Patent Publication Number: US-2006009469-A1

Title: Particulate-stabilized injectable pharmacutical compositions of posaconazole

Description:
This application claims priority benefits of application No. 60/575,126 filed May 28, 2004, the entire disclosure of which is incorporated herein by reference. 
    
    
     FIELD OF THE INVENTION  
      The present invention relates to formulations useful for treating infections. Specifically, these formulations include the active pharmaceutical ingredient posaconazole in an injectable suspension that is stable when subjected to terminal steam sterilization, and throughout the shelf life of the product.  
     BACKGROUND OF THE INVENTION  
      Posaconazole, an anti-fungal agent, represented by the following chemical structural formula  
                 
 
 is being developed as an oral suspension (40 mg/ml) under the trademark NOXAFIL® by Schering Corporation, Kenilworth, N.J. See, for example, U.S. Pat. Nos. 5,703,079, 5,661,151, WO 02/80678 published Oct. 17, 2002, and EP 1 372 394 published Jan. 2, 2004. In addition, other formulations of posaconazole have been disclosed. A solid (capsule/tablet) of posaconazole is disclosed in U.S. Pat. Nos. 5,972,381 and 5,834,472. Lastly, a topical form of posaconazole, e.g., a lotion, cream, ointment, or “lacquer nail polish” is contemplated based on other similar formulations, e.g., U.S. Pat. No. 4,957,730 (PENLAC® available from Dermik®). 
 
      Certain aspects of stabilization of micronized particles in pharmaceutical compositions are addressed in the literature. For example, U.S. Pat. No. 5,858,410 discloses pharmaceutical compositions containing particles of active agents of average diameter less than 5 microns, having been comminuted, without prior conversion into a melt, by using a piston-gap homogenizer. U.S. patent application Ser. No. 10/440,368 discloses the use of a phospholipid surface active agent to stabilize microparticles of solid fenofibrate in an orally administered pharmaceutical composition. U.S. Pat. No. 5,091,188 discloses the use of phospholipids, to prevent coalescence of microcrystalline active agents in injectable pharmaceutical compositions. Examples of disclosed phospholipids include lecithin, phosphatidic acid, phosphatidyl ethanolamine, cholesterol, stearylamine, glycolipids and mono-glycerides.  
      None of the aforementioned references however, discloses an injectable suspension of posaconazole, that is stable when subjected to terminal steam sterilization and throughout the shelf life of the product. There is a need for such a formulation as it is desirable to ensure the physical stability of the sterilized end product.  
     SUMMARY OF THE INVENTION  
      The present invention provides formulations of posaconazole that are stable when subjected to terminal steam sterilization. These formulations are useful for the treatment of infections. In particular, an aqueous injectable suspension of posaconazole that is homogenously suspended in vehicle with the aid of a phospholipid. In addition a thermoprotectant agent is employed to reduce autoclave-induced particle size growth, as well as a buffer system to stabilize the phospholipid during autoclaving. The formulations provided remain stable after 20 minutes of autoclaving at 121° C. and after subsequent storage at 4° C. to 40° C. for at least 6 months.  
      The present invention provides formulations comprising a suspension of posaconazole, stabilized by a phospholipid, in a mixture comprising a thermoprotectant, and a buffer system.  
      In some embodiments, the formulation has been sterilized by autoclaving or by irradiation.  
      In some embodiments, the buffer system comprises sodium phosphate, which may be provided as sodium phosphate monobasic monohydrate, sodium phosphate dibasic anhydrous, or the combination of the two.  
      In some embodiments, the buffer system comprises an organic buffer.  
      In some embodiments, the buffer system comprises at least one of histidine, citric acid, glycine, sodium citrate, ammonium sulfate, or acetic acid.  
      In some embodiments, the buffer system maintains a pH of about 3.0 to about 9.0.  
      In some embodiments, the buffer system maintains a pH of about 6.0 to about 8.0.  
      In some embodiments, the buffer system maintains a pH of about 6.4 to about 7.6.  
      In some embodiments, the phospholipid comprises a natural phospholipid.  
      In some embodiments, the phospholipid comprises a synthetic phospholipid.  
      In some embodiments, the phospholipid comprises a natural phospholipid and a synthetic phospholipid.  
      In some embodiments, the phospholipid comprises 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC).  
      In some embodiments, the thermoprotectant comprises trehalose.  
      In some embodiments, the phospholipid comprises 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), the thermoprotectant comprises trehalose, and the buffer system comprises sodium phosphate monobasic monohydrate, sodium phosphate dibasic anhydrous, or the combination of sodium phosphate monobasic monohydrate and sodium phosphate dibasic anhydrous.  
      In some embodiments, the posaconazole has a particle size distribution whose median value is between about 1.0 and about 8.0 microns, with not more than about 3000 particles of 10 microns or greater size and not more than about 300 particles of 25 microns or greater size.  
      In some embodiments, the posaconazole has a particle size distribution whose median value is between about 1.0 and about 5.0 microns, with not more than about 3000 particles of 10 microns or greater size and not more than about 300 particles of 25 microns or greater size.  
      In some embodiments, the posaconazole has a particle size distribution whose median value is between about 1.2 and about 4.5 microns, with not more than about 3000 particles of 10 microns or greater size and not more than about 300 particles of 25 microns or greater size.  
      In some embodiments, the formulation has ingredients comprising:  
                                                   Ingredient   Concentration range                                                        Posaconazole   about 50   mg/ml           POPC   about 40   mg/ml           Sodium Phosphate,   0.345   mg/ml           monobasic, monohydrate,           USP           Sodium Phosphate, dibasic,   1.065           anhydrous, USP           Trehalose   250   mg/ml           Water for Injection, USP q.s.   1   ml           ad                      
 
      In some embodiments, the formulation has ingredients comprising:  
                                                   Ingredient   Concentration range                                                        Posaconazole   about 1 to about 100   mg/ml           POPC   about 10 to about 60   mg/ml           Sodium Phosphate,   about 0.01 to about 0.6   mg/ml           monobasic, monohydrate,           USP           Sodium Phosphate, dibasic,   about 0.04 to about 1.5   mg/ml           anhydrous, USP           Trehalose   about 10 to about 300   mg/ml           Water for Injection, USP q.s.   about 1   ml           ad                      
 
      In some embodiments, the formulation has ingredients comprising:  
                                                   Ingredient   Concentration range                                                        Posaconazole   about 40 to about 60   mg/ml           POPC   about 20 to about 50   mg/ml           Trehalose   about 100 to about 250   mg/ml           Water for Injection, USP q.s.   about 1   ml           ad                      
 
      In some embodiments, the formulation has ingredients comprising:  
                                                   Ingredient   Concentration                                                        Posaconazole   50   mg/ml           POPC   40   mg/ml           Histidine   3   mg/ml           Citric acid monohydrate   0.24   mg/ml           Trehalose   250   mg/ml           Water q.s. ad   1   ml                      
 
 at a pH of about 6.4. 
 
      In some embodiments, the formulation has ingredients further comprising an antioxidant.  
      In some embodiments, the antioxidant comprises propyl gallate at a concentration of about 0.02 to about 0.005 mg/ml.  
      In some embodiments, the antioxidant comprises butylated hydroxytoluene at a concentration of about 0.1 to about 0.02 mg/ml.  
      In some embodiments, the antioxidant comprises alpha-D-tocopherol at a concentration of about 0.5 to about 0.01 mg/ml.  
      In some embodiments, the formulation has ingredients comprising:  
                                                   Ingredient   Concentration                                                        Posaconazole   50   mg/ml           POPC   40   mg/ml           Histidine   3   mg/ml           Citric acid monohydrate   0.24   mg/ml           Propyl gallate   0.01   mg/ml           Butylated hydroxytoluene   0.05   mg/ml           Trehalose   250   mg/ml           Water q.s. ad   1   ml                      
 
 at a pH of about 6.4. 
 
      In some embodiments, the formulation has ingredients comprising:  
                                                   Ingredient   Concentration                                                        Posaconazole   50   mg/ml           POPC   40   mg/ml           Histidine   3   mg/ml           Citric acid monohydrate   0.24   mg/ml           Alpha-D-tocopherol   0.05   mg/ml           Trehalose   250   mg/ml           Water q.s. ad   1   ml                      
 
 at a pH of about 6.5. 
 
