Patent Application
20140274989
This disclosure relates to processes for the manufacture of pharmaceutical compositions comprising a beta-lactam antibiotic and a beta-lactam inhibitor compound also containing a beta-lactam moiety, including compositions comprising ceftolozane and tazobactam, and resulting pharmaceutical compositions made by these processes.
The United States Food and Drug Administration (FDA) recently published guidance relating to the manufacture of antibiotics with a chemical structure containing a beta-lactam moiety, including cephalosporins. See U.S. Department of Health and Human Services Food and Drug Administration, Center for Drug Evaluation and Research, Non-Penicillin Beta-Lactam Drugs: A CGMP Framework for Preventing Cross-Contamination (April 2013) (“FDA Guidance”). Under the FDA Guidance, certain beta-lactam beta-lactamase inhibitor compounds such as tazobactam are considered “potential sensitizing agents” for allergic reactions, and should be the subject of manufacturing controls to reduce the risk of cross-contamination with all beta-lactam products. The FDA Guidance can pose significant limitations on facilities that manufacture products combining: (a) a beta-lactamase inhibitor having a chemical structure containing a beta-lactam moiety (“BL-BLI,” e.g., tazobactam) and (b) a cephalosporin antibiotic (e.g., ceftolozane) or antibiotics having chemical structures containing a beta-lactam moiety (“beta-lactam antibiotics”). To prevent cross-contamination, the manufacture and handling of such a product cannot occur in a facility handling other beta-lactam antibiotics in the absence of the BL-BLI, nor can such a facility handle other beta-lactam antibiotics in any of the four other recognized structural classes (i.e., penicillins, penems, carbacephems and monobactams), to which the beta-lactam antibiotic does not itself belong, even in combination with the BL-BLI. Ceftolozane is a cephalosporin antibacterial agent. The antibacterial activity of ceftolozane is believed to result from its interaction with penicillin binding proteins (PBPs) to inhibit the biosynthesis of the bacterial cell wall which acts to stop bacterial replication. Ceftolozane is also referred to as CXA-101, FR264205, (6R,7R)-3-[(5-amino-4-{[(2-aminoethyl)carbamoyl]amino}-1-methyl-1H-pyrazol-2-ium-2-yl)methyl]-7-({(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(1-carboxy-1-methylethoxy)imino]acetyl}amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, or (6R,7R)-3-[5-Amino-4-[3-(2-aminoethyl)ureido]-1-methyl-1H-pyrazol-2-ium-2-ylmethyl]-7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(Z)-1-carboxy-1-methylethoxyimino]acetamido]-3-cephem-4-carboxylic acid). U.S. Pat. No. 7,129,232 discloses ceftolozane and various ceftolozane salts. Ceftolozane sulfate (formula (I)) is an example of a pharmaceutically acceptable salt of ceftolozane that can be combined with sodium chloride and other components to obtain an antibiotic composition.
Tazobactam is a BLI compound approved for use in combination with piperacillin in an injectable antibacterial product available under commercial names ZOSYN (U.S.) and TAZOCIN (e.g., in Canada, and the United Kingdom). Tazobactam sodium, a derivative of the penicillin nucleus, is a penicillanic acid sulfone having the chemical name chemical name is sodium (2S,3S,5R)-3-methyl-7-oxo-3-(1H-1,2,3-triazol-1-ylmethyl)-4-thia-1azabicyclo[3.2.0]heptane-2-carboxylate-4,4-dioxide. The chemical formula is C10H11N4NaO5S and the molecular weight is 322.3. The chemical structure of formula (IIa) is tazobactam sodium:
Another injectable antibiotic composition called CXA-201 (ceftolozane/tazobactam) comprises ceftolozane and tazobactam in a 2:1 weight ratio formulated for reconstitution prior to parenteral administration. In one presentation, CXA-201 can be provided as a composition comprising ceftolozane sulfate and tazobactam sodium, administered by reconstituting a vial of solid CXA-201 to form a reconstituted injectable formulation. Each vial of CXA-201 contains 1000 mg of ceftolozane active (free base equivalent weight, e.g., provided as a pharmaceutically acceptable salt such as ceftolozane sulfate) and sterile tazobactam sodium at a quantity equivalent of 500 mg of tazobactam free acid, in a solid form. CXA-201 includes other components such as sodium chloride and L-arginine. CXA-201 displays potent antibacterial activity against various gram-negative infections such as, for example, complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI), or hospital acquired/ventilator-associated bacterial pneumonia (HABP/VABP).
Products containing ceftolozane and tazobactam include both a non-penicillin beta-lactam cephalosporin (ceftolozane) and a beta-lactamase inhibitor with a beta-lactam moiety (tazobactam). There is a need for methods of manufacturing antibiotic compositions comprising ceftolozane and tazobactam for sale in the United States in compliance with the FDA Guidance, as well as antibiotic compositions manufactured in accordance with the FDA Guidance without affecting the purity, stability, and safety of the resulting composition.
Provided herein are methods of manufacturing or preparing pharmaceutical compositions containing two or more beta-lactam compounds in accordance with FDA Guidance, as well as pharmaceutical compositions manufactured in compliance with FDA Guidance. Specifically, certain manufacturing methods are provided herein that conform to standards recommended by FDA Guidance for the avoidance of cross-contamination of non-penicillin beta-lactam drugs.
In one aspect, provided herein is a method of manufacturing a composition comprising a non-penicillin beta-lactam antibiotic and a beta-lactam BLI compound in a dedicated production area or in the absence of any compound belonging to a different class of beta-lactam containing compounds. The non-penicillin antibiotic can be a cephalosporin and the beta-lactam BLI compound can be tazobactam. When the composition includes a cephalosporin and a beta-lactam BLI, the manufacturing can be carried out in the absence of any compound belonging to other classes of beta-lactam containing compounds, including: penicillins, penems, carbacephems, and monobactams. A composition comprising ceftolozane and tazobactam can be manufactured by a process that includes the step of combining ceftolozane with tazobactam in a dedicated production area or in the absence of any other finished pharmaceuticals or any other pharmaceutical ingredients with chemical structures containing a beta-lactam moiety that would be deemed cross-contaminants under the FDA Guidance. For example, the finished pharmaceutical or active pharmaceutical ingredient can be any non-penicillin beta-lactam of a different class than ceftolozane or tazobactam.
Certain methods of manufacturing a composition comprising ceftolozane and tazobactam can include the steps of: (a) receiving the ceftolozane and tazobactam at a dedicated production area; (b) sequential, aseptic filling of the ceftolozane and tazobactam into a container (e.g., a bag or vial); (c) blanketing the container with an inert gas; (d) sealing the container; and (e) inspecting the container prior to secondary packaging.
