 16.947 5.23254 1.2 4.96 253 0.169 17.581 5.04332 6.8 24.8 1429 0.182 18.046 4.91261 48.7 184 10242 0.189 18.863 4.70152 2.6 9.41 545 0.159 19.418 4.5672 31.6 115 6637 0.166 19.943 4.44853 9.3 33.8 1966 0.181 21.31 4.1658 41.4 151 8714 0.192 22.797 3.89704 9.1 33.2 1921 0.201 23.587 3.76939 14.7 53.1 3082 0.171 24.345 3.65381 19.6 71.2 4116 0.208 25.169 3.53603 2.3 8.44 479 0.185 25.895 3.43955 5.4 19.7 1129 0.152 26.221 3.39654 5.0 15.6 1061 0.146 26.689 3.33736 11.1 40 2329 0.192 27.249 3.27088 5.0 19.1 1052 0.25 28.09 3.17445 5.6 20.2 1184 0.269 28.886 3.08881 3.2 11.4 666 0.219 30.129 2.96435 4.2 15.6 884 0.184 30.585 2.92187 1.8 6.17 369 0.313 31.413 2.84617 5.6 20.1 1174 0.212 32.162 2.78029 2.8 9.87 583 0.285 33.878 2.64293 1.1 2.36 236 0.109 34.419 2.60386 3.2 11.5 676 0.239 35.529 2.52408 6.0 21.9 1254 0.344 36.598 2.45267 3.0 11 621 0.269 37.924 2.37119 1.8 6.41 371 0.276 38.818 2.31643 1.4 2.74 295 0.172 39.398 2.28753 1.1 3.56 236 0.196 -
TABLE 2 Beta-lactam compounds No. IUPAC Name CAS No. 1 (2S,5R,6R)-6-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2- 61477-96-1 phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-l-azabicyclo[3.2.0]heptane- 2-carboxylic acid 2 (2S,5R,6R)-3,3-dimethyl-7-oxo-6- (2-phenylacetamido)-4-thia-1- 61-33-6 zabicyclo[3.2.0]heptane-2-carboxylic acid 3 (5R,6S)-6- [(1R)-1-hydroxyethyl]-3- ({2-[(iminomethyl)amino]ethyl}thio)- 74431-23-5 7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4 (5R,6S)-6-((R)-1-hydroxyethyl)-7-oxo-3-((R)-tetrahydrofuran-2-yl)-4-thia- 106560-14-9 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid faropenem 5 (2S ,5R,6R)-6-{[3-(2-chlorophenyl)-5-methyl-oxazole-4-carbonyl]amino }- 61-72-3 3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 6 (6R,7R,Z)-7-(2-(2-aminothiazol-4-yl)-2-(2-carboxypropan-2- 72558-82-8 yloxyimino)acetamido)-8-oxo-3-(pyridinium-1-ylmethyl)-5-thia-1-aza- bicyclo[4.2.0] oct-2-ene-2-carboxylate 7 (6R,7R,Z)-3-(acetoxymethyl)-7- (2- (2-aminothiazol-4-yl)-2- 63527-52-6 (methoxyimino)acetamido)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2- carboxylic acid 8 (6R,7R)-7-[(2Z)-2-ethoxyimino-2- [5-(phosphonoamino)-1,2,4-thiadiazol- 400827-46-5 3-yl]acetyl]amino] -3- [4-(1-methylpyridin-1-ium-4-yl)-1,3-thiazol-2- yl]sulfanyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 9 (6R,7R,Z)-7-(2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)- 88040-23-7 3-((1-methylpyrrolidinium-1-yl)methyl)-8-oxo-5-thia-1-aza- bicyclo[4.2.0]oct-2-ene-2-carboxylate 10 (6R,7R)-3-{[(aminocarbonyl)oxy]methyl}-7-{[(2Z)-2- (2-furyl)-2- 55268-75-2 (methoxyimino) acetyl]amino}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene- 2-carboxylic acid 11 (6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2- 73384-59-5 (methoxyimino)acetyl]amino}-3-{[(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro- 1,2,4-triazin-3-yl)thio]methyl}-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene- 2-carboxylic acid 12 (2S,5R,6R)- 6-{[(2R)-2-amino-2-(4-hydroxyphenyl)-acetyl]amino}-3,3- 26787-78-0 dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 13 3-[5-(dimethylcarbamoyl) pyrrolidin-2-yl] sulfanyl-6- (1-hydroxyethyl)-4- 119478-56-7 methyl-7-oxo- 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid -
TABLE 3 Solvent solubility screen results Solvent Solubility @ 22° C. (mg/ml) Solubility @ 50° C. (mg/ml) Acetic acid >100 mg/ml >200 mg/ml Acetone <10 mg/ml <10 mg/ml Acetonitrile <10 mg/ml <10 mg/ml 1-butanol <10 mg/ml <10 mg/ml Cyclohexane <10 mg/ml <10 mg/ml Dichloromethane <10 mg/ml <10 mg/ml Diisopropyl ether <10 mg/ml <10 mg/ml Dimethylformamide <10 mg/ml <10 mg/ml Dimethylsulfoxide <10 mg/ml ca. 10 mg/ml 1,4-Dioxane <10 mg/ml <10 mg/ml Ethanol <10 mg/ml <10 mg/ml Ethyl acetate <10 mg/ml <10 mg/ml Heptane <10 mg/ml <10 mg/ml Methanol <10 mg/ml <10 mg/ml Isopropyl acetate <10 mg/ml <10 mg/ml Methyl acetate <10 mg/ml <10 mg/ml Methylethyl ketone <10 mg/ml <10 mg/ml Methyl isobutyl ketone <10 mg/ml <10 mg/ml N-Methyl-2-pyrrolidone <10 mg/ml <10 mg/ml Nitromethane <10 mg/ml <10 mg/ml 2-Propanol <10 mg/ml <10 mg/ml tert-Butylmethyl ether <10 mg/ml <10 mg/ml Tetrahydrofuran <10 mg/ml <10 mg/ml Toluene <10 mg/ml <10 mg/ml Water >100 mg/ml >200 mg/ml
