HK1179115A

HK1179115A - Parenteral formulations of macrolide antibiotics

Info

Publication number: HK1179115A
Application number: HK13106355.1A
Authority: HK
Inventors: D.E.佩雷拉; P.费尔南德斯
Original assignee: 森普拉制药公司
Priority date: 2010-03-10
Filing date: 2011-03-10
Publication date: 2013-09-27

Abstract

Described herein are pharmaceutical compositions adapted for the parenteral administration of macrolide antibiotics, such as triazole-containing and fluoroketolide antibiotics. Also described herein are methods for their use in the treatment of bacterial, protozoal, and other infections.

Description

Parenteral formulations of macrolide antibiotics

Cross Reference to Related Applications

Priority of U.S. provisional application No. 61/312,417, filed 3/10/2010, the disclosure of which is incorporated by reference in its entirety, is claimed in this application as 35u.s.c § 119 (e).

Technical Field

The invention described herein relates to macrolide antibiotics, such as triazole-containing antibiotics and fluoroketolide antibiotics, suitable for parenteral administration. The invention described herein also relates to methods of using the pharmaceutical compositions for the treatment of bacterial, protozoal and other infections.

Background and summary of the invention

Macrolide antibiotics, characterized by a macrolide ring to which one or more deoxy sugars (usually erythromycaminos and desosamine) are attached, are antimicrobial drugs active against aerobic and anaerobic gram-positive cocci and are prescribed for the treatment of a variety of infections, including respiratory and soft tissue infections. Macrolides, which are natural products of the polyketide class, act by reversibly binding to the 50S subunit of bacterial ribosomes, blocking protein synthesis and preventing bacterial growth and reproduction. Although this effect is primarily bacteriostatic, certain fluoroketolides triazole-containing macrolides are bactericidal. Other macrolides may be bactericidal at higher concentrations.

Ketolides, which are semi-synthetic derivatives of the 14-membered macrolide erythromycin a, belong to the class of drugs used for the treatment of respiratory tract infections. These drugs are effective against macrolide-resistant bacteria because they are able to bind to two sites on the bacterial ribosome. Nevertheless, acquisition of bacterial resistance to macrolides may still occur, for example by post-transcriptional methylation of the 23S bacterial ribosome. This resistance results in cross-resistance to macrolides, lincomycins and streptogramins. Although rare, acquired resistance can also result from the production of drug inactivating enzymes such as esterases or kinases, as well as the production of active ATP-dependent efflux proteins that transport macrolides out of the cell. A significant portion of pneumococci are resistant to currently available antibiotics.

Erythromycin and the semi-synthetic derivatives azithromycin and clarithromycin belong to the class of marketed macrolide antibiotics. Telithromycin and cethromycin (cethromycin) belong to the ketolides of antibiotics. Oral administration has been achieved for a number of macrolides and ketolides including erythromycin, clarithromycin, telithromycin, and azithromycin. However, corresponding parenteral administration, such as Intravenous (IV) and Intramuscular (IM) administration of known macrolides and ketolides, especially approved macrolides such as erythromycin, clarithromycin, telithromycin and azithromycin, is limited by the pharmacologic pain following administration, QT prolongation observed, hepatotoxicity, inflammation and other adverse events. For example, erythromycin, clarithromycin, and azithromycin have been reported to cause pain when administered parenterally, which leads to limitations on their use, problems with patient compliance, and other disadvantages. In addition, it has been reported that clarithromycin and telithromycin cause unacceptable QT prolongation when administered parenterally. Without being bound by theory, it is believed herein that Pharmacokinetic (PK) and/or Pharmacodynamic (PD) characteristics associated with parenteral administration of approved macrolides cause and/or exacerbate one or both of these adverse events. Additionally, but not to be bound by theory, it is believed herein that the reported preferential tissue distribution of parenterally administered macrolides to myocardial tissue may also lead to and/or exacerbate QT prolongation.

Currently, areas outside the united states only approve both macrolides, clarithromycin and azithromycin, for Intravenous (IV) administration, while only azithromycin is approved in the united states. Currently, ketolides are not approved for parenteral administration in any part of the world. Even if approved, the use of IV administered clarithromycin and azithromycin may be severely limited by the aforementioned observed adverse events. Accordingly, there is a need for alternative parenteral formulations of macrolides, particularly ketolides, to address the ever-present problem of current and developing drug resistance, and for methods for treating bacterial, protozoal and other infections using such parenteral formulations. Provided herein are pharmaceutical compositions suitable for parenteral administration containing triazole antibiotics and fluoroketolide antibiotics, such as CEM-101 and related compounds, and methods of using them for the treatment of bacterial, protozoal, and other infections.

It has been found herein that triazole-containing antibiotics and fluoroketolide antibiotics, such as CEM-101 and related compounds, can be formulated for parenteral administration, including IV and IM administration. It has also been found herein that triazole-containing antibiotics and fluoroketolide antibiotics such as CEM-101 and related compounds do not cause pharmacological pain after injection. In addition, it has been found herein that triazole-containing antibiotics and fluoroketolide antibiotics, such as CEM-101 and related compounds, do not accumulate in myocardial tissue and do not cause QT prolongation.

In the international patent application published under number WO 2004/080391, a family of triazole-containing antibiotics and fluoroketolide antibiotics is disclosed. Illustrative examples of these antibiotics are compounds of the formula:

and pharmaceutically acceptable salts, hydrates, solvates, esters and prodrugs thereof, wherein:

R₁₀is hydrogen or acyl;

x is H; and Y is OR₇Wherein R is₇Is a monosaccharide or disaccharide, alkyl, aryl, heteroaryl, acyl; or C (O) NR₈R₉Wherein R is₈And R₉Each independently selected from the group consisting of: hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, heteroalkyl, aryl, heteroaryl, alkoxy, dimethylaminoalkyl, acyl, sulfonyl, ureido, and carbamoyl; or X and Y taken together with the attached carbon form a carbonyl;

v is C (O), C (═ NR)₁₁)、CH(NR₁₂，R₁₃) Or N (R)₁₄₎CH₂Wherein N (R)₁₄) To the C-10 carbon of the compound; wherein R is₁₁Is hydroxy or alkoxy, R₁₂And R₁₃Each independently selected from the group consisting of: hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureido, and carbamoyl; r₁₄Is hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureido, or ammoniaA formyl group;

w is H, F, Cl, Br, I or OH;

a is CH₂、C(O)、C(O)O、C(O)NH、S(O)₂、S(O)₂NH、C(O)NHS(O)₂；

B is (CH)₂)_nWherein n is an integer from 0 to 10, or B is an unsaturated carbon chain of 2 to 10 carbons; and is

C is hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, aminoaryl, alkylaminoaryl, acyl, acyloxy, sulfonyl, ureido, or carbamoyl, each of which is optionally substituted.

Another illustrative example of these compounds is CEM-101 having chemical abstracts accession number 760981-83-7 and the following structure:

and pharmaceutically acceptable salts, hydrates, solvates, esters and prodrugs thereof.

Detailed Description

CEM-101 and related compounds are highly potent macrolides that retain activity against drug resistant strains, including exhibiting potent activity against streptococcus pneumoniae (s. pneumoconiae), and have an extended spectrum of activity against community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA), enterococcus (enterococci), mycobacterium avium (m.avium), and show efficacy in animal malaria models. They also have activity against atypical bacteria such as legionella (Leginella), Mycoplasma (Mycoplasma) and Ureaplasma (ureapsma) as well as against gonococci and other organisms that cause urogenital infections. By way of illustration, CEM-101 is 8-16 times more potent than azithromycin and has activity against azithromycin resistant strains. Without being bound by theory, it is believed herein that the activity of CEM-101 and related compounds against resistant strains may be due to their ability to bind to three sites on bacterial ribosomes, as compared to one or two sites of currently available macrolides.

In one embodiment, a pharmaceutical composition suitable for parenteral administration (including IV and/or IM administration) is provided comprising one or more antibiotic compounds selected from the group consisting of: triazole-containing macrolides and ketolides, as well as fluoroketolides, such as CEM-101 and related compounds and combinations thereof. In another embodiment, the compound is a triazolofluoroketolide-containing compound. In another embodiment, the composition is a concentrate. In another embodiment, the composition is a solid, such as a lyophilized, freeze-dried, or spray-dried powder. In another embodiment, the composition can be diluted, redissolved, reconstituted and/or resuspended in one or more aqueous diluents such as water, including sterile water for injection (SWFI), prior to administration. In another embodiment, the composition further comprises one or more acidulants. In another embodiment, the composition further comprises one or more aqueous diluents. In another embodiment, the composition further comprises one or more stabilizers. In another embodiment, the composition further comprises one or more antioxidants. In another embodiment, the composition further comprises one or more excipients, such as fillers, flocculants, binders and the like.

In another embodiment, the compound is of the formula:

R₁₀is hydrogen or acyl;

x is H; and Y is OR₇(ii) a Wherein R is₇Is a monosaccharide or disaccharide, alkyl, aryl, heteroaryl, acyl; or C (O) NR₈R₉Wherein R is₈And R₉Each independently selected from the group consisting of: hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, heteroalkyl, aryl, heteroaryl, alkoxy, dimethylaminoalkyl, acyl, sulfonyl, ureido, and carbamoyl; or X and Y taken together with the attached carbon form a carbonyl;

v is C (O), C (═ NR)₁₁)、CH(NR₁₂，R₁₃) Or N (R)₁₄)CH₂Wherein N (R)₁₄) To the C-10 carbon of the compound; wherein R is₁₁Is hydroxy or alkoxy, R₁₂And R₁₃Each independently selected from the group consisting of: hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureido, and carbamoyl; r₁₄Is hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureido, or carbamoyl;

w is H, F, Cl, Br, I or OH;

a is CH₂、C(O)、C(O)O、C(O)NH、S(O)₂、S(O)₂NH、C(O)NHS(O)₂；

B is (CH2)_nWherein n is an integer from 0 to 10, or B is an unsaturated carbon chain of 2 to 10 carbons; and is

In another embodiment, a is CH₂. In another embodiment, B is alkenylene. In another embodimentWherein C is a substituted phenyl group. In another embodiment, C is aminophenyl. In another embodiment, C is 3-aminophenyl. In another embodiment, V is c (o). In another embodiment, W is fluoro. In another embodiment, W is hydrogen. In another embodiment, X and Y are taken together with the attached carbon to form a carbonyl. In another embodiment, R¹⁰Is hydrogen.