Compositions formed by sequential, aseptic combination within a unit dosage form container of a lyophilized ceftolozane composition obtained in the absence of tazobactam and a separate, lyophilized tazobactam composition obtained in the absence of ceftolozane, resulted in ceftolozane-tazobactam compositions with less than 0.03% of a compound of formula (III) as measured by high performance liquid chromatography (HPLC), as determined by HPLC using a Develosil column ODS-UG-5; 5 micrometers; 250×4.6 mm, a mobile phase of sodium perchlorate buffer solution (pH 2.5)/CH3CN 90:10 (v/v) at a 1.0 mL/min flow rate and oven temperature of 45° C. The compound of formula (III) was formed in a lyophilized product obtained by lyophilizing a solution comprising both ceftolozane and tazobactam.
In one embodiment, a pharmaceutical composition can include ceftolozane and tazobactam with less than 1%, 0.15%, 0.10%, 0.05% or 0.03% by weight; or from 0.03-0.05%, 0.03-0.1% or 0.03-0.15% by HPLC or even undetectable amounts of the compound of formula (III) (e.g., less than about 0.03% of the compound of Formula (III) measured by HPLC). These pharmaceutical compositions can be obtained by a process comprising the steps of (a) lyophilizing ceftolozane in the absence of tazobactam to obtain a lyophilized ceftolozane composition; and (b) combining the lyophilized ceftolozane with tazobactam under conditions suitable to obtain said pharmaceutical composition with the aforementioned purity levels. The combination of the lyophilized ceftolozane composition with tazobactam can include blending the lyophilized ceftolozane composition with lyophilized or crystalline tazobactam material.
In one aspect, provided herein is a pharmaceutical composition comprising a blend of separately lyophilized tazobactam and ceftolozane sulfate in an amount providing 1,000 mg of ceftolozane active per 500 mg of tazobactam active, further comprising less than 0.15%, 0.10%, 0.05% or 0.03% by weight; from 0.03-0.05%, 0.03-0.1% or 0.03-0.15% by HPLC; or even undetectable amounts (e.g., less than about 0.03% by HPLC) of a compound of formula (III) detectable at a retention time relative to ceftolozane of 1.22 by high performance liquid chromatography (HPLC) using a Develosil column ODS-UG-5; 5 micrometers; 250×4.6 mm, a mobile phase of sodium perchlorate buffer solution (pH 2.5)/CH3CN 90:10 (v/v) at a 1.0 mL/min flow rate and oven temperature of 45° C. (hereinafter referred to as the “method of Example 9”).
CXA-201 compositions comprising less than about 0.15%, 0.10%, 0.05% or 0.03% by weight; or from 0.03-0.05%, 0.03-0.1% or 0.03-0.15% by HPLC of the compound of formula (III) can be obtained by a process comprising the steps of: (a) forming a first aqueous solution comprising ceftolozane (e.g., in a pharmaceutically acceptable salt such as formula (I)), (b) lyophilizing the first aqueous solution to obtain a lyophilized ceftolozane composition, and (c) blending the lyophilized ceftolozane composition with a tazobactam composition (e.g., tazobactam acid lyophilized in the absence of ceftolozane) in an amount that provides a 2:1 weight ratio between the amount of ceftolozane active and tazobactam active.
The ceftolozane can also be a ceftolozane drug product intermediate. In one embodiment, the ceftolozane drug product intermediate further comprises sodium chloride. The ceftolozane drug product intermediate can be prepared by a method comprising: (a) compounding a ceftolozane solution for lyophilization; (b) filtering the solution; (c) lyophilizing the solution into powder; (d) grinding and sieving the powder; and (e) aseptic packaging the powder for delivery to the dedicated production area.
In another aspect, provided herein is a method of receiving ceftolozane and tazobactam at a dedicated production area, and combining the ceftolozane with tazobactam in the absence of any finished pharmaceuticals or active pharmaceutical ingredients other than ceftolozane and tazobactam to produce a pharmaceutical composition suitable for administration to a subject.
A pharmaceutical composition comprising ceftolozane and tazobactam can be prepared in a dedicated production area in the absence of materials with chemical structures containing a beta-lactam moiety, other than ceftolozane or tazobactam. The pharmaceutical composition is preferably prepared in a dedicated production area for manufacturing antibiotic compounds comprising a non-penicillin beta-lactam compound (e.g., a cephalosporin) and a beta-lactamase inhibitor (BLI) compound with a beta-lactam ring (e.g., tazobactam). Accordingly, the facility that manufactures a product containing both cephalosporin and a beta-lactam containing BLI such as tazobactam for sale in the United States is not simultaneously or subsequently used to manufacture or handle any other products within another (non-cephalosporin) Beta-Lactam Class, nor to produce another cephalosporin product without tazobactam (or beta-lactam compound from the same structural class).
Unless otherwise indicated herein, the phrase “1000 mg ceftolozane” or “1 g ceftolozane” refers to an amount of ceftolozane containing the free base equivalent weight of ceftolozane provided in any suitable salt form. For example, a composition containing 1000 mg of ceftolozane in the ceftolozane sulfate solid form will include greater than 1000 mg of material (e.g., due to at least the additional weight of the sulfate counter ion). Preferably, a composition containing “1000 mg of ceftolozane” includes an amount of ceftolozane sulfate comprising 1000 mg of the ceftolozane molecule in free base equivalent form. For example, as shown in Table 11, 1147 mg ceftolozane sulfate corresponds to 1000 mg of ceftolozane free base.
Likewise, the phrases “250-750 mg tazobactam,” “250-700 mg tazobactam,” “300-700 mg tazobactam,” “300-650 mg tazobactam,” “350-650 mg tazobactam,” “350-600 mg tazobactam,” “400-600 mg tazobactam,” “400-550 mg tazobactam,” “450-550 mg tazobactam,” or “about 500 mg tazobactam” refer to an amount of tazobactam containing the free acid equivalent weight of tazobactam provided in any suitable salt form. For example, a composition containing 500 mg of tazobactam in the tazobactam sodium solid form will include greater than 500 mg of material (e.g., due to at least the additional weight of the sodium counter ion). For example, as shown in Table 11, 537 mg tazobactam sodium corresponds to 500 mg of tazobactam free acid. Preferably, a composition containing “500 mg of tazobactam” includes an amount of tazobactam sodium comprising 500 mg of the tazobactam molecule in free acid equivalent form.
