Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/66—Phosphorus compounds
  • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/54—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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
  • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
• • 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
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to new dosage forms of cephem compounds, useful for the treatment of bacterial infections.
• the dosage forms are stable, exhibit enhanced solubility, and are particularly well suited for, e.g., parenteral administration.
• U.S. Patent No. 6,417,175 discloses phosphonocephem derivatives having excellent antibacterial activities for a broad range of Gram-positive and Gram-negative bacteria. These compounds are of the general formula:
• R ⁇ -R 4 , Q, X, Y and n are as defined therein.
• One such compound is 7 ⁇ -[2(Z)- ethoxyimino-2-(5-phosphonoamino-l,2,4-thiadiazol-3-yl)acetamido]-3-[4-(l-methyl-4- pyridinio)-2-thiazolythio]-3-cephem-4-carboxylate.
• U.S. Patent No. 6,417,175 discloses methods for preparing this compound (see, e.g., Examples 1, 2, 5 and 6), and generically discloses formulations of the compounds described therein.
• X is CH 3 COOH, CH 3 CH 2 COOH or CH 3 CN and n is 0-5.
• One such compound (where X is CH 3 COOH and n is 1) is (6R,7R)-7-[[2(Z)-ethoxyimino-[5- (phosphonoamino)- 1 ,2,4-thiadiazol-3 -yl] acetyljamino] -3 -[[4-(I -methyl-pyridinium-4- yl)thiazol-2-yl]sulfanyl]-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-en-2-carboxylate monoacetate monohydrate, which is also known as pyridinium, 4-[2-[[(6R,7R)-2-carboxy-7-[[2(Z)- ethoxyimino-[5-(phosphonoamino)-l,2,4-thiadiazol-3-yl]acety
• ceftaroline fosamil refers to the following compound: 4-[2-[[(6R,7R)-2-carboxy-7-[[2(Z)-ethoxyimino- [5-(phosphonoamino)- 1 ,2,4-thiadiazol-3-yl]acetyl]amino]-8-oxo-5-thia- 1 - azabicyclo[4.2.0]oct-2-en-3-yl]thio-4-thiazolyl]-l -methyl-, inner salt.
• ceftaroline fosamil refers to ceftaroline fosamil on an anhydrous, acetate free corrected basis (molecular formula C 22 H 2 iNg0gPS 4 , molecular weight 684.68)
• prodrugs When administered parenterally (such as by intravenous, intramuscular or subcutaneous administration), prodrugs, such as 7 ⁇ -[2(Z)-ethoxyimino-2-(5-phosphonoamino- l,2,4-thiadiazol-3-yl)acetamido]-3-[4-(l-methyl-4-pyridinio)-2-thiazolythio]-3-cephem-4- carboxylate and ceftaroline fosamil (USAN and INN), are converted by body fluids into the active antibacterial moiety ceftaroline (molecular formula C 22 H 22 NgOsS 4 , molecular weight 604.71)
• Antibacterial compounds may be administered by several routes, including parenterally, for example, by intravenous (IV) bolus, IV infusion and by intramuscular (IM) injection. Adsorption of the drug is dependent on its bioavailability. Drugs administered intravenously directly enter the systemic circulation, and are typically assumed to be 100% bioavailable. However, drugs administered intramuscularly must cross one or more biological membranes to reach the systemic circulation. It is desirable to have the same bioavailabilty (i.e, the same are under the curve (AUC)) for all parenteral dosage forms. However, the pharmacokinetic profiles for IV and IM formulations may be different, and obtaining desirable bioavailability (i.e., AUC) following intramuscular administration is not straightforward.
• IV intravenous
• IM intramuscular
• IM administration blood flow per gram of tissue greatly affects capillary absorption of small molecules when administered intramuscularly.
• the absorption site can affect the absorption rate.
• absorption of the drug after IM administration may be delayed or erratic for salts of poorly soluble bases and acids.
• an IM formulation or dosage form must have sufficient solubility to be able to deliver the required dose in a small injectable volume with minimal local irritation.
• bolus IV administration typically leads to fast elimination of the drug from a patient's system.
• Slow IV infusion of a dosage form may be desirable in such cases.
• the dosage form must be stable in and compatible with the IV fluid (e.g., 0.9% sodium chloride solution or 5% sugar solution) for the duration of the treatment.
• the IV fluid e.g. 0.9% sodium chloride solution or 5% sugar solution
• there remains a need in the art to provide new dosage forms containing cephem compounds which are stable, bioavailable and exhibit suitable pharmacokinetic parameters when administered, e.g., parenterally.
• Applicants have developed dosage forms containing cephem compounds, such as ceftaroline fosamil, having enhanced solubility that are suitable for parenteral e.g., IV and IM administrations.
• cephem compounds such as ceftaroline fosamil
• the dosage forms are stable and exhibit excellent pharmacokinetic parameters when administered, for example, intramuscularly or intravenously.
• the present invention relates to new dosage forms of cephem compounds, wherein the active agent has enhanced solubility.
• the dosage forms are particularly well suited for parenteral (e.g., intravenous and intramuscular) administration.
• dosage forms comprising ceftaroline, or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof, and a solubilizing agent, wherein the molarity of the solubilizing agent in an aqueous solution of the dosage form is greater than about 0.1 M are described.
• dosage forms comprising ceftaroline, or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof, in which the active agent has a solubility greater than about 40 mg/mL are described.
• the dosage form comprises a prodrug of ceftaroline, e.g., ceftaroline fosamil.
• dosage forms comprising about 223 to about 2005 mg of ceftaroline fosamil, wherein a single dose parenteral administration of the dosage form provides an in vivo plasma profile for ceftaroline comprising a mean a mean AUCo- ⁇ of more than about 10650 ng.hr/mL.
• dosage forms comprising about 223 to about 2005 mg of ceftaroline fosamil, wherein a single dose IM administration of the dosage form provides an in vivo plasma profile for ceftaroline comprising a mean a mean AUCo- ⁇ of more than about 10650 ng.hr/mL and a mean C max of less than about 39500 ng/niL are described.
• dosage forms comprising about 223 to about 2005 mg of ceftaroline fosamil, wherein a single dose IM administration of the dosage form provides an in vivo plasma profile for ceftaroline comprising a mean a mean AUCo- ⁇ of more than about 10650 ng.hr/mL, a mean C max of less than about 39500 ng/mL and a mean T max of about 1 or more hours are described.