The antibiotic compound CEM-101 or related compound as described above may be prepared as described in WO 2004/080391 or WO 2009/055557, or by conventional procedures, or by procedures analogous to one of the procedures described or known.

In another embodiment, the compound is CEM-101 or one or more pharmaceutically acceptable salts, hydrates, solvates, esters, and prodrugs thereof, or a combination thereof.

In another embodiment, the composition is one in which the excipients include, but are not limited to, mannitol, sucrose, glycine, and combinations thereof.

In another embodiment, the composition is one in which the acidulant includes, but is not limited to, ascorbic acid, citric acid, and/or tartaric acid, or combinations thereof. In another embodiment, the acidulant is tartaric acid, such as L-tartaric acid.

In another embodiment of the composition, the concentration of the acidifying agent is from about 30mM to about 70 mM. In another embodiment of the composition, the concentration of the acidifying agent is from about 50mM to about 60 mM. In another embodiment of the composition, the concentration of the acidifying agent is about 60 mM. In another embodiment of the composition, the ratio of CEM-101 or related compound to acidulant is in the range of about 100:1 to about 2: 1. In another embodiment of the composition, the ratio of CEM-101 or related compound to acidulant is in the range of from about 20:1 to about 5: 1. In each of the foregoing embodiments, the composition may be used as a concentrate as described herein, or alternatively, may be used as a dried form of the composition, such as a lyophilized, freeze-dried, or spray-dried powder.

Another embodiment of the compositions herein is a composition as follows: it comprises a compound described herein, such as CEM-101 (about 5%), L- (+) -tartaric acid (about 0.6%), sodium hydroxide (about 0.05%) and water for injection (to 100%) on a weight to weight or weight to volume percentage basis. Another embodiment of the compositions herein is a composition as follows: it comprises on a weight to weight or weight to volume percent basis a compound described herein, such as CEM-101 (5.0%), L- (+) -tartaric acid (0.58%), sodium hydroxide (0.046%) and water for injection (to 100%). In one variation, the composition is a concentrate, which may be applied or adapted for dilution prior to application. In another variation, the composition is a dry residue or solid suitable for reconstitution as a concentrate that can be applied or suitable for dilution prior to application. In another variation, the composition is a dry residue or solid suitable for reconstitution in a diluent for application.

Another embodiment of the compositions herein is a composition as follows: it comprises a compound described herein, such as CEM-101 (about 5%), L- (+) -tartaric acid (about 0.6%), sodium hydroxide (about 0.05%), 1-thioglycerol (about 0.5%) and water for injection (to 100%) on a weight to weight or weight to volume percent basis. Another embodiment of the compositions herein is a composition as follows: it comprises on a weight to weight or weight to volume percent basis a compound described herein, such as CEM-101 (5.0%), L- (+) -tartaric acid (0.58%), sodium hydroxide (0.046%), 1-thioglycerol (0.50%) and water for injection (to 100%). In one variation, the composition is a concentrate, which may be applied or adapted for dilution prior to application. In another variation, the composition is a dry residue or solid suitable for reconstitution as a concentrate that can be applied or suitable for dilution prior to application. In another variation, the composition is a dry residue or solid suitable for reconstitution in a diluent for application.

Another embodiment of the compositions herein is a composition as follows: it comprises a compound described herein, such as CEM-101 (about 5%), L- (+) -tartaric acid (about 0.6%), sodium hydroxide (about 0.05%), mannitol (about 3-20%) and water for injection (to 100%) on a weight to weight or weight to volume percentage basis. Another embodiment of the compositions herein is a composition as follows: it comprises a compound described herein, such as CEM-101 (5.0%), L- (+) -tartaric acid (0.58%), sodium hydroxide (0.046%), mannitol (5.0%) and water for injection (to 100%) on a weight to weight or weight to volume percentage basis. Another embodiment of the compositions herein is a composition as follows: it comprises on a weight to weight or weight to volume percent basis a compound described herein, such as CEM-101 (5.0%), L- (+) -tartaric acid (0.58%), sodium hydroxide (0.046%), mannitol (10%) and water for injection (to 100%). In one variation, the composition is a concentrate, which may be applied or adapted for dilution prior to application. In another variation, the composition is a dry residue or solid suitable for reconstitution as a concentrate that can be applied or suitable for dilution prior to application. In another variation, the composition is a dry residue or solid suitable for reconstitution in a diluent for application.

Another embodiment of the compositions herein is a composition as follows: it comprises a compound described herein, such as CEM-101 (about 5%), L- (+) -tartaric acid (about 0.6%), sodium hydroxide (about 0.05%), mannitol (about 3-20%), 1-thioglycerol (about 0.5%) and water for injection (to 100%) on a weight to weight or weight to volume percentage basis. Another embodiment of the compositions herein is a composition as follows: it comprises on a weight to weight or weight to volume percent basis a compound described herein, such as CEM-101 (5.0%), L- (+) -tartaric acid (0.58%), sodium hydroxide (0.046%), mannitol (5.0%), 1-thioglycerol (0.50%) and water for injection (to 100%). Another embodiment of the compositions herein is a composition as follows: it comprises on a weight to weight or weight to volume percent basis a compound described herein, such as CEM-101 (5.0%), L- (+) -tartaric acid (0.58%), sodium hydroxide (0.046%), mannitol (10%), 1-thioglycerol (0.50%) and water for injection (to 100%). In one variation, the composition is a concentrate, which may be applied or adapted for dilution prior to application. In another variation, the composition is a dry residue or solid suitable for reconstitution as a concentrate that can be applied or suitable for dilution prior to application. In another variation, the composition is a dry residue or solid suitable for reconstitution in a diluent for application.

In another embodiment, the composition herein is a composition as follows: comprising about 50mg/mL of a compound described herein, such as CEM-101; about 50, about 100, or about 200mg/mL of one or more excipients, wherein the excipients are selected from the group consisting of mannitol, glycine, sucrose, and combinations thereof; about 6mg/mL of tartaric acid, such as L- (+) -tartaric acid; about 0.5mg/mL of sodium hydroxide; and sterile water for injection. In one variation, the total volume is 1mL, 2mL, 4mL, 8mL, or 16 mL.

In each of the foregoing embodiments, a lyophilized formulation may be prepared. The lyophilized formulation can be reconstituted for administration, for example, by dissolving in any of a variety of IV solutions, including but not limited to SWFI, PBS (such as physiological PBS), saline (such as physiological saline, 1N NaCl, 0.5N NaCl, etc.), D5W, Ringer's solution, and the like.

Another embodiment of the composition is a composition further comprising an alkalizing agent. In one embodiment, the alkalizing agent is sodium hydroxide. In one embodiment, the pH of the composition is not less than 2.5. In another embodiment, the pH of the composition is between about 3.7 and about 4.4. In another embodiment, the pH of the composition is between about 3.8 and about 4.2. In another embodiment, the pH of the composition is about 4. It will be understood that the relative amount of alkalizing agent may depend on the amount of acidifying agent, or the ratio of CEM-101 or related compound to acidifying agent.

One embodiment of the compositions herein is a composition wherein the concentration of CEM-101 is at least about 5 mg/mL. Another embodiment of the compositions herein is a composition wherein the concentration of CEM-101 is at least about 10 mg/mL. Another embodiment of the compositions herein is a composition wherein the concentration of CEM-101 is at least about 25 mg/mL. Another embodiment of the compositions herein is a composition wherein the concentration of CEM-101 is at least about 30 mg/mL. Another embodiment of the compositions herein is a composition wherein the concentration of CEM-101 is at least about 50 mg/mL. Another embodiment of the compositions herein is a composition wherein the concentration of CEM-101 is about 50 mg/mL. In another embodiment of the compositions herein, the concentration of CEM-101 or a related compound is less than about 100 mg/mL.

In one embodiment of the compositions herein, the saturated solubility of CEM-101 is at least about 50 mg/mL. In another embodiment of the compositions herein, the saturated solubility of CEM-101 is at least about 80 mg/mL. In another embodiment of the compositions herein, the concentration of CEM-101 or a related compound is less than about 100 mg/mL.

Another embodiment of the compositions herein is a composition further comprising an antioxidant and/or a chelating agent. In one embodiment, the chelating agent is EDTA. In one embodiment, the antioxidant is 1-thioglycerol (also known as thioglycerol or MTG). In one embodiment, the concentration of the antioxidant is about 5 mg/mL.

It will be appreciated that in each case the above compositions may alternatively be expressed on a weight to weight percent basis.

Examples of formulations of such pharmaceutical compositions comprising the antibiotic compound CEM-101 suitable for parenteral administration are provided in the examples below.

In one embodiment, the pharmaceutical composition described herein is administered directly. In another embodiment, the pharmaceutical composition described herein is administered after further dilution. In another embodiment, the pharmaceutical composition described herein is administered after further reconstitution, reconstitution and/or resuspension.

Another embodiment is a single or multiple dose pharmaceutical dosage unit comprising a therapeutically effective amount of a pharmaceutical composition suitable for parenteral administration as described herein. In one embodiment, the dosage unit is an ampoule, vial, pre-filled syringe or bag. In one embodiment, the dosage unit is a single dose unit. In another embodiment, the dosage unit is a multiple dosage unit.