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US20140274993A1 (en) | 2013-03-15 | 2014-09-18 | Cubist Pharmaceuticals, Inc. | Ceftolozane-tazobactam pharmaceutical compositions |
US9872906B2 (en) | 2013-03-15 | 2018-01-23 | Merck Sharp & Dohme Corp. | Ceftolozane antibiotic compositions |
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US20150094293A1 (en) | 2013-09-27 | 2015-04-02 | Calixa Therapeutics, Inc. | Solid forms of ceftolozane |
US10125149B2 (en) | 2014-08-15 | 2018-11-13 | Merck Sharp & Dohme Corp. | Synthesis of cephalosporin compounds |
US11541105B2 (en) | 2018-06-01 | 2023-01-03 | The Research Foundation For The State University Of New York | Compositions and methods for disrupting biofilm formation and maintenance |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1706388A (en) * | 2004-06-09 | 2005-12-14 | 北京盛世伟唐科技有限公司 | New antibiotic composition |
US20110190252A1 (en) * | 2008-07-30 | 2011-08-04 | Alan Watson | Compositions including clavulanic acid and related methods of use |
Family Cites Families (216)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL37879A (en) | 1970-10-27 | 1974-12-31 | Ciba Geigy Ag | 3-unsubstituted cephalosporin derivatives,process for their manufacture and compositions containing them |
US4299829A (en) | 1976-03-12 | 1981-11-10 | Fujisawa Pharmaceutical Co., Ltd. | 2-Lower alkyl-7-substituted-2 or 3-cephem 4-carboxylic acid compounds |
US4464369A (en) | 1977-03-14 | 1984-08-07 | Fujisawa Pharmaceutical Co., Ltd. | 7-Acylamino-3-cephem-4-carboxylic acid derivatives and pharmaceutical compositions |
US4409217A (en) | 1977-03-14 | 1983-10-11 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds |
PH17188A (en) | 1977-03-14 | 1984-06-14 | Fujisawa Pharmaceutical Co | New cephem and cepham compounds and their pharmaceutical compositions and method of use |
US4496562A (en) | 1977-03-14 | 1985-01-29 | Fujisawa Pharmaceutical Co., Ltd. | 7-Substituted-3-cephem-4-carboxylic acid esters |
JPS543087A (en) | 1977-06-03 | 1979-01-11 | Fujisawa Pharmaceut Co Ltd | Preparation of cephalosporin compound |
GB1604738A (en) | 1977-07-28 | 1981-12-16 | Yamanouchi Pharma Co Ltd | 1,3-dithietane-2-carboxylic acid derivatives and the preparation thereof |
JPS609719B2 (en) | 1977-08-06 | 1985-03-12 | 武田薬品工業株式会社 | Cephalosporin derivatives and their production method |
US4370326A (en) | 1977-09-13 | 1983-01-25 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds and composition |
IT1192287B (en) | 1977-11-14 | 1988-03-31 | Fujisawa Pharmaceutical Co | PHARMACEUTICAL ACTION DERIVATIVES OF CEPHALOSPORANIC ACID AND RELATED PREPARATION PROCEDURE |
US4363807A (en) | 1978-04-06 | 1982-12-14 | Fujisawa Pharmaceutical Company, Limited | Cepham compounds |
SE7804231L (en) | 1978-04-14 | 1979-10-15 | Haessle Ab | Gastric acid secretion |
AR228726A1 (en) | 1978-05-26 | 1983-04-15 | Glaxo Group Ltd | PROCEDURE FOR THE PREPARATION OF ANTIBIOTIC (6R, 7R) -7 - ((Z) -2- (2-AMINOTIAZOL-4-IL) -2- (2-CARBOXIPROP-2-OXIIMINO) ACETAMIDO) -3- (1- PIRIDINIOMETIL) CEF-3-EM-4-CARBOXILATO |
US4264597A (en) | 1978-06-06 | 1981-04-28 | Masashi Hashimoto | Cephalosporin analogues and processes for the preparation thereof |
US4268509A (en) | 1978-07-10 | 1981-05-19 | Fujisawa Pharmaceutical Co., Ltd. | New cephem compounds and processes for preparation thereof |
US4284631A (en) | 1978-07-31 | 1981-08-18 | Fujisawa Pharmaceutical Co., Ltd. | 7-Substituted cephem compounds and pharmaceutical antibacterial compositions containing them |
US4305937A (en) | 1978-08-17 | 1981-12-15 | Fujisawa Pharmaceutical Co., Ltd. | 2-Lower alkyl-7-substituted-2 or 3-cephem-4-carboxylic acid compounds and antibacterial pharmaceutical compositions containing them |
US4703046A (en) | 1978-09-08 | 1987-10-27 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds and processes for preparation thereof |
DE2967053D1 (en) | 1978-09-12 | 1984-07-19 | Fujisawa Pharmaceutical Co | Starting compounds for preparing cephem compounds and processes for their preparation |
US4327093A (en) | 1978-10-24 | 1982-04-27 | Fujisawa Pharmaceutical Co., Ltd. | 3,7-Disubstituted-2 or 3-cephem-4-carboxylic acid compounds |
DE2945248A1 (en) | 1978-11-13 | 1980-05-22 | Fujisawa Pharmaceutical Co | CEPHEM COMPOUNDS, METHOD FOR THEIR PRODUCTION AND ANTIBACTERIAL PHARMACEUTICAL AGENTS CONTAINING THE SAME |