• the present invention relates to new dosage forms of cephem compounds which are stable, exhibit enhanced solubility, and are particularly well suited for, e.g., parenteral (e.g., IV, IM) administration.
• parenteral e.g., IV, IM
• Ceftaroline is an active antibacterial compound useful for treating a broad range of Gram-positive and Gram-negative bacteria.
• the aqueous solubility of ceftaroline is limited ( ⁇ 2-3 mg/mL) and is, therefore, too low to enable ceftaroline to be used directly in parenteral formulations.
• the maximum dosage of ceftaroline that could be administered from a 100 mL volume IV infusion bag is only about 200-300 mg.
• Ceftaroline fosamil a prodrug of ceftaroline
• Ceftaroline fosamil has a higher aqueous solubility (about 36 mg/mL).
• solubility of the prodrug is greater than that for the active moiety ceftaroline
• the aqueous solubility of ceftaroline fosamil is still not sufficient to enable ceftaroline fosamil to be used directly for IM administration, where volumes administered are typically 5 mL or less per site.
• the maximum dosage of ceftaroline fosamil that could be administered intramuscularly using 5 mL of solution is only about 180 mg per site.
• the soluble dosage forms are therefore useful for parenteral (both IV and IM) administration and enable higher doses of the active ingredient to be administered using smaller solution volumes.
• the dosage forms comprise a cephem compound, e.g., ceftaroline or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof, as active agent and a solubilizing agent, wherein the solubilizing agent is present at a molarity such that the solubility of the active agent is increased. For example, the solubility of the active agent is increased relative to a corresponding dosage form that does not contain the solubilizing agent.
• the present invention relates to dosage forms comprising ceftaroline, or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof, (e.g., ceftaroline fosamil) and a solubilizing agent wherein the solubilizing agent is present at a molarity greater than about 0.1 M.
• ceftaroline or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof, (e.g., ceftaroline fosamil) and a solubilizing agent wherein the solubilizing agent is present at a molarity greater than about 0.1 M.
• the solubilizing agent is present at a molarity greater than about 0.2 M, greater than about 0.3 M, greater than about 0.4 M, greater than about 0.5 M, greater than about 0.6 M, greater than about 0.7 M, greater than about 0.8 M, greater than about 0.9 M, greater than about 1.0 M, greater than about 1.1 M, greater than about 1.2 M, greater than about 1.3 M, greater than about 1.4 M, greater than about 1.5 M, greater than about 1.75 M, greater than about 2.0 M, greater than about 2.3 M or greater than about 2.5 M.
• the solubilizing agent is present at a molarity of about 0.5 M, about 0.6 M, about 0.7 M, about 0.8 M, about 0.9 M about 1.0 M, about 1.1 M, about 1.2 M, about 1.3 M, about 1.4 M, about 1.5 M, about 1.6 M, about 1.7 M, about 1.8 M, about 1.9 M, about 2.0 M about 2.3 M or about 2.5 M.
• the solubilizing agent is present at a molarity of about 0.5 M, about 1.0 M, about 1.5 M, about 2.0 M or about 2.3 M.
• Suitable solubilizing agents include, but are not limited to, acids, such as carboxylic acids, amino acids.
• the solubilizing may be selected from saturated carboxylic acids, unsaturated carboxylic acids, fatty acids, keto acids, aromatic carboxylic acids, dicarboxylic acids, tricarboxylic acids, ⁇ -hydroxy acids, amino acids, and combinations thereof.
• solubilizing agents include, but are not limited to, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, lauric acid, stearic acid, acrylic acid, docosahexaenoci acid, eicosapentaenoic acid, pyruvic acid, benzoic acid, salicylic acid, aldaric acid, oxalic acid, malonic acid, malic acid, succinic acid, glutaric acid, adipic acid, citric acid, lactic acid, alanine, arginine, aspargine, aspartic acid, cysteine, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, praline, serine, threonine, tryptophan, tyrosine,
• the solubilizing agent is selected from acetic acid, salts thereof and combinations thereof, (e.g., acetic acid/sodium acetate), citric acid, salts thereof and combinations thereof (e.g., citric acid/sodium citrate), DL arginine, L-arginine and histadine.
• the solubilizing agent is DL-arginine.
• the solubilizing agent is L-arginine.
• the solubilizing agent is acetic acid/sodium acetate.
• the solubilizing agent is citric acid/sodium citrate.
• the solubility of the active agent in the dosage form is greater than about 40 mg/mL, such as greater than about 50 mg/mL, greater than about 75 mg/mL, greater than about 100 mg/mL, greater than about 125 mg/mL, greater than about 150 mg/mL, greater than about 175 mg/mL, greater than about 200 mg/mL or greater than about 250 mg/mL, when measured, for example, in water at 25 0 C.
• the solubility of the active agent in the dosage form is from about 100 to about 250 mg/mL, from about 150 to about 250 mg/ml, from about 180 to about 200 mg/mL or from about 200 to about 250 mg/mL, when measured, for example, in water at 25 0 C.
• the dosage form comprises a prodrug of ceftaroline, e.g., ceftaroline fosamil.
• ceftaroline e.g., ceftaroline fosamil.
• suitable dosage forms are given in Tables 1-4.
• a dose of about 668 mg of ceftaroline fosamil (USAN) is equivalent to a dose of about 530 mg of ceftaroline
• a dose of about 668 mg of ceftaroline fosamil (USAN) is equivalent to a dose of about530 mg of ceftaroline
• the dosage forms may be prepared, for example, by mixing a prodrug of the active agent (e.g., ceftaroline fosamil) and the solubilizing agent (e.g., DL arginine, L-arginine, citric acid/sodium citrate, acetic acid/sodium acetate) in a blender under sterile conditions until a uniform blend is obtained.
• a prodrug of the active agent e.g., ceftaroline fosamil
• the solubilizing agent e.g., DL arginine, L-arginine, citric acid/sodium citrate, acetic acid/sodium acetate
• Pre-sterilized vials may then be filled with an appropriate amount of the sterile blend.