As used herein, “125 to 1000 mg sodium chloride per 1000 mg of ceftolozane” refers to a ratio of sodium chloride to ceftolozane free base equivalent. For example, “125 to 1000 mg sodium chloride per 1000 mg of ceftolozane” includes, for example, 62.5 to 500 mg sodium chloride per 500 mg of ceftolozane, as well as, for example, 25 to 200 mg sodium chloride per 200 mg ceftolozane, etc.
As used herein, the term “blending” refers to a process comprising physically combining ceftolozane and tazobactam, wherein each of ceftolozane and tazobactam have been individually lyophilized (i.e., lyophilized in the absence of one another) prior to blending. Blending refers to mixing the components in a powdered form, which can occur within a unit dosage form container. Blending of ceftolozane and tazobactam is described in Examples 3 and 4, and in
As used herein, the term “vial” means a container for storing pharmaceutical preparations. A single vial may be suitable for holding a single preparation, or may be configured to hold two or more separate preparations simultaneously without mixing. The vial may hold enough preparation for a single dose or multiple doses. The vial may be formed of any suitable material, such as glass or plastic, and various means may be used to seal the vial (e.g., stoppering and crimping).
As used herein, the term “dedicated production area” refers to a manufacturing facility that complies with U.S. Department of Health and Human Services Food and Drug Administration, Center for Drug Evaluation and Research, Non-Penicillin Beta-Lactam Drugs: A CGMP Framework for Preventing Cross-Contamination (April 2013) (“FDA Guidance”). The FDA Guidance identifies five beta-lactam antibiotic classes: penicillins, cephalosporins, penems, carbacephems and monobactams (“Beta-Lactam Classes”). With reference to the manufacture of a product containing both a compound from a Beta-Lactam Class and a compound having a chemical structure with a beta-lactam moiety, a dedicated production area cannot be simultaneously or subsequently used to manufacture or handle another product containing a compound from another Beta-Lactam Class. A “dedicated production area” can include but is not limited to facilities, air handling equipment, and/or process equipment. See section IV.D Containment (4.4) of the ICH Q7 guidance.
As used herein, a beta-lactam BLI refers to any beta-lactamase inhibitor compound with a chemical structure including a beta-lactam moiety (e.g., tazobactam).
Unless otherwise indicated, HPLC measurements reported herein are obtained using a Develosil column ODS-UG-5; 5 micrometers; 250×4.6 mm, a mobile phase of sodium perchlorate buffer solution (pH 2.5)/CH3CN 90:10 (v/v) at a 1.0 mL/min flow rate and oven temperature of 45° C.
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.
As used herein, the term “ceftolozane active” refers to active portion of a salt form of ceftolozane, i.e., the free base form of ceftolozane.
As used herein, the term “tazobactam active” refers to the active portion of a salt form of tazobactam, i.e., tazobactam free acid.
As used herein, references to an amount of a substance as “% of the compound of . . . ” or “% by HPLC” (unless otherwise indicated) refer to the % of a compound detected by high performance liquid chromatography (HPLC) according to the method of Example 9.
As used herein, the term “FDA Guidance” refers to the document U.S. Department of Health and Human Services Food and Drug Administration, Center for Drug Evaluation and Research, Non-Penicillin Beta-Lactam Drugs: A CGMP Framework for Preventing Cross-Contamination (April 2013) (“FDA Guidance”).
The FDA Guidance states that manufacturing facilities dedicated to manufacturing a sensitizing non-penicillin beta-lactam compound should be “completely and comprehensively separated” from areas in the facility in which any class of sensitizing beta-lactam is manufactured. The FDA also considers separation of production facilities for penicillins to be good manufacturing practice. The FDA Guidance can be understood to require the use of a dedicated facility to manufacture antibiotic compounds comprising a non-penicillin beta-lactam compound (e.g., a cephalosporin) and a BLI compound with a beta-lactam ring (e.g., tazobactam). Accordingly, a facility that manufactures a product containing both cephalosporin and a beta-lactam containing BLI such as tazobactam for sale in the United States cannot be subsequently used to manufacture any other products containing beta-lactam ring (e.g., other non-penicillin beta-lactam compounds including other cephalosporin antibiotics cannot be subsequently manufactured in the facility).
The FDA Guidance relates to manufacturing and handling beta-lactam antibiotics and other pharmaceutical ingredients having a chemical structure containing a beta-lactam ring. Beta-lactam antibiotics, including penicillin and the non-penicillin classes, share a basic chemical structure that includes a three-carbon, one-nitrogen cyclic amine structure known as the beta-lactam ring. The side chain associated with the beta-lactam ring is a variable group attached to the core structure by a peptide bond; the side chain variability contributes to antibacterial activity. As of the date of this publication, the FDA has approved over 34 beta-lactam compounds as active ingredients in drugs for human use. (see, e.g.,
Antibiotic pharmaceutical compositions comprising a beta-lactam antibiotic compound (i.e., an antibiotic compound possessing one or more beta-lactam moieties) such as a cephalosporin (e.g., ceftolozane) can be administered with a beta-lactamase inhibitor (BLI) compound. The BLI can be selected to irreversibly inhibit beta-lactamase enzymes responsible for resistance to the beta-lactam antibiotic, thereby increasing susceptibility of bacteria to the antibiotic that would otherwise be resistant in the absence of the BLI. Beta-lactam inhibitor compounds such as clavulanic acid, tazobactam, and sulbactam have weak antibacterial activity but are irreversible inhibitors of many beta-lactamases. Accordingly, BLI compounds can be used in combination with specific beta-lactam antibiotic agents to provide antibacterial compositions with an extended antibacterial spectrum.
Under the FDA Guidance, a manufacturing facility handling a product for sale in the United States containing both a cephalosporin (e.g, ceftolozane) and a penicillin nucleus (e.g., tazobactam) cannot be subsequently used in the manufacture of any other class of beta-lactam products, including all other penicillins, cephalosporins, penems, carbacephems and monobactams or in the manufacture of other finished pharmaceuticals or active pharmaceutical ingredients. The FDA Guidance states that (non-penicillin) cephalosporin beta-lactam compounds (e.g., such as ceftolozane) for sale in the United States must be “completely and comprehensively separated from” manufacturing areas that handle any other class of beta-lactam compound (e.g., compounds in the penicillin class).