US4390534A (en) | 1978-12-29 | 1983-06-28 | Fujisawa Pharmaceutical Co., Ltd. | Cephem and cepham compounds |
US4332798A (en) | 1978-12-29 | 1982-06-01 | Fujisawa Pharmaceutical Co., Ltd. | 7-Amino-thia-diazole oxyimino derivatives of cephem and cephem compounds |
AU536842B2 (en) | 1978-12-29 | 1984-05-24 | Fujisawa Pharmaceutical Co., Ltd. | Cephalosporin antibiotics |
US4291031A (en) | 1979-02-19 | 1981-09-22 | Fujisawa Pharmaceutical Co., Ltd. | 3-Phosphonocephalosporanic acid derivatives, and pharmaceutical composition comprising the same |
US4339449A (en) | 1979-03-27 | 1982-07-13 | Fujisawa Pharmaceutical Company, Limited | Analogous compounds of cephalosporins, and pharmaceutical composition comprising the same |
FR2462439A1 (en) | 1979-07-26 | 1981-02-13 | Roussel Uclaf | NOVEL PROCESS FOR THE PREPARATION OF PRODUCTS DERIVED FROM 7 - / (2-ARYL) 2-HYDROXYIMINO ACETAMIDO / CEPHALOSPORANIC ACID |
EP0025199B1 (en) | 1979-09-03 | 1984-10-31 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds, processes for their preparation and pharmaceutical compositions containing them |
US4332800A (en) | 1979-10-12 | 1982-06-01 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds |
US4338313A (en) | 1979-10-12 | 1982-07-06 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds |
US4381299A (en) | 1980-03-07 | 1983-04-26 | Fujisawa Pharmaceutical Co., Ltd. | 7-Amino-thiadiazole oxyimino derivatives of cephem and cepham compounds |
US4409215A (en) | 1979-11-19 | 1983-10-11 | Fujisawa Pharmaceutical Co., Ltd. | 7-Acylamino-3-substituted cephalosporanic acid derivatives and processes for the preparation thereof |
US4409214A (en) | 1979-11-19 | 1983-10-11 | Fujisawa Pharmaceutical, Co., Ltd. | 7-Acylamino-3-vinylcephalosporanic acid derivatives and processes for the preparation thereof |
US4420477A (en) | 1979-11-30 | 1983-12-13 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds |
US4443443A (en) | 1979-12-17 | 1984-04-17 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds |
US4405617A (en) | 1980-02-11 | 1983-09-20 | Fujisawa Pharmaceutical Co., Ltd. | 3-(Propynyltetrazol)thiomethyl-3-cephems |
JPS56125392A (en) | 1980-03-06 | 1981-10-01 | Fujisawa Pharmaceut Co Ltd | Cepham and cephem compound and preparation thereof |
US4470980A (en) | 1980-03-07 | 1984-09-11 | Interx Research Corp. | Method of increasing oral absorption of β-lactam antibiotics |
US4369312A (en) | 1980-07-04 | 1983-01-18 | Fujisawa Pharmaceutical Co., Ltd. | Method of producing oxo-containing azetidinone compounds |
US4443444A (en) | 1980-08-11 | 1984-04-17 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds |
DE3175156D1 (en) | 1980-08-29 | 1986-09-25 | Fujisawa Pharmaceutical Co | New cephem compounds and processes for preparation thereof |
US4416879A (en) | 1980-09-08 | 1983-11-22 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds |
GR78245B (en) | 1980-09-12 | 1984-09-26 | Ciba Geigy Ag | |
US4367228A (en) | 1980-10-29 | 1983-01-04 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compound and composition |
US4431642A (en) | 1980-12-01 | 1984-02-14 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds |
DK554481A (en) | 1980-12-15 | 1982-06-16 | Fujisawa Pharmaceutical Co | METHOD OF PREPARING CEPHALOSPORANIC ACID DERIVATIVES |
DE3177090D1 (en) | 1980-12-31 | 1989-09-28 | Fujisawa Pharmaceutical Co | 7-acylaminocephalosporanic acid derivatives and processes for the preparation thereof |
US4427677A (en) | 1980-12-31 | 1984-01-24 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds |
GR76342B (en) | 1981-02-02 | 1984-08-06 | Fujisawa Pharmaceutical Co | |
US4336253A (en) | 1981-03-11 | 1982-06-22 | Eli Lilly And Company | Cephalosporin antibiotics |
JPS6011917B2 (en) | 1981-04-09 | 1985-03-28 | 山之内製薬株式会社 | Novel cephalosporin compounds |
DE3118732A1 (en) | 1981-05-12 | 1982-12-02 | Hoechst Ag, 6000 Frankfurt | CEPHALOSPORINE DERIVATIVES AND METHOD FOR THEIR PRODUCTION |
JPS57193489A (en) | 1981-05-21 | 1982-11-27 | Fujisawa Pharmaceut Co Ltd | Syn-isomer of 7-substituted-3-cephem-4-carboxylic acid ester and its preparation |
GR75487B (en) | 1981-06-22 | 1984-07-23 | Fujisawa Pharmaceutical Co | |