• the predetermined amount of sterile blend may then be mixed with a solvent, e.g., water, saline, about 5-10 % sugar (e.g., glucose, dextrose) solution
• the solubilizing agent may be used in solid or in solution form.
• the solubilizing agent and the prodrug of the active ingredient e.g., ceftaroline fosamil
• the solubilizing agent and the prodrug of the active ingredient may be mixed together as described above, then solvent added prior to parenteral administration.
• the prodrug of the active ingredient e.g., ceftaroline fosamil
• the solubilizing agent may be mixed with a solution of the solubilizing agent prior to parenteral administration.
• the dosage form comprises from about 177 to about 2005 mg ceftaroline, or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof, such as from about 177 mg to about 1337 mg ceftaroline, or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof, for example from about 353 to about 891 mg ceftaroline, or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof, for further example from about 353 mg to about 668 mg of ceftaroline, or a pharmaceutically acceptable salt and/or solvate and/or prodrug thereof.
• the dosage form comprises from about 223 to about 2005 mg ceftaroline fosamil, such as from about 223 mg to about 1337 mg ceftaroline fosamil, for example from about 446 to about 891 mg ceftaroline fosamil, for further example from about 446 mg to about 668 mg of ceftaroline fosamil.
• ceftaroline fosamil USAN
• ceftaroline fosamil (USAN) (molecular formula C 22 H 2I N 8 O 8 PS 4 . C 2 H 4 O 2 . H 2 O, molecular weight 762.75).
• the dosage form contains about 223 mg ceftaroline fosamil. In one embodiment, the dosage form contains about 446 mg ceftaroline fosamil. In one embodiment, the dosage form contains about 557 mg ceftaroline fosamil. In one embodiment, the dosage form contains about 668 mg ceftaroline fosamil. In one embodiment, the dosage form contains about 891 mg ceftaroline fosamil. In one embodiment, the dosage form contains about 1114 mg ceftaroline fosamil. In one embodiment, the dosage form contains about 1337 mg ceftaroline fosamil. In one embodiment, the dosage form contains about 2005 mg ceftaroline fosamil. For example, ceftaroline fosamil (USAN) (molecular formula C 22 H 2 IN 8 O 8 PS 4 . C 2 H 4 O 2 . H 2 O, molecular weight 762.75).
• the dosage form contains about 200 mg ceftaroline fosamil. In one embodiment, the dosage form contains about 400 mg ceftaroline fosamil. In one embodiment, the dosage form contains about 500 mg ceftaroline fosamil. In one embodiment, the dosage form contains about 600 mg ceftaroline fosamil. In one embodiment, the dosage form contains about 800 mg ceftaroline fosamil. In one embodiment, the dosage form contains about 1000 mg ceftaroline fosamil. In one embodiment, the dosage form contains about 1200 mg ceftaroline fosamil. In one embodiment, the dosage form contains about 1800 mg ceftaroline fosamil.
• ceftaroline fosamil (INN) ( anhydrous, acetate free corrected basis, molecular formula C 22 H 2 IN 8 O 8 PS 4 , molecular weight 684.68)
• the dosage form comprises from about 177 to about 1589 mg ceftaroline, such as from about 177 mg to about 1060 mg ceftaroline, for example from about 353 to about 706 mg ceftaroline, for further example from about 353 mg to about 618 mg of ceftaroline, for further example from about 353 mg to about 530 mg of ceftaroline.
• the dosage form contains about 177 mg ceftaroline, about 353 mg ceftaroline, about 442 mg ceftaroline, about 530 mg ceftaroline, about 618 mg ceftaroline, about 706 mg ceftaroline, about 883 mg ceftaroline, about 1060 mg ceftaroline or about 1589 mg ceftaroline.
• ceftaroline molecular formula C 22 H 22 NgOsS 4 , molecular weight 604.71.
• the dosage form contains about 668 mg ceftaroline fosamil (USAN). In one embodiment, the dosage form contains about 600 mg ceftaroline fosamil
• the dosage form contains about 446 mg ceftaroline fosamil (USAN). In one embodiment, the dosage form contains about 400 mg ceftaroline fosamil
• the dosage form contains about 530 mg ceftaroline
• the dosage form contains about 353 mg ceftaroline.
• Pharmacodynamics can establish the relationship between the dose of an anti- infective drug and its antimicrobial activity.
• a combined pharmacokinetic/pharmacodynamic (PK/PD) evaluation includes relating drug concentrations in plasma to the in-vitro susceptibility of the target microorganisms and/or clinical outcomes.
• plasma drug concentrations are related to the minimum inhibitory concentration (MIC).
• the drug concentration-time profile can be transformed to a single measure of exposure (e.g., area under the curve (AUC) or time above the minimum inhibitory concentration (T>MIC) and related to microbiological and/or clinical outcome to determine the optimal dosage regimen.
• AUC area under the curve
• T>MIC time above the minimum inhibitory concentration
• the choice of pharmacodynamic variable e.g., AUC/MIC, Peak Plasma Concentration (C max) /MIC, T>MIC depends upon the mechanism of antimicrobial effect.
• the AUC is the measure of total exposure of the antibiotic drug to the circulation over time.
• the product of these two factors is represented by the area under the serum concentration-time curve (AUC). Bacterial killing is therefore a function of AUC.
• the AUC values observed after IM administration of the dosage form should be similar to the AUC values observed for the drug when the dosage form is administered intravenously.
• suitable MIC criteria must be met in order for IM administration of the drug to be effective.
• the dosage forms described herein provide the following pharmacokinetic parameters.
• a time of maximum plasma concentration (T max ) for ceftaroline (active moiety) in human patients of about 1 or more hours (e.g., about 1.5 or more hours) is observed.
• a T max of ceftaroline (active moiety) in human patients ranging from between about 1 to about 4 hours, for example, between about 1 to about 3 hours, such between about 1.5 and about 2 hours is observed.
• a T max for ceftaroline fosamil (prodrug) in human patients of about 0.05 or more hours is observed. The time of maximum plasma concentration is measured once infusion is complete.
• the present invention relates to a dosage form comprising from about 223 mg to about 2005 mg ceftaroline fosamil (USAN), wherein a single dose parenteral administration of the dosage form provides an in vivo plasma profile for ceftaroline comprising a mean AUCo- ⁇ of more than about 10650 ng.hr/mL.