A further embodiment is a method for preparing a pharmaceutical composition suitable for parenteral administration as described herein, comprising:

the desired amounts of tartaric acid and sodium hydroxide were dissolved in approximately 50-80% of the desired water for injection to form a first solution,

the desired amount of 1-thioglycerol is dissolved in the above solution to form another solution,

dissolving the desired amount of CEM-101 in the above solution, optionally adding more water for injection, and

the solution was made up to final volume with water for injection.

In each of the foregoing, one or more steps are optionally performed in an inert atmosphere, such as nitrogen and/or argon. In each of the foregoing, one or more steps are optionally performed with water for injection using a nitrogen spray and/or an argon spray. In another embodiment, the methods described herein comprise the step of nitrogen sparging and/or nitrogen purging.

In another embodiment, the methods described herein comprise the step of sterilizing the formulation. Sterilization may be performed by any conventional method steps, including but not limited to by autoclaving (terminal sterilization), such as at a temperature of about 100 ℃ to about 125 ℃, or at about 121 ℃; filtration is carried out by filtration, such as using SUPOR membrane filter (0.2 μm) -hydrophilic polyethersulfone, DURAPORE membrane filter (0.22 μm) -polyvinylidene fluoride (hydrophilic), NYLON membrane filter (0.2 μm) -hydrophilic NYLON, and the like.

In another embodiment, the compositions described herein are solids that can be redissolved, reconstituted or resuspended prior to use in preparing a composition for parenteral administration. By way of illustration, a solid is a powder, semi-crystalline or crystalline material prepared by lyophilization, freeze-drying, spray-drying, or the like. Solids include CEM-101 and/or related compounds including fluoroketolides, triazole-containing macrolides, triazole-containing ketolides, and triazole-containing fluoroketolides, and optionally one or more acidifying agents, basifying agents, and/or excipients, such as one or more fillers. It is understood herein that solids can be prepared from a solution of CEM-101 and/or related compounds, acidifying agents, and diluents. It will also be appreciated that solids may be prepared from a solution of CEM-101 and/or related compounds, acidifying agents, basifying agents, and diluents. It will also be appreciated that solids may be prepared from a solution of CEM-101 and/or related compounds, acidifying agents, basifying agents, fillers, and diluents. Without being bound by theory, it is believed herein that the one or more bulking agents may at least partially contribute to the resulting solid providing fast redissolution, reconstitution or re-suspension characteristics. Without being bound by theory, it is understood herein that excipients may contribute to the physiologically acceptable osmolarity of the formulation.

In another embodiment, the compositions described herein include a filler. Exemplary bulking agents include sugars or carbohydrates such as mannitol, sucrose, and the like; amino acids such as glycine and the like; and combinations thereof. In another embodiment, the ratio of bulking agent to CEM-101 or related compound is in the range of about 1:2 to about 10: 1. In another embodiment, the ratio of bulking agent to CEM-101 or related compound is in the range of about 1:1 to about 5: 1. In another embodiment, the ratio of bulking agent to CEM-101 or related compound is in the range of about 1:1 to about 4: 1.

Another embodiment is a lyophilized pharmaceutical composition suitable for dilution to provide a pharmaceutical composition for parenteral administration comprising CEM-101 or a related compound, an acidifying agent, an alkalinizing agent, and at least one additional excipient. In particular, the excipients may be used as fillers, tonicity adjusting agents, stabilizers, buffers, antioxidants and/or cryoprotectants.

In one embodiment of the lyophilized composition, the acidifying agent is ascorbic acid, citric acid, or tartaric acid. In another embodiment, the acidifying agent is L-tartaric acid. In one embodiment, L-tartaric acid is present in a ratio to CEM-101 or related compound in a range from about 0.01:1 to about 0.5: 1.

In one embodiment of the lyophilized composition, the alkalizing agent is sodium hydroxide.

One embodiment of the lyophilized composition comprises the excipients glycine, sucrose or mannitol or related bulking agents. In another embodiment, a bulking agent, such as mannitol, is present in a ratio to CEM-101 or related compound ranging from about 0.5:1 to about 5: 1. In another embodiment, the bulking agent is mannitol present in a ratio to CEM-101 or related compound ranging from about 1:1 to about 4: 1. In another embodiment, the bulking agent is glycine, which is present in a ratio to CEM-101 or related compound ranging from about 1:1 to about 4: 1. In another embodiment, the bulking agent is sucrose, which is present in a ratio to CEM-101 or related compound ranging from about 1:1 to about 4: 1.

In another embodiment, the composition comprises a stabilizer. Exemplary stabilizers include antioxidants, chelating agents, and the like, such as, but not limited to, ascorbic acid, cysteine, ethylenediaminetetraacetic acid (EDTA), glutathione, 1-thioglycerol, sodium bisulfite, sodium metabisulfite, and the like. Exemplary concentrations of stabilizers (including antioxidants) include, but are not limited to, 0.05%, 0.15%, 0.25%, 0.5%, and 1.0%, among others. Exemplary levels of antioxidants other than EDTA include, but are not limited to, 0.25%, 0.5%, and 1.0%, among others. Exemplary levels of EDTA include, but are not limited to, 0.05%, 0.15%, and 0.25%.

Another embodiment includes a single or multiple dose pharmaceutical dosage unit comprising a therapeutically effective amount of a lyophilized pharmaceutical composition as described herein. In one embodiment, the dosage unit is an ampoule or vial. In one embodiment, the dosage unit is a single dose unit. In one embodiment, the dosage unit is a multiple dosage unit.

Another embodiment includes a kit comprising a pharmaceutical dosage unit comprising a therapeutically effective amount of a lyophilized composition as described herein, and optionally further comprising a vehicle for diluting the pharmaceutical composition. In another aspect, the kit can include instructions for use. In one exemplary kit, CEM-101 or related compound is present in a single or multiple dose concentrate. It will be appreciated that the concentrate may be administered directly, or further diluted into a diluent for administration, such as a 500mL IV bag containing a suitable carrier, such as 0.5N or 1N saline, D5W, ringer's solution, PBS, and the like, as described herein.

In another exemplary kit, CEM-101 or related compound is present as a single dose or multiple dose solid. In one variation, the kit also includes a reconstitution solution. It will be appreciated that the reconstituted solution may be used to prepare a concentrate for direct administration or further dilution into a diluent for administration, such as a 500mL IV bag containing a suitable carrier, such as 0.5N or 1N saline, D5W, ringer's solution, PBS, and the like, as described herein.

It will be understood in the description and claims herein that CEM-101, which is basic, and related compounds, which are basic, will be present in protonated form in the acid-containing solution. Thus, CEM-101 and related compounds represent not only the free base, but also the protonated form in the case of pharmaceutical compositions suitable for parenteral administration. It will be understood that the acidifying agent and the alkalizing agent as described herein form a buffer when used together in an aqueous system, and are optionally represented as, for example, L-tartaric acid/NaOH buffers, citric acid/NaOH buffers, and the like.

As used herein, the term "alkyl" includes a chain of carbon atoms, which is optionally branched. As used herein, the terms "alkenyl" and "alkynyl" include chains comprising carbon atoms, which are optionally branched, and include at least one double or triple bond, respectively. It is understood that alkynyl groups may also include one or more double bonds. It is also understood that in certain embodiments, alkyl groups are advantageousThe ground has a finite length, including C₁-C₂₄、C₁-C₁₂、C₁-C₈、C₁-C₆And C₁-C₄. It is also to be understood that in certain embodiments, alkenyl and/or alkynyl groups may advantageously each have a finite length, including C₂-C₂₄、C₂-C₁₂、C₂-C₈、C₂-C₆And C₂-C₄. It is understood herein that shorter alkyl, alkenyl and/or alkynyl groups may add less lipophilicity to the compound and thus will have different pharmacokinetic properties. Exemplary alkyl groups are, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, heptyl, octyl and the like.

As used herein, the term "cycloalkyl" includes chains of carbon atoms, which are optionally branched, wherein at least a portion of the chains are cyclic. It is understood that cycloalkylalkyl is a subset of cycloalkyl. It is understood that the cycloalkyl group can be polycyclic. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, 2-methylcyclopropyl, cyclopentylethyl-2-yl, adamantyl, and the like. As used herein, the term "cycloalkenyl" includes a chain of carbon atoms, which is optionally branched, and includes at least one double bond, wherein at least a portion of the chain is cyclic. It is understood that one or more double bonds can be located within the cyclic portion of the cycloalkenyl group and/or within the non-cyclic portion of the cycloalkenyl group. It is understood that cycloalkenylalkyl and cycloalkenylalkenyl are each a subset of cycloalkenyl. It is understood that the cycloalkyl group can be polycyclic. Exemplary cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexylethylene-2-yl, cycloheptenylpropenyl, and the like. It will also be appreciated that the chains forming the cycloalkyl and/or cycloalkenyl groups advantageously have a limited length, including C₃-C₂₄、C₃-C₁₂、C₃-C₈、C₃-C₆And C₅-C₆. It is understood herein that shorter alkyl and/or alkenyl chains forming cycloalkyl and/or cycloalkenyl groups, respectively, add to the compoundLess lipophilic and will therefore have different pharmacokinetic properties.

As used herein, the term "heteroalkyl" includes a chain of atoms (including carbon and at least one heteroatom) and is optionally branched. Exemplary heteroatoms include nitrogen, oxygen, and sulfur. In certain variations, exemplary heteroatoms further include phosphorus and selenium. As used herein, the term "cycloheteroalkyl," including heterocyclyl and heterocyclic rings, includes chains of atoms (including carbon and at least one heteroatom), such as heteroalkyl, and optionally branched, wherein at least a portion of the chain is cyclic. Exemplary heteroatoms include nitrogen, oxygen, and sulfur. In certain variations, exemplary heteroatoms further include phosphorus and selenium. Exemplary cycloheteroalkyl groups include, but are not limited to, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl, quinuclidinyl, and the like.