IE53429B1 (en) | 1981-08-03 | 1988-11-09 | Fujisawa Pharmaceutical Co | New cephem compounds and processes for preparation thereof |
US4430499A (en) | 1981-09-08 | 1984-02-07 | Eli Lilly And Company | 7-[2-(2-Aminooxazol-4-yl)-2-(oximino)acetamido]cephalosporin antibiotics |
US4577014A (en) | 1981-09-08 | 1986-03-18 | Eli Lilly And Company | Thieno and furopyridinium-substituted cephalosporins |
US4436912A (en) | 1981-09-08 | 1984-03-13 | Eli Lilly And Company | 7-[2-(2-Aminooxazol-4-yl)-2-(oximino)acetamido cephalosporin antibiotics and intermediates therefor |
JPS5859991A (en) | 1981-09-14 | 1983-04-09 | Fujisawa Pharmaceut Co Ltd | Novel cephem compound and its preparation |
US4521413A (en) | 1981-09-14 | 1985-06-04 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds |
US4450270A (en) | 1981-10-02 | 1984-05-22 | Eli Lilly And Company | Dioximino cephalosporin antibiotics |
US4402955A (en) | 1981-10-02 | 1983-09-06 | Eli Lilly And Company | Dioximino cephalosporin antibiotics |
US4501739A (en) | 1982-01-19 | 1985-02-26 | Eli Lilly And Company | Thieno and furopyridinium-substituted cephalosporins |
DE3207840A1 (en) | 1982-03-04 | 1983-09-15 | Hoechst Ag, 6230 Frankfurt | "CEPHALOSPORINE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF" |
US4640915A (en) | 1982-03-29 | 1987-02-03 | Fujisawa Pharmaceutical Co., Ltd. | 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid derivatives |
JPS58225091A (en) | 1982-06-21 | 1983-12-27 | Taiho Yakuhin Kogyo Kk | Penicillin derivative and its preparation |
AU541028B2 (en) | 1982-06-21 | 1984-12-13 | Taiho Pharmaceutical Co., Ltd. | 6-unsubstituted penicillin derivatives |
US4563449A (en) | 1982-07-19 | 1986-01-07 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds |
US4546101A (en) | 1982-09-10 | 1985-10-08 | Fujisawa Pharmaceutical Co., Ltd. | New cephem compounds useful for treating infectious diseases in human being and animals and processes for preparation thereof |
GB8323034D0 (en) | 1983-08-26 | 1983-09-28 | Fujisawo Pharmaceutical Co Ltd | 7-substituted-3-vinyl-3-cephem compounds |
US4609730A (en) | 1982-11-22 | 1986-09-02 | Fujisawa Pharmaceutical Co., Ltd. | 7-[substituted imino-2-(2-aminothiazol-4-yl)-acetamido]-3(2,2-dihalovinyl or ethynyl)-3-cephem-4-carboxylic acid (syn isomers), having antimicrobial activities |
GR79043B (en) | 1982-12-06 | 1984-10-02 | Fujisawa Pharmaceutical Co | |
US4608373A (en) | 1982-12-13 | 1986-08-26 | Yamanouchi Pharmaceutical Co., Ltd. | Cephem compounds |
US4487768A (en) | 1982-12-22 | 1984-12-11 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds |
US4463003A (en) | 1982-12-22 | 1984-07-31 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds |
DE3247613A1 (en) | 1982-12-23 | 1984-07-05 | Hoechst Ag, 6230 Frankfurt | CEPHALOSPORINE DERIVATIVES AND METHOD FOR THEIR PRODUCTION |
US4562073A (en) | 1982-12-24 | 1985-12-31 | Taiho Pharmaceutical Company Limited | Penicillin derivatives |
US4499088A (en) | 1983-01-04 | 1985-02-12 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds |
DE3316798A1 (en) | 1983-05-07 | 1984-11-08 | Hoechst Ag, 6230 Frankfurt | METHOD FOR PRODUCING CEPHEM COMPOUNDS |
FR2550200B1 (en) | 1983-08-01 | 1988-04-08 | Fujisawa Pharmaceutical Co | PROCESS FOR THE PREPARATION OF CEPHEM COMPOUNDS WITH ANTIMICROBIAL ACTIVITY AND NOVEL PRODUCTS THUS OBTAINED |
EP0137442A3 (en) | 1983-10-08 | 1986-01-15 | Hoechst Aktiengesellschaft | Cephalosporin derivatives and process for their preparation |
US4690921A (en) | 1983-10-11 | 1987-09-01 | Yamanouchi Pharmaceutical Co., Ltd. | Cephalosporin compounds and salts thereof |
US4692443A (en) | 1983-10-17 | 1987-09-08 | Eli Lilly And Company | 3-bicyclicpyridinium-methyl cephalosporins |
US4748172A (en) | 1983-10-17 | 1988-05-31 | Eli Lilly And Company | 3-bicyclicpyridinium-methyl cephalosporins |
GB8329030D0 (en) | 1983-10-31 | 1983-11-30 | Fujisawa Pharmaceutical Co | Cephem compounds |
GB8401093D0 (en) | 1984-01-16 | 1984-02-15 | Fujisawa Pharmaceutical Co | Cephem compounds |
JPS60169486A (en) | 1984-02-10 | 1985-09-02 | Yamanouchi Pharmaceut Co Ltd | Preparation of 7-amino-3-substituted methyl-3-cephem-4- carboxylic acid and lower alkylsilyl derivative thereof |
GB8406231D0 (en) | 1984-03-09 | 1984-04-11 | Fujisawa Pharmaceutical Co | Cephem compounds |