• the dosage form comprises from about 223 mg to about 2005 mg ceftaroline fosamil (USAN), wherein a single dose IM administration of the dosage form provides an in vivo plasma profile for ceftaroline comprising a mean C max of less than about 39500 ng/niL
• the dosage form comprises from about 223 mg to about 2005 mg ceftaroline fosamil (USAN), wherein a single dose IM administration of the dosage form provides an in vivo plasma profile for ceftaroline comprising a a mean AUCo- ⁇ of more than about 10650 ng.hr/mL and a mean C max of less than about 39500 ng/niL.
• the dosage form comprises from about 223 mg to about 2005mg ceftaroline fosamil (USAN), wherein a single dose IM administration of the dosage form provides an in vivo plasma profile for ceftaroline comprising a mean AUCo- ⁇ of more than about 10650 ng.hr/mL, a mean C max of less than about 39500 ng/mL and a mean T max of about 1 or more hours.
• the present invention relates to a dosage form comprising about 223 mg ceftaroline fosamil (USAN), wherein a single dose parentral administration of the dosage form provides an in vivo plasma profile for ceftaroline comprising a mean AUCo- ⁇ of more than about 10650 ng.hr/mL.
• the dosage form comprises about 223 mg ceftaroline fosamil (USAN), wherein a single dose IM administration of the dosage form provides an in vivo plasma profile for ceftaroline comprising a mean C max of less than about 4900 ng/mL.
• the dosage form comprises about 223 mg ceftaroline fosamil (USAN), wherein a single dose IM administration of the dosage form provides an in vivo plasma profile for ceftaroline comprising a mean AUCo- ⁇ of more than about 10650 ng.hr/mL and a mean C max of less than about 4900 ng/mL.
• the dosage form comprises about 223 mg ceftaroline fosamil (USAN), wherein a single dose IM administration of the dosage form provides an in vivo plasma profile for ceftaroline comprising a mean AUCo- ⁇ of more than about 10650 ng.hr/mL, a mean C max of less than about 4900 ng/mL and a mean T max of about 1 or more hours.
• the present invention relates to a dosage form comprising about 446 mg ceftaroline fosamil (USAN), wherein a single dose parenteral administration of the dosage form provides an in vivo plasma profile for ceftaroline comprising a mean AUCo- ⁇ of more than about 21350 ng.hr/mL.
• the dosage form comprises about 446 mg ceftaroline fosamil (USAN), wherein a single dose IM administration of the dosage form provides an in vivo plasma profile for ceftaroline comprising a mean C max of less than about 9800 ng/mL.
• the dosage form comprises about 446 mg ceftaroline fosamil (USAN), wherein a single dose IM administration of the dosage form provides an in vivo plasma profile for ceftaroline comprising a mean AUCo_ ⁇ of more than about 21350 ng.hr/mL and a mean C max of less than about 9800 ng/mL.
• the dosage form comprises about 446 mg ceftaroline fosamil (USAN), wherein a single dose IM administration of the dosage form provides an in vivo plasma profile for ceftaroline comprising a mean AUCo_ ⁇ of more than about 21350 ng.hr/mL, a mean C max of less than about 9800 ng/mL and a mean T max of about 1 or more hours.
• the present invention relates to a dosage form comprising about 557 mg ceftaroline fosamil (USAN), wherein a single dose parenteral administration of the dosage form provides an in vivo plasma profile for ceftaroline comprising a mean AUCo- ⁇ of more than about 25800 ng.hr/mL.
• the dosage form comprises about 557 mg ceftaroline fosamil (USAN), wherein a single dose IM administration of the dosage form provides an in vivo plasma profile for ceftaroline comprising a mean C max of less than about 11100 ng/mL.
• the dosage form comprises about 557 mg ceftaroline fosamil (USAN), wherein a single dose IM administration of the dosage form provides an in vivo plasma profile for ceftaroline comprising a mean AUCo- ⁇ of more than about 25800 ng.hr/mL and a mean C max of less than about 11100 ng/mL.
• the dosage form comprises about 557 mg ceftaroline fosamil (USAN), wherein a single dose IM administration of the dosage form provides an in vivo plasma profile for ceftaroline comprising a mean AUCo- ⁇ of more than about 25800 ng.hr/niL, a mean C max of less than about 11100 ng/mL and a mean T max of about 1 or more hours.
• the present invention relates to a dosage form comprising about 668 mg ceftaroline fosamil (USAN), wherein a single dose parenteral administration of the dosage form provides an in vivo plasma profile for ceftaroline comprising a mean AUCo- ⁇ of more than about 28800 ng.hr/mL.
• the dosage form comprises about 668 mg ceftaroline fosamil (USAN), wherein a single dose IM administration of the dosage form provides an in vivo plasma profile for ceftaroline comprising a mean C max of less than about 12000 ng/mL.
• the dosage form comprises about 668 mg ceftaroline fosamil (USAN), wherein a single dose IM administration of the dosage form provides an in vivo plasma profile for ceftaroline comprising a mean AUCo_ ⁇ of more than about 28800 ng.hr/mL and a mean C max of less than about 12000 ng/mL.
• the dosage form comprises about 668 mg ceftaroline fosamil (USAN), wherein a single dose IM administration of the dosage form provides an in vivo plasma profile for ceftaroline comprising a mean AUCo_ ⁇ of more than about 28800 ng.hr/mL, a mean C max of less than about 12000 ng/mL and a mean T max of about 1 or more hours.
• the present invention relates to a dosage form comprising about 891 mg ceftaroline fosamil (USAN), wherein a single dose parenteral administration of the dosage form provides an in vivo plasma profile for ceftaroline comprising a mean AUCo_ ⁇ of more than about 49000 ng.hr/mL.
• the dosage form comprises about 891 mg ceftaroline fosamil (USAN), wherein a single dose IM administration of the dosage form provides an in vivo plasma profile for ceftaroline comprising a mean C max of less than about 17750 ng/mL.
• the dosage form comprises about 891 mg ceftaroline fosamil (USAN), wherein a single dose IM administration of the dosage form provides an in vivo plasma profile for ceftaroline comprising a mean AUCo- ⁇ of more than about 49000 ng.hr/mL and a mean C max of less than about 17750 ng/mL.