As used herein, the term "aryl" includes monocyclic and polycyclic aromatic carbocyclic groups, each of which may be optionally substituted. Exemplary aromatic carbocyclic groups described herein include, but are not limited to, phenyl, naphthyl, and the like. As used herein, the term "heteroaryl" includes aromatic heterocyclic groups, each of which may be optionally substituted. Exemplary aromatic heterocyclic groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, quinolinyl, quinazolinyl, quinoxalinyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, and the like.

As used herein, the term "amino" includes the group NH₂Alkylamino and dialkylamino wherein the two alkyl groups in the dialkylamino group can be the same or different, i.e. alkylalkylamino. The amino group includes, for example, a methylamino group, an ethylamino group, a dimethylamino group, and a methylethylamino group. In addition, it will be understood that when an amino group is modified or modified by another term, such as aminoalkyl or acylamino, the foregoing of the term aminoVariations are included. Illustratively, aminoalkyl includes H₂N-alkyl, methylaminoalkyl, ethylaminoalkyl, dimethylaminoalkyl, methylethylaminoalkyl, and the like. As an illustration, acylamino includes acylamino, and the like.

As used herein, the term "amino and derivatives thereof" includes amino as described herein, as well as alkylamino, alkenylamino, alkynylamino, heteroalkylamino, heteroalkenylamino, heteroalkynylamino, cycloalkylamino, cycloalkenylamino, cycloheteroalkylamino, cycloheteroalkenylamino, arylamino, arylalkylamino, arylalkenylamino, arylalkynylamino, heteroarylamino, heteroarylalkylamino, heteroarylalkenylamino, heteroarylalkynylamino, acylamino, and the like, each of which is optionally substituted. The term "amino derivative" also includes urea, carbamate, and the like.

As used herein, the term "hydroxy and derivatives thereof" includes OH, as well as alkoxy, alkenyloxy, alkynyloxy, heteroalkoxy, heteroalkenyloxy, heteroalkynyloxy, cycloalkoxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, arylalkoxy, arylalkenyloxy, arylalynyloxy, heteroaryloxy, heteroarylalkoxy, heteroarylalkenyloxy, heteroarylalkynyloxy, acyloxy, and the like, each of which is optionally substituted. The term "hydroxy derivative" also includes carbamates and the like.

As used herein, the term "thio and derivatives thereof" includes SH, as well as alkylthio, alkenylthio, alkynylthio, heteroalkylthio, heteroalkenylthio, heteroalkynylthio, cycloalkylthio, cycloalkenylthio, cycloheteroalkylthio, cycloheteroalkenylthio, arylthio, arylalkylthio, heteroarylthio, heteroarylalkylthio, heteroarylalkenylthio, heteroarylalkynylthio, acylthio, and the like, each of which is optionally substituted. The term "thio derivative" also includes thiocarbamates and the like.

As used herein, the term "acyl" includes formyl, and alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, heteroalkylcarbonyl, heteroalkenylcarbonyl, heteroalkynylcarbonyl, cycloalkylcarbonyl, cycloalkenylcarbonyl, heterocycloalkylcarbonyl, heterocycloalkenylcarbonyl, arylcarbonyl, arylalkylcarbonyl, arylalkenylcarbonyl, arylalkynylcarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl, heteroarylalkenylcarbonyl, heteroarylalkynylcarbonyl, acylcarbonyl, and the like, each of which is optionally substituted.

As used herein, the term "carbonyl and derivatives thereof" includes the groups c (o), c(s), c (nh), and substituted amino derivatives thereof.

As used herein, the term "sulfonyl group or derivative thereof" includes SO₃H and salts thereof, and esters and amides thereof.

As used herein, the term "optionally substituted" includes replacement of a hydrogen atom with another functional group on the optionally substituted group. Such other functional groups illustratively include, but are not limited to, amino, hydroxyl, halo, mercapto, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, nitro, sulfonic acids and derivatives thereof, carboxylic acids and derivatives thereof, and the like. Illustratively, any of amino, hydroxyl, mercapto, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, and/or sulfonic acid is optionally substituted.

As used herein, the terms "optionally substituted aryl" and "optionally substituted heteroaryl" include replacement of a hydrogen atom with another functional group on the optionally substituted aryl or heteroaryl. Such other functional groups illustratively include, but are not limited to, amino, hydroxyl, halo, thio, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, nitro, sulfonic acids and derivatives thereof, carboxylic acids and derivatives thereof, and the like. Illustratively, any of amino, hydroxy, thio, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, and/or sulfonic acid is optionally substituted.

Exemplary substituents include, but are not limited to, the group- (CH)₂)_xZ^XWherein x is an integer of 0 to 6, and Z^XSelected from halogen, hydroxy, alkanoyloxy (including C)₁-C₆Alkanoyloxy), optionally substituted aroyloxy, alkyl (including C)₁-C₆Alkyl), alkoxy (including C)₁-C₆Alkoxy), cycloalkyl (including C)₃-C₈Cycloalkyl), cycloalkoxy (including C)₃-C₈Cycloalkoxy), alkenyl (including C)₂-C₆Alkenyl), alkynyl (including C)₂-C₆Alkynyl), haloalkyl (including C)₁-C₆Haloalkyl), haloalkoxy (including C)₁-C₆Haloalkoxy), halocycloalkyl (including C)₃-C₈Halocycloalkyl), halocycloalkoxy (including C)₃-C₈Halogenated cycloalkoxy), amino, C₁-C₆Alkylamino radical, (C)₁-C₆Alkyl) (C₁-C₆Alkyl) amino, alkylcarbonylamino, N- (C)₁-C₆Alkyl) alkylcarbonylamino, aminoalkyl, C₁-C₆Alkylaminoalkyl, (C)₁-C₆Alkyl) (C₁-C₆Alkyl) aminoalkyl, alkylcarbonylaminoalkyl, N- (C)₁-C₆Alkyl) alkylcarbonylaminoalkyl, cyano or nitro; or Z^XSelected from-CO 2R⁴and-CONR⁵R⁶Wherein each occurrence of R⁴、R⁵And R⁶Each independently selected from hydrogen and C₁-C₆Alkyl, aryl-C₁-C₆Alkyl and heteroaryl-C₁-C₆An alkyl group.

Monosaccharides (monosaccharide/simple surgar) consist of a single polyhydroxyaldehyde or ketone unit. Representative monosaccharides include, by way of example only, hexoses such as D-glucose, D-mannose, D-xylose, D-galactose, L-fucose and the like; pentoses such as D-ribose or D-arabinose; and ketoses such as D-ribulose or D-fructose. Disaccharides contain two monosaccharide units joined by glycosidic bonds. Disaccharides include, for example, sucrose, lactose, maltose, cellobiose, and the like. Oligosaccharides typically contain 2 to 10 monosaccharide units linked by glycosidic linkages.

The term "prodrug" as used herein generally refers to any compound that, when administered to a biological system, produces a biologically active compound as a result of one or more spontaneous chemical reactions, enzymatic chemical reactions, and/or metabolic chemical reactions, or a combination thereof. In vivo, prodrugs are usually acted upon by enzymes (such as esterases, amidases, phosphatases, etc.) in vivo by simple biochemical or other processes to release or regenerate the more pharmacologically active drug. Such activation may be by the action of endogenous host enzymes or non-endogenous enzymes administered to the host before, after or during administration of the prodrug. Other details of prodrugs are described in U.S. patent No. 5,627,165; and Pathalk et al, enzymatic protective group technologies in organic synthesis, Stereosel.Biocat.775-797 (2000). It will be appreciated that the prodrug is advantageously converted to the original drug as soon as possible after achieving the goal (such as targeted delivery, safety, stability, etc.), and then the release residue of the group forming the prodrug is subsequently rapidly eliminated.

Prodrugs can be prepared by attaching groups which ultimately cleave in vivo into one or more functional groups present on the compound (such as-OH-, -SH, -CO)₂H、-NR₂) But are prepared from the compounds described herein. Exemplary prodrugs include, but are not limited to, carboxylic acid esters, wherein the group is alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl; and esters of hydroxy, mercapto and amine, wherein the attached groups are acyl groups, alkoxycarbonyl, aminocarbonyl; a phosphate or a sulfate. Exemplary esters also refer to active esters, including but not limited to 1-indanyl, N-oxysuccinimide; acyloxyalkyl radicals, such as acetoxymethyl, pivaloyloxymethyl, beta-acetoxyethyl, beta-pivaloyloxyethyl, 1- (cyclohexylcarbonyloxy) prop-1-yl, (1-aminoethyl) carbonylOxymethyl groups and the like; alkoxycarbonyloxyalkyl groups such as ethoxycarbonyloxymethyl, α -ethoxycarbonyloxyethyl, β -ethoxycarbonyloxyethyl and the like; dialkylaminoalkyl groups, including di-lower alkylaminoalkyl groups, such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl, diethylaminoethyl, and the like; 2- (alkoxycarbonyl) -2-alkenyl groups such as 2- (isobutoxycarbonyl) pent-2-enyl, 2- (ethoxycarbonyl) but-2-enyl, and the like; and lactone groups such as phthalidyl, dimethoxyphthalidyl, and the like.

Additional exemplary prodrugs contain chemical moieties, such as amide or phosphorus groups, that function to increase the solubility and/or stability of the compounds described herein. Additional exemplary prodrugs for amino groups include, but are not limited to, (C3-C20) alkanoyl; halo- (C3-C20) alkanoyl; (C3-C20) alkenoyl; (C4-C7) cycloalkoyl; (C3-C6) -cycloalkyl (C2-C16) alkanoyl; optionally substituted aroyl, such as unsubstituted aroyl or aroyl substituted with 1 to 3 substituents selected from the group consisting of: halogen, cyano, trifluoromethanesulfonyloxy, (C1-C3) alkyl and (C1-C3) alkoxy, each of which is optionally further substituted with one or more of 1 to 3 halogen atoms; optionally substituted aryl (C2-C16) alkanoyl and optionally substituted heteroaryl (C2-C16) alkanoyl, such as aryl or heteroaryl groups which are unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of: halogen, (C1-C3) alkyl, and (C1-C3) alkoxy, each of which is optionally further substituted with 1 to 3 halogen atoms; and optionally substituted heteroarylalkanoyl having 1 to 3 heteroatoms selected from O, S and N in the heteroaryl portion and 2 to 10 carbon atoms in the alkanoyl portion, such as a heteroaryl group that is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of: halogen, cyano, trifluoromethanesulfonyloxy, (C1-C3) alkyl and (C1-C3) alkoxy, each of which is optionally further substituted by 1 to 3 halogen atoms. The groups shown are exemplary, not exhaustive, and can be prepared by conventional procedures.