JPS60214792A (en) | 1984-04-06 | 1985-10-28 | Taiho Yakuhin Kogyo Kk | Penamylacid ester derivative |
US4705851A (en) | 1984-09-28 | 1987-11-10 | Fujisawa Pharmaceutical Co., Ltd. | Process for the preparation of 3-phosphoniummethyl-3-cephem compounds |
US4761410A (en) | 1985-01-14 | 1988-08-02 | Fujisawa Pharmaceutical Co., Ltd. | Cephem Compounds |
JPS61267583A (en) | 1985-01-21 | 1986-11-27 | Sankei Yakuhin Kk | Novel beta-lactam antibiotic |
GB8504072D0 (en) | 1985-02-18 | 1985-03-20 | Fujisawa Pharmaceutical Co | Cephem compounds |
JPS6230789A (en) | 1985-08-01 | 1987-02-09 | Yamanouchi Pharmaceut Co Ltd | 7-formylaminocephalosporin compound and production thereof |
CN86107947A (en) | 1985-11-22 | 1987-05-27 | 藤沢药品工业株式会社 | New cephem compounds and preparation method thereof |
EP0237735B1 (en) | 1986-03-17 | 1994-03-30 | Fujisawa Pharmaceutical Co., Ltd. | 3,7-Disubstituted-3-cephem compounds and process for production of the same |
US4833134A (en) | 1986-08-19 | 1989-05-23 | Takeda Chemical Industries, Ltd. | Cephem compounds |
CA1293719C (en) | 1986-09-22 | 1991-12-31 | Takao Takaya | Cephem compounds and processes for preparation thereof |
US5162520A (en) | 1986-09-22 | 1992-11-10 | Fujisawa Pharmaceutical Co., Ltd. | Intermediates for cephem compounds |
US4882434A (en) | 1986-10-29 | 1989-11-21 | Takeda Chemical Industries, Ltd. | Gamma-lactonecarboxylic acid derivatives and their use as antibacterial agents or intermediates |
KR880006244A (en) | 1986-11-24 | 1988-07-22 | 후지사와 도모 기찌 로 | 3-Pyrrolidinylthio-1-azabibischloro [3.2.0] hapt2-ene-2-carboxylic acid compound and preparation method thereof |
ES2053508T3 (en) | 1986-11-24 | 1994-08-01 | Fujisawa Pharmaceutical Co | COMPOUNDS OF 3-PIRROLIDINYL-THIO-1-AZABICICLO (3.2.0) HEPT-2-ENO-2-CARBOXILICOS. |
AU1630988A (en) | 1987-05-30 | 1988-12-01 | Kyoto Pharmaceutical Industries, Ltd. | Cephalosporin compound and pharmaceutical composition thereof |
IE61679B1 (en) | 1987-08-10 | 1994-11-16 | Fujisawa Pharmaceutical Co | Water-soluble antibiotic composition and water-soluble salts of new cephem compounds |
US5138066A (en) | 1987-08-14 | 1992-08-11 | Hoffmann-La Roche, Inc. | Intermediates for cephalosporins with sulfur-containing oxyimino side chain |
US5073550A (en) | 1987-08-14 | 1991-12-17 | Hoffmann-La Roche Inc. | Cephalosphorins with sulfur-containing oxyimino side chain |
EP0303172A3 (en) | 1987-08-14 | 1991-05-15 | F. Hoffmann-La Roche Ag | Oxyimino-cephalosporins |
ZA885709B (en) | 1987-08-19 | 1989-04-26 | Fujisawa Pharmaceutical Co | Novel crystalline 7-(2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido)-3-vinyl-3-cephem-4-carboxylic acid(syn isomer) |
US5663163A (en) | 1987-09-07 | 1997-09-02 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds and processes for preparation thereof |
US5210080A (en) | 1987-09-07 | 1993-05-11 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds |
IE63094B1 (en) | 1987-09-14 | 1995-03-22 | Fujisawa Pharmaceutical Co | Cephem compound and a process for preparation thereof |
DK637888A (en) | 1987-11-24 | 1989-05-25 | Hoffmann La Roche | carboxylic esters |
GB8804058D0 (en) | 1988-02-22 | 1988-03-23 | Fujisawa Pharmaceutical Co | 3-alkenyl-1-azabicyclo(3 2 0)hept-2-ene-2-carboxylic acid compounds |
JP2648750B2 (en) | 1988-03-02 | 1997-09-03 | 大塚化学株式会社 | Method for producing β-lactam derivative |
US5173485A (en) | 1988-03-09 | 1992-12-22 | Fujisawa Pharmaceutical Company, Ltd. | Cephem compounds |
CS273349B2 (en) | 1988-03-31 | 1991-03-12 | Hoffmann La Roche | Method of cephalosporin's new derivatives production |
US5336768A (en) | 1988-05-24 | 1994-08-09 | Hoffmann-La Roche Inc. | Antibacterial cephalosporin compounds |
KR900006811B1 (en) | 1988-05-11 | 1990-09-21 | 주식회사 럭 키 | Cephalosphorin derivatives and its process |
US4963544A (en) | 1988-05-23 | 1990-10-16 | Fujisawa Pharmaceutical Company, Ltd. | 3-pyrrolidinylthio-1-azabicyclo[3.2.0]-hept-2-ene-2-carboxylic acid compounds |
US5244890A (en) | 1988-06-06 | 1993-09-14 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds |
EP0366189A3 (en) | 1988-10-24 | 1992-01-02 | Norwich Eaton Pharmaceuticals, Inc. | Novel antimicrobial lactam-quinolones |
JP2785195B2 (en) | 1989-01-11 | 1998-08-13 | ソニー株式会社 | Optical encoder for disk drive |