• the dosage form comprises about 891 mg ceftaroline fosamil (USAN), wherein a single dose IM administration of the dosage form provides an in vivo plasma profile for ceftaroline comprising a mean AUCo- ⁇ of more than about 49000 ng.hr/mL, a mean C max of less than about 17750 ng/mL and a mean T max of about 1 or more hours.
• the present invention relates to a dosage form comprising about 1114 mg ceftaroline fosamil (USAN), wherein a single dose parenteral administration of the dosage form provides an in vivo plasma profile for ceftaroline comprising a mean AUCo_ ⁇ of more than about 66000 ng.hr/mL.
• the dosage form comprises about 1114 mg ceftaroline fosamil (USAN), wherein a single dose IM administration of the dosage form provides an in vivo plasma profile for ceftaroline comprising a mean C max of less than about 22500 ng/mL.
• the dosage form comprises about 1114 mg ceftaroline fosamil (USAN), wherein a single dose IM administration of the dosage form provides an in vivo plasma profile for ceftaroline comprising a mean AUCo- ⁇ of more than about 66000 ng.hr/mL and a mean C max of less than about 22500 ng/mL.
• the dosage form comprises about 1114 mg ceftaroline fosamil (USAN), wherein a single dose IM administration of the dosage form provides an in vivo plasma profile for ceftaroline comprising a mean AUCo- ⁇ of more than about 66000 ng.hr/mL, a mean C max of less than about 22500 ng/mL and a mean T max of about 1 or more hours.
• the present invention relates to a dosage form comprising about 1337 mg ceftaroline fosamil (USAN), wherein a single dose parenteral administration of the dosage form provides an in vivo plasma profile for ceftaroline comprising a mean AUCo- ⁇ of more than about 79500 ng.hr/mL.
• the dosage form comprises about 1337 mg ceftaroline fosamil (USAN), wherein a single dose IM administration of the dosage form provides an in vivo plasma profile for ceftaroline comprising a mean C max of less than about 26500 ng/mL.
• the dosage form comprises about 1337 mg ceftaroline fosamil (USAN), wherein a single dose IM administration of the dosage form provides an in vivo plasma profile for ceftaroline comprising a mean AUCo- ⁇ of more than about 79500 ng.hr/mL and a mean C max of less than about 26500 ng/mL.
• the dosage form comprises about 1337 mg ceftaroline fosamil (USAN), wherein a single dose IM administration of the dosage form provides an in vivo plasma profile for ceftaroline comprising a mean AUCo- ⁇ of more than about 79500 ng.hr/mL, a mean C max of less than about 26500 ng/mL and a mean T max of about 1 or more hours.
• the present invention relates to a dosage form comprising about 2005 mg ceftaroline fosamil (USAN), wherein a single dose parenteral administration of the dosage form provides an in vivo plasma profile for ceftaroline comprising a mean AUCo_ ⁇ of more than about 126000 ng.hr/mL.
• the dosage form comprises about 2005 mg ceftaroline fosamil (USAN), wherein a single dose IM administration of the dosage form provides an in vivo plasma profile for ceftaroline comprising a mean C max of less than about 39500 ng/mL.
• the dosage form comprises about 2005 mg ceftaroline fosamil (USAN), wherein a single dose IM administration of the dosage form provides an in vivo plasma profile for ceftaroline comprising a mean AUCo- ⁇ of more than about 126000 ng.hr/mL and a mean C max of less than about 39500 ng/mL.
• the dosage form comprises about 2005 mg ceftaroline fosamil (USAN), wherein a single dose IM administration of the dosage form provides an in vivo plasma profile for ceftaroline comprising a mean AUCo- ⁇ of more than about 126000 ng.hr/mL, a mean C max of less than about 39500 ng/mL and a mean T max of about 1 or more hours.
• the dosage form of any of the embodiments described above may comprise the corresponding amount of ceftaroline fosamil (INN) or ceftaroline.
• INN ceftaroline fosamil
• ceftaroline fosamil USAN
• a dose of about 223 mg ceftaroline fosamil (USAN) is equivalent to a dose of about 200 mg ceftaroline fosamil (INN) which is equivalent to a dose of about 177 mg ceftaroline.
• a dose of about 446 mg ceftaroline fosamil (USAN) is equivalent to a dose of about 400 mg ceftaroline fosamil (INN) which is equivalent to a dose of about 353 mg ceftaroline.
• a dose of about 557 mg ceftaroline fosamil (USAN) is equivalent to a dose of about 500 mg ceftaroline fosamil (INN) which is equivalent to a dose of about 442 mg ceftaroline.
• a dose of about 668 mg ceftaroline fosamil (USAN) is equivalent to a dose of about 600 mg ceftaroline fosamil (INN) which is equivalent to a dose of about 530 mg ceftaroline.
• a dose of about 891 mg ceftaroline fosamil (USAN) is equivalent to a dose of about 800 mg ceftaroline fosamil (INN) which is equivalent to a dose of about 706 mg ceftaroline.
• a dose of about 1114 mg ceftaroline fosamil (USAN) is equivalent to a dose of about 1000 mg ceftaroline fosamil (INN) which is equivalent to a dose of about 883 mg ceftaroline.
• a dose of about 1337 mg ceftaroline fosamil (USAN) is equivalent to a dose of about 1200 mg ceftaroline fosamil (INN) which is equivalent to a dose of about 1060 mg ceftaroline.
• a dose of about 2005 mg ceftaroline fosamil (USAN) is equivalent to a dose of about 1800 mg ceftaroline fosamil (INN) which is equivalent to a dose of about 1589 mg ceftaroline.
• the dosage forms provide these pharmacokinetic parameters when administered parenterally. In one embodiment, the dosage forms provide these pharmacokinetic parameters when administered intramuscularly. In another embodiment, the dosage forms provide these pharmacokinetic parameters when administered intravenously. For example, when administered intramuscularly at a concentration of about 228 mg ceftaroline fosamil (INN)/mL, In another example, when administered intramuscularly at a concentration of about 165 mg ceftaroline fosamil (INN)/mL. In another example, when administered intravenously at a concentration of about 1.2 to about 12 mg ceftaroline fosamil (INN)/mL.
• the dosage form comprises ceftaroline fosamil and L-arginine. In another embodiment, the dosage form consists essentially of ceftaroline fosamil and L- arginine. In a further embodiment, the dosage form consists of ceftaroline fosamil and L- arginine.