According to the FDA Guidance, non-penicillin beta-lactam drugs can be sensitizing agents and cross-contamination with these types of drugs can initiate the same types of drug-induced hypersensitivity reactions that can be triggered by penicillins, such as life-threatening allergic reactions. Allergic reactions associated with these beta-lactam-type drugs range from rashes to life-threatening anaphylaxis. These allergic reactions are mediated by Immunoglobulin E (IgE) and are a primary concern because they can be associated with significant morbidity and mortality. Patients with a history of hypersensitivity to penicillin may also experience IgE-mediated reactions to other beta-lactams, such as cephalosporins (e.g., ceftolozane) (see, e.g., Saxon, A, G N Beall, A S Rohr, and D C Adelman, 1987, Immediate hypersensitivity reactions to beta-lactam antibiotics, Ann Intern Med, 107(2):204-215).
Further, the FDA Guidance can be understood to take the position that non-penicillin beta-lactams (including, e.g., tazobactam) have the potential to sensitize individuals, and subsequent exposure to penicillin may result in severe allergic reactions. The FDA Guidance also states that beta-lactam intermediates and derivatives (precursors to the Active Pharmaceutical Ingredients), including the product prior to purification, can have sensitizing properties or result in antigenic responses that produce allergic reactions. Thus the FDA Guidance states that chemical manufacturing processes associated with non-penicillin beta-lactam drugs should also be designed to reduce the risk of cross-contamination. The FDA Guidance also can be understood to take the position that there is a lack of suitable animal or receptor testing models that are predictive of human sensitivity (see, e.g., Olson, H. et al., 2000, Concordance of the toxicity of pharmaceuticals in humans and in animals, Regul. Toxicol. Pharmacol., 32:56-67), and the threshold dose at which allergenic response could occur is extremely low and difficult to detect with current analytical methods (see, e.g., Pimiento, A. P. et al., 1998, Aztreonam and ceftazidime: evidence of in vivo cross-allergenicity, Allergy, 53:624625 and Shepard, G. M., 1991, Allergy to β-lactam antibiotics, Immunol. Allergy Clin. North Am., 11(3):611-633).
The FDA Guidance also states that while beta-lactam antibiotics are similar to one another in many ways, they may differ in pharmacokinetics, antibacterial activity, and potential to cause serious allergic reactions. Because allergy testing methods have not been well-validated, it is clinically difficult to determine the occurrence and rate of cross-reactivity between beta-lactam antibiotics in humans. (Bernstein, I L, et al., 2008, Allergy diagnostic testing: an updated practice parameter, Ann. Allergy Asthma Immunol., 100:S1-S148). Therefore, undiagnosed or underreported cases of cross-reactivity likely exist. Some beta-lactam antibiotics have negligible potential for cross-reactivity with beta-lactams of other classes, whereas other beta-lactam compounds may exhibit sensitizing activity as derivatives before the incorporation of side chains that confer antibacterial activity. According to the FDA Guidance, although there have been no case reports confirming anaphylactic reactions to a beta-lactamase inhibitor that is also a beta-lactam, these compounds are potentially sensitizing agents, and manufacturers should implement controls to reduce the risk of cross-contamination with beta-lactamase inhibitors as with all other beta-lactam products.
There is a need for methods for preventing cross-contamination in compliance with the FDA Guidance for the manufacture of pharmaceutical compositions comprising two or more beta-lactam molecules with different structures (e.g., ceftolozane and tazobactam), given the position taken in the FDA Guidance that it is difficult to define the minimal dose below which allergic responses are unlikely to occur in humans. (see, e.g., Dayan, A. D., 1993, Allergy to antimicrobial residues in food: assessment of the risk to man, Vet. Microbiol., 35:213-226 and Blanca M., et al., 1996, Anaphylaxis to penicillins after non-therapeutic exposure: an immunological investigation, Clin. Exp. Allergy, 26:335-340). Given the health risks associated with cross-reactivity (cross-sensitivity) of any beta-lactams, and the uncertainty in quantifying the risk, implementing methods for preventing cross-contamination of any pharmaceutical product with beta-lactam-type drugs is of current concern to the FDA. Just as the FDA considers the separation of production facilities for penicillins to be current good manufacturing practice, FDA expects manufacturers to treat sensitizing non-penicillin beta-lactam-based products similarly. Specifically, the FDA recommends that manufacturers establish appropriate separation and control systems designed to prevent two types of contamination: (1) the contamination of a non-penicillin beta-lactam by any other non-penicillin beta-lactam, and (2) the contamination of any other type of product by a non-penicillin beta-lactam. Accordingly, the FDA recommends that the area in which any class of sensitizing beta-lactam is manufactured be separated from areas in which any other products are manufactured, and have an independent air handling system (“dedicated production area”). Dedicated production areas can include separate facilities, air handling equipment, and/or process equipment (see, e.g., IV.D Containment (4.4) of the ICH Q7 guidance, available at http://www.fda.gov/Drugs/Guidance ComplianceRegulatoryInformation/Guidances/default.htm). This control applies to each of the five classes of sensitizing beta-lactams; the area in which any class of sensitizing beta-lactam is manufactured should be separated from areas in which any other products are manufactured, including any other class of sensitizing beta-lactam.
The FDA Guidance also recommends that firms that manufacture beta-lactam intermediates or receive them for further processing, as well as firms whose manufacturing processes result in beta-lactam derivatives, should evaluate their manufacturing operations for the possibility of cross-contamination and implement appropriate controls to reduce or mitigate the potential for cross-contamination. As with penicillin and non-penicillin beta-lactam drugs, such controls could include, but are not limited to, isolation and separation of intermediate and derivative materials, facilities, equipment, and personnel.
Referring to
More particularly, the ceftolozane composition in
Ceftolozane and/or pharmaceutically acceptable salts thereof are also referred to as CXA-101, FR264205, or by chemical names such as (6R,7R)-3-[(5-amino-4-{[(2-aminoethyl)carbamoyl]amino}-1-methyl-1H-pyrazol-2-ium-2-yl)methyl]-7-({(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(1-carboxy-1-methylethoxy)imino]acetyl}amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, and 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-{3-amino-4-[3-(2-aminoethyl)ureido]-2-methyl-1-pyrazolio}methyl-3-cephem-4-carboxylate. Ceftolozane can be obtained as a pharmaceutically acceptable salt. U.S. Pat. No. 7,129,232 discloses ceftolozane and various ceftolozane salts. For example, a ceftolozane hydrogen sulfate salt is disclosed among ceftolozane salts that can be formed “with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt [e.g., sodium salt, potassium salt, etc.], an alkaline earth metal salt [e.g., calcium salt, magnesium salt, etc.], an ammonium salt; a salt with an organic base, for example, an organic amine salt [e.g., trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt, etc.]; an inorganic acid addition salt [e.g., hydrochloride, hydrobromide, sulfate, hydrogen sulfate, phosphate, etc.]; an organic carboxylic or sulfonic acid addition salt [e.g., formate, acetate, trifluoroacetate, maleate, tartrate, citrate, fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.]; and a salt with a basic or acidic amino acid [e.g., arginine, aspartic acid, glutamic acid, etc.].” Ceftolozane sulfate is a pharmaceutically acceptable ceftolozane salt of formula (I) that can be formulated for intravenous administration or infusion.