It is understood that a prodrug may not possess significant biological activity itself, but rather undergoes one or more spontaneous, enzymatic, and/or metabolic chemical reactions, or a combination thereof, upon in vivo administration to produce a compound described herein that is biologically active or a precursor of a biologically active compound. It will be appreciated, however, that in some instances, the prodrug is biologically active. It will also be appreciated that prodrugs may improve drug efficacy or safety, typically through improved oral bioavailability, pharmacodynamic half-life, and the like. Prodrugs also refer to derivatives of the compounds described herein that include groups that simply mask undesirable drug properties or improve drug delivery. For example, one or more of the compounds described herein may exhibit undesirable properties that are advantageously blocked or reduced, which may be a pharmacological, pharmaceutical, or pharmacokinetic disorder in clinical drug applications, such as low oral drug absorption, lack of site specificity, chemical instability, toxicity, and poor patient acceptance (bad taste, odor, injection site pain, etc.), among others. It is understood herein that prodrugs or strategies using reversible derivatives may be used to optimize the clinical application of the drug.

As used herein, the term "composition" generally refers to any product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. It is to be understood that the compositions described herein can be prepared from the isolated compounds described herein or from the salts, solutions, hydrates, solvates, and other forms of the compounds described herein. It is also to be understood that the compositions can be prepared from various amorphous, non-amorphous, partially crystalline, and/or other morphological forms of the compounds described herein. It is also understood that the compositions can be prepared from various hydrates and/or solvates of the compounds described herein. Accordingly, reference to such pharmaceutical compositions of the compounds described herein should be understood to include each and any combination of the various morphological forms and/or solvate or hydrate forms of the compounds described herein. Illustratively, the composition may include one or more carriers, diluents, and/or excipients. The compounds described herein or compositions containing them can be formulated in therapeutically effective amounts in any conventional dosage forms suitable for use in the methods described herein. The compounds described herein, or compositions containing them, including such formulations, can be administered by a variety of conventional routes and in a variety of dosage forms for The methods described herein using known procedures (see generally, The Science and practice of Pharmacy, 21 st edition, 2005)).

As used herein, the term "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated. In one aspect, a therapeutically effective amount is an amount that can treat or alleviate a disease or a symptom of a disease at a reasonable benefit/risk ratio applicable to any drug treatment. It will be understood, however, that the total daily amount of the compounds and compositions described herein can be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for a particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the specific composition employed; the age, weight, general health, sex, and diet of the patient; time of administration, route of administration, and rate of excretion of the particular compound employed; the duration of the treatment; drugs used in combination or concomitantly with the specific compound employed; and similar factors well known to researchers, veterinarians, physicians, or other physicians having ordinary skill.

Macrolides such as erythromycin, clarithromycin, and azithromycin have been reported to cause pain upon parenteral administration. As described herein, it has been found that CEM-101 and related compounds cause little or no pain after injection compared to other macrolide and ketolide antibiotics. Another embodiment is a pharmaceutical composition suitable for parenteral administration comprising antibiotic compound CEM-101 or a related compound as described herein, which is painless or substantially painless after parenteral administration.

Macrolides such as clarithromycin, and especially other ketolides such as telithromycin, have been reported to cause the QT effect. In addition, clarithromycin has been reported to accumulate in cardiac muscle tissue. Thus, while not being bound by theory, it is believed herein that such high cardiac levels may lead to QT effects, such as QT prolongation observed with macrolides and ketolides. Without being bound by theory, it is also believed herein that this QT effect is exacerbated by Pharmacokinetics (PK) and Pharmacodynamics (PD) associated with parenteral delivery when compared to oral delivery. Such PK and PD may limit the use of clarithromycin due to the potential for a higher than expected Cmax and earlier than expected Tmax. As described herein, CEM-101 and related compounds have been found to cause low or no QT effect compared to other macrolides and especially ketolides. It has been found herein that CEM-101 and related compounds do not exhibit high myocardial tissue levels compared to other macrolides and ketolides. Thus, while not being bound by theory, it is believed herein that low cardiac levels may result in a low QT effect or the complete absence of a QT effect, such as QT prolongation.

It has also been found that parenteral administration of CEM-101 and related compounds can be rapid. Without being bound by theory, it is believed that other known macrolides and ketolides cannot be administered rapidly due to the undesirable concomitant effects associated with the PK of the compound upon parenteral administration compared to PK following oral administration. For example, it will be appreciated that parenteral administration may result in a higher Cmax and/or a shorter Tmax than other routes of delivery used (such as the oral route) when other macrolides and ketolides are administered. Thus, side effects associated with those altered PK parameters, such as QT prolongation and pain, may cause further problems when other macrolides and ketolides are administered parenterally. Thus, it may be necessary to try to administer other macrolides and ketolides more slowly to balance PK and PD associated with parenteral administration with undesirable side effects (such as QT effects, pain and inflammation).

Without being bound by theory, it is believed herein that the relatively low pH of known parenteral compositions contributes to, exacerbates, or causes inflammation. Without being bound by theory, it is believed herein that slow administration of a low pH composition may contribute to, exacerbate, or cause inflammation at the site of administration due to prolonged pH changes. Thus, current parenteral formulations of macrolides may be limited or excluded due to inflammatory side effects. It has been found herein that rapid infusion of parenteral compositions can reduce and/or avoid inflammatory reactions in patients. However, as described herein, current rapid infusion of macrolides and ketolides is precluded due to other undesirable side effects that may accompany rapid infusion.

It has also been found that CEM-101 and related compounds can be rapidly infused and/or administered without concomitant side effects (such as pain and/or QT effects) and/or inflammation caused by prolonged pH changes at or near the site of administration. Thus, also described herein are compositions and methods suitable for parenteral administration of CEM-101 and related compounds.

Current formulations of erythromycin and clarithromycin include lactobionic acid in a ratio of at least 1:1 to overcome the poor solubility of macrolides. Similarly, current formulations of azithromycin include citric acid in a ratio of at least 1:1 to overcome the poor solubility of macrolides. It has been unexpectedly found that CEM-101 and related compounds can be solubilized with significantly lower relative amounts of acidifying agent. For example, a clear solution of CEM-101 and related compounds is obtained with an acidifying agent, such as tartaric acid, in a ratio of about 1:2, 1:5, 1:10, etc., to CEM-101.

As another embodiment of the present invention, there is provided a method of treating a bacterial infection, a protozoal infection, or a disorder associated with a bacterial infection or protozoal infection, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition suitable for parenteral administration comprising the antibiotic compound CEM-101 or a related compound as described herein.

As another embodiment of the invention, there is provided the use of a pharmaceutical composition suitable for parenteral administration comprising the antibiotic compound CEM-101 or a related compound as described herein for the treatment of a bacterial infection, a protozoal infection, or a disorder associated with a bacterial infection or protozoal infection.

As another embodiment of the invention, there is provided the use of a pharmaceutical composition suitable for parenteral administration comprising the antibiotic compound CEM-101 or a related compound as described herein for the manufacture of a medicament for the treatment of a bacterial infection, a protozoal infection, or a disorder associated with a bacterial infection or protozoal infection.

As another embodiment, the above method or use is wherein the subject is a mammal, a fish, a bird, or a reptile. As another embodiment, a method or use is provided wherein the subject is a mammal. As another embodiment, a method or use is provided wherein the subject is a human.

In an exemplary embodiment, the use or method described herein is for treating moderate or severe Community Acquired Pneumonia (CAP). Thus, the method comprises parenterally administering one or more compounds described herein to a patient having or in need of CAP relief.

In another embodiment, the use or method described herein is for treating severe Community Acquired Pneumonia (CAP). One embodiment is as follows, which includes the uses and methods described herein and additionally includes parenteral co-administration of CEM-101 or a related compound and another antibiotic for the treatment of severe CAP.

In another embodiment, the use or method described herein is for the treatment of syphilis. In another embodiment, the use or method described herein is for the treatment of a gonococcal infection, such as gonococcal urethritis. It will be appreciated herein that oral administration requiring multiple doses in the treatment of syphilis and/or gonococcal infections such as gonococcal urethritis is not optimal. It will also be appreciated that parenteral administration of the compositions described herein may comprise a single administration dose. In another embodiment, described herein is a method for treating syphilis and/or gonococcal infections such as gonococcal urethritis, wherein the method comprises the step of parenterally administering the composition described herein. In another embodiment, described herein is a method for treating syphilis and/or gonococcal infections such as gonococcal urethritis, wherein the method comprises the step of parenterally administering a single dose of the composition described herein.

Another embodiment is the method or use described herein, wherein the parenteral administration comprises intravenous injection. In one embodiment, the intravenous injection is a continuous infusion. In another embodiment, the intravenous injection is a bolus injection.

Another embodiment is the method or use described herein, wherein the parenteral administration comprises intramuscular injection. In one embodiment, the intramuscular injection is a continuous infusion. In another embodiment, the intramuscular injection is a bolus injection.

The following examples further illustrate specific embodiments of the present invention; however, the following illustrative examples should not be construed as limiting the invention in any way.