GB8905301D0 (en) | 1989-03-08 | 1989-04-19 | Fujisawa Pharmaceutical Co | New cephem compound and a process for preparation thereof |
US5081116A (en) | 1989-04-12 | 1992-01-14 | Yamanouchi Pharmaceutical Co., Ltd. | Cephalosporin derivatives |
US5102877A (en) | 1989-04-28 | 1992-04-07 | Fujisawa Pharmaceutical Co., Ltd. | 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid compounds |
NO903360L (en) | 1989-08-11 | 1991-02-12 | Ici Pharma | ANTIBIOTIC COMPOUNDS. |
GB8923844D0 (en) | 1989-10-23 | 1989-12-13 | Fujisawa Pharmaceutical Co | Carbapenem compounds |
US5215982A (en) | 1989-11-10 | 1993-06-01 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds |
US4982596A (en) | 1990-01-26 | 1991-01-08 | Buell Industries, Inc. | Die for manufacturing a fastener blank |
KR910015587A (en) | 1990-02-27 | 1991-09-30 | 후지사와 토모키치로 | Cefem compound |
US5095012A (en) | 1990-08-23 | 1992-03-10 | Bristol-Myers Squibb Company | Antibiotic c-7 catechol-substituted cephalosporin compounds, compositions, and method of use thereof |
US5234920A (en) | 1990-08-23 | 1993-08-10 | Bristol-Myers Squibb Company | Antibiotic C-7 catechol-substituted cephalosporin compounds, compositions, and method of use thereof |
US5286721A (en) | 1990-10-15 | 1994-02-15 | Fujisawa Pharmaceutical Co., Ltd. | 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid compounds |
US5281589A (en) | 1991-06-15 | 1994-01-25 | Cheil Foods & Chemicals, Inc. | 3-fused pyridiniummethyl cephalosporins |
US5523400A (en) | 1993-04-16 | 1996-06-04 | Hoffmann-La Roche Inc. | Cephalosporin antibiotics |
KR100194994B1 (en) | 1993-06-05 | 1999-06-15 | 손경식 | New cefem compound |
AU679800B2 (en) | 1993-11-06 | 1997-07-10 | Taiho Pharmaceutical Co., Ltd. | Crystalline penicillin derivative, and its production and use |
EP0664117A1 (en) | 1994-01-25 | 1995-07-26 | F. Hoffmann-La Roche Ag | Liposome solutions |
TW293010B (en) | 1994-04-20 | 1996-12-11 | Hui-Po Wang | Method for preparing cephalosporin derivatives |
EP0723966A4 (en) | 1994-08-16 | 1997-01-29 | Meiji Seika Co | Novel cephem derivative |
DE4440141A1 (en) | 1994-11-10 | 1996-05-15 | Hoechst Ag | Novel crystalline cephem acid addition salts and process for their preparation |
CA2250002C (en) | 1996-04-04 | 2008-03-25 | Shionogi & Co., Ltd. | Cephem compounds and drugs containing the compounds |
WO2000004915A1 (en) | 1998-07-23 | 2000-02-03 | Intrabiotics Pharmaceuticals, Inc. | Compositions and methods for the treatment or prevention of pulmonary infections |
TW526202B (en) | 1998-11-27 | 2003-04-01 | Shionogi & Amp Co | Broad spectrum cephem having benzo[4,5-b]pyridium methyl group of antibiotic activity |
US6207661B1 (en) | 1999-02-22 | 2001-03-27 | Baxter International Inc. | Premixed formulation of piperacillin sodium and tazobactam sodium injection |
AU7059800A (en) | 1999-08-16 | 2001-03-13 | Revaax Pharmaceuticals, Llc | Neurotherapeutic composition and method |
WO2011101710A1 (en) | 2010-02-16 | 2011-08-25 | Wockhardt Research Centre | Efflux pump inhibitors |
JP3743823B2 (en) | 2000-08-11 | 2006-02-08 | 大塚化学ホールディングス株式会社 | Penicillin crystals and production method thereof |
JP3743822B2 (en) | 2000-08-11 | 2006-02-08 | 大塚化学ホールディングス株式会社 | Penicillin crystals and production method thereof |
US6599893B2 (en) | 2000-08-29 | 2003-07-29 | Essential Therapeutics, Inc. | Cephalosporin antibiotics and prodrugs thereof |
JP3306473B1 (en) | 2001-05-01 | 2002-07-24 | 大塚化学株式会社 | Anhydrous crystal of β-lactam compound and method for producing the same |
ATE318269T1 (en) | 2001-05-01 | 2006-03-15 | Astellas Pharma Inc | CEPHEM COMPOUNDS |
JP2002338578A (en) | 2001-05-14 | 2002-11-27 | Otsuka Chem Co Ltd | HYDRATE CRYSTAL OF beta-LACTAM COMPOUND |
US7166626B2 (en) | 2001-06-18 | 2007-01-23 | Revaax Pharmaceuticals, Llc | Therapeutic treatment for sexual dysfunction |
TWI335332B (en) | 2001-10-12 | 2011-01-01 | Theravance Inc | Cross-linked vancomycin-cephalosporin antibiotics |
AU2003210925A1 (en) | 2002-02-07 | 2003-09-02 | Rutgers, The State University | Antibiotic polymers |
TW200305422A (en) | 2002-03-18 | 2003-11-01 | Shionogi & Co | Broad spectrum cefem compounds |
ATE556088T1 (en) | 2002-05-24 | 2012-05-15 | Theravance Inc | CONJUGATE CONTAINING CEPHALOSPORIN AND GLYCOPEPTIDE ANTIBIOTIC |