      In some embodiments, the formulation has a wt. ratio of phospholipid to posaconazole between about 60:1 and about 1:10.  
      In some embodiments, the formulation has a wt. ratio of phospholipid to posaconazole between about 1:1 and about 1:5.  
      In some embodiments, the formulation has a wt. ratio of phospholipid to posaconazole between about 1:1 and about 4:5.  
      In some embodiments, the formulation has a the wt. ratio of thermoprotectant to posaconazole between about 300:1 and about 1:10.  
      In some embodiments, the formulation has a wt. ratio of thermoprotectant to posaconazole between about 1:1 and about 6:1.  
      In some embodiments, the formulation has a wt. ratio of thermoprotectant to phospholipid between about 30:1 and about 1:6.  
      In some embodiments, the formulation has a wt. ratio of thermoprotectant to phospholipid between about 5:4 and about 30:4.  
      In some embodiments, the invention encompasses a method of treating or preventing an infection inan animal in need thereof which comprises administering to said animal an effective amount of the formulation. In some embodiments, the animal is a mammal, a bird, a fish, or a reptile.  
      In some embodiments, the animal is a mammal, including but not limited to a human.  
      In some embodiments, the infection is caused by a fungus or a parasite.  
      In some embodiments, the infection is selected from the group consisting of:  
      oropharyngeal or esophageal candidiasis;  
      refractory oropharyngeal and esophageal candidiasis;  
      invasive aspergfilosis, candidiasis, fusariosis, scedosporiosis, infections due to dimorphic fungi, zygomycosis, and invasive infections due to rare molds and yeasts;  
      invasive mycoses in patients who are refractory to, or intolerant of, other therapies;  
      Candidiasis, invasive mould infections in patients who have undergone intensive chemotherapy and/or radiation therapy for hematologic malignancies, bone marrow or peripheral stem cell transplant conditioning regimens, and patients receiving combination immunosuppressive therapy for the treatment of acute or chronic graft-versus-host disease or prevention of solid organ transplantation;  
      Chagas disease; and,  
      Leishmaniasis.  
      In some embodiments, the invention encompasses a method wherein said formulation is administered intravenously.  
      In some embodiments, the invention encompasses a method wherein said formulation is administered intramuscularly, subcutaneously, ophthalmically, subconjuctivally, intraocularly, via anterior eye chamber injection, intravitreally, intraperitoneally, intrathecally, intracystically, intrapleurally, intranasally, topically, via wound irrigation, intradermally, intrabuccally, intra-abdominally, intra-articularly, intra-aurally, intrabronchially, intracapsularly, intrameningeally, intrapulmonarilly, via inhalation, via endotracheal or endobronchial installation, via direct installation into pulmonary cavities, intraspinally, intrasynovially, intrathoracically, via thoracostomy irrigation, vaginally, epidurally, rectally, intracistemally, intravascularly, intraventricularly, intraosseously, via irrigation of infected bone, or via application as part of any admixture with cement for prosthetic devices.  
      In some embodiments, the formulation further comprises a second active ingredient selected from one or more of the group consisting of: antifungals such as azoles; amphotericin B; deoxycholate amphotericin B; flucytosine; terbinafine; antibacterials; antivirals; steroids; nonsteroidal anti-inflammatory drugs (“NSAIDs”); chemotherapeutics; and anti-emitics.  
      In some embodiments, the invention encompasses a method further comprising administering a second active ingredient selected from one or more of the group consisting of: antifungals such as azoles; amphotericin B; deoxycholate amphotericin B; flucytosine; terbinafine; antibacterials; antivirals; steroids; nonsteroidal anti-inflammatory drugs (“NSAIDs”); chemotherapeutics; and, anti-emitics.  
      In some embodiments, the formulation is further characterized by providing a mean maximum plasma concentration (C max ) of posaconazole of at least about 467 ng/ml at steady state, and a mean plasma Area Under the Curve over 24 hours (AUC) value of posaconazole of at least about 9840 ng.hr/ml at steady state, when said formulation is infused over about 1 hour to deliver 100 mg of posaconazole, and repeated at an interval of about 24 hours.  
      In some embodiments, the formulation is further characterized by providing a mean maximum plasma concentration (C max ) of posaconazole of at least about 852 ng/ml at steady state, and a mean plasma Area Under the Curve over 24 hours (AUC) value of posaconazole of at least about 24,600 ng.hr/ml at steady state, when said formulation is infused over about 1 hour to deliver 200 mg of posaconazole, and repeated at an interval of about 24 hours.  
      In some embodiments, the formulation is further characterized by providing, after administration of a dosage of about 100 mg of said posaconazole, at least one of: a mean plasma half-life in a range of about 14.9 to about 38.4 hours; and a mean plasma steady state volume of distribution of about 200-500 L.  
      In some embodiments, the formulation is further characterized by providing a mean maximum plasma concentration (C max ) of posaconazole of at least about 1480 ng/ml at steady state, and a mean plasma Area Under the Curve over 24 hours (AUC) value of posaconazole of at least about 24,600 ng.hr/ml at steady state, when said formulation is infused over about 1 hour to deliver at least 200 mg of posaconazole, and repeated at an interval of about 24 hours.  
      In some embodiments, the formulation is further characterized as providing, after administration of a dosage of about 200 mg of said posaconazole, at least one of: a mean plasma half-life of about 18.7 to about 35.5 hours; and a mean plasma steady state volume of distribution of about 200-500 L.  
      In some embodiments, the formulation is further characterized as providing, after administration of a dosage of about 400 mg of said posaconazole, at least one of: a mean plasma half-life of about 18.5 to about 51.4 hours; and a mean plasma steady state volume of distribution of about 200-500 L.  
      In some embodiments, the formulation is further characterized as providing, after administration of a dosage of about 600 mg of said posaconazole, at least one of: a mean plasma half-life of about 27.2 to about 50.6 hours; and a mean plasma steady state volume of distribution of about 200-500 L.  
      In some embodiments, the formulation is further characterized as providing a mean posaconazole blood concentration profile substantially similar to that of  FIG. 1 , when said formulation is infused over about 1 hour to deliver 25-600 mg of posaconazole.  
      In some embodiments, the formulation is further characterized as providing a mean posaconazole plasma concentration profile substantially similar to that of  FIG. 2 , when said formulation is infused over about 1 hour to deliver 25-600 mg of posaconazole.  
      In some embodiments, the formulation is further characterized as providing a ratio of mean posaconazole blood C max  to mean posaconazole plasma C max  of between about 1.5 and about 3.8, when a single dose of said formulation is infused over about 1 hour to deliver 25-600 mg of posaconazole.  
      In some embodiments, the formulation is further characterized as providing a ratio of mean posaconazole blood C max  to mean posaconazole plasma C max  of between about 2.1 and about 3.3, when a single dose of said formulation is infused over about 1 hour to deliver 25 mg of posaconazole.  
      In some embodiments, the formulation is further characterized as providing a ratio of mean posaconazole blood C max  to mean posaconazole plasma C max  of between about 1.9 and about 3.8, when a single dose of said formulation is infused over about 1 hour to deliver 50 mg of posaconazole.  
      In some embodiments, the formulation is further characterized as providing a mean posaconazole blood C max  to mean posaconazole plasma C max  of between about 2.2 and about 3.3, when a single dose of said formulation is infused over about 1 hour to deliver 100 mg of posaconazole.  
      In some embodiments, the formulation is further characterized as providing a ratio of mean posaconazole blood C max  to mean posaconazole plasma C max  of between about 1.5 and about 3.2, when a single dose of said formulation is infused over about 1 hour to deliver 200 mg of posaconazole.  
      In some embodiments, the formulation is further characterized as providing a ratio of mean posaconazole blood C max  to mean posaconazole plasma C max  of between about 1.7 and about 3.3, when a single dose of said formulation is infused over about 1 hour to deliver 400 mg of posaconazole.  
      In some embodiments, the formulation is further characterized as providing a ratio of mean posaconazole blood C max  to mean posaconazole plasma C max  of between about 1.9 and about 3.1, when a single dose of said formulation is infused over about 1 hour to deliver 600 mg of posaconazole.  
      In some embodiments, the formulation is further characterized as providing a ratio of mean posaconazole blood C max  to mean posaconazole plasma C max  of between about 1.2 and about 2.5, at steady state when said formulation is infused over about 1 hour to deliver 25-600 mg of posaconazole, and repeated on a 24-hour basis.  
      In some embodiments, the formulation is further characterized as providing a ratio of mean posaconazole blood C max  to mean posaconazole plasma C max  of between about 1.5 and about 2.3, at steady state when said formulation is infused over about 1 hour to deliver 25 mg of posaconazole, and repeated on a 24-hour basis.  
      In some embodiments, the formulation is further characterized as providing a ratio of mean posaconazole blood C max  to mean posaconazole plasma C max  of between about 1.5 and about 2.4, at steady state when said formulation is infused over about 1 hour to deliver 50 mg of posaconazole, and repeated on a 24-hour basis.  
      In some embodiments, the formulation is further characterized as providing a ratio of mean posaconazole blood C max  to mean posaconazole plasma C max  of between about 1.7 and about 2.5, at steady state when said formulation is infused over about 1 hour to deliver 100 mg of posaconazole, and repeated on a 24-hour basis.  
      In some embodiments, the formulation is further characterized as providing a ratio of mean posaconazole blood C max  to mean posaconazole plasma C max  of between about 1.2 and about 2.0, at steady state when said formulation is infused over about 1 hour to deliver 200 mg of posaconazole, and repeated on a 24-hour basis.  
      In some embodiments, the formulation is further characterized as providing a ratio of mean posaconazole blood C max  to mean posaconazole plasma C max  of between about 1.2 and about 2.2, at steady state when said formulation is infused over about 1 hour to deliver 400 mg of posaconazole, and repeated on a 24-hour basis.  
      In some embodiments, the formulation is further characterized as providing a ratio of mean posaconazole blood C max  to mean posaconazole plasma C max  of between about 1.3 and about 1.7, at steady state when said formulation is infused over about 1 hour to deliver 600 mg of posaconazole, and repeated on a 24-hour basis.  
      In some embodiments, the water in the formulation has been removed by lyophilization.  
      In some embodiments, the animal treated is human, while in other embodiments the animal treated is non-human.  
      In some embodiments, the formulation is one that is bioequivalent to a formulation disclosed herein.  
      In some embodiments, the method further comprises administering a bolus loading dose of said formulation and then administering an intravenous maintenance dose of said formulation.  
      In some embodiments, the method comprises administering to said animal an effective amount of posaconazole to provide a mean maximum plasma concentration (C max ) of posaconazole of at least about 467 ng/ml at steady state, and a mean plasma Area Under the Curve over 24 hours (AUC) value of posaconazole of at least about 9840 ng.hr/ml at steady state, when said formulation is infused over about 1 hour to deliver 100 mg of posaconazole, and repeated at an interval of about 24 hours. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       FIG. 1  shows posaconazole mean blood concentration-time profiles in healthy volunteers after 1 hr intravenous infusions of 25, 50, 100, 200, 400, and 600 mg posaconazole.  
       FIG. 2  shows posaconazole mean plasma concentration-time profiles in healthy volunteers after 1 hr intravenous infusions of 25, 50, 100, 200, 400, and 600 mg posaconazole.  
       FIG. 3  shows posaconazole mean plasma and blood concentration-time profiles in healthy volunteers after 1 hr intravenous infusion of 25 mg posaconazole.  
       FIG. 4  shows posaconazole mean plasma and blood concentration-time profiles in healthy volunteers after 1 hr intravenous infusion of 600 mg posaconazole. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION  
      The present invention encompasses formulations suitable for parenteral administration, e.g., by injection, for treating an infection. These formulations comprise a suspension of posaconazole, stabilized by a phospholipid, in a mixture comprising water, a thermoprotectant, and a buffer system. Since posaconazole is minimally soluble in water, a suspension formulation is advantageous. Phospholipids have been found to be effective surfactants in forming stable suspensions of posaconazole in water or an aqueous medium.  
      These phospholipids can degrade when subjected to the temperature excursions experienced during terminal sterilization (e.g., autoclaving), a step which is necessary to assure the sterility of any injectable formulation. Thus, a thermoprotectant is used to prevent agglomeration and crystal growth of the posaconazole particles during autoclaving.  
      Parenteral buffer systems are typically designed to be at physiological pH of about 7.4. Phospholipids are known to be stable at a pH range of about 6 to about 7. Furthermore, pH adjustment of injectable formulations can be necessary to achieve physiological compatibility, and thus, for example, to minimize injection-site irritation. In addition, the rate of phospholipid hydrolysis can be temperature-sensitive. Thus, in the present formulations, the buffer systems are designed to meet physiological pH requirements, and to maintain the temperature/pH-dependent chemical stability of the phospholipid in the formulation during high temperature excursions (such as experienced during autoclaving), and throughout shelf life.  
      In accordance with the above, it was found that POPC, an ingredient that acts as a suspension stabilizer, was sensitive to autoclaving. Certain buffer systems were found to control degradation of POPC-containing posaconazole formulations during autoclaving. For example, such formulations were found to be stable after 20 minutes of autoclaving at 121° C. In addition, these buffer systems stabilize such formulations during storage at 4° C. to 25° C. for at least 18 months following autoclaving. Similarly, other phospholipids that are similar to POPC could be used to stabilize the formulations disclosed herein. For example, unsaturated phospholipids with an acyl chain length ranging from C 12  to C 20  wherein the degree of unsaturation of the acyl chain ranges from 1 to 4; as well as saturated phospholipids with an acyl chain length ranging from C 12  to C 18  are useful according to the present invention. Examples of useful unsaturated phospholipids include:  
                 
 
 or combinations thereof 
 
      Examples of saturated phospholipids include:  
                 
 
 or combinations thereof. 
 