Examples

For any of the embodiments herein that include CEM-101, the source of CEM-101 may be in any form or mixture thereof, including a solution, suspension, or solid. The solid form may be an amorphous form or one or more crystalline forms, or a mixture thereof. An exemplary crystal form of CEM-101 is described in U.S. provisional application No. 61/316,063, the disclosure of which is incorporated herein by reference.

Example 1 pharmaceutical composition of CEM-101 containing an antioxidant for parenteral administration in buffered solution. This example provides a method for preparing a 50mg/mL IV solution at pH 3.7-4.2 (target 3.8) on a laboratory scale (typically 10 to 500 mL) for administration of CEM-101 as a bolus or by infusion. CEM-101 drug substance should be protected from light when in solution and from oxidation by nitrogen spraying and purging. The amounts in the table below are for a 1mL ratio.

The method comprises the following steps: optionally using nitrogen spray water for injection (WFI) for the preparation process, and also optionally purging the headspace within each vial with nitrogen prior to dimpling (crimp); weighing the required amounts of tartaric acid and sodium hydroxide into an amber volumetric flask; dispense approximately 80% of the required volume of nitrogen sparged WFI into volumetric flasks, ensure complete dissolution of all or substantially all solid materials by sonication or stirring with a magnetic bar; ensuring that the solution is completely or substantially clear; the required amount of 1-thioglycerol was added and complete dissolution was ensured by stirring with a magnetic bar; adding the required amount of the raw material medicine, and ensuring the complete dissolution of the raw material medicine by stirring or ultrasonic treatment; ensure that the resulting solution is clear. If the drug substance is not readily soluble, optionally more nitrogen sparged WFI is added and mixing is performed by stirring and sonication. The stir bar was removed and WFI was sparged with nitrogen to make up to the final volume. Ensure that the resulting solution is clear.

For every 1mL of brown clear solution, using 2mL amber vial and a fluoroetec west RS 13mm injection plug, the resulting solution (a) is filled into amber vials, purged with nitrogen, corrugated and terminally sterilized with an autoclave; or (b) sterile filtered through a 0.2 μm pore size Fluorodyne filter, filled into amber vials, purged with nitrogen and corrugated.

Example 2 CEM-101 compositions for parenteral administration in buffered solution. This example provides a method for preparing a 50mg/mL IV solution at pH 3.7-4.2 (target 3.8) on a laboratory scale (typically 10 to 500 mL) for administration of CEM-101 as a bolus or by infusion. CEM-101 drug substance should be protected from light when in solution and from oxidation by nitrogen spraying and purging. The amounts in the table below are for a 1mL ratio.

Nitrogen sparged water for injection (WFI) was used for the preparation process and the headspace in each vial was also purged with nitrogen prior to dimpling. The required amounts of tartaric acid and sodium hydroxide were weighed into an amber volumetric flask. The desired volume of about 80% of the nitrogen sparged WFI was dispensed into the volumetric flask. All or substantially all of the solid material is ensured to be completely dissolved by sonication or stirring with a magnetic bar. Ensure that the solution is completely clear. The required amount of drug substance is then added and complete dissolution of the drug substance is ensured by stirring or sonication. Ensure that the resulting solution is clear. If the drug substance is not readily soluble, more nitrogen sparged WFI is added and mixing is performed by stirring and sonication. The stir bar was removed and WFI was sparged with nitrogen to make up to the final volume. Ensure that the resulting solution is clear.

Example 3a. study in CEM-101 composition for parenteral administration in unbuffered solution and 0.9% NaCl solution (-5% w/v CEM-101). 51.38mg CEM-101 was dissolved in 1mL of 60mM tartaric acid (pH 2.16) and allowed to mix overnight. The resulting clear solution (50.4 mg/mL by HPLC) was divided into two portions by pipetting 0.1mL (5% initial formulation) and to the residue was added 0.9% w/v NaCl (5% NaCl formulation). Upon addition of NaCl, the resulting solution became clear after 1 hour of mixing (53.0 mg/mL by HPLC). Thus, the incorporation of 0.9w/v% NaCl in a tartaric acid solution containing about 50mg/mL CEM-101 did not have any effect on the solubility of CEM-101; and an IV formulation with a drug load of no more than 5% (equivalent to 50mg/mL) will not cause precipitation of CEM-101 upon addition of 0.9% NaCl under ambient conditions.

The physical stability of the above formulations upon storage was evaluated by storing in a 4 ℃ refrigerator and checking the precipitation. Samples prepared as above for the 5% starting formulation were kept in solution for at least 3 days; however, after 1 night, precipitation occurred in the 5% NaCl formulation.

Example 3b. study in CEM-101 composition for parenteral administration in unbuffered solution and 0.9% NaCl solution (-8% w/v CEM-101). Approximately 90mg of CEM-101 was dissolved in 1mL of 60mM tartaric acid (pH 2.16) and allowed to mix overnight. The resulting clear solution (83.0 mg/mL by HPLC, saturated solubility) was divided into two portions by pipetting 0.1mL (8% initial formulation) and 0.9% w/v NaCl (8% NaCl formulation) was added to the residue. Upon addition of NaCl, the resulting solution formed white lumps or spheres, indicating that the addition of 0.9% NaCl caused precipitation of CEM-101. The resulting solution was mixed for about 2 hours and then CEM-101 was measured by HPLC to be 3.9 mg/mL. Thus, the maximum solubility observed for CEM-101 in tartaric acid was 83.0mg (approximately 8%) 60% higher than the target dose (50mg/mL, 5% drug loading) for the CEM-101IV formulation.

Example 4. pharmaceutical composition of CEM-101 containing mannitol and antioxidant for parenteral administration in buffered solution.

a. Preparation of vehicle (also used as control):

an illustration of the final volume of 1000mL of vehicle will be generated:

1. approximately 600g of sterile water for injection, USP, was weighed.

2. 30g of mannitol were added.

3. Weigh and add 5.773g L (+) -tartaric acid.

4. 11.5g of 1N NaOH were added and mixed until clear.

5. 5g of 1-thioglycerol are weighed into a glove box under nitrogen, added to the solution, mixed and the pH measured.

6. The pH was adjusted to 4.2. + -. 0.2 with 0.1 or 1N NaOH or HC 1.

7. QS was performed with sterile water for injection to a final volume of 1000 mL.

The vehicle formulation can be mixed on a stir plate with a stir bar.

Preparation of CEM-101 stock solution (5mg/mL CEM-101):

1. approximately 60ML of the vehicle described above was measured.

2. 525mg (in this case 500mg corrected for purity, correction factor 1.05) of CEM-101 are weighed into the vehicle, mixed and the pH measured.

3. The pH was adjusted to 4.2. + -. 0.2 with 0.1 or 1N NaOH or HC 1.

4. QS was performed with the control/vehicle article formulation to a final volume of 100 mL.

The stock solution can be mixed on a stir plate with a stir bar. Stock solutions can also be prepared using glass rods and/or sonication.

c, preparation of CEM-101 administration preparation:

1. an appropriate volume of stock solution (5mg/mL CEM-101) was measured.

2. Stock solutions were diluted with appropriate volumes of the above vehicle to achieve the desired concentration.

3. Mix and measure pH.

The formulations can be mixed on a stir plate with a stir bar or by inversion.

Each final dosing formulation (including control/vehicle) was filtered through a 0.22 μm PVDF filter.

Example 5 solubility of CEM-101 in a range of vehicles. Approximately 50mg of CEM-101 was dissolved in each of the vehicles detailed in the table below and allowed to mix on a roller mixer for at least 48 hours. Additional CEM-101 was added to the vehicle which completely dissolved the CEM-101API over 24 hours.

The samples were allowed to mix for a total of 72 hours. Once mixed, the samples were visually evaluated, centrifuged, and then diluted to the appropriate concentration for analysis by HPLC to determine saturation solubility.

Saturation and visual solubility of CEM-101 in a series of vehicles

Visual solubility evaluations were repeated on these vehicles to confirm the initial results (see table below).

Without being bound by theory, it is believed herein that the vehicle is an in situ salt-forming compound when mixed with CEM-101. The study was conducted by weighing approximately 1000mg of each vehicle into multiple vials. A known amount of CEM-101 was then added to each vial, and the resulting mixture was vortex mixed and then mixed overnight on a roller mixer.

Solubility values of 100mg/mL were observed in all 1 molar acid solutions studied (in situ salt formation, excipients 15-19). The pH values of the resulting solutions are reported in the previous table above.

Example 6 characterization of antioxidant-free solutions for parenteral administration. The following formulations, approximately 50mg/mL, prepared in 10mL batch sizes were further studied and characterized as follows:

dilution studies were performed using 0.9% sodium chloride solution. Dilution factors 10 and 50 were studied. No sign of precipitation was observed for all formulations studied.

Assay analysis was performed by using HPLC method and is shown in the following table. The turbid sample was centrifuged before analysis. Total impurities were assessed by HPLC peak area%.

Preparation	Measurement (mg/mL)	Assay%	Total impurities
				Pre-formulations			2.34
A	47.01	94.01	1.95
				B	46.02	92.03	1.89
C	47.34	94.68	1.91

Example 7 characterization of unbuffered formulation C solution sprayed with nitrogen and incorporating an antioxidant, with or without a chelating agent. Development studies were performed using formulation C, sample C and their corresponding blank formulations. The following table details the composition of the active formulation of formulation C and the corresponding blank.

Batch number LS1P LS1A LS2P LS2A

The above solution was prepared by first dissolving the stabilizer in a vehicle (60mM tartaric acid) prepared beforehand in nitrogen sparge water. Once dissolved, the CEM-101API was slowly added and allowed to mix until complete dissolution was achieved.

The prepared formulation was filled into a vial, crimped with an aluminum cap containing a PTFE septum, and then autoclaved. Nitrogen purge was performed on each vial prior to corrugation.

HPLC analysis was performed on autoclaved and non-autoclaved samples. The results in the table below are summary data on the assay and impurities.