A ceftolozane composition can also include other components such as (without limitation) sodium chloride, citric acid and L-arginine. The use of sodium chloride results in greater ceftolozane stability (e.g., 125-500 mg sodium chloride per 1,000 mg of ceftolozane active in the ceftolozane composition. L-arginine can be included in the ceftolozane composition to adjust pH of the aqueous solution such that the composition is suitable for injection (e.g., to pH 5-7, including 6-7) prior to lyophilization and to increase the solubility of ceftolozane.
Preferably, the first aqueous solution comprises the composition of Table 11 in the Examples. The ceftolozane can be included in the ceftolozane composition as an amount of ceftolozane sulfate of formula (I) containing a therapeutically effective amount of ceftolozane such as at least about 1,000 mg ceftolozane active (e.g., about 1,147 mg ceftolozane sulfate). In certain embodiments, the ceftolozane composition comprises 125-500 mg sodium chloride per 1000 mg of ceftolozane active, more preferably about 450-500 mg (including, e.g., 480-500 mg) of sodium chloride per 1,000 mg of ceftolozane active. In one embodiment, the composition comprises about 487 mg sodium chloride per 1000 mg of ceftolozane active (e.g., about 1,147 mg of ceftolozane sulfate), and an amount of tazobactam sodium providing the equivalent of about 500 mg of tazobactam active.
As shown in
Unless otherwise indicated, tazobactam can be a free acid, a sodium salt, an arginine salt, or a hydrate or solvate thereof. In an embodiment, the tazobactam is tazobactam sodium. The tazobactam sodium powder can be generated by neutralizing tazobactam acid with an alkalizing agent, such as sodium bicarbonate or sodium hydroxide, followed by lyophilization. Alternatively, the tazobactam sodium can be generated by neutralizing tazobactam acid with an alkalizing agent, such as sodium bicarbonate or sodium hydroxide. In other embodiments, the tazobactam composition can include a crystalline form of tazobactam, such as tazobactam arginine crystal, for combination with the ceftolozane composition.
The pharmaceutical antibiotic composition comprising ceftolozane and tazobactam in a 2:1 weight ratio of ceftolozane active to tazobactam acid (“CXA-201”) displays potent antibacterial activity, including antibiotic activity against infections caused by many Gram-negative pathogens such as Pseudomonas aeruginosa (P. aeruginosa), Escherichia coli (E. coli), Klebsiella pneumonia (K. pneumonia). In particular, CXA-201 is a pharmaceutical composition useful for intravenous administration for the treatment of complicated intra-abdominal infections and/or complicated urinary tract infections, and is being evaluated for treatment of pneumonia. In CXA-201, ceftolozane is combined with the β-lactamase inhibitor (“BLI”) tazobactam. Tazobactam is a BLI against Class A and some Class C β-lactamases, with well-established in vitro and in vivo efficacy in combination with active β-lactam antibiotics.
The pharmaceutical compositions comprising CXA-201 are useful, for example, for the treatment of bacterial infections in a mammal, comprising administering to said mammal a therapeutically effective amount of a pharmaceutical composition prepared according to the methods described herein. A method for the treatment of bacterial infections in a mammal can comprise administering to said mammal a therapeutically effective amount of a pharmaceutical composition comprising ceftolozane sulfate and sodium chloride. 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 melaminogenica). In certain embodiments of the methods described herein, bacterial infection is associated with one or more of the following conditions: complicated intra-abdominal infections, complicated urinary tract infections (cUTIs) and pneumonia (e.g., community-acquired, or nosocomial pneumonia). Community-acquired pneumonia (moderate severity only) can include infections 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.
The manufacturing process for the pharmaceutical compositions can be selected to comply with the FDA Guidance while reducing decomposition of the constituent drug substances and to produce a composition that is stable under a variety of storage conditions. The facility can include separation and control systems, or dedicated production areas, that prevent the contamination of a non-penicillin beta-lactam with another non-penicillin beta-lactam and the contamination of any other product by a non-penicillin beta-lactam.
Pharmaceutical compositions comprising one or more drug substances can be prepared by lyophilization of various solutions containing the drug substance(s). Lyophilization is a process of freeze-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).
The pharmaceutical compositions comprising ceftolozane and tazobactam can be prepared by a blending process, wherein the ceftozolane and tazobactam are individually lyophilized in the absence of one another, followed by blending the individually lyophilized ceftozolane and tazobactam.
Surprisingly, pharmaceutical compositions comprising ceftolozane and tazobactam prepared by blending (e.g., as described in Example 3) have a different composition compared to compositions prepared by co-lyophilization (e.g., as described in Example 1). In particular, ceftolozane and tazobactam individually lyophilized prior to blending, led to a pharmaceutical composition comprising a much lower amount of the compound of formula (III):
This compound of formula (III) has a relative retention time (RRT) of 1.22 (relative to ceftolozane using the HPLC analysis). This compound is also referred to herein as “the compound RRT 1.22.” Without being bound by theory, the compound RRT 1.22 can be formed by a reaction between ceftolozane and formylacetic acid, a by-product of tazobactam as illustrated in Marunaka et al. (Chem. Pharm. Bull. 1988, Vol. 36 (11), pp. 4478-4487.
The presence of compound RRT 1.22 was detected by HPLC in compositions of ceftolozane and tazobactam, wherein the compositions were formed through co-lyophilization, i.e., the ceftolozane and tazobactam were combined and co-lyophilized together, as opposed to being individually lyophilized and blended together (see, e.g., Examples 1 and 2).
Compositions with controlled amounts of the compound RRT1.22 (formula (III)) (e.g., up to 1% by weight of formula III) can be obtained by blending a first composition comprising a therapeutically effective amount of ceftolozane in the absence of tazobactam with a second composition comprising a therapeutically effective amount of tazobactam in the absence of ceftolozane to form a blended pharmaceutical composition.