      Unsaturated phospholipids are known be to prone to oxidation. To prevent such oxidation, an antioxidant can be employed. In some embodiments, the antioxidant comprises propyl gallate, preferably at a concentration of about 0.02 to about 0.005 mg/ml. In other embodiments, the antioxidant comprises butylated hydroxytoluene, preferably at a concentration of about 0.1 to about 0.02 mg/ml. In related embodiments, the antioxidant comprises propyl gallate, preferably at a concentration of about 0.02 to about 0.005 mg/ml, in combination with butylated hydroxytoluene, preferably at a concentration of about 0.1 to about 0.02 mg/ml. In yet other embodiments, the antioxidant comprises alpha-D-tocopherol, preferably at a concentration of about 0.5 to about 0.01 mg/ml.  
      The inventors have found certain ratios of components to result in advantageous formulations. For example, the weight ratio of phospholipid to posaconazole is preferably between about 1:0.1 and about 1:10, more preferably, between about 1:1 and about 1:5, still more preferably, between about 1:1 and about 4:5. The weight ratio of thermoprotectant to posaconazole is preferably between about 0.5:1 and about 6:1, more preferably, between about 2:1 and about 6:1. The weight ratio of thermoprotectant to phospholipid is preferably, between about 20:1 and about 5:4, more preferably, between about 20:4 and about 30:4.  
      The formulations of the present invention comprise a suspension of solid particles of posaconazole of specific particle size distribution in an aqueous phase. The particle size distribution displayed in the suspended particles is critical for physiological compatibility, syringeability, physical stability of the suspension, re-suspendability, and for pharmacokinetic characteristics and bio-distribution (i.e., sequestration within specific bodily tissues). Since these characteristics are critical to the formulation as delivered to the patient, it is important that processes that contribute to changes in particle size distribution after micronization are controlled.  
      Such processes can include agglomeration during autoclaving, and de-suspension due to temperature excursions and/or agitation experienced during shipping and storage. It is the particle size distribution in the formulation as ready for administration to the patient that influences pharmacokinetic characteristics and bio-distribution.  
      The inventors of the present invention have determined that for injectable formulations of posaconazole, these characteristics are brought within advantageous ranges with particle size distributions whose median values are between about 1.0 to about 8.0 microns, preferably, between about 1.0 to about 5.0 microns, more preferably between about 1.2 to about 4.5 microns. In each case, the particle size distributions display not more than about 3000 particles of 10 microns or greater size and not more than about 300 particles of 25 microns or greater size.  
      In the injectable formulations of the present invention, which include POPC, it has been found useful to maintain a pH range of between about 3.0 and about 9.0, preferably between about 6.0 and about 8.0, and more preferably between about 6.4 and about 7.6.  
      The inventors have found that certain organic buffers, e.g., histidine and citric acid, are more advantageous in controlling the pH-related degradation of POPC in the formulation. Components used in pH adjustment systems can also function as components of the buffer system, after pH adjustment has been achieved. Non-limiting examples of pH adjustment system components that function in this way include sodium hydroxide, hydrochloric acid, and phosphoric acid.  
      Anti-Infective Applications  
      The present invention encompasses methods of prevention and treatment of a variety of infections caused by a broad spectrum of infectious agents. The term “infection” is understood to include, but not be limited to, those disease states caused by molds, yeasts and other infectious agents, such as: Candida, dermatophytes, Dimorphics, Dematiaceous (e.g., Alternaria and Bipolaris), Aspergillus, Acremonium, Basidiomycetes, Bjerkandera, Coprinus, Paecilomyces, Microsporum, Trichophyton, Pseudallescheria, Schizophyllum, Crytococcus, Histoplasma, Blastomyces, Coccidioides, Fusarium, Exophiala, Zygomycocetes (e.g., Mucor, Rhizopus, and Rhizomucor), Kluyveromyces, Saccharomyces, Yarrowia, Pichia, Epidermophyton, Paracoccidioides, Scedosporium, Apophysomyces, Curvularia, Penicillium, Fonsecaea, Wangiella, Sporothrix, Pneumocystis, Trichosporon, Absidia, Cladophialophora, Ramichloridium, Syncephalastrum, Madurella, Scytalidium, Leshmania, protozoa, bacteria, gram negatives, gram positives, anaerobes, including Legionella Borrelia, Mycoplasma, Treponema, Gardneralla, Trichomononas and Trypanosoma.  
      The present invention is intended to treat both opportunistic and non-opportunistic infections, where the term “opportunistic” as used herein denotes those infections caused by organisms capable of causing a disease only in a host whose resistance is lowered, e.g., by chemotherapy or H.I.V.  
      In particular, posaconazole is useful in the prevention and/or treatment of the following disease states:  
      Initial (first line) treatment of oropharyngeal or esophageal candidiasis;  
      Salvage therapy of azole-refractory oropharyngeal and esophageal candidiasis (e.g., in patients who have failed oral fluconazole and/or itraconazole);  
      Initial treatment of invasive aspergillosis, candidiasis, fusariosis, scedosporiosis, infections due to dimorphic fungi (e.g., cryptococcosis, coccidioidomycosis, paracoccidioidomycosis, histoplasmosis, blastomycosis), zygomycosis, and invasive infections due to rare moulds and yeasts;  
      Salvage therapy for invasive mycoses in patients who are refractory to or intolerant of other therapies (e.g., amphotericin B, lipid formulations of amphotericin B, caspofungin, voriconazole and/or itraconazole);  
      Prevention of invasive Candidiasis, invasive mould infections (including zygomycosis and aspergillosis) in patients at high risk, including patients who have undergone intensive chemotherapy and/or radiation therapy for hematologic malignancies, bone marrow or peripheral stem cell transplant conditioning regimens, and patients receiving combination immunosuppressive therapy for the treatment of acute or chronic graft-versus-host disease or prevention of solid organ transplantation;  
      Chagas disease (Trypanosomiasis due to T. cruzi) including acute and chronic forms; and,  
      Leishmaniasis, including visceral and localized forms.  
      Administration  
      Immuno-suppressant therapy (e.g., chemotherapy, radiation therapy, myeloablative conditioning regimens) often results in one or more of the above-referenced infections. The present invention encompasses the administration of a posaconazole formulation adjunctive to immuno-suppressant therapy, wherein the posaconazole formulation functions prophylactically with regard to opportunistic infections including the above-referenced disease states.  
      The present invention encompasses a variety of modes of administration to any part, organ, interstice or cavity ofan animal&#39;s body that is subject to an infection. A non-limiting set of examples of modes by which the posaconasole formulations of the present invention may be administered includes: intravenously, intramuscularly, subcutaneously, ophthalmically, subconjuctivally, intraocularly, via anterior eye chamber injection, intravitreally, intraperitoneally, intrathecally, intracystically, intrapleurally, intranasally, topically, via wound irrigation, intradermally, intrabuccally, intra-abdominally, intra-articularly, intra-aurally, intrabronchially, intracapsularly, intrameningeally, intrapulmonarilly, via inhalation, via endotracheal or endobronchial installation, via direct installation into pulmonary cavities, intraspinally, intrasynovially, intrathoracically, via thoracostomy irrigation, vaginally, epidurally, rectally, intracisternally, intravascularly, intraventricularly, intraosseously, via irrigation of infected bone, and via application as part of any admixture with cement for prosthetic devices.  
      Co-formulations comprising combinations of posaconazole and at least one other active ingredient are also within the scope of the present invention. Non-limiting examples of such active ingredients include: antifungals such as echinocandins (including caspofungin, micafungin, and anidulafungin) and azoles (including voriconazole, itraconazole, fluconazole, ketoconazole, ravuconazole); amphotericin B; deoxycholate amphotericin B; flucytosine; and terbinafine.  
      Also within the scope of this invention are combinations with an antibacterial, antiviral, steroid, or nonsteroidal anti-inflammatory drugs (“NSAIDs”), chemotherapeutics, and/or anti-emitics. Similarly, co-administration of posaconazole with at least one of the above active ingredients, aside from within a single formulation, is also within the scope of the present invention.  
      Also within the scope of the present invention are a variety of dosing regimens, each consisting of a frequency of dosing and a duration of administration. Preferred frequencies of dosing include once every 12, 24, 36 and 48 hours. Preferred durations of administration are within the range of 30 minutes to 4 hours, more preferably, 1 to 2 hours. Also included within the scope of preferred administration is bolus dosing, at various rates and various doses, and combinations of a bolus loading dose, or several bolus loading doses, with an intravenous infusion maintenance dose that provides therapeutic plasma concentration ranges similar to or exceeding those described in Table 14 infra.  
      As used herein, the following terms shall have the definitions set forth below.  
      As used herein, the phrase “phospholipid” refers to a lipid compound that yields on hydrolysis phosphoric acid, an alcohol, fatty acid and a nitrogenous base. Examples include natural and synthetic phoshpholipids, which include lecithin, cephalin, sphingomyelin and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (“POPC”).  
      As used herein, the phrase “natural phospholipid” refers to a phospholipid occurring in nature, or derived from a natural source. Non-limiting examples of natural phospholipids include egg phospholipids, soy phospholipids, and animal tissue phospholipids. Combinations of more than one natural phospholipid are within the scope of the present invention.  
      As used herein, the phrase “synthetic phospholipid” refers to a man-made phospholipid. Non-limiting examples of synthetic phospholipids include 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-oleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-Dilauryl-sn-Glycero-3-Phosphocholine (DLPC), 1,2-Dimyristoyl-sn-Glycero-3-Phosphocholine (DMPC), 1,2-Dipalmitoyl-sn-Glycero-3-Phosphocholine (DPPC) and 1,2-Stearoyl-sn-Glycero-3-Phosphocholine (DSPC). Combinations of more than one synthetic phospholipid are within the scope of the present invention.  
      As used herein, the phrase “buffer system” refers to a buffer comprising one or more components that maintains a particular pH range. Non-limiting examples of suitable buffer systems include: phosphoric acid; glycine; sodium citrate; histidine; citric acid; acetic acid; tromethamine; ammonium sulfate; and combinations thereof. The aforementioned components are understood to include the salts, hydrates and solvates thereof. Thus, for example, phosphoric acid includes the sodium phosphate or potassium phosphate salts, among other salts. Preferred buffer systems include sodium phosphate monobasic, sodium phosphate dibasic, or a combination thereof. More preferred buffer systems include sodium phosphate monobasic monohydrate, sodium phosphate dibasic anhydrous, or a combination thereof. As used herein, the phrase “organic buffer” refers to a buffer comprising at least one organic compound. Non-limiting examples of suitable organic buffers include: glycine; sodium citrate; histidine; citric acid; acetic acid; and combinations thereof.  
      As used herein, the term “antioxidant” refers to an agent that hinders oxidation. Exemplary antioxidants include propyl gallate, butylated hydroxytoluene, and alpha-D-tocopherol.  
      As used herein, the phrase “median particle size” refers to the particle size present in the volume-weighted 50 th  percentile, as ascertained by Malvern®, Sympatec®, or Horibe® laser diffraction particle size analysis. Particle sizes are measured throughout, and at the termination of, the shelf life, typically up to 24 months after manufacture, when held at either refrigerated or room temperatures. Particle sizes are also measured and maintained when the formulation is diluted into large volume parenterals, e.g., 5% dextrose or water for injection.  
      As used herein, the phrase “initial median particle size” refers to the particle size present within 1 week after a specified timepoint. For example, the initial median particle size after autoclaving refers to the median particle size present within 1 week after autoclaving has been completed.  
      As used herein, the term “autoclaving” refers to sterilization by the terminal steam sterilization method. For example, autoclaving for 20 minutes at 121° C. suffices to sterilize the posaconazole formulations disclosed herein.  
      As used herein, the phrase “thermoprotectant” refers to an agent that stabilizes the phospholipid during temperature excursions. In the present invention, a thermoprotectant is used to preserve the phospholipid, which is necessary to control crystal growth and aggolomeration of the posaconazole particles during autoclaving. Thermoprotectants are typically water soluble polyhydroxyl compounds. For example, trehalose is a thermoprotectant agent that may be used in conjunction with posaconazole. Others include maltose, sorbitol, dextrose, sucrose, lactose and mannitol.  
      As used herein, the term “prodrug” refers to a compound that is a drug precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield posaconazole or a salt and/or solvate thereof.  
      As used herein, the term “solvate” refers to a physical association between a compound with one or more solvent molecules. This physical association involves varying degrees of ionic and/or covalent bonding, including hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. The term “solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include hydrates, ethanolates, and methanolates.  
      As used herein, the term “injectable” means adapted to parenteral administration.  
      As used herein, the term “fungus” means one of the diverse morphologic forms of yeasts and molds. Fungi include Candida, dermatophytes, Dimorphics, Dematiaceous (e.g., Altemaria and Bipolaris), Aspergillus, Acremonium, Basidiomycetes, Bjerkandera, Coprinus, Paecilomyces, Microsporum, Trichophyton, Pseudallescheria, Schizophyllum, Crytococcus, Histoplasma, Blastomyces, Coccidioides, Fusarium, Exophiala, Zygomycocetes (e.g., Mucor, Rhizopus, and Rhizomucor), Kluyveromyces, Saccharomyces, Yarrowia, Pichia, Epidermophyton, Paracoccidioides, Scedosporium, Apophysomyces, Curvularia, Penicillium, Fonsecaea, Wangiella, Sporothrix, Pneumocystis, Trichosporon, Absidia, Cladophialophora, Ramichloridium, Syncephalastrum, Madurella, Scytalidium, Leshmania, gram negatives, gram positives, Mycoplasma, Treponema, Gardneralla, and Trichomononas.  
      As used herein, the term “Dematiaceous” means dark conidia and/or hyphae, and includes as non-limiting examples Altemaria and Bipolaris.  
      As used herein, the term “Zygomycocete” means a class of fungi characterized by sexual reproduction resulting in the formation of zygospore, and asexual reproduction by means of nonmotile spores called sporangiospores or conidia, and includes as non-limiting examples Mucor, Rhizopus, and Rhizomucor.  
      As used herein, the term “anaerobe” means a microorganism that can live and grow in the absence of oxygen, and includes as non-limiting examples Legionella Borrelia, Mycoplasma, Treponema, Gardneralla, and Trichomononas.  
      As used herein, the term “parasite” means an organism that lives on or in another and draws its nourishment therefrom. Parasites include Leshmania and Trypansoma, among others.  
      As used herein, the term “antifungal” means an agent having activity against one or more fungi, and includes echinocandins such as caspofungin, micafungin, and anidulafungin.  
      As used herein, the term “azole” means divinylenimine, and includes voriconazole, itraconazole, fluconazole, ketoconazole, ravuconazole.  
      As used herein, the term “mean maximum concentration (C max )” when followed by the term “at steady state” means that mean maximum concentration value that occurs after administration of a sufficient number of repeated doses of the formulation to generate maximum blood or plasma concentrations that are substantially equivalent to one another in value. Thus, the subsequent maximum concentration values are no longer rising, but rather each peak achieves substantially the same maximum value as the previous one and the next one.  
      As used herein, the term “animal” is understood to include humans, non-human mammals, fish, birds and reptiles.  
      As used herein, the term “bioequivalent” is understood as having that meaning assigned to the term by the U.S. Food &amp; Drug Administration. “Bioequivalence means the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.” 21 CFR 320.1(e). Methodologies for determining bioequivalence are given in “Guidance for Industry: Statistical Approaches to Establishing Bioequivalence,” U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER) June, 2001.  
     EXAMPLES  
      The following non-limiting examples illustrate certain aspects of the invention.  
      Exemplary formulations of posaconazole in conjunction with POPC and trehalose using various buffer systems are detailed below in Tables 1-3. These formulations provide ranges for buffer systems that maintain a particular pH range.  
               TABLE 1                          Representative posaconazole formulations at a pH range of 6.4-7.4                                 Function   Ingredient   Concentration range                                                 Active   Posaconazole   50   mg/ml           Stabilizer   POPC   40   mg/ml           Buffer   Glycine   3.5-10.5   mg/ml           Buffer   Sodium citrate dihydrate   4-10.2   mg/ml           Buffer   Citric acid monohydrate   0.01-0.02   mg/ml           Stabilizer   Trehalose   250   mg/ml           Solvent   Water q.s. ad   1   ml                      
 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                   
               