KR100671881B1 (en) | 2002-06-07 | 2007-01-19 | 오키드 케미칼즈 앤드 파마수티컬즈 리미티드 | Process for preparation of penam derivatives from cepham derivatives |
WO2004019901A2 (en) | 2002-08-30 | 2004-03-11 | Orchid Chemicals & Pharmaceuticals Ltd. | Sustained release pharmaceutical composition |
US9211259B2 (en) | 2002-11-29 | 2015-12-15 | Foamix Pharmaceuticals Ltd. | Antibiotic kit and composition and uses thereof |
JP4448821B2 (en) | 2002-10-30 | 2010-04-14 | アステラス製薬株式会社 | Cephem compound |
WO2004039776A2 (en) | 2002-11-01 | 2004-05-13 | Orchid Chemicals & Pharmaceuticals Ltd | A process for the preparation of benzyl 2-oxo-4- (heteroaryl) dithio-alpha-isoprenyl-1- azetidineazetate derivatives |
DE10304403A1 (en) | 2003-01-28 | 2004-08-05 | Röhm GmbH & Co. KG | Process for the preparation of an oral dosage form with immediate disintegration and drug release |
ES2298672T3 (en) | 2003-04-14 | 2008-05-16 | Wyeth Holdings Corporation | COMPOSITIONS CONTAINING PIPERACILIN AND TAZOBACTAM USEFUL FOR INJECTION. |
AU2003230899A1 (en) | 2003-04-14 | 2004-11-26 | Wyeth Holdings Corporation | Compositions containing piperacillin and tazobactam useful for injection |
US7067481B2 (en) | 2003-05-23 | 2006-06-27 | Theravance, Inc. | Cross-linked glycopeptide-cephalosporin antibiotics |
DE602004012269T2 (en) | 2003-07-11 | 2009-04-30 | Theravance, Inc., South San Francisco | CROSS-LINKED GLYCOPEPTIDE-CEPHALOSPORIN ANTIBIOTICS |
US8173840B2 (en) | 2003-07-29 | 2012-05-08 | Signature R&D Holdings, Llc | Compounds with high therapeutic index |
US7589233B2 (en) | 2003-07-29 | 2009-09-15 | Signature R&D Holdings, Llc | L-Threonine derivatives of high therapeutic index |
US7273935B2 (en) | 2003-08-21 | 2007-09-25 | Orchid Chemicals & Pharmaceuticals, Ltd. | Process for the preparation of 3-methylcepham derivatives |
JP4643577B2 (en) | 2003-09-18 | 2011-03-02 | アステラス製薬株式会社 | Cephem compound |
FR2860235A1 (en) | 2003-09-29 | 2005-04-01 | Yang Ji Chemical Company Ltd | USE OF A COMPOUND OF FORMULA (I) INHIBITOR OF AROMATASE FOR THERAPEUTIC PURPOSES AND COMPOUNDS OF FORMULA (I) AS SUCH |
TW200523264A (en) | 2003-10-09 | 2005-07-16 | Otsuka Chemical Co Ltd | CMPB crystal and method for producing the same |
TW200519119A (en) | 2003-10-10 | 2005-06-16 | Otsuka Chemical Co Ltd | PENAM crystal and process for producing the same |
JP4535366B2 (en) | 2003-12-03 | 2010-09-01 | 塩野義製薬株式会社 | Method for producing cephem agent |
JP2007519747A (en) | 2004-01-30 | 2007-07-19 | ワイス | A composition comprising piperacillin and tazobactam and substantially free of galactomannan |
US20070219191A1 (en) | 2004-03-05 | 2007-09-20 | Yasuhiro Nishitani | 3-Pyridinium Methyl Cephem Compound |
US7417143B2 (en) | 2004-04-07 | 2008-08-26 | Orchid Chemicals & Pharmaceuticals Limited | Process for the preparation of Tazobactam in pure form |
BRPI0516583A (en) | 2004-10-14 | 2008-09-16 | Wyeth Corp | pharmaceutical composition and method of treating a bacterial infection |
US20060099253A1 (en) | 2004-10-20 | 2006-05-11 | Wyeth | Antibiotic product formulation |
US20060173177A1 (en) | 2005-01-28 | 2006-08-03 | Gego Csaba L | Process for preparation of penam derivatives |
KR100822519B1 (en) | 2005-02-15 | 2008-04-16 | 주식회사종근당 | Gastric-retentive controlled release mono-matrix tablet |
CA2611577A1 (en) | 2005-06-07 | 2007-09-07 | Foamix Ltd. | Antibiotic kit and composition and uses thereof |
ITMI20051630A1 (en) | 2005-09-02 | 2007-03-03 | Acs Dobfar Spa | INJECTABLE STERILE PHARMACEUTICAL FORMULATION CONTAINING AT LEAST TWO ACTIVE PRINCIPLES |
EP1787641A1 (en) | 2005-11-22 | 2007-05-23 | Helm AG | Tazobactam-piperacillin lyophilisate |
PL1959933T3 (en) | 2005-12-05 | 2011-04-29 | Sandoz Ag | Process for the preparation of lyophilized piperacillin sodium in combination with tazobactam sodium, with improved stability after reconstitution |
WO2007086014A1 (en) | 2006-01-25 | 2007-08-02 | Jegannathan Srinivas | Formulation comprising cefpirome, tazobactam and linezolid |
WO2007086013A1 (en) | 2006-01-25 | 2007-08-02 | Jegannathan Srinivas | Formulation comprising of ceftazidime, tazobactam and linezolid |
WO2007086011A1 (en) | 2006-01-25 | 2007-08-02 | Jegannathan Srinivas | Formulation comprising cefepime, tazobactam and linezolid |