Pharmaceutical compositions comprising ceftolozane and tazobactam with reduced or even undetectable levels of the compound of formula (III) (e.g., including levels of compound of formula (III) that are not detectable by HPLC according to Example 9 and/or comprise less than 1%, 0.15%, 0.10%, 0.05% or 0.03% by weight; or from 0.03-0.05%, 0.03-0.1% or 0.03-0.15% by HPLC according to Example 9) can be obtained by blending a ceftolozane composition comprising a therapeutically effective amount of ceftolozane in the absence of tazobactam with a tazobactam composition comprising a therapeutically effective amount of tazobactam in the absence of ceftolozane to form a blended pharmaceutical composition.
More specifically, the pharmaceutical compositions can be obtained by a method comprising:
a) combining ceftolozane and an amount of sodium chloride effective to stabilize the ceftolozane (e.g., 125-500 mg sodium chloride per 1,000 mg ceftolozane active) to form a ceftolozane aqueous solution;
b) lyophilizing the ceftolozane aqueous solution in the absence of tazobactam to obtain the ceftolozane composition in
c) combining the ceftolozane composition with tazobactam obtained in the absence of ceftolozane (e.g., by lyophilizing a tazobactam solution comprising tazobactam acid and sodium bicarbonate to obtain the Tazobactam Composition in
In another embodiment of the pharmaceutical composition provided herein, the composition is prepared by a method comprising:
In one aspect of the invention, an antibiotic pharmaceutical composition is formulated for parenteral administration for the treatment of infections. The composition has a therapeutically effective amount of ceftolozane sulfate and tazobactam in a ratio of 1,000 mg ceftolozane active per 500 mg of tazobactam active. The pharmaceutical composition is obtained by a process comprising the steps of lyophilizing a first aqueous solution in the absence of tazobactam, wherein the first aqueous solution comprises ceftolozane sulfate, 125 mg to 500 lyophilizing a first aqueous solution in the absence of tazobactam, the first aqueous solution comprising ceftolozane sulfate, to obtain a first lyophilized ceftolozane composition, and blending the lyophilized ceftolozane composition with a tazobactam composition comprising tazobactam prepared and provided in the absence of ceftolozane. The process is performed in the absence of other non-cephalosporin beta-lactam compounds.
According to a first embodiment of the invention, the pharmaceutical composition comprises an amount of ceftolozane sulfate providing 2,000 mg of ceftolozane active and an amount of tazobactam providing 1,000 mg of tazobactam acid. In another embodiment, composition further comprises 125 mg-500 mg of sodium chloride per 1,000 mg of ceftolozane active. In still another embodiment, the composition of claim 1, manufactured in the absence of any compound belonging to the following classes of beta-lactam containing compounds: penicillins, penems, carbacephems, and monobactams.
Another embodiment discloses combining ceftolozane with tazobactam within a dedicated production area that does not simultaneously house a cephalosporin other than ceftolozane, or any compound selected from the group consisting of: penicillins, penems, carbacephems, and monobactams. According to one embodiment, the tazobactam composition is obtained by lyophilizing a second solution in the absence of ceftolozane, and the second solution comprises tazobactam to form a second lyophilized tazobactam composition. The second solution may comprise tazobactam acid and sodium bicarbonate. The pharmaceutical composition further comprises 125 mg-500 mg of sodium chloride per 1,000 mg of ceftolozane active. The ceftolozane and tazobactam are combined in the absence of any compound belonging to the following classes of beta-lactam containing compounds: penicillins, penems, carbacephems, and monobactams.
In a further embodiment, a the unit dosage form is formulated for parenteral administration for the treatment of complicated intra-abdominal infections or complicated urinary tract infections; and the pharmaceutical composition comprises an amount of ceftolozane sulfate providing 1,000 mg of ceftolozane active and an amount of tazobactam providing 500 mg of tazobactam acid.
According to still another embodiment, the pharmaceutical composition in the unit dosage form is formulated for parenteral administration for the treatment of pneumonia; and the pharmaceutical composition comprises an amount of ceftolozane sulfate providing 2,000 mg of ceftolozane active and an amount of tazobactam providing 1,000 mg of tazobactam acid.
In one aspect of the invention, a method of manufacturing a composition comprising ceftolozane and tazobactam comprises the steps of receiving the ceftolozane and tazobactam at the dedicated production area; filling a vial with a blend of the ceftolozane and tazobactam; and sealing the vial.
In one aspect, antibiotic pharmaceutical compositions comprising ceftolozane and tazobactam with less than about 0.15%, 0.10%, 0.05% or 0.03% by weight; or from 0.03-0.05%, 0.03-0.1% or 0.03-0.15% by HPLC of the compound of formula (III) are obtained by a process comprising the steps of: (a) lyophilizing ceftolozane in the absence of tazobactam to obtain a lyophilized ceftolozane composition, and (b) blending the lyophilized ceftolozane composition with a composition comprising tazobactam under conditions suitable for attaining the aforementioned purity levels, e.g., by blending with crystalline tazobactam or lyophilized tazobactam.
In another aspect, antibiotic pharmaceutical compositions comprising ceftolozane and tazobactam and less than about 0.15%, 0.10%, 0.05% or 0.03% by weight; or from 0.03-0.05%, 0.03-0.1% or 0.03-0.15% by HPLC of the compound of formula (III) are obtained by a process comprising the steps of: (a) lyophilizing tazobactam in the absence of ceftolozane to obtain a lyophilized tazobactam composition, and (b) blending the lyophilized tazobactam composition with a composition comprising ceftolozane (e.g., lyophilized ceftolozane sulfate).
In a third aspect, antibiotic pharmaceutical compositions comprising ceftolozane and tazobactam and less than about 0.15%, 0.10%, 0.05% or 0.03% by weight; or from 0.03-0.05%, 0.03-0.1% or 0.03-0.15% by HPLC of the compound of formula (III) are obtained by a process comprising the steps of: (a) lyophilizing tazobactam in the absence of ceftolozane to obtain a lyophilized tazobactam composition, (b) lyophilizing ceftolozane in the absence of tazobactam to obtain a lyophilized ceftolozane composition, and (c) blending the lyophilized tazobactam composition with the lyophilized ceftolozane composition.
Other pharmaceutical antibiotic compositions can include ceftolozane sulfate and the compound of formula (III). For example, pharmaceutical compositions comprising up to 1% by weight (e.g., 0.13%, 0.15%, 0.30%, 0.38%, 0.74% or 0.97%) of the compound of formula (III) are herein. The pharmaceutical antibiotic compositions can be provided in a unit dosage form (e.g., in a vial). The unit dosage form can be dissolved with a pharmaceutically acceptable carrier, and then intravenously administered. The unit dosage form comprises 1000 mg of ceftolozane active and 500 mg tazobactam, typically 1000 mg ceftolozane active as ceftolozane sulfate and 500 mg of tazobactam active as tazobactam sodium, argininate or free acid. The unit dosage forms are commonly stored in vials.