               
                 Representative posaconazole formulations at a pH range of 6.4-6.6 
               
            
           
           
               
               
               
               
            
               
                   
                 Function 
                 Ingredient 
                 Concentration range 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 Active 
                 Posaconazole 
                 50 
                 mg/ml 
               
               
                   
                 Stabilizer 
                 POPC 
                 40 
                 mg/ml 
               
               
                   
                 Buffer 
                 Glycine 
                 1.5-4.5 
                 mg/ml 
               
               
                   
                 Buffer 
                 Citric acid monohydrate 
                 0.12-0.36 
                 mg/ml 
               
               
                   
                 Stabilizer 
                 Trehalose 
                 250 
                 mg/ml 
               
               
                   
                 Solvent 
                 Water q.s. ad 
                 1 
                 ml 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                   
               
               
                 Representative posaconazole formulations at a pH range of 6.6-6.8 
               
            
           
           
               
               
               
               
            
               
                   
                 Function 
                 Ingredient 
                 Concentration range 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 Active 
                 Posaconazole 
                 50 
                 mg/ml 
               
               
                   
                 Stabilizer 
                 POPC 
                 40 
                 mg/ml 
               
               
                   
                 Buffer 
                 Histidine 
                 1.5-4.5 
                 mg/ml 
               
               
                   
                 Buffer 
                 Ammonium sulfate 
                 1-3 
                 mg/ml 
               
               
                   
                 Buffer 
                 Hydrochloric acid 
                 0.1-0.3 
                 mg/ml 
               
               
                   
                 Stabilizer 
                 Trehalose 
                 250 
                 mg/ml 
               
               
                   
                 Solvent 
                 Water q.s. ad 
                 1 
                 ml 
               
               
                   
                   
               
            
           
         
       
     
      An exemplary posaconazole formulation for each of the buffer systems described in Tables 1-3 is provided in Examples 1-3, respectively.  
     Example 1  
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                   
               
               
                   
                 Ingredient 
                 Concentration 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                   
                 Posaconazole 
                 50 
                 mg/ml 
               
               
                   
                 POPC 
                 40 
                 mg/ml 
               
               
                   
                 Glycine 
                 7 
                 mg/ml 
               
               
                   
                 Sodium citrate dihydrate 
                 8 
                 mg/ml 
               
               
                   
                 Trehalose 
                 250 
                 mg/ml 
               
               
                   
                 Water q.s. ad 
                 1 
                 ml 
               
               
                   
                   
               
            
           
         
       
     
      Of note, the pH is 7.4 in Example 1.  
     Example 2 
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                   
               
               
                   
                 Ingredient 
                 Concentration 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                   
                 Posaconazole 
                 50 
                 mg/ml 
               
               
                   
                 POPC 
                 40 
                 mg/ml 
               
               
                   
                 Histidine 
                 3 
                 mg/ml 
               
               
                   
                 Citric acid monohydrate 
                 0.24 
                 mg/ml 
               
               
                   
                 Trehalose 
                 250 
                 mg/ml 
               
               
                   
                 Water q.s. ad 
                 1 
                 ml 
               
               
                   
                   
               
            
           
         
       
     
      Of note, the pH is 6.4 in Example 2.  
     Example 3 
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                   
               
               
                   
                 Ingredient 
                 Concentration 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                   
                 Posaconazole 
                 50 
                 mg/ml 
               
               
                   
                 POPC 
                 40 
                 mg/ml 
               
               
                   
                 Histidine 
                 3 
                 mg/ml 
               
               
                   
                 Ammonium sulfate 
                 2 
                 mg/ml 
               
               
                   
                 Hydrochloric acid 
                 0.2 
                 mg/ml 
               
               
                   
                 Trehalose 
                 250 
                 mg/ml 
               
               
                   
                 Water q.s. ad 
                 1 
                 ml 
               
               
                   
                   
               
            
           
         
       
     
      Of note, the pH is 6.6 in Example 3.  
      In addition, exemplary posaconazole formulations that include antioxidant are described in Examples 4-6.  
     Example 4  
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                   
               
               
                   
                 Ingredient 
                 Concentration 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                   
                 Posaconazole 
                 50 
                 mg/ml 
               
               
                   
                 POPC 
                 40 
                 mg/ml 
               
               
                   
                 Glycine 
                 7 
                 mg/ml 
               
               
                   
                 Sodium citrate dihydrate 
                 8 
                 mg/ml 
               
               
                   
                 Propyl gallate 
                 0.01 
                 mg/ml 
               
               
                   
                 Butylated hydroxytoluene 
                 0.05 
                 mg/ml 
               
               
                   
                 Trehalose 
                 250 
                 mg/ml 
               
               
                   
                 Water q.s. ad 
                 1 
                 ml 
               
               
                   
                   
               
            
           
         
       
     
      Of note, the pH is 7.4 in Example 4.  
     Example 5  
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                   
               
               
                   
                 Ingredient 
                 Concentration 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                   
                 Posaconazole 
                 50 
                 mg/ml 
               
               
                   
                 POPC 
                 40 
                 mg/ml 
               
               
                   
                 Histidine 
                 3 
                 mg/ml 
               
               
                   
                 Citric acid monohydrate 
                 0.24 
                 mg/ml 
               
               
                   
                 Propyl gallate 
                 0.01 
                 mg/ml 
               
               
                   
                 Butylated hydroxytoluene 
                 0.05 
                 mg/ml 
               
               
                   
                 Trehalose 
                 250 
                 mg/ml 
               
               
                   
                 Water q.s. ad 
                 1 
                 ml 
               
               
                   
                   
               
            
           
         
       
     
      The pH is 6.4 in Example 5.  
     Example 6  
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                   
               
               
                   
                 Ingredient 
                 Concentration 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                   
                 Posaconazole 
                 50 
                 mg/ml 
               
               
                   
                 POPC 
                 40 
                 mg/ml 
               
               
                   
                 Histidine 
                 3 
                 mg/ml 
               
               
                   
                 Citric acid monohydrate 
                 0.24 
                 mg/ml 
               
               
                   
                 Alpha-D-tocopherol 
                 0.05 
                 mg/ml 
               
               
                   
                 Trehalose 
                 250 
                 mg/ml 
               
               
                   
                 Water q.s. ad 
                 1 
                 ml 
               
               
                   
                   
               
            
           
         
       
     
      The pH is 6.5 in Example 6.  
      Example 7 is a preferred embodiment of the present invention.  
     Example 7  
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                   
               
               
                   
                 Ingredient 
                 Concentration 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                   
                 Posaconazole 
                 50 
                 mg/ml 
               
               
                   
                 POPC 
                 40 
                 mg/ml 
               
               
                   
                 Sodium Phosphate, Monobasic, 
                 0.345 
                 mg/ml 
               
               
                   
                 Monohydrate, USP 
               
               
                   
                 Sodium Phosphate, Dibasic, 
                 1.065 
                 mg/ml 
               
               
                   
                 Anhydrous, USP 
               
               
                   
                 Trehalose 
                 250 
                 mg/ml 
               
            
           
           
               
               
               
            
               
                   
                 Sodium Hydroxide, NF (1.0 N) 
                 for pH adjustment 
               
               
                   
                 Phosphoric Acid, NF (20% w/w) 
                 for pH adjustment 
               
            
           
           
               
               
               
               
            
               
                   
                 Water for injection, USP 
                 qs 1 
                 ml 
               
               
                   
                   
               
            
           
         
       
     
      The pH is 7.2 in Example 7.  
      The following is an exemplary placebo formulation wherein the pH is 6.4. This exemplary placebo formulation was utilized in the comparative stability data study described below.  
                                                   Ingredient   Concentration                                                        Placebo                   POPC   40   mg/ml           Glycine   1   mg/ml           Sodium citrate dihydrate   0.3   mg/ml           Citric acid monohydrate   0.016   mg/ml           Trehalose   250   mg/ml           Water q.s. ad   1   ml                      
 