• the dosage form comprises ceftaroline fosamil and DL-arginine. In another embodiment, the dosage form consists essentially of ceftaroline fosamil and DL- arginine. In a further embodiment, the dosage form consists of ceftaroline fosamil and DL- arginine.
• the dosage form comprises ceftaroline fosamil and acetic acid/sodium acetate. In another embodiment, the dosage form consists essentially of ceftaroline fosamil and acetic acid/sodium acetate. In a further embodiment, the dosage form consists of ceftaroline fosamil and acetic acid/sodium acetate.
• the dosage form comprises ceftaroline fosamil and citric acid/sodium citrate. In another embodiment, the dosage form consists essentially of ceftaroline fosamil and citric acid/sodium citrate. In a further embodiment, the dosage form consists of ceftaroline fosamil and citric acid/sodium citrate.
• the dosage form is a dry powder.
• the dosage form further comprises a solvent, such as water, physiological saline, about 5% to about 10 % glucose or dextrose solution, and combinations thereof.
• the dosage form comprises about 668 mg ceftaroline fosamil and about 400 mg L-arginine, about 668 mg ceftaroline fosamil and about 348 mg L-arginine, about 668 mg ceftaroline fosamil and about 174 mg L-arginine.
• the dosage form comprises about 668 mg ceftaroline fosamil and about 400 mg DL-arginine, about 668 mg ceftaroline fosamil and about 348 mg DL- arginine, about 668 mg ceftaroline fosamil and about 174 mg DL-arginine.
• the dosage form comprises about 668 mg ceftaroline fosamil and about 164 mg acetic acid/sodium acetate, about 668 mg ceftaroline fosamil and about 120 mg acetic acid/sodium acetate, about 668 mg ceftaroline fosamil and about 82 mg acetic acid/sodium acetate. In certain embodiments, the dosage form comprises about 668 mg ceftaroline fosamil and about 558 mg citric acid/sodium citrate, about 668 mg ceftaroline fosamil and about 440 mg citric acid/sodium citrate, about 668 mg ceftaroline fosamil and about 294 mg citric acid/sodium citrate.
• the dosage form comprises about 446 mg ceftaroline fosamil and about 267 mg L-arginine, about 446 mg ceftaroline fosamil and about 230 mg L-arginine, about 446 mg ceftaroline fosamil and about 116 mg L-arginine.
• the dosage form comprises about 446 mg ceftaroline fosamil and about 267 mg DL-arginine, about 446 mg ceftaroline fosamil and about 230 mg DL- arginine, about 446 mg ceftaroline fosamil and about 116 mg DL-arginine.
• the dosage form comprises about 446 mg ceftaroline fosamil and about 110 mg acetic acid/sodium acetate, about 446 mg ceftaroline fosamil and about 82 mg acetic acid/sodium acetate, about 446 mg ceftaroline fosamil and about 55 mg acetic acid/sodium acetate.
• the dosage form comprises about 446 mg ceftaroline fosamil and about 374 mg citric acid/sodium citrate, comprises about 446 mg ceftaroline fosamil and about 293 mg citric acid/sodium citrate, about 446 mg ceftaroline fosamil and about 197 mg citric acid/sodium citrate.
• the drug (ceftaroline) or its prodrug (e.g. ceftaroline fosamil) and solubilizing agent are in the form of a solid (e.g., dry powder). In other embodiments, the drug or prodrug and solubilizing agent are in the form of a solution. In further embodiments, the drug (ceftaroline) or its prodrug (e.g. ceftaroline fosamil) and solubilizing agent are in the form of a slurry.
• the solubilizing agent(s) is/are in liquid form.
• the drug (ceftaroline) or its prodrug (e.g., ceftaroline fosamil) may be mixed with the liquid solubilizing agent (either with or without an additional solvent being added) prior to parenteral administration.
• Ceftaroline fosamil (USAN, molecular formula Of C 22 H 2 IN 8 O 8 PS 4 .C 2 H 4 O 2 . H 2 O) and ceftaroline fosamil (INN, anhydrous, acetate free, molecular formula C 22 H 2 IN 8 O 8 PS 4 , molecular weight 684.68) are N-phosphonoamino prodrugs of ceftaroline (molecular formula Of C 22 H 22 N 8 OsS 4 ). Ceftaroline displays broad antibacterial potency against aerobic and some anaerobic Gram-positive and Gram-negative bacteria.
• ceftaroline has excellent activity against multiple drug-resistant staphylococci, including methicillin-resistant Staphylococcus aureus (MSRA), vancomycin-intermediate-susceptible S. aureus (VISA), vancomycin-resistant S. aureus (VSRA) and methicillin-resistant or vancomycin- intermediate-susceptible coagulase-negative staphylococci (MR-CoNS or VI-CoNS).
• MSRA methicillin-resistant Staphylococcus aureus
• VISA vancomycin-intermediate-susceptible S. aureus
• VSRA vancomycin-resistant S. aureus
• MR-CoNS or VI-CoNS methicillin-resistant Staphylococcus aureus
• the dosage forms of the present invention can be used to treat a wide range of bacterial infections in a patient, such as respiratory infections and urinary tract infections.
• the present invention relates to methods of treating bacterial infections by administering to a patient in need thereof a dosage form according to one or more of the embodiments recited above.
• the dosage form is administered parenterally (e.g., intravenously, intramuscularly) as a solution or suspension in a solvent, such as water, physiological saline, about a 5 % to about 10 % sugar (e.g., glucose, dextrose) solution, and combinations thereof.
• a solvent such as water, physiological saline, about a 5 % to about 10 % sugar (e.g., glucose, dextrose) solution, and combinations thereof.
• bioavailability refers to the extent to which the active ingredient or active moiety is absorbed from a drug product and becomes systematically available.
• the term “effective amount” means the amount of the dosage form, which when administered to a patient (e.g., a mammal) for treating a disease, contains sufficient active ingredient to effect such treatment for the disease, so as to achieve the objectives of the invention.
• the “effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness, etc., of the patient to be treated.
• the pharmacokinetic parameters described herein include area under the plasma concentration-time curve (AUC 0-t and AUCo_ ⁇ ), maximum plasma concentration (C max ), and time of maximum plasma concentration (T max ). Terminal elimination half-life (Ty 2 ) may also be provided.