WO2008075207A2 (en) | 2006-04-04 | 2008-06-26 | Foamix Ltd. | Anti-infection augmentation foamable compositions and kit and uses thereof |
WO2007129176A2 (en) | 2006-04-28 | 2007-11-15 | Wockhardt Ltd | Improvements in therapy for treating resistant bacterial infections |
US20070286818A1 (en) | 2006-06-07 | 2007-12-13 | Wyeth | Treating cystic fibrosis with antibiotics via an aerosol drug |
PE20080329A1 (en) | 2006-06-07 | 2008-04-09 | Wyeth Corp | TREATMENT OF CYST FIBROSIS WITH ANTIBIOTICS VIA A DRUG IN AEROSOL |
US20070286817A1 (en) | 2006-06-07 | 2007-12-13 | Wyeth | Treating cystic fibrosis with antibiotics via a swirler delivery |
WO2007145866A1 (en) | 2006-06-07 | 2007-12-21 | Wyeth | Treating cystic fibrosis with antibiotics via a swirler delivery |
SI2046802T1 (en) | 2006-07-12 | 2014-03-31 | Allecra Therapeutics Gmbh C/O Loeba Treuhand Gmbh | 2-substituted methyl penam derivatives |
CN101129381B (en) | 2006-08-25 | 2012-02-01 | 天津和美生物技术有限公司 | Antibiotic compound containing beta-lactam antibiotic and ion chelating agent |
CN101129382B (en) | 2006-08-25 | 2013-12-25 | 天津和美生物技术有限公司 | Antibiotic compound containing beta-lactam antibiotic and buffering component |
CN101129383B (en) | 2006-08-25 | 2014-04-02 | 天津和美生物技术有限公司 | Antibiotic compound containing aminoglycoside antibiotic |
CA2662827C (en) | 2006-09-07 | 2015-04-07 | Merial Limited | Soft chewable, tablet, and long-acting injectable veterinary antibiotic formulations |
FI119678B (en) | 2006-11-28 | 2009-02-13 | Ipsat Therapies Oy | Use of beta-lactamase |
CA2671938C (en) | 2006-12-10 | 2017-10-17 | Chongxi Yu | Transdermal delivery systems of beta-lactam antibiotics |
DE102007009242A1 (en) | 2007-02-22 | 2008-09-18 | Evonik Röhm Gmbh | Pellets with enteric-coated matix |
EP2136844B1 (en) | 2007-03-20 | 2018-10-31 | SCF Pharma Inc. | Compositions comprising polyunsaturated fatty acid monoglycerides or derivatives thereof and uses thereof |
ITMI20070568A1 (en) | 2007-03-22 | 2008-09-23 | Acs Dobfar Spa | INJECTABLE STERILE PHARMACEUTICAL COMOSIATION HAVING PIPERACILLIN SODIUM AND TAZOBACTAM SODIUM AS ACTIVE PRINCIPLES |
US20090098088A1 (en) | 2007-10-10 | 2009-04-16 | The Procter & Gamble Company | Methods And Kits For The Treatment Of Diverticular Conditions |
ITPI20080025A1 (en) | 2008-03-31 | 2009-10-01 | Italmed S R L | COMPOSITION FOR DENTAL USE FOR THE TREATMENT OF PERIMPLANTS |
EP2280713A1 (en) | 2008-05-01 | 2011-02-09 | The Procter & Gamble Company | Methods and kits for the treatment of inflammatory bowel disorder conditions |
KR102102972B1 (en) | 2009-06-10 | 2020-04-22 | 테크필즈 바이오켐 코., 엘티디. | High penetration compositions or prodrugs of antimicrobials and antimicrobial-related compounds |
US8343944B2 (en) | 2009-07-28 | 2013-01-01 | Anacor Pharmaceuticals, Inc. | Trisubstituted boron-containing molecules |
US20130203726A1 (en) | 2010-03-09 | 2013-08-08 | Terry Roemer | FtsZ INHIBITORS AS POTENTIATORS OF BETA-LACTAM ANTIBIOTICS AGAINST METHICILLIN-RESISTANT STAPHYLOCOCCUS |
EP2555767A4 (en) | 2010-04-06 | 2013-08-28 | Prescience Labs Llc | Methods of treatment using 3-bromopyruvate and other selective inhibitors of atp production |
EP2753326A4 (en) | 2011-09-09 | 2015-04-15 | Cubist Pharm Inc | Methods for treating intrapulmonary infections |
US8476425B1 (en) | 2012-09-27 | 2013-07-02 | Cubist Pharmaceuticals, Inc. | Tazobactam arginine compositions |
-
2012
- 2012-09-27 US US13/628,742 patent/US8476425B1/en active Active
-
2013
- 2013-03-14 US US13/828,534 patent/US8685957B1/en active Active
-
2014
- 2014-02-14 US US14/181,041 patent/US20140228337A1/en not_active Abandoned
- 2014-11-14 US US14/541,890 patent/US20150072957A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1706388A (en) * | 2004-06-09 | 2005-12-14 | 北京盛世伟唐科技有限公司 | New antibiotic composition |
US20110190252A1 (en) * | 2008-07-30 | 2011-08-04 | Alan Watson | Compositions including clavulanic acid and related methods of use |
Non-Patent Citations (1)
Title |
---|
Sanders, Eugene. Clinical Infections Diseases, 1996; 22: 107-23. * |
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US8476425B1 (en) | 2013-07-02 |
US8685957B1 (en) | 2014-04-01 |
US20140088067A1 (en) | 2014-03-27 |
US20150072957A1 (en) | 2015-03-12 |
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