 Comparative Stability Data Study 
 
      The stability of POPC in formulation Examples 1-3 was compared with the aforementioned exemplary placebo both before and after autoclaving for 20 min at 121° C. In addition, posaconazole stability, particle size, pH, and a physical observation were ascertained for each formulation before and after autoclaving. Each formulation was also examined following an additional period of storage at 4° C., 25° C., and 40° C. (i.e., 4° C.±2° C. at 60%±5% relative humidity; 25° C.±2° C. at 60%±5% relative humidity; and 40° C.±2° C. at ambient relative humidity, respectively) for 1 month, 3 months, and 6 months after autoclaving. Notably, particle size was determined using the Malvern laser diffraction particle size analysis technique. Particle sizes are characterized by values for median (“50 th  percentile”) and maximum (“100 th  percentile”). The stability data from these comparative studies are compiled below for formulations reflected in Examples 1-6, shown in Tables 4-9, respectively.  
               TABLE 4                          Stability data for posaconazole formulation Example 1                             Particle size               (microns)                                         Interval/   Posaconazole   POPC   50 th     100 th         Physical       Condition   (mg/ml)   (mg/ml)   percentile   percentile   pH   Observation                                                 Initial -   51.3   41.4   1.11   3.77   7.4   Milky white       Before       Autoclaving       Initial -   50.8   40.9   1.49   6.63   7.3   Milky white       After       Autoclaving                                             1    4° C.   50.2   39.0   1.48   5.49   7.2   Milky white       month   25° C.   50.7   39.2   1.48   5.49   7.2   Milky white           40° C.   50.6   39.1   1.49   5.49   7.1   Milky white       3    4° C.   55.1   41.8   1.47   5.49   7.2   Milky white       months   25° C.   55.4   41.5   1.48   6.63   7.2   Milky white           40° C.   55.4   40.0   1.49   6.63   7.1   Milky white       6    4° C.   51.7   44.4   1.44   4.88   7.3   Milky white       months   25° C.   50.3   42.3   1.50   5.69   7.3   Milky white           40° C.   51.5   36.0   1.57   5.69   7.3   Milky white                  
 
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                   
               
               
                 Stability data for posaconazole formulation Example 2 
               
            
           
           
               
               
               
            
               
                   
                 Particle size 
                   
               
               
                   
                 (microns) 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Interval/ 
                 Posaconazole 
                 POPC 
                 50 th   
                 100 th   
                   
                 Physical 
               
               
                 Condition 
                 (mg/ml) 
                 (mg/ml) 
                 percentile 
                 percentile 
                 pH 
                 Observation 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Initial - 
                 46.4 
                 38.2 
                 1.41 
                 6.63 
                 6.4 
                 Milky white 
               
               
                 Before 
               
               
                 Autoclaving 
               
               
                 Initial - 
                 46.3 
                 38.2 
                 1.76 
                 6.63 
                 6.4 
                 Milky white 
               
               
                 After 
               
               
                 Autoclaving 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 1 
                 4° C. 
                 45.8 
                 37.9 
                 1.70 
                 6.63 
                 6.4 
                 Milky white 
               
               
                 month 
                 25° C. 
                 45.3 
                 37.0 
                 1.70 
                 6.63 
                 6.4 
                 Milky white 
               
               
                   
                 40° C. 
                 45.8 
                 37.4 
                 1.72 
                 6.63 
                 6.4 
                 Milky white 
               
               
                 3 
                  4° C. 
                 44.8 
                 36.1 
                 1.69 
                 6.63 
                 6.4 
                 Milky white 
               
               
                 months 
                 25° C. 
                 45.9 
                 36.8 
                 1.70 
                 6.63 
                 6.4 
                 Milky white 
               
               
                   
                 40° C. 
                 45.6 
                 35.7 
                 1.76 
                 35.98 
                 6.4 
                 Milky white 
               
               
                 6 
                  4° C. 
                 44.1 
                 38.8 
                 1.65 
                 6.63 
                 6.6 
                 Milky white 
               
               
                 months 
                 25° C. 
                 46.1 
                 40.1 
                 1.71 
                 6.63 
                 6.6 
                 Milky white 
               
               
                   
                 40° C. 
                 46.1 
                 40.1 
                 1.70 
                 6.63 
                 6.6 
                 Milky white 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                   
               
               
                 Stability data for posaconazole formulation Example 3 
               
            
           
           
               
               
               
            
               
                   
                 Particle size 
                   
               
               
                   
                 (microns) 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Interval/ 
                 Posaconazole 
                 POPC 
                 50 th   
                 100 th   
                   
                 Physical 
               
               
                 Condition 
                 (mg/ml) 
                 (mg/ml) 
                 percentile 
                 percentile 
                 pH 
                 Observation 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Initial - 
                 46.1 
                 36.7 
                 1.39 
                 5.49 
                 6.6 
                 Milky white 
               
               
                 Before 
               
               
                 Autoclaving 
               
               
                 Initial - 
                 45.9 
                 36.2 
                 1.75 
                 6.63 
                 6.6 
                 Milky white 
               
               
                 After 
               
               
                 Autoclaving 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 1 
                  4° C. 
                 45.3 
                 34.6 
                 1.76 
                 6.63 
                 6.5 
                 Milky white 
               
               
                 month 
                 25° C. 
                 44.9 
                 34.4 
                 1.76 
                 6.63 
                 6.5 
                 Milky white 
               
               
                   
                 40° C. 
                 44.9 
                 34.5 
                 1.75 
                 6.63 
                 6.5 
                 Milky white 
               
               
                 3 
                  4° C. 
                 46.9 
                 35.0 
                 1.77 
                 6.63 
                 6.5 
                 Milky white 
               
               
                 months 
                 25° C. 
                 46.9 
                 34.9 
                 1.78 
                 6.63 
                 6.5 
                 Milky white 
               
               
                   
                 40° C. 
                 47.5 
                 34.5 
                 1.75 
                 6.63 
                 6.5 
                 Milky white 
               
               
                 6 
                  4° C. 
                 47.0 
                 35.3 
                 2.18 
                 6.63 
                 6.6 
                 Milky white 
               
               
                 months 
                 25° C. 
                 46.3 
                 35.1 
                 1.75 
                 5.69 
                 6.5 
                 Milky white 
               
               
                   
                 40° C. 
                 49.4 
                 32.5 
                 2.03 
                 6.63 
                 6.6 
                 Milky white 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                   
               
               
                 Stability data for posaconazole formulation Example 4 
               
            
           
           
               
               
               
            
               
                   
                 Particle size 
                   
               
               
                   
                 (microns) 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Interval/ 
                 Posaconazole 
                 POPC 
                 50 th   
                 100 th   
                   
                 Physical 
               
               
                 Condition 
                 (mg/ml) 
                 (mg/ml) 
                 percentile 
                 percentile 
                 pH 
                 Observation 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Initial - 
                 65.4 
                 50.3 
                 1.21 
                 5.49 
                 7.3 
                 Milky white 
               
               
                 Before 
               
               
                 Autoclaving 
               
               
                 Initial - 
                 65.5 
                 50.2 
                 1.66 
                 6.63 
                 7.2 
                 Milky white 
               
               
                 After 
               
               
                 Autoclaving 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 1 
                  4° C. 
                 65.2 
                 50.2 
                 1.65 
                 6.63 
                 7.2 
                 Milky white 
               
               
                 month 
                 25° C. 
                 65.1 
                 50.4 
                 1.64 
                 6.63 
                 7.2 
                 Milky white 
               
               
                   
                 40° C. 
                 67.1 
                 50.6 
                 1.67 
                 6.63 
                 7.2 
                 Milky white 
               
               
                 3 
                  4° C. 
                 68.1 
                 50.9 
                 1.64 
                 6.63 
                 7.4 
                 Milky white 
               
               
                 months 
                 25° C. 
                 68.4 
                 51.0 
                 1.64 
                 6.63 
                 7.4 
                 Milky white 
               
               
                   
                 40° C. 
                 69.5 
                 49.2 
                 1.67 
                 29.82 
                 7.3 
                 Milky white 
               
               
                 6 
                  4° C. 
                 66.7 
                 53.3 
                 1.61 
                 5.68 
                 7.2 
                 Milky white 
               
               
                 months 
                 25° C. 
                 64.9 
                 52.6 
                 1.54 
                 4.88 
                 7.0 
                 Milky gray 
               
               
                   
                 40° C. 
                 65.4 
                 47.3 
                 1.64 
                 56.23 
                 6.8 
                 Milky white 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                   
               
               
                 Stability data for posaconazole formulation Example 5 
               
            
           
           
               
               
               
            
               
                   
                 Particle size 
                   
               
               
                   
                 (microns) 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Interval/ 
                 Posaconazole 
                 POPC 
                 50 th   
                 100 th   
                   
                 Physical 
               
               
                 Condition 
                 (mg/ml) 
                 (mg/ml) 
                 percentile 
                 percentile 
                 pH 
                 Observation 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Initial - 
                 50.8 
                 39.7 
                 1.61 
                 6.63 
                 6.5 
                 Milky white 
               
               
                 After 
               
               
                 Autoclaving 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 1 
                  4° C. 
                 50.9 
                 39.6 
                 1.61 
                 6.63 
                 6.5 
                 Milky white 
               
               
                 month 
                 25° C. 
                 51.1 
                 39.8 
                 1.60 
                 6.63 
                 6.5 
                 Milky white 
               
               
                   
                 40° C. 
                 50.7 
                 39.4 
                 1.62 
                 6.63 
                 6.5 
                 Milky white 
               
               
                 3 
                  4° C. 
                 53.0 
                 40.5 
                 1.62 
                 6.63 
                 6.6 
                 Milky white 
               
               
                 months 
                 25° C. 
                 53.1 
                 40.6 
                 1.62 
                 6.63 
                 6.6 
                 Milky white 
               
               
                   
                 40° C. 
                 51.9 
                 39.0 
                 1.62 
                 6.63 
                 6.7 
                 Milky white 
               
               
                 6 
                  4° C. 
                 54.2 
                 46.2 
                 1.59 
                 5.69 
                 6.5 
                 Milky white 
               
               
                 months 
                 25° C. 
                 53.2 
                 44.6 
                 1.59 
                 5.69 
                 6.5 
                 Milky white 
               
               
                   
                 40° C. 
                 52.2 
                 41.2 
                 1.58 
                 5.69 
                 6.5 
                 Milky white 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                   
               
               
                 Stability data for posaconazole formulation Example 6 
               
            
           
           
               
               
               
            
               
                   
                 Particle size 
                   
               
               
                   
                 (microns) 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Interval/ 
                 Posaconazole 
                 POPC 
                 50 th   
                 100 th   
                   
                 Physical 
               
               
                 Condition 
                 (mg/ml) 
                 (mg/ml) 
                 percentile 
                 percentile 
                 pH 
                 Observation 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Initial - 
                 46.8 
                 36.5 
                 1.32 
                 6.63 
                 6.5 
                 Milky white 
               
               
                 Before 
               
               
                 Autoclaving 
               
               
                 Initial - 
                 46.5 
                 36.4 
                 1.61 
                 6.63 
                 6.5 
                 Milky white 
               
               
                 After 
               
               
                 Autoclaving 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 1 
                  4° C. 
                 46.2 
                 35.8 
                 1.61 
                 6.63 
                 6.5 
                 Milky white 
               
               
                 month 
                 25° C. 
                 47.6 
                 36.9 
                 1.60 
                 6.63 
                 6.5 
                 Milky white 
               
               
                   
                 40° C. 
                 47.3 
                 36.4 
                 1.62 
                 6.63 
                 6.5 
                 Milky white 
               
               
                 3 
                  4° C. 
                 48.3 
                 36.8 
                 1.63 
                 6.63 
                 6.5 
                 Milky white 
               