• the time of maximum concentration, T max is determined as the time corresponding to C max .
• Area under the plasma concentration-time curve up to the time corresponding to the last measurable concentration (AUCo-t) is calculated by numerical integration using the linear trapezoidal rule as follows:
• C is the plasma memantine concentrations at the corresponding sampling time point t; and n is the number of time points up to and including the last quantifiable concentration.
• the terminal half-life (Ty 2 ) is calculated using the following equation:
• T 172 Eq. 2 where ⁇ z is the terminal elimination rate constant.
• the area under the plasma concentration-time curve from time zero to infinity is calculated according to the following equation:
• treat refers to one or more of the following:
• a subject or patient in whom administration of the therapeutic compound is an effective therapeutic regimen for a disease or disorder is preferably a human, but can be any animal, including a laboratory animal in the context of a clinical trial or screening or activity experiment.
• the methods, compounds and compositions of the present invention are particularly suited to administration to any animal, particularly a mammal, and including, but by no means limited to, humans, domestic animals, such as feline or canine subjects, farm animals, such as but not limited to bovine, equine, caprine, ovine, and porcine subjects, wild animals (whether in the wild or in a zoological garden), research animals, such as mice, rats, rabbits, goats, sheep, pigs, dogs, cats, etc., avian species, such as chickens, turkeys, songbirds, etc., i.e., for veterinary medical use.
• Pharmaceutically acceptable salts include those obtained by reacting the main compound, functioning as a base with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, and carbonic acid.
• Pharmaceutically acceptable salts also include those in which the main compound functions as an acid and is reacted with an appropriate base to form, e.g., sodium, potassium, calcium, magnesium, ammonium, and choline salts.
• acid addition salts may be prepared by reaction of a compound with the appropriate inorganic or organic acid via any of a number of known methods.
• alkali and alkaline earth metal salts can be prepared by reacting a compound with the appropriate base via a variety of known methods.
• acid salts that can be obtained by reaction with inorganic or organic acids: acetates, adipates, alginates, citrates, aspartates, benzoates, benzenesulfonates, bisulfates, butyrates, camphorates, digluconates, cyclopentanepropionates, dodecylsulfates, ethanesulfonates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, fumarates, hydrobromides, hydroiodides, 2-hydroxy-ethanesulfonates, lactates, maleates, methanesulfonates, nicotinates, 2-naphthalenesulfonates, oxalates, palmoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates,
• prodrug means a compound that is a drug precursor which upon administration to a subject undergoes chemical conversion by metabolic or chemical processes to yield a compound an active moiety.
• Suitable prodrugs of ceftaroline include, e.g., ceftaroline fosamil (USAN, INN) and 7 ⁇ -[2(Z)-ethoxyimino-2-(5-phosphonoamino- l,2,4-thiadiazol-3-yl)acetamido]-3-[4-(l-methyl-4-pyridinio)-2-thiazolythio]-3-cephem-4- carboxylate.
• Solvates of a compound may form when a solvent molecule(s) is incorporated into the crystalline lattice structure of the compound molecule during, for example, a crystallization process.
• Suitable solvates include, e.g., hydrates (monohydrate, sesquihydrate, dihydrate), solvates with organic compounds (e.g., CH 3 CO 2 H, CH 3 CH 2 CO 2 H, CH 3 CN), and combinations thereof.
• Ceftaroline fosamil may be prepared as described in U.S. Patent No. 6,906,055.
• ceftaroline fosamil ranges from about 25 mg/mL to about 36 mg/mL over a wide range of pH (about 3 to about 8, 0.05 M).
• the solubility of ceftaroline fosamil increases significantly as the acetate ion ionic strength increases (e.g., the solubility is greater than 200 mg/mL at acetate concentrations of 1.0 M and higher).
• the solubility of ceftaroline fosamil increases significantly as the citrate ion ionic strength increases (e.g., the solubility is greater than 200 mg/mL at citrate concentrations of 0.5 M and higher).
• the solubility of ceftaroline fosamil increases significantly as the DL arginine ionic strength increases (e.g., the solubility is greater than 200 mg/mL at DL arginine concentrations of 1.0 M and higher).
• the solubility of ceftaroline fosamil increases significantly as the L-arginine ionic strength increases (e.g., the solubility is greater than 200 mg/mL at L-arginine concentrations of 0.5 M and higher).
• a formulation containing 668 mg ceftaroline fosamil and 400 mg L-arginine was prepared.
• the aqueous solution stability of this formulation (at a concentration of 338 mg ceftaroline fosamil anhydrous, acetate free corrected basis per mL) was determined under the following conditions: (i) 25 0 C and (ii) 2-8 0 C.
• the results of these studies are set forth in Tables 14 and 15, respectively.
• the ceftaroline fosamil/L-arginine solution is stable at room temperature for more than 6 hours, and is therefore suitable for IM administration.
• the stability of the ceftaroline fosamil/L-arginine solution in a 250 mL home infusion bag was determined under the following conditions: (i) 25 0 C and ambient relative humidity (RH) and (ii) 2-8 0 C at ambient RH. The results are set forth in Tables 16 and 17, respectively.
• ceftaroline fosamil/L-arginine solution is stable at room temperature for several days and is therefore suitable for IV infusion use.
• ceftaroline fosamil/L-arginine blend in 0.9% sodium chloride IV bags was determined at ceftaroline fosamil concentrations of approximately 5 mg/mL under refrigerated (2-8 0 C) conditions for 24 or 48 hours followed by 6 hours at ambient conditions (25 0 C and ambient light). The results are shown in Table 18.
• the pH of the solution over the course of the study was unchanged.
• the solution may be used for intravenous administration.
• Example 7 Preparation of Formulations Suitable for IM and IV Administration
• ceftaroline fosamil (USAN) is equivalent to about 530 mg ceftaroline; 446 mg ceftaroline fosamil (USAN) is equivalent to about 353 mg ceftaroline; 223 mg ceftaroline fosamil (USAN) is equivalent to 176 mg ceftaroline.