According to one embodiment, the pharmaceutical composition in a unit dosage form is formulated for parenteral administration for the treatment of pneumonia. Citric acid can be included in an aqueous ceftolozane solution that is lyophilized to obtain the ceftolozane composition in an amount effective to prevent discoloration of the product, due to its ability to chelate metal ions. In one embodiment, the citric acid is anhydrous citric acid. In another embodiment, the amount of the citric acid is 5-40 mg anhydrous citric acid per 1000 mg of ceftolozane active (including, e.g, 5-35 mg anhydrous citric acid per 1000 mg of ceftolozane, about 21 mg anhydrous citric acid per 1000 mg of ceftolozane and other ranges between 5-40 mg citric acid per 1,000 mg of ceftolozane active).
An aqueous ceftolozane solution that is lyophilized to obtain the ceftolozane composition can further comprise L-arginine, in an amount effective to provide a pH of about 5-7, preferably 6-7, alone or in combination with citric acid and/or ceftolozane sulfate. In one embodiment, the amount of the L-arginine is 450-750 mg L-arginine per 1000 mg of ceftolozane active, (including intermediate ranges and values, e.g, 450-700 mg L-arginine per 1000 mg of ceftolozane active, 550-600 mg L-arginine per 1000 mg of ceftolozane active, or about 587 mg L-arginine per 1000 mg of ceftolozane active). In one specific embodiment, the amount of the L-arginine is about 600 mg L-arginine per 1000 mg of ceftolozane active.
In an embodiment, provided herein is a facility for manufacturing a pharmaceutical composition formulated for parenteral administration for the treatment of complicated intra-abdominal infections or complicated urinary tract infections, the pharmaceutical composition comprising ceftolozane sulfate and tazobactam in a ratio of 1,000 mg ceftolozane active per 500 mg of tazobactam active, the pharmaceutical composition obtained by a process comprising the steps of (a) lyophilizing a first aqueous solution in the absence of tazobactam, the first aqueous solution comprising ceftolozane sulfate, 125 mg to 500 mg of sodium chloride per 1,000 mg of ceftolozane active, to obtain a first lyophilized ceftolozane composition, (b) lyophilizing a second solution comprising tazobactam in the absence of ceftolozane to form a second lyophilized tazobactam composition; and (c) blending the first lyophilized ceftolozane composition and the second lyophilized tazobactam composition to obtain the antibacterial composition; wherein the process is performed in the absence of any additional non-cephalosporin beta-lactam compounds.
The manufacturing process of a CXA-201 composition comprising tazobactam and ceftolozane by co-lyophilization is shown in
1Sodium content is approximately 78 mg/g of tazobactam in drug product after lyophilization.
2Water is removed during the lyophilization process and is controlled at no more than 4% by weight.
The components of the co-lyophilized CXA-201 composition are shown in Table 2. This composition was prepared, as described above in Example 1.
Stability studies of this CXA-201 composition prepared by co-lyophilization were carried out at 25° C. and 40° C. The composition was analyzed using HPLC. The following Tables 3 and 4 are summaries of the HPLC measurements at time zero, after one month (T1), and after three months (T2).
A new compound having RRT=1.22 was observed in the co-lyophilized CXA-201 compositions. While not wishing to be bound by theory, the compound RRT 1.22 was identified as a compound formed by a reaction between ceftolozane and formylacetic acid, which was a by-product of tazobactam as illustrated in Marunaka et al. (Chem. Pharm. Bull. 1988, Vol. 36 (11), pp. 4478-4487). The stability data at 25° C. and at 40° C. have confirmed the continued formation of the compound RRT 1.22 over the course of time.
A low energy drum blender that agitates the material by tumbling and also moving the bed up and down is used. A representative process of blending is described as follows, also shown in
1Theoretical value: 33.96% Acceptance limits are 90%-110% of the theoretical value.
2Theoretical value: 16.99% Acceptance limits are 90%-110% of the theoretical value.
3 Three samples are taken at each time point at three places to measure the percentage by weight of ceftolozane and tazobactam. The “Mean” is the average of the percentages or the weight ratios of Ceftolozane/tazobactam.
4Acceptance limits were established based on batch history.
B. Packaging into Sterbags®
The blended powder is then discharged into Sterbags®.
A fill and finish process is utilized for the final drug product, which is a pharmaceutical composition comprising CXA-101 and tazobactam at a ratio of 1000 mg/500 mg. Glass vials are washed with WFI and depyrogenated in a Class 100 depyrogenation tunnel at a temperature of 320° C. Pre-washed and pre-siliconized stoppers are autoclaved for 40 minutes at 121° C. The bulk drug product is packaged in a Sterbag® system comprised of three bags. The outer bag is cleaned with disinfectant in a Class 10,000 clean room. The bag system is placed in a pass-through UV box where it is subjected to UV radiation (>20 μW/cm2) for 20 minutes to sterilize the surface of the outer bag. The outer bag is removed and left in the UV box. The middle bag is placed in a Class A laminar airflow (LAF) hood. The sterile middle bag is removed under LAF. The sterile, bottle-shaped inner bag is then placed in a sterile stainless steel carrier and attached to the filling machine.
Sterile bulk CXA-101/tazobactam drug product is filled under a nitrogen blanket into 30-mL, Type I clear glass vials. The sterile drug product is gravity-fed into the filling machine under LAF. Vial fill weights are periodically checked throughout the filling operation to ensure proper operation of the filling line. Filling and stoppering operations are performed under Class 100 LAF conditions. Capping and vial washing are done in the Class 10,000 clean room.
The blend drug product was prepared, as described above in Example 3, on lab scale using a small blender. The components of the blend composition are shown in Table 6.
Stability studies of this CXA-201 composition prepared by the blending process were carried out at 25° C. and 40° C. The composition was analyzed by HPLC. The following Tables 7 and 8 are summaries of the HPLC measurements at time zero, after one month (T1), and after three months (T2).
The data at both 25° C. and at 40° C. have shown that the blending process completely inhibits formation of the compound RRT=1.22.
A recently published (April 2013) Food and Drug Administration Guidance for Industry Non-Penicillin Beta-Lactam Drugs: A CGMP Framework for Preventing Cross-Contamination provides direction on prevention of cross-contamination for facilities that manufacture non-penicillin beta-lactam drugs. Provided herein are steps for the development and implementation of a system to prevent cross-contamination due to the introduction of both sterile ceftolozane drug product intermediate and tazobactam sodium into a facility that is in conformance with FDA Guidance.