               
                 months 
                 25° C. 
                 48.6 
                 37.1 
                 1.62 
                 6.63 
                 6.6 
                 Milky white 
               
               
                   
                 40° C. 
                 49.1 
                 36.4 
                 1.61 
                 6.63 
                 6.4 
                 Milky white 
               
               
                 6 
                  4° C. 
                 47.9 
                 36.3 
                 1.60 
                 5.69 
                 6.5 
                 Milky white 
               
               
                 months 
                 25° C. 
                 47.3 
                 36.1 
                 1.60 
                 5.69 
                 6.5 
                 Milky white 
               
               
                   
                 40° C. 
                 48.8 
                 34.0 
                 1.60 
                 5.69 
                 6.5 
                 Milky white 
               
               
                   
               
            
           
         
       
     
      Activities of posaconazole against a broad spectrum of infectious agents have been tested in vitro. Tables 10 and 11 display a subset of the results of this in vitro testing, showing some of those infectious agents against which posaconazole is most active.  
               TABLE 10                          Geometric Mean MIC and MIC[90] Values (μg/mL) for Strains Tested (n) in Posaconazole (POS),       Fluconazole (FLU) and Itraconazole (ITZ)                                 POS   FLZ   ITZ                                                     Organism   n   Mean   MIC[90]   n   Mean   MIC[90]   n   Mean   MIC[90]                                                               Aspergillus flavus     241   0.079   0.25   94   220.898   256.0   203   0.213   1.0         Aspergillus fumigatus     2,158   0.118   0.5   735   247.922   512.0   1560   0.397   1.0         Aspergillus nidulans     33   0.055   0.25   8   76.109    (32.0-128.0)   21   0.186   0.5         Aspergillus niger     171   0.195   0.5   64   234.753   256.0   153   0.834   2.0         Aspergillus sydowii     8   0.177   (0.031-0.5)    7   115.933    (64.0-256.0)   8   0.500   (0.125-2.0)          Aspergillus terreus     100   0.052   0.25   37   208.327   256.0   56   0.229   0.5         Aspergillus ustus     7   1.641   (0.25-8.0)    7   172.275    (64.0-256.0)   7   0.906   (0.125-2.0)          Candida albicans     8,847   0.037   0.25   7,879   0.415   2.0   7,686   0.064   0.25         Candida dubliniensis     339   0.062   0.25   231   0.454   32.0   197   0.107   0.5         Candida glabrata     2,507   0.672   2.0   2,197   9.719   64.0   2,188   0.853   4.0         Candida krusei     496   0.335   1.0   386   32.521   64.0   383   0.576   1.0         Candida parapsilosis     2,126   0.073   0.125   1,916   0.910   2.0   1,903   0.161   0.5         Cryptococcus laurentii     5   0.095   (0.008-0.5)    3   5.040   (4.0-8.0)   3   0.397   (0.25-0.5)          Cryptococcus neoformans     1,427   0.119   0.25   1,237   1.781   8.0   1,269   0.444   4.0         Coccidioides immitis     50   0.304   1.0   25   16.450   32.0   50   0.198   0.25         Fonsecae pedrosoi     4   0.250   (0.25)   2   64.000   (64.0)   4   0.063   (0.008-0.5)          Histoplasma capsulatum     58   0.038   0.25   8   19.027    (8.0-32.0)   53   0.018   0.063         Pseudallescheria boydii     66   0.365   1.0   41   41.237   128.0   61   0.506   1.0         Alternaria  spp   13   0.101   0.25   0   —   —   13   0.326   1.0         Exophiala dermatidis     3   0.125   (0.125)   2   8.000   (8.0)   2   1.000   (1.0)         Exophiala jeanselmei     10   0.287   0.5   0   —   —   10   0.467   1.0         Exophiala moniliae     2   0.016   (0.016)   0   —   —   2   0.031   (0.031)         Fusarium  spp   38   2.319   16.0   27   249.512   256.0   30   13.300   16.0         Ramichloridium obovoideum     2   0.044   (0.031-0.063)   2   22.627   (16.0-32.0)   2   0.016   (0.016)         Rhizomucor  spp   2   0.016   (0.016)   0   —   —   2   0.016   (0.016)         Mucor  spp   17   0.694   16.0   10   207.937   256.0   12   2.378   16.0         Rhizopus  spp   29   1.000   4.0   19   229.461   256.0   21   3.281   16.0         Candida famata     44   0.125   0.5   44   4.084   32.0   27   0.348   1.0         Candida guilliermondii     143   0.178   0.5   106   4.000   32.0   82   0.479   1.0         Candida lusitaniae     306   0.048   0.125   221   0.627   2.0   202   0.216   1.0         Candida kefyr     53   0.081   0.25   51   0.500   4.0   39   0.188   0.5         Candida rugosa     26   0.039   0.5   21   3.391   16.0   17   0.196   4.0         Candida tropicalis     1,645   0.081   0.25   1,476   0.961   4.0   1,450   0.167   0.5         Candida zeylanoides     4   0.031   (0.008-0.25)    4   0.354   (0.125-1.0)    4   0.105   (0.031-0.5)          Kluyveromyces marxianus     6   0.079   (0.063-0.25)    6   0.500   (0.25-1.0)    6   0.070   (0.031-0.125)         Saccharomyces cerevisiae     86   0.249   1.0   59   2.845   16.0   54   0.418   2.0         Yarrowia lipolytica     5   0.144   (0.016-1.0)    5   1.741   (0.125-32.0)    0   —   —         Pichia anomala     13   0.689   1.0   12   2.670   4.0   12   0.375   1.0         Pichia etchel     2   0.125   (0.125)   2   0.125   (0.125)   0   —   —         Pichia ohmeri     1   0.016   (0.016)   1   4.000   (4.0)   0   —   —         Trichosporon  spp   6   0.630   (0.5-1.0)   6   12.699    (4.0-64.0)   6   1.123   (0.5-2.0)         Bjerkandera adusta     14   0.250   0.25   14   4.000   4.0   14   0.057   0.063         Blastomyces dermatitidis     43   0.053   0.125   38   2.191   16.0   38   0.045   2.0         Epidermophyton floccosum     70   0.029   0.125   15   1.447   2.0   18   0.088   32.0         Paracoccidioides brasiliensis     13   0.048   0.125   13   0.766   4.0   13   0.025   0.063         Scedosporium apiospermum     32   0.173   1.0   15   84.449   256.0   26   1.341   32.0         Sporothrix schenckii     16   0.771   2.0   0   —   —   11   0.302   0.5         Wangiella dermatitidis     4   0.088   (0.063-0.125)   2   256.000   (256.0)   4   0.500   (0.063-1.0)          Absidia  spp   8   0.177   (0.031-0.5)    6   143.675   (128.0-256.0)   8   0.229   (0.063-2.0)          Apophysomyces  spp   9   0.340   (0.031-4.0)    4   128.000   (128.0)   6   0.707   (0.031-8.0)          Bipolaris  spp   8   0.354   (0.125-1.0)    2   64.000   (64.0)   2   0.250   (0.25)         Curvularia  spp   5   0.072   (0.031-0.125)   2   16.000   (16.0)   2   0.500   (0.5)         Microsporum audouinii     1   0.250   (0.25)   0   —   —   1   0.125   (0.125)         Microsporum canis     86   0.034   0.5   11   2.000   4.0   23   0.041   2.0         Microsporum fulvum     1   0.500   (0.5)   0   —   —   1   4.000   (4.0)         Microsporum gypseum     5   0.042   (0.008-0.5)    4   16.000    (4.0-128.0)   4   0.044   (0.016-0.5)          Microsporum persicolor     1   0.250   (0.25)   1   128.000   (128.0)   1   0.500   (0.5)         Paecilomyces  spp   16   0.239   0.5   14   141.323   256.0   14   0.640   2.0         Penicillium  spp   93   0.308   1.0   66   220.996   256.0   83   0.853   2.0         Trichophyton mentagrophytes     84   0.036   0.125   30   9.190   64.0   29   0.041   0.25         Trichophyton raubitschekii     1   0.250   (0.25)   1   128.000   (128.0)   1   0.250   (0.25)         Trichophyton rubrum     148   0.047   0.25   93   4.407   32.0   91   0.074   0.25         Trichophyton soudanense     1   0.500   (0.5)   1   128.000   (128.0)   1   4.000   (4.0)         Trichophyton  spp   10   0.036   0.064   0   —   —   0   —   —         Trichophyton terrestre     1   0.125   (0.125)   1   1.000   (1.0)   1   0.250   (0.25)         Trichophyton tonsurans     74   0.029   0.125   24   3.775   32.0   23   0.036   0.063                  
 