Determination and impurity level

The observed assay results for formulation C containing various combinations of stabilizers were approximately 100%. The unknown impurity products observed for both formulations were similar to those observed for the active compound, except that an impurity peak after autoclaving was observed at RRT 0.98.

The total levels of unknown impurity products observed for both formulations were lower than those observed for the active compound. The data indicate that both formulations studied are as stable as the active compound before and after the autoclaving cycle.

Studies from previous experiments investigating a series of stabilizers showed impurity levels as high as 4%, with measurements as low as 88%. The data detailed in this example show the improvement in degradation product control observed with these formulations and nitrogen spray.

Example 8. compatibility assays for excipients of lyophilized pharmaceutical compositions. High sensitivity multicellular differential scanning calorimetry (HS-MCDSC) was used to assess excipient compatibility. The high-sensitivity multicellular differential scanning calorimeter is an analytical instrument designed to measure heat capacity and the change in heat capacity with temperature.

HS-MCDSC was used for compatibility evaluation because it was sensitive enough to allow nondestructive analysis of the sample (i.e., it did not cause any additional degradation compared to the degradation that would have occurred upon storage). This example details the results of compatibility studies on drug/excipient mixtures, which were confirmed to be acceptable using HS-MCDSC.

In HS-MCDSC, the heat flow to or from the sample (power,expressed in μ W). Integration of the power-time data yields the change in enthalpy (enthalpy, Δ H, expressed in μ J). Because heat is prevalent, virtually any sample can be studied using this technique, so long as a representative sample can be loaded into the chamber, and the heat flow of all chemical or physical processes occurring in the sample is recorded. This allows the study of complex systems that are typically outside the scope of traditional analytical techniques, but often produce complex data that is difficult to interpret. It also means that sample preparation is of utmost importance; inadvertent sample preparation may result in erroneous heat flow that will subsequently prevent proper data interpretation.

In HS-MCDSC, the heat generated by or absorbed by the sample is ideally exchanged well with the surrounding heat sink, keeping the sample in a wide temperature range. Typically, the reference cell (cell #4) is loaded with an inert material having a similar heat capacity and a similar amount to the sample, and data is obtained as a differential reaction between the sample and the reference. Therefore, when blank data (running empty cells before actual sample testing) is subtracted from the sample data, most of the noise generated by temperature fluctuations is removed.

Stability (individual component) is generally assessed by loading the sample material into the cell and measuring heat flow as a function of time. The instrument should detect rapidly any degradation process that occurs and by the absence of any thermal reaction, confirm that the system under study is stable.

Similar methods can be used to test binary mixtures of Active Pharmaceutical Ingredients (APIs) and excipients. The thermal properties of the active ingredient alone and the excipient alone over a wide temperature range were recorded and compared to the thermal properties determined for the binary drug-excipient mixture. Any unexpected power change recorded in the drug-excipient mixture indicates a possible interaction between the two components.

Calorimetric data were recorded using a high sensitivity MCDSC (CSC type 4100MCDSC, USA). Samples were run using API alone (approximately 50mg), excipient alone (approximately 50mg), and API-excipient binary pairs (approximately 25mg:25mg, 1:1 ratio). The samples were weighed directly into the chamber, which was sealed with a metal cap and rubber sealing disc provided to ensure hermetic sealing. The experiment was designed as follows:

hold at 30 ℃ for 10800 seconds(s) before moving to the next temperature.

Heating: heating to 30-40 deg.C at a scanning rate of 0.5 deg.C/min.

Maintaining: kept isothermally at 40 ℃ for 10800 s.

Heating: heating to 40-50 deg.C at a scanning rate of 0.5 deg.C/min.

Maintaining: kept isothermally at 50 ℃ for 10800 s.

Heating: heating to 50-60 deg.C at a scanning rate of 0.5 deg.C/min.

Maintaining: kept isothermally at 60 ℃ for 10800 s.

Heating: heating to 60-70 deg.C at a scanning rate of 0.5 deg.C/min.

Maintaining: kept isothermally at 70 ℃ for 10800 s.

Heating: heating to 70-80 deg.C at a scanning rate of 0.5 deg.C/min.

Maintaining: kept isothermally at 80 ℃ for 10800 s.

And (3) cooling: cooled from 80 ℃ back to 30 ℃.

MCDSC consisted of four chambers contained in a loading chamber. The cells 1, 2 and 3 were filled with sample, while the 4 th cell was always left empty and run as blank. Prior to analysis, cells 1 to 3 were left empty of sample to record blank results, which were then subtracted from subsequent results obtained from the samples analyzed. Data was recorded every 10s using the proprietary software package CpCalc. Data analysis was performed using CpCalc and Microsoft Excel.

The calorimeter records all events that occurred in each sample cell. The method employed here was used to calculate the power-time data obtained for the individual active ingredients and excipients. The calculated data was then used to create an "expected" theoretical trace as an average of the signals from the 1:1 ratio mixture of API and vehicle. These data are then compared to those obtained for the actual binary mixture. Any significant difference in the power-time data (different shapes or intensities of their heat flow reactions over the experimental time period) indicates incompatibility. MC-DSC showed that mannitol, glycine and sucrose were compatible with CEM-101 in a 1:1 ratio.

Example 9 characterization of the properties of excipients used for lyophilization to prepare lyophilized pharmaceutical compositions. Based on the above results, a freeze-drying study was conducted by initially assessing the solubility of each excipient in a CEM-101IV solution (50mg/mL, prepared in the same manner as described in example 2 above), as follows:

1mL of CEM-101IV solution was dispersed in clear glass vials, followed by careful addition of small amounts of the vehicle under study (50 or 100 mg). The solution in the vial was mixed using a vortex mixer and sonicated until a clear solution was observed. The final data are shown below and reflect the maximum possible amount of each excipient used in the lyophilized formulation. Subsequently, all clear vials were frozen at-25 ℃ for 2 h. The lid was then removed and the vial was covered with a small piece of tissue paper and placed in a freeze dryer for 24h (in the dark). The precipitate was then examined and subsequently visually observed as detailed in the table below.

Summary of the precipitates obtained during the Freeze drying experiments and MC-DSC analysis

Based on the above results, three excipients that did not interact with the API were selected, and solutions containing various ratio combinations of API and excipient were prepared. These solutions were frozen at-25 ℃ and then lyophilized in the dark for 24 hours. The resulting precipitate was then visually inspected to determine the integrity of the plug. The results are shown in the following table.

Visual inspection of the lyophilized product

The precipitate was stored at 5 deg.C, 25 deg.C/60% RH and 40 deg.C/75% RH. Samples were evaluated on days 7, 13 and 28. In all cases, the assay remained unchanged for all three fillers. The mannitol and glycine formulation precipitates remained white throughout the study. Some yellowing precipitate was observed in a portion of the sucrose formulation sample.

Example 10 in vivo Pharmacokinetics (PK) in monkeys following IV administration. Pharmaceutical compositions suitable for parenteral administration comprising the antibiotic compound CEM-101 prepared as described herein were administered intravenously to male (M) and female (F) cynomolgus monkeys (Macaca fascicularis), 2-5kg, young, acclimated) at 5, 12.5 and 25mg/kg/d daily for 14 or 28 days, and compared to vehicle-treated animals. Plasma levels of CEM-101 and toxicokinetics were measured at 0-24 hours (venipuncture, predose, then infusion was immediately completed at 0, 0.5, 1, 4, 8 and 24 hours). Animal body weights were also measured periodically.

The high dose was selected to provide a multiple of 1 μ g/mL of the exemplary human Cmax exposure, and the low dose was selected to provide the exemplary human exposure at or slightly higher than the typical dose. The total dose volume was 15mL/kg and the intravenous infusion was performed over about 90 minutes (10mL/kg/h) through a disposable indwelling catheter into one of the brachial and/or saphenous veins. The vein or vein position is changed at least every 7 days. Control animals received vehicle only. An exemplary formulation is CEM-101 in a vehicle comprising or consisting essentially of: l (+) -tartaric acid, D-mannitol, SWFI, 1N HaOH, and optionally 1-thioglycerol, as described herein.

Immediately after dosing, a portion of the animals were euthanized for necropsy evaluation. For the "recovery" group, additional 28 hours were observed without drug administration, and then euthanized for necropsy evaluation.

Example 11 Pharmacokinetics (PK) in dogs following IV administration. Pharmaceutical compositions suitable for parenteral administration comprising the antibiotic compound CEM-101 as prepared herein are administered intravenously to male (M) and female (F) beagle dogs (Canis familiaris), 7-10kg, 5-7 months old, 2-3 weeks acclimatized) at 5, 10 and 15mg/kg/d daily for 14 or 28 days and compared to vehicle-treated animals. Plasma levels of CEM-101 and toxicokinetics were measured at hours 0-24 (jugular venipuncture, predose, then infusion was immediately completed at hours 0, 0.5, 1, 4, 8 and 24). Animal body weights were also measured periodically.

The high dose was selected to provide a multiple of 1 μ g/mL of the exemplary human Cmax exposure, and the low dose was selected to provide the exemplary human exposure at or slightly higher than the typical dose. The total dose volume was 15mL/kg and intravenous infusion was performed over about 90 minutes (10mL/kg/h) through a disposable indwelling catheter into one of the cephalic and/or saphenous veins. The vein or vein position was changed at least every 7 days. Control animals received vehicle only. An exemplary formulation is CEM-101 in a vehicle comprising or consisting essentially of: l (+) -tartaric acid, D-mannitol, SWFI, 1N HaOH, and optionally 1-thioglycerol, as described herein.

Immediately after dosing, a portion of the animals were euthanized for necropsy evaluation. For the "recovery" group, observations were made without dosing for an additional 28 days, and then euthanized for necropsy evaluation.

It will be appreciated that monkeys and dogs exhibit particular sensitivity to pain and therefore can be observed for pain response upon administration of the test article. In each case, no response was observed in the animals following IV administration of CEM-101, indicating that the administration was pain-free or substantially pain-free.