Segregation steps to conform with FDA Guidance can include, but are not limited to:
An example of a batch formulae for ceftolozane composition (compounding of ceftolozane substance with excipients such as citric acid, sodium chloride, and L-arginine followed by sterile lyophilization) is found below in Table 9.
1)Ceftolozane sulfate is charged based on its measured potency to obtain 150 mg free base/g solution.
2) L-arginine is added as needed to obtain pH 6.5 ± 0.5 in the bulk solution; 90 mg per gram solution is considered a representative amount.
An example of a batch formula for the ceftolozane/tazobactam drug product is presented in Table 10 below.
1)The target fill for ceftolozane is 1000 mg free base, added to the vial as the composition. The amount 2255 mg is based on 100% theoretical potency of the composition. Actual weight will vary based on composition measured potency.
2)The target fill for tazobactam is 500 mg free acid, added to the vial as its sodium salt form. The amount 537 mg is based on 100% theoretical potency.
3)Nitrogen is used as a processing aid to blanket vials after powder filling and prior to insertion of stopper.
An example of the unit composition of ceftolozane/tazobactam drug product for injection is presented in Table 11 below.
1)Actual amount of ceftolozane composition will vary based on the measured potency. Ceftolozane sulfate, 1147 mg, corresponds to 1000 mg ceftolozane free base.
2)L-arginine is added as needed to achieve pH 6.5 ± 0.5; 600 mg per vial is considered a representative total amount.
3)Actual weight of tazobactam sodium will vary based on the measured potency. Tazobactam sodium 537 mg, corresponds to 500 mg tazobactam free acid
4)Nitrogen blanket is applied after powders are dispensed to the vial and prior to insertion of stopper.
As a product intended for intravenous use, several properties are important for physiological compatibility. These include particulate matter, sterility, endotoxin limit, pH, and osmolality. Particulate matter and sterility are controlled at the point of manufacture. The drug product is processed aseptically throughout the entire manufacturing process, inclusive of ceftolozane, tazobactam sodium, and ceftolozane/tazobactam in-vial drug product.
The ceftolozane/tazobactam drug product is controlled to a pH suitable for making an injectable product, e.g., 5-7, including 6-7, to provide physiological comfort, while still assuring adequate stability for the drug substances. The ceftolozane drug product intermediate is controlled during compounding to pH 6.5±0.5 and is controlled at release to pH 5 to 7. The tazobactam sodium is controlled at release to pH 5 to 7.
Ceftolozane/tazobactam following reconstitution with normal saline and dilution for infusion also in normal saline (10 mg/mL ceftolozane; 5 mg/mL tazobactam) is slightly hypertonic, with osmolality approximately 500 mOsm/kg. However, slightly hypertonic intravenous infusion solutions are not uncommon as drug products are commonly prepared and diluted with already-isotonic solutions, such as normal saline. The generally accepted maximum upper limit for peripheral intravenous administration is approximately 900 mOsm/kg, though admixtures 600 to 900 mOsm/kg are typically administered through a central line. Therefore, to be within the limits of this range, the infusion product is less than 600 mOsm/kg.
The excipients in ceftolozane composition were chosen to ensure stability and processability of the ceftolozane drug substance into the drug product. The specific excipients, their quantities and functions are provided in Table 12. All excipients are compendial and typical for sterile pharmaceutical dosage forms, requiring no additional treatment prior to use in the formulation. The excipients are used in levels within the range established in other FDA approved products as described in the Inactive Ingredients Database (IID).
1)L-arginine is added as needed to achieve pH 6.5 ± 0.5; 600 mg per vial is considered a representative total amount.
Unless otherwise indicated, HPLC measurements reported herein are obtained using a Develosil column ODS-UG-5; 5 micrometers; 250×4.6 mm, a mobile phase of sodium perchlorate buffer solution (pH 2.5)/CH3CN 90:10 (v/v) at a 1.0 mL/min flow rate and oven temperature of 45° C.
Sodium Perchlorate Buffer Solution was made by dissolving 14.05 g of sodium perchlorate Monohydrate in 1000.0 mL of water followed by adjusting pH to 2.5 with diluted perchloric acid (1 in 20),
Mobile Phase was then made by mixing Sodium Perchlorate. Buffer Solution (pH 2.5) and acetonitrile in the ratio 90:10 (v/v).
Sodium Acetate Buffer Solution pH 5.5 (Diluent) was made by dissolving 1.36 g of sodium acetate trihydrate in 1000.0 mL of water followed by adjusting to pH 5.5 with diluted acetic acid (1 in 10).
Sample solution: dissolve 20.0 mg, exactly weighed, of Sample, in 20.0 mL of water (Prepare just before injection into HPLC system).
System Suitability Solution (1%): take 1.0 mL of the Sample Solution (use first sample if more are present) and transfer into a 100.0 mL volumetric flask, dilute with water to volume and mix.
1. Inject Blank (water)
2. Inject System Suitability Solution and check for tailing factor and theoretical plate number for CXA-101 peak:
4. Inject System Suitability Solution and check for tailing factor and theoretical plate number for CXA-101 peak.
I. Report for each related substance its amount as expressed by area percent.
wherein:
Ci=Amount of related substance i in the Sample, area %
Ai=Peak area of related substance i in the Sample chromatogram
At=Area of CXA-101 peak in the Sample chromatogram
At+ΣAi=Total peaks area in the Sample chromatogram
Consider as any Unspecified Impurity, each peak in the chromatogram except CXA-101, peaks from 1 to 11 and every peak present in the blank chromatogram and report the largest.
II. Report the total impurities content as expressed by the following formula:
wherein:
CT=total impurities content in the Sample, area %
At=area of CXA-101 peak in the sample chromatogram
Σ Ai=total peak areas of impurities in the sample chromatogram
This application claims priority to U.S. Provisional Application No. 61/792,092, filed Mar. 15, 2013; U.S. Provisional Application No. 61/793,007, filed Mar. 15, 2013; U.S. Provisional Application No. 61/882,936, filed Sep. 26, 2013; and U.S. Provisional Application No. 61/893,436, filed Oct. 21, 2013. The contents of these applications are incorporated hereby by reference in their entirety.
| Number | Date | Country | |
|---|---|---|---|
| 61793007 | Mar 2013 | US | |
| 61792092 | Mar 2013 | US | |
| 61882936 | Sep 2013 | US | |
| 61893436 | Oct 2013 | US |