                     TABLE 11                          Geometric Mean MIC and MIC[90] Values (μg/mL) for # Strains Tested (n) in Posaconazole (POS),       Amphotericin (AMB) and Voriconazole (VOR)                                 POS   AMB   VOR                                                     Organism   n   Mean   MIC[90]   n   Mean   MIC[90]   n   Mean   MIC[90]                                                               Aspergillus flavus     241   0.079   0.25   177   0.910   2.0   89   0.339   1.0         Aspergillus fumigatus     2.158   0.118   0.5   1.567   0.683   1.0   1149   0.282   0.5         Aspergillus nidulans     33   0.055   0.25   20   0.758   2.0   6   0.070   (0.031-0.125)         Aspergillus niger     171   0.195   0.5   152   0.360   1.0   101   0.480   2.0         Aspergillus sydowii     8   0.177   (0.031-0.5)    3   1.260   (1.0-2.0)   3   0.397   (0.25-1.0)          Aspergillus terreus     100   0.052   0.25   54   1.759   4.0   22   0.312   0.5         Aspergillus ustus     7   1.641   (0.25-8.0)    7   0.673   (0.25-1.0)    4   1.189   (0.25-2.0)          Candida albicans     8.847   0.037   0.25   6.651   0.686   1.0   3.790   0.021   0.063         Candida dubliniensis     339   0.062   0.25   211   0.513   1.0   177   0.028   0.125         Candida glabrata     2.507   0.672   2.0   1.881   0.798   1.0   1.264   0.305   2.0         Candida krusei     496   0.335   1.0   282   0.976   2.0   210   0.346   0.5         Candida parapsilosis     2.126   0.073   0.125   1.655   0.761   1.0   1.011   0.036   0.125         Cryptococcus laurentii     5   0.095   (0.008-0.5)    3   0.794   (0.5-1.0)   1   0.250   (0.25)         Cryptococcus neoformans     1.427   0.119   0.25   1.122   0.667   1.0   277   0.054   0.125         Coccidioides immitis     50   0.304   1.0   25   0.390   0.5   0   —   —         Fonsecae pedrosoi     4   0.250   (0.25)   2   1.000   (1.0)   1   0.500   (0.5)         Histoplasma capsulatum     58   0.038   0.25   53   0.250   0.5   0   —   —         Pseudallescheria boydii     66   0.365   1.0   41   1.718   4.0   3   0.250   (0.125-0.5)          Alternaria  spp   13   0.101   0.25   13   0.852   4.0   0   —   —         Exophiala dermatidis     3   0.125   (0.125)   2   0.500   (0.5)   1   0.063   (0.063)         Exophiala jeanselmei     10   0.287   0.5   10   0.660   1.0   9   0.794   (0.5-1.0)         Exophiala moniliae     2   0.016   (0.016)   2   0.177   (0.125-0.25)    0   —   —         Fusarium  spp   38   2.319   16.0   30   1.203   2.0   14   4.416   16.0         Ramichloridium obovoideum     2   0.044   (0.031-0.063)   2   1.000   (1.0)   0   —   —         Rhizomucor  spp   2   0.016   (0.016)   2   0.063   (0.063)   1   2.000   (2.0)         Mucor  spp   17   0.694   16.0   15   0.274   1.0   8   24.675     (1.0-128.0)         Rhizopus  spp   29   1.000   4.0   29   0.635   2.0   9   8.000    (1.0-32.0)         Candida famata     44   0.125   0.5   28   0.841   2.0   5   0.072   (0.008-0.5)          Candida guilliermondii     143   0.178   0.5   76   0.553   1.0   26   0.112   8.0         Candida lusitaniae     306   0.048   0.125   164   0.506   1.0   89   0.023   0.063         Candida kefyr     53   0.081   0.25   25   0.779   1.0   14   0.031   0.031         Candida rugosa     26   0.039   0.5   17   0.665   1.0   15   0.072   0.5         Candida tropicalis     1.645   0.081   0.25   1.209   0.774   1.0   765   0.075   0.5         Candida zeylanoides     4   0.031   (0.008-0.25)    3   1.000   (1.0)   3   0.039   (0.008-0.125)         Kluyveromyces marxianus     6   0.079   (0.063-0.25)    6   1.000   (1.0)   0   —   —         Saccharomyces cerevisiae     86   0.249   1.0   38   0.775   1.0   22   0.050   0.125         Yarrowia lipolytica     5   0.144   (0.016-1.0)    2   0.500   (0.5)   0   —   —         Pichia anomala     13   0.689   1.0   10   0.707   1.0   0   —   —         Pichia etchel     2   0.125   (0.125)   2   0.063   (0.063)   0   —   —         Pichia ohmeri     1   0.016   (0.016)   0   —   —   0   —   —         Trichosporon spp     6   0.630   (0.5-1.0)   5   1.320   (1.0-2.0)   1   0.125   (0.125)         Bjerkandera adusta     14   0.250   0.25   14   0.215   0.25   14   0.216   0.25         Blastomyces dermatitidis     43   0.053   0.125   38   0.153   0.5   0   —   —         Epidermophyton floccosum     70   0.029   0.125   0   —   —   10   0.015   0.016         Paracoccidioides brasiliensis     13   0.048   0.125   13   0.096   0.25   0   —   —         Scedosporium apiospermum     32   0.173   1.0   27   2.274   8.0   14   0.098   0.5         Sporothrix schenckii     16   0.771   2.0   10   0.574   1.0   0   —   —         Wangiella dermatitidis     4   0.088   (0.063-0.125)   3   0.630   (0.25-1.0)    1   1.000   (1.0)         Absidia  spp   8   0.177   (0.031-0.5)    8   0.545   (0.25-2.0)    6   40.318     (8.0-128.0)         Apophysomyces  spp   9   0.340   (0.031-4.0)    7   0.500   (0.031-4.0)    5   42.224     (16.0-128.0)         Bipolaris  spp   8   0.354   (0.125-1.0)    2   0.250   (0.25)   1   1.000   (1.0)         Curvularia spp     5   0.072   (0.031-0.125)   2   0.500   (0.5)   1   0.125   (0.125)         Microsporum audouinii     1   0.250   (0.25)   0   —   —   0   —   —         Microsporum canis     86   0.034   0.5   0   —   —   10   0.018   0.031         Microsporum fulvum     1   0.500   (0.5)   0   —   —   0   —   —         Microsporum gypseum     5   0.042   (0.008-0.5)    0   —   —   0   —   —         Microsporum persicolor     1   0.250   (0.25)   0   —   —   0   —   —         Paecliomyces  spp   16   0.239   0.5   14   1.104   16.0   8   0.324   (0.031-2.0)          Penicillium  spp   93   0.308   1.0   83   1.025   4.0   35   0.622   2.0         Trichophyton mentagrophytes     84   0.036   0.125   2   1.000   (1.0)   11   0.038   0.25         Trichophyton raubitschekii     1   0.250   (0.25)   0   —   —   0   —   —         Trichophyton rubrum     148   0.047   0.25   0   —   —   10   0.021   0.063         Trichophyton soudanense     1   0.500   (0.5)   0   —   —   0   —   —         Trichophyton  spp   10   0.036   0.064   0   —   —   0   —   —         Trichophyton terrestre     1   0.125   (0.125)   0   —   —   0   —   —         Trichophyton tonsurans     74   0.029   0.125   3   1.260   (0.5-8.0)   11   0.043   0.063                    
 Pharmacokinetics 
 
      The pharmacokinetic characteristics of the posaconazole formulation were evaluated in a Phase-1, single-site, randomized, evaluator-blinded (within dose level), placebo-controlled, rising-single-dose study, with up to six groups of 12 healthy subjects. The purpose of the study was to evaluate the safety, tolerability, and pharmacokinetics of the posaconazole intravenous drug product formulation (hereinafter referred to as “POS IV”) when delivered intravenously. Table 12 shows the POS IV formulation, and Table 13 shows the physical characteristics of this formulation after sterilization, but before dilution in 5% dextrose.  
               TABLE 12                          POS IV Formulation, 50 mg/mL                     Ingredient   mg/mL                             Posaconazole, micronized   50.0       1-Palmitoyl-2-Oleoyl-sn-glycero-3-Phosphocholine,   40.0       Powder, Endotoxin tested (POPC)       Sodium Phoshate, Monobasic, Monohydrate, Crystal, USP   0.040       Sodium Phosphate, Dibasic, Anhydrous, USP   1.378       Trehalose   250.0       Sodium Hydroxide, N.F. (1.0 N)   AN       Phosphoric Acid, N.F. (20% w/w)   AN       Water Injection, USP, q.s. ad   1                 AN = As needed for pH adjustment             
 
     
       
         
           
               
             
               
                 TABLE 13 
               
             
            
               
                   
               
               
                   
               
               
                 Physical Characteristics of POS IV, 50 mg/mL 
               
            
           
           
               
               
               
            
               
                   
                 Description: 
                 milky liquid 
               
               
                   
                   
               
               
                   
                 pH: 
                 ˜6-8 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                   
               
             
            
               
                   
                 Osmolality: 
                 ˜875 mOsm/kg (isotonic upon 
               
               
                   
                   
                 admixing) 
               
               
                   
                 Particulates: 
                 meets USP Particulate Matter tests 
               
               
                   
                 Particle Size: 
                 Median 1.0-1.8 μm 100% &lt;˜10 μm 
               
               
                   
                 Sterility/ 
                 meets USP tests 
               
               
                   
                 Endotoxins: 
               
               
                   
                   
               
            
           
         
       
     
      Within each dose group, subjects were randomized on Day 1 according to a computer-generated schedule provided by Schering-Plough Research Institute.  
      Healthy adult males or females 18 to 45 years of age having body mass indices (BMIs) of 19 to 27 were eligible for inclusion in Groups 1 to 4 of the study. Healthy adult males or females 18 to 45 years of age having BMIs of 19 to 27 and having body weights of &gt;60 kg were eligible for inclusion in Groups 5 and 6 of the study.  
      POS IV (50 mg/mL) was diluted in 5% dextrose in water (D 5 W) in IV bags. Subjects assigned to active drug received in a 100-mL volume one of the following single doses administered intravenously over 1 hour: Group 1, 25 mg; Group 2, 50 mg; Group 3, 100 mg; Group 4, 200 mg; Group 5, 400 mg; Group 6, a 125-mL volume a single dose of 600 mg administered intravenously over 1 hour and 15 minutes.  
      Blood samples (10 mL each) for the determination of posaconazole concentrations were collected immediately prior to dosing (0 hour), and at 0.25, 0.5, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 24, 48, 72, 96, and 120 hours after the start of infusion, as well as on the follow-up visit on Day 14. The blood samples were collected into two tubes containing ethylenediaminetetraacetate salt (EDTA) with each tube containing 4 mL to 5 mL of blood, one tube for determination of posaconazole in whole blood and other in plasma. For determination of posaconazole in plasma, the tube of blood (4 mL to 5 mL) was centrifuged within approximately 15 minutes of collection at approximately 4° C. and 1500 g for 10 minutes to completely separate red blood cells from plasma. All blood and plasma samples were immediately frozen to at least −20° C. and maintained in the frozen state until assayed. The blood and plasma concentrations of posaconazole were determined using validated high performance liquid chromatographic-mass spectrometric (LC-MS/MS) assays. The lower limit of quantitation (LLOQ) of this assay was 5.0 ng/mL and the calbration range was 5 to 5000 ng/niL.  
      The following pharmacokinetic parameters were determined: maximum plasma concentration (C max ); time of maximum plasma concentration (T max ); the area under the plasma concentration versus time curve to infinity (AUC[I]); the area under the plasma concentration versus time curve to the final measurable sampling time (AUC[tf]); terminal phase half-life (t 1/2 ); total body clearance (CL); and, volume of distribution at steady-state (Vdss).  
      Posaconazole blood and plasma concentrations above the LLOQ were used for the non-compartmental pharmacokinetic analyses. Pharsight® Knowledgebase Server®: version 2.0.1 (PKS) with WinNonlin version 4.0.1 (Pharsight Corporation, Cary, N.C.) was used to conduct the pharmacokinetic analysis. The C max  and T max  were the observed values. The terminal phase rate constant (k) was calculated as the negative of the slope of the log-linear terminal portion of the serum concentration-time curve using linear regression. The terminal phase half-life, t 1/2 , was calculated as 0.693/k.  
      The area under the serum concentration-time curve from time 0 to the time of final quantifiable sample [AUC(tf)] was calculated using the linear trapezoidal rule. AUC(tf) was then extrapolated to infinity (I) as follows: 
 
 AUC ( I )= AUC ( tf )+ Ces ( tf )/ k 
 
 where Ces(tf) is the estimated concentration determined from linear regression at final measurable sampling time, tf. 
 
      Total body clearance, CL, was calculated by the following equation: 
 
 CL= Dose/ AUC ( I )
 
      The apparent volume of distribution at steady-state, Vdss, was calculated as: 
 
 Vdss=CL×MRT 
 
 where MRT is the mean residence time (adjusted for infusion duration) determined from moment analysis. 
 