• ceftaroline fosamil (USAN) is equivalent to about 530 mg ceftaroline; 446 mg ceftaroline fosamil (USAN) is equivalent to about 353 mg ceftaroline; 223 mg ceftaroline fosamil (USAN) is equivalent to 176 mg ceftaroline.
• ceftaroline fosamil (USAN) is equivalent to about 530 mg ceftaroline; 446 mg ceftaroline fosamil (USAN) is equivalent to about 353 mg ceftaroline; 223 mg ceftaroline fosamil (USAN) is equivalent to 176 mg ceftaroline.
• ceftaroline fosamil (USAN) is equivalent to about 530 mg ceftaroline; 446 mg ceftaroline fosamil (USAN) is equivalent to about 353 mg ceftaroline; 223 mg ceftaroline fosamil (USAN) is equivalent to 176 mg ceftaroline.
• ceftaroline fosamil/L-arginine blend of Example 1 of Table 19 i.e., 668 mg ceftaroline fosamil (USAN) (equivalent of 530 mg ceftaroline) and 400 mg L-arginine
• 668 mg ceftaroline fosamil (USAN) equivalent of 530 mg ceftaroline
• 400 mg L-arginine i.e., 668 mg ceftaroline fosamil (USAN) (equivalent of 530 mg ceftaroline) and 400 mg L-arginine
• injections can be administered at two intramuscular sites of a patient.
• EXAMPLE 8 A Randomized, Two Part, Single- and Multiple Dose Study of Ceftaraoline Fosamil Parenterally Administered by Intramuscular Injection and Intravenous Injection in Healthy Human Subjects
• ceftaroline fosamil and its the active moiety, ceftaroline administered parenterally (both intramuscular injection and intravenous injection).
• Part A of the study was a single-dose open-label study.
• Part B of the study was a multiple-dose study.
• A-D Twenty four subjects (six subjects per treatment group) were randomized to one of four treatment groups (A-D): The following doses were administered using vials containing 668 mg ceftaroline fosamil (USAN, molecular formula C 22 H 2 IN 8 O 8 PS 4 . C 2 H 4 O 2 . H 2 O, molecular weight 762.75).
• Group A Day 1 - Single IM injection of 400 mg ceftaroline fosamil (anhydrous, acetate free basis, 228 mg /mL solution) ( ⁇ 353 mg ceftaroline)
• Group B Day 1 - Single IM injection of 600mg ceftaroline fosamil (anhydrous, acetate free basis, 165 mg/mL solution) ( ⁇ 530 mg ceftaroline)
• Group C Day 1 - Single IM injection of 600 mg ceftaroline fosamil (anhydrous, acetate free basis, 228 mg /mL solution) ( ⁇ 530 mg ceftaroline)
• Group D Day 1 - Single IM injection of 1000 mg ceftaroline fosamil (anhydrous, acetate free basis, 228 mg /mL solution) ( ⁇ 883 mg ceftaroline)
• Group E Days 1-4 - IM injection of 600 mg ceftaroline fosamil (anhydrous, acetate free basis 228 mg /mL solution) ( ⁇ 530 mg ceftaroline) every 12 hours
• Control Group F Days 1-4 - IM injection of cefepime hydrochloride 1000 mg every 12 hours
• ceftaroline fosamil (USAN) is equivalent to about 530 mg ceftaroline; 446 mg ceftaroline fosamil (USAN) is equivalent to about 353 mg ceftaroline and 1114 mg ceftaroline fosamil (USAN) is equivalent to about 883 mg ceftaroline.
• the pharmacokinetic parameters for ceftaroline fosamil and ceftaroline were determined using a standard assay. Blood for pharmacokinetic parameter analysis was collected from all subjects as follows: The first blood sample was collected at about 5 minutes (about 0.06 hours) after completion of the administration. Measurement was considered essentially zero prior to this point.
• Part A 5, 15, and 30 minutes and 1, 2, 4, 6, 8, 12, 18, 24, 36 and 48 hours after injection.
• blood were be collected from subjects receiving IV infusion immediately prior to drug injection on day 8 and at 20, 40, 60 (immediately before the end of the study-drug infusion), 65 and 75 minutes, and 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours after the start of the drug infusion on Day 8.
• Part B Drug injection on Days 1 and 5, at 5, 15, and 30 minutes and 1, 2, 4, 6, 8 and hours after the first injection on Day 1, immediately prior to (within 15 minutes) of injection of morning dose on Day 4, at 12 hours post Day 4 morning dose (before evening dose) and at 5, 15 and 30 minutes and 1, 2, 4, 6, 8, 12, 24, 36 and 48 hours after the last (morning) injection on Day 5.
• Pharmacokinetic parameters for ceftaroline fosamil obtained from Part A of this study are presented in Table 24.
• the AUC 0 - * and C max values increase or decrease proportionally with the dosage of ceftaroline fosamil.
• ceftaroline fosamil or other prodrugs of ceftaroline used in a particular dosage form of the invention.
• the pro-drug in the blood is converted rapidly to the active moiety ceftaroline.
• the systemic exposure (AUCo- ⁇ ) of ceftaroline (active moiety) following dosing with equivalent of 600 mg ceftaroline fosamil (INN) ( ⁇ 530 mg ceftaroline) by IM injection at a concentration of 228 mg/mL defined per Table 23 (Day 1) is approximately equivalent to the systemic exposure following an IV infusion of equivalent of 600 mg ceftaroline fosamil (INN) ( ⁇ 530 mg ceftaroline) (Day 8), resulting in an absolute bioavailability of approximately 100%.
• the C max value of ceftaroline for IM injection in Treatment Group C is approximately 57% lower than the C max value following IV infusion.
• the T max following IM injection is about 1 to 2 hours, while the T max following IV infusion occurred around the time of the end of the infusion ( ⁇ 1 hour).
• Ceftaroline values for 177, 442, 706, 1060 and 1589 mg are calculated based on linear assumption
• ceftaroline fosamil (USAN) is equivalent to 530 mg ceftaroline.
• Values for ceftaroline fosamil (USAN) 223, 557, 891, 1337 and 2005 mg are calculated based on linear assumptions
• ceftaroline for example, 668 mg of ceftaroline fosamil (USAN) is equivalent to 530 mg ceftaroline
• ceftaroline for example, 668 mg of ceftaroline fosamil (USAN) is equivalent to 530 mg ceftaroline

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