Claims

1. A pharmaceutical composition suitable for parenteral administration comprising one or more antibacterial compounds of the formula:

or pharmaceutically acceptable salts thereof, and combinations thereof, wherein:

R₁₀is hydrogen or acyl;

x is H; and Y is OR₇WhereinR₇Is a monosaccharide or disaccharide, alkyl, aryl, heteroaryl, acyl; or C (O) NR₈R₉Wherein R is₈And R₉Each independently selected from the group consisting of: hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, heteroalkyl, aryl, heteroaryl, alkoxy, dimethylaminoalkyl, acyl, sulfonyl, ureido, and carbamoyl; or X and Y taken together with the attached carbon form a carbonyl;

v is C (O), C (═ NR)₁₁)、CH(NR₁₂，R₁₃) or-N (R)₁₄)CH₂Wherein N (R)₁₄) A C-10 carbon attached to said compound; wherein R is₁₁Is hydroxy or alkoxy, R₁₂And R₁₃Each independently selected from the group consisting of: hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureido, and carbamoyl; r₁₄Is hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureido, or carbamoyl;

w is H, F, Cl, Br, I or OH;

a is CH₂、C(O)、C(O)O、C(O)NH、S(O)₂、S(O)₂NH、C(O)NHS(O)₂；

C is hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, aminoaryl, alkylaminoaryl, acyl, acyloxy, sulfonyl, ureido, or carbamoyl; and

one or more acidulants; wherein the composition is capable of being reconstituted in one or more aqueous diluents.

2. The composition of claim 1, wherein a is CH₂。

3. The composition of claim 1, wherein B is alkenylene.

4. The composition of claim 1, wherein C is aminophenyl.

5. The composition of claim 1, wherein C is 3-aminophenyl.

6. The composition of claim 1, wherein C is C (o).

7. The composition of claim 1, wherein W is fluoro.

8. The composition of claim 1, wherein W is hydrogen.

9. The composition of claim 1, wherein X and Y are taken together with the attached carbon to form a carbonyl group.

10. The composition of claim 1, wherein R¹⁰Is hydrogen.

11. The composition of claim 1, wherein at least one compound is CEM-101.

12. The composition of any one of claims 1 to 11, further comprising one or more carriers.

13. The composition of claim 12, wherein at least one carrier is water.

14. The composition of claim 12, further comprising one or more fillers.

15. The composition of any one of claims 1 to 11, further comprising one or more fillers.

16. The composition of claim 15, wherein at least one of the fillers is selected from the group consisting of: mannitol, sucrose and glycine.

17. The composition of claim 15, wherein at least one of the fillers is mannitol.

18. The composition of any one of claims 1 to 11, wherein the acidulant is selected from the group consisting of: ascorbic acid, citric acid, tartaric acid, and combinations thereof.

19. The composition of claim 18, wherein the acidifying agent is L-tartaric acid.

20. The composition of any one of claims 1 to 11, wherein the acidifying agent is at a concentration of about 30mM to about 70 mM.

21. The composition of any one of claims 1 to 11, wherein the acidifying agent is at a concentration of about 50mM to about 60 mM.

22. The composition of any one of claims 1 to 11, wherein the acidifying agent is at a concentration of about 60 mM.

23. The composition of any one of claims 1 to 11, wherein the aqueous diluent is water.

24. The composition of any one of claims 1 to 11, further comprising an alkalizing agent.

25. The composition of claim 24, wherein the alkalizing agent is sodium hydroxide.

26. The composition according to any one of claims 1 to 11, wherein the pH is not less than 2.5.

27. The composition of any one of claims 1 to 11, wherein the pH is between about 3.7 and about 4.4.

28. The composition of any one of claims 1 to 11, wherein the pH is between about 3.8 and about 4.2.

29. The composition of claim 11 wherein the concentration of CEM-101 is at least about 30 mg/mL.

30. The composition of claim 11 wherein the concentration of CEM-101 is at least about 50 mg/mL.

31. The composition of claim 11, wherein the concentration of CEM-101 is about 50 mg/mL.

32. The composition of claim 11, wherein the saturated solubility of CEM-101 is at least about 50 mg/mL.

33. The composition of claim 11, wherein the saturated solubility of CEM-101 is at least about 80 mg/mL.

34. The composition of any one of claims 1 to 11, further comprising an antioxidant, a chelating agent, or a combination thereof.

35. The composition of claim 34, wherein the chelating agent is EDTA.

36. The composition of any one of claims 1 to 11, further comprising an antioxidant.

37. The composition of claim 36, wherein the antioxidant is 1-thioglycerol.

38. The composition of claim 37, wherein the antioxidant is at a concentration of about 5 mg/mL.

39. The composition of any one of claims 1 to 11, comprising CEM-101 (about 5%), L- (+) -tartaric acid (about 0.6%), sodium hydroxide (about 0.05%), and water for injection (to 100%) on a weight volume percentage basis.

40. The composition according to any one of claims 1 to 11, comprising CEM-101 (5.0%), L- (+) -tartaric acid (0.58%), sodium hydroxide (0.046%) and water for injection (to 100%) on a weight-volume percentage basis.

41. The composition of any one of claims 1 to 11, comprising CEM-101 (about 5%), L- (+) -tartaric acid (about 0.6%), sodium hydroxide (about 0.05%), 1-thioglycerol (about 0.5%), and water for injection (to 100%) on a weight to volume percentage basis.

42. The composition according to any one of claims 1 to 11, comprising CEM-101 (5.0%), L- (+) -tartaric acid (0.57%), sodium hydroxide (0.046%), 1-thioglycerol (0.50%) and water for injection (to 100%) on a weight volume percentage basis.

43. The composition of claim 12, wherein the composition is administered directly.

44. The pharmaceutical composition according to any one of claims 1 to 11, wherein the composition is administered after further dilution.

45. A single-or multi-dose pharmaceutical dosage unit comprising a therapeutically effective amount of a pharmaceutical composition suitable for parenteral administration according to any one of claims 1 to 11.

46. The dosage unit of claim 45, which is an ampoule, vial, pre-filled syringe or bag.

47. The dosage unit of claim 45, which is a single dose unit.

48. The dosage unit of claim 45, which is a multiple dosage unit.

49. A process for the preparation of a pharmaceutical composition suitable for parenteral administration according to any one of claims 1 to 11, which comprises spraying water for injection, optionally under nitrogen and optionally with nitrogen:

dissolving desired amounts of tartaric acid and sodium hydroxide in about 50-80% of desired water for injection to form a first solution;

dissolving the desired amount of CEM-101 in the above solution, optionally adding more of said water for injection, and

the solution was made up to final volume with water for injection.

50. A lyophilized pharmaceutical composition suitable for dilution as a pharmaceutical composition for parenteral administration comprising CEM-101, an acidifying agent, an alkalinizing agent, and at least one additional excipient.

51. The composition of claim 50, wherein the acidulant is ascorbic acid, citric acid, or tartaric acid, or a combination thereof.

52. The composition of claim 50, wherein the acidifying agent is L-tartaric acid.

53. The composition of claim 52, wherein the L-tartaric acid is present in a ratio to the CEM-101 or related compound ranging from about 0.01:1 to about 0.5: 1.

54. The composition of any one of claims 50 to 53, wherein the alkalizing agent is sodium hydroxide.

55. The composition of any one of claims 50-53, wherein the excipient is glycine, sucrose, or mannitol, or a combination thereof.

56. The composition of claim 55, wherein the excipient is present in a ratio to the CEM-101 ranging from about 0.5:1 to about 5: 1.

57. The composition of claim 55, wherein the excipient is mannitol present in a ratio to the CEM-101 ranging from about 1:1 to about 4: 1.

58. The composition of claim 55, wherein the excipient is glycine present in a ratio to the CEM-101 ranging from about 1:1 to about 4: 1.

59. The composition of claim 55, wherein the excipient is sucrose, which is present in a ratio to the CEM-101 ranging from about 1:1 to about 4: 1.

60. The composition of any one of claims 50 to 53, wherein the composition further comprises a stabilizer.

61. A single-or multi-dose pharmaceutical dosage unit comprising a therapeutically effective amount of the lyophilized pharmaceutical composition of claim 55.

62. The dosage unit of claim 61, which is an ampoule or vial.

63. The dosage unit of claim 61 or 62, which is a single dose unit.

64. The dosage unit of claim 61 or 62, which is a multiple dosage unit.

65. A kit comprising the pharmaceutical dosage unit of claim 61 and further comprising a vehicle for diluting the pharmaceutical composition.

66. A method for treating a bacterial infection, a protozoal infection, or a condition associated with a bacterial infection or protozoal infection in a patient, the method comprising the step of administering to the patient a therapeutically effective amount of a pharmaceutical composition suitable for parenteral administration comprising the composition of any one of claims 1-11.

67. Use of a pharmaceutical composition suitable for parenteral administration comprising a composition according to any one of claims 1-11 for treating a bacterial infection, a protozoal infection, or a condition associated with a bacterial infection or protozoal infection.

68. Use of a pharmaceutical composition suitable for parenteral administration comprising a composition according to any one of claims 1-11 for the manufacture of a medicament for the treatment of a bacterial infection, a protozoal infection, or a condition associated with a bacterial infection or protozoal infection.

69. The method of claim 66, wherein the patient is a mammal.

70. The method of claim 66, wherein the patient is a human.

71. The method of claim 66, wherein the method is for treating moderate or severe Community Acquired Pneumonia (CAP).

72. The method of claim 66, wherein the method is for treating severe Community Acquired Pneumonia (CAP).

73. The method of claim 66, wherein the method is for treating syphilis.

74. The method of claim 66, wherein the method is for treating gonococcal urethritis.

75. The method of claim 66, wherein the parenteral administration comprises intravenous injection.

76. The method of claim 66, wherein the parenteral administration comprises intramuscular injection.