      The observed single dose plasma concentrations were used for pharmacokinetic modeling and simulation and to project steady-state concentrations for once-a-day (QD) dosing regimen. A nonparameteric superposition method was used for the pharmacokinetic modeling and simulation under the assumption of linear pharmacokinetics (see Gibaldi M, Perrier D., Pharmacokinetics, 2nd ed., New York: Marcel Dekker, Inc., 1982:409-17).  
      After cessation of infusion of POS IV, posaconazole plasma concentrations declined unusually rapidly, and then, surprisingly, increased subsequently, followed by a slow declining terminal phase (see  FIGS. 1-4 ). This pharmacokinetic profile is believed to be atypical and unique among known azoles. Moreover, this pharmacokinetic pattern was also observed after the intravenous administration of posaconazole in animals. It is indicative of a rapid distribution of posaconazole to the liver and spleen and subsequent slow release from these tissues. Therefore, as noted in the literature with respect to another pharmaceutically active agent (Townsend R W, Zutshi A, Bekersky I., “Biodistribution of 4-[14C]cholesterol-Ambisome following a single intravenous administration to rats”,  Drug Metabolism and Disposition.  2001;29:681-5), POS IV may be initially sequestrated in tissues, such as the liver and spleen, via uptake through the reticuloendothelial system (“RES”). Although not intended to be limited to any single mechanism of action, it is believed that the resulting high concentrations of posaconazole in these tissues due to sequestration of the drug may contribute to enhanced anti-infective activity, since these tissues are often the sites of infection.  
      In order to determine the target dosing for intravenous administration, it was necessary to determine a target range for mean C avg  and mean C max . Previous studies on orally administered posaconazole are instructive in this regard. Table 14 displays pharmacokinetic data resulting from such oral administration, arranged by quartile based on the observed range of posaconazole plasma concentration values. For each quartile, the response rate for apergfilosis is displayed.  
               TABLE 14                          Pharmacokinetic Results of Orally Administered       Posaconazole                                 Plasma C max                     (ng/mL)   Plasma C avg  (ng/mL)(b)   Response                                     Quartile   Mean(a)   % CV   Mean(a)   % CV   (%)                                             1   142   51   134   45   24       2   467   27   411   21   53       3   852   15   719   12   53       4   1480   16   1250   28   71                 a: n = 17, with the exception of Quartile 4 where n = 16            b: C avg  = average plasma concentration across time points in the same subject             
 
      The table shows that the target mean C max  for a response rate of at least 50% should be in the range of 467 to 1480 ng/mL, or higher. The pharmacokinetic modeling and steady-state projection based on the pharmacokinetic results of POS IV once-a-day (QD) dosing regimen show that the projected posaconazole mean C max  at a 100 mg POS IV QD dose will be 714 ng/mL (see Table 17, 100 mg dose), which exceeds 467 ng/mL, the minimum clinically relevant mean plasma C max . The data in Table 17 suggest that there exists a dose between 50 and 100 mg which will result in the minimum clinically relevant mean plasma C max  of about 467. However, in terminal disease states, it is desirable to treat the patient with the maximum tolerated dose. Thus, having established that a dose of 100 mg is projected to achieve the minimum clinically relevant mean plasma C max , it may be desirable to dose at higher quantities, e.g., 200 mg, 400 mg, or 600 mg, subject to tolerability.  
      After intravenous administration of POS IV formulation, posaconazole was slowly eliminated from plasma with an average terminal half-life of 21 to 39 hours. The half-life was higher at the higher dose compared to that at lower dose groups (see Tables 15 and 16), in a range of about 15 hours (with a 100 mg dose) to about 51 hours (with a 400 mg dose). A long half-life is desirable as it provides the sustained and high plasma concentration of antifungal agent over the entire dosing interval, likely contributing to better antifungal activity. The systemic clearance appeared to decrease with increasing doses and ranged from 13 to 6 L/hr (see Tables 15 and 16). The mean volume of distribution was large (326 to 408 L) exceeding total body water volume of about 40 L. This suggests extensive tissue distribution and penetration into the tissues, a characteristic that likely contributes to enhanced anti-infective activity. The range in the data for Vdss was from 219 to 516 L. This is consistent with the coefficient of variation of the data, which suggests that the volume distribution could have a range of 200 to 500 L.  
      The preferable ratios of blood to plasma posaconazole C max  and AUC values are shown in Tables 18 and 19. Overall posaconazole exposure (AUC) was higher in plasma compared to that in blood (see Tables 18 and 19—AUC ratio). However, the posaconazole concentrations were greater in blood than in plasma during the infusion and approximately up to 1 hr post-infusion (see  FIGS. 3 and 4 ; Tables 18 and 19, C max  ratio). These unique differences between blood and plasma concentrations may contribute to the preferential sequestration of posaconazole in the liver and spleen, as previously noted. The coefficient of variation of the data suggests that the ratio of blood to plasma posaconazole C max  could have a range of 1.8 to 3.5 for single dose infused over 1 hour to deliver 25-600 mg of posaconazole. The coefficient of variation of the data suggests that the ratio of blood to plasma posaconazole C max  could have a range of 1.0 to 2.3 at steady state when posaconazole is infused over about 1 hour, and repeated on a 24-hour basis, to deliver 25-600 mg of posaconazole. A ratio different than that shown in Table 18 may provide different distribution properties that could translate into differences in anti-infective activity.  
               TABLE 15                          Mean (n = 9) Posaconazole Blood Pharmacokinetic Parameters in Subjects after a       Single-dose 1 hr IV Infusion of Posaconazole IV Formulation                                             25 mg   50 mg   100 mg   200 mg   400 mg   600 mg                                                                 Parameter   Mean   CV(%)   Mean   CV(%)   Mean   CV(%)   Mean   CV(%)   Mean   CV(%)   Mean   CV(%)                                                                         Cmax   244   18   540   11   1130   22   2150    8   4330   14   4410    9       (ng/mL)       Tmax a  (hr)   1   —   1   —   1   —   1   —   1   —   1.25   —       range   0.5-1.0       0.5-1.0       0.5-1.0       0.5-1.0       0.25-1.0       0.5-1.25       AUC(tf)   1450   28   3370   16   8110   21   19500   20   44800   23   76300   15       (ng · hr/mL)       AUC(l)   1680   27   3620   17   8630   22   20700   21   50900   29   87300   16       (ng · hr/mL)       t½ (hr)   21.1   25   22.6   19   27.8   23   26.5   19   37.5   31   39.0   22       CL   15.7   23   14.2   18   12.3   31   10.1   24   8.33   23   7.01   14       (L/hr)       Vdss (L)   408   14   395   11   408   12   379   19   427   22   393   24                   a median             
 
     
       
         
           
               
             
               
                 TABLE 16 
               
             
            
               
                   
               
               
                   
               
               
                 Mean (n = 9) Posaconazole Plasma Pharmacokinetic Parameters in Subjects 
               
               
                 after a Single-dose 1 hr IV Infusion of Posaconazole IV Formulation 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 25 mg 
                 50 mg 
                 100 mg 
                 200 mg 
                 400 mg 
                 600 mg 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 Parameter 
                 Mean 
                 CV (%) 
                 Mean 
                 CV (%) 
                 Mean 
                 CV (%) 
                 Mean 
                 CV (%) 
                 Mean 
                 CV (%) 
                 Mean 
                 CV (%) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 Cmax 
                 103 
                 25 
                 206 
                 26 
                 426 
                 25 
                 898 
                 27 
                 1780 
                 21 
                 1850 
                 21 
               
               
                 (ng/mL) 
               
               
                 Tmax a  (hr) 
                 1 
                 — 
                 1 
                 — 
                 1 
                 — 
                 1 
                 — 
                 1 
                 — 
                 1.25 
                 — 
               
               
                 range 
                 0.5-1.0 
                   
                 0.25-4.0 
                   
                 0.5-1.0 
                   
                 0.25-1.0 
                   
                 0.5-1.0 
                   
                 1.0-10.0 
               
               
                 AUC (tf) 
                 1820 
                 35 
                 4490 
                 18 
                 9320 
                 22 
                 23300 
                 21 
                 49000 
                 29 
                 83700 
                 16 
               
               
                 (ng.hr/mL) 
               
               
                 AUC (l) 
                 2040 
                 34 
                 4740 
                 18 
                 9890 
                 24 
                 24700 
                 23 
                 55400 
                 36 
                 96700 
                 18 
               
               
                 (ng.hr/mL) 
               
               
                 t½ (hr) 
                 21.4 
                 18 
                 21.7 
                 23 
                 26.5 
                 25 
                 27.1 
                 22 
                 35.4 
                 29 
                 39.4 
                 23 
               
               
                 CL (L/hr) 
                 13.3 
                 29 
                 10.9 
                 21 
                 10.9 
                 37 
                 8.57 
                 27 
                 7.84 
                 27 
                 6.36 
                 16 
               
               
                 Vdss (L) 
                 396 
                 20 
                 331 
                 12 
                 389 
                 13 
                 324 
                 18 
                 378 
                 22 
                 356 
                 23 
               
               
                   
               
               
                     a median    
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 17 
               
             
            
               
                   
               
               
                   
               
               
                 Mean Projected Steady-state Plasma and Blood Posaconazole PK 
               
               
                 Parameters in Subjects Receiving a Daily Dose of POS IV 
               
               
                 infusion over 1-1.25 hr 
               
            
           
           
               
               
               
            
               
                   
                 Plasma 
                 Blood 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Cmax 
                 AUC (0-24 hr) 
                 Cmax 
                 AUC (0-24 hr) 
               
               
                   
                 (ng/mL) 
                 (ng.hr/mL) 
                 (ng/mL) 
                 (ng.hr/mL) 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 Dose 
                   
                 CV, 
                   
                 CV, 
                   
                 CV, 
                   
                 CV, 
               
               
                 (mg) 
                 Mean 
                 % 
                 Mean 
                 % 
                 Mean 
                 % 
                 Mean 
                 % 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 25 
                 155 
                 26 
                 1960 
                 36 
                 281 
                 18 
                 1580 
                 29 
               
               
                 50 
                 335 
                 16 
                 4690 
                 19 
                 628 
                 10 
                 3560 
                 17 
               
               
                 100 
                 714 
                 23 
                 9840 
                 24 
                 1360 
                 21 
                 8570 
                 22 
               
               
                 200 
                 1670 
                 22 
                 24600 
                 23 
                 2760 
                 9 
                 20600 
                 21 
               
               
                 400 
                 3540 
                 27 
                 54500 
                 35 
                 5870 
                 12 
                 50000 
                 28 
               
               
                 600 
                 5100 
                 16 
                 94900 
                 17 
                 7260 
                 10 
                 85800 
                 16 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 18 
               
             
            
               
                   
               
               
                   
               
               
                 Ratio of Mean Blood and Plasma Posaconazole PK Parameters in 
               
               
                 Subjects receiving a Single Dose of POS IV infusion over 1-1.25 hr 
               
            
           
           
               
               
            
               
                   
                 Blood/Plasma Ratio 
               
            
           
           
               
               
               
            
               
                   
                 C max   
                 AUC (I) 
               
            
           
           
               
               
               
               
               
            
               
                 Dose 
                   
                   
                   
                   
               
               
                 (mg) 
                 Mean 
                 CV, % 
                 Mean 
                 CV, % 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 25 
                 2.42 
                 17 
                 0.839 
                 7 
               
               
                 50 
                 2.76 
                 25 
                 0.772 
                 13 
               
               
                 100 
                 2.71 
                 13 
                 0.878 
                 6 
               
               
                 200 
                 2.50 
                 18 
                 0.844 
                 6 
               
               
                 400 
                 2.50 
                 19 
                 0.933 
                 8 
               
               
                 600 
                 2.45 
                 17 
                 0.904 
                 5 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 19 
               
             
            
               
                   
               
               
                   
               
               
                 Ratio of Mean Projected Steady-state Blood and Plasma 
               
               
                 Posaconazole PK Parameters in Subjects receiving a Daily Dose 
               
               
                 of POS IV infusion over 1-1.25 hr 
               
            
           
           
               
               
            
               
                   
                 Blood/Plasma Ratio 
               
            
           
           
               
               
               
            
               
                   
                 Cmax 
                 AUC (τ) 
               
            
           
           
               
               
               
               
               
            
               
                 Dose 
                   
                   
                   
                   
               
               
                 (mg) 
                 Mean 
                 CV, % 
                 Mean 
                 CV, % 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 25 
                 1.85 
                 12 
                 0.822 
                 9 
               
               
                 50 
                 1.90 
                 15 
                 0.766 
                 13 
               
               
                 100 
                 1.93 
                 12 
                 0.877 
                 6 
               
               
                 200 
                 1.70 
                 13 
                 0.843 
                 7 
               
               
                 400 
                 1.72 
                 19 
                 0.932 
                 8 
               
               
                 600 
                 1.44 
                 10 
                 0.908 
                 5 
               
               
                   
               
            
           
         
       
     
      It is to be understood that all formulations that are bioequivalent to those disclosed herein are also within the scope of the present invention.  
      The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims.  
      Various publications are cited herein, the disclosures of which are inorporated by reference in their entireties.