KR20070027564A - Injectable Pharmaceutical Suspensions Containing Posaconazole - Google Patents

Abstract

The present invention provides formulations useful for treating infections, in particular formulations comprising Posaconazole, an active pharmaceutical ingredient in an injectable suspension that is stable when subjected to final steam sterilization.

Description

Injectable pharmaceutical suspension comprising posaconazole

The present invention relates to formulations useful for treating infections. In particular, these formulations comprise the pharmaceutically active ingredient Posaconazole in an injectable suspension that is stable throughout the shelf life of the product and when subjected to final steam sterilization.

Posaconazole, an antifungal agent of the formula, is being developed by Schering Corporation, Kenilworth, NJ, as an oral suspension (40 mg / ml) under the tradename NOXAFIL ^® (October 17, 2002). Published US Pat. Nos. 5,703,079, 5,661,151, WO 02/80678, and European Patent No. 1 372 394 published January 2, 2004).

In addition, other formulations of Posaconazole are also described. Solid forms (capsules / tablets) of Posaconazole are described in US Pat. Nos. 5,972,381 and 5,834,472. Finally, topical forms of Posaconazole, such as lotions, creams, ointments or other "lacquer nail polish" similar formulations, such as US Pat. No. 4,957,730 (available from Dermik ^®) . PENLAC ^® ) is considered on the basis.

Certain aspects of stabilization of finely divided particles in pharmaceutical compositions are mentioned in the literature. For example, US Pat. No. 5,858,410 describes pharmaceutical compositions containing particles of active agent having an average particle size of less than 5 microns without prior conversion to the melt by using a piston-gap homogenizer. Doing. US Patent Application No. 10 / 440,368 describes the use of phospholipid surface active agents to stabilize microparticles of solid fenofibrate in orally administered pharmaceutical compositions. US Pat. No. 5,091,188 describes the use of phospholipids to prevent coalescence of microcrystalline actives in injectable pharmaceutical compositions. Examples of phospholipids described include lecithin, phosphatidic acid, phosphatidyl ethanolamine, cholesterol, stearylamine, glycolipids and mono-glycerides.

However, none of the above mentioned documents describes injectable suspensions of Posaconazole, which are stable when applied to final steam sterilization and throughout the shelf life of the product. Such formulations are required because they are desirable in ensuring the physical stability of stabilized end products.

Summary of the Invention

The present invention provides a formulation of Posaconazole that is stable when applied to final steam stabilization. The formulations are useful for the treatment of infections. In particular, an injectable aqueous suspension of Posaconazole is homogeneously suspended in a vehicle with the aid of phospholipids. In addition, heat protectants are used to reduce autoclave or autoclave-induced particle size growth, as well as buffer systems to stabilize phospholipids during autoclaving or autoclaving. . The provided formulations remain stable for at least 6 months after autoclaving at 121 ° C. and subsequent storage at 4 ° C. to 40 ° C.

The present invention provides a formulation comprising a suspension of Posaconazole stabilized by phospholipids in a mixture comprising a heat protectant and a buffer system.

In some embodiments, the formulation is stabilized by autoclaving or irradiation.

In some embodiments, the buffer system comprises sodium phosphate, which may be provided as a combination of sodium phosphate monobasic monohydrate, sodium phosphate dibasic anhydride, or both.

In some embodiments, the buffer system comprises an organic buffer.

In some embodiments, the buffer system comprises one or more histidines, 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 phospholipids comprise natural phospholipids.

In some embodiments, the phospholipids include synthetic phospholipids.

In some embodiments, phospholipids include natural phospholipids and synthetic phospholipids.

In some embodiments, the phospholipid comprises 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC).

In some embodiments, the heat protectant comprises trehalose.

In some embodiments, the phospholipid comprises 1-palitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), the heat protectant comprises trehalose and the buffer system is sodium phosphate monobasic Monohydrate, sodium phosphate dibasic anhydride, or a combination of sodium phosphate monobasic monohydrate and sodium phosphate dibasic anhydride.

In some embodiments, the Posaconazole has a median or median value of about 1.0 to about 8.0 microns, up to about 3000 particles at least 10 microns in size and at most about 300 particles at least 25 microns in size. Has a particle size distribution.

In some embodiments, Posaconazole has a particle size distribution with a median value of about 1.0 to about 5.0 microns and a particle size distribution of up to about 3000 particles that are at least 10 microns in size and at most about 300 particles that are at least 25 microns in size.

In some embodiments, Posaconazole has a particle size distribution with a median value of about 1.2 to about 4.5 microns and a particle size distribution of up to about 3000 particles at least 10 microns in size and at most about 300 particles at least 25 microns in size.

In some embodiments, the formulation has ingredients that include:

ingredient  Concentration range Posaconazole  About 50mg / ml POPC   About 40mg / ml Sodium Phosphate, Monobasic, Monohydrate, USP  0.345mg / ml Sodium Phosphate, Dibasic, Anhydride, USP  1.065 Trehalose  250 mg / ml Remaining amount of infusion water, USP   1ml

In some embodiments, the formulation has ingredients that include:

ingredient  Concentration range Posaconazole  About 1 to about 100 mg / ml POPC  About 10 to about 60 mg / ml Sodium Phosphate, Monobasic, Monohydrate, USP  About 0.01 to about 0.6 mg / ml Sodium Phosphate, Dibasic, Anhydride, USP  About 0.04 to about 1.5 mg / ml Trehalose  About 10 to about 300 mg / ml Remaining amount of infusion water, USP   1 ml

In some embodiments, the formulation has ingredients that include:

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 Remaining amount of infusion water, USP   1 ml

In some embodiments, the formulation has ingredients that include:

ingredient  density Posaconazole  50 mg / ml POPC  40mg / ml Histidine  3mg / ml Citric Acid Monohydrate  0.24mg / ml Trehalose  250 mg / ml Remaining adequate amount of water at pH about 6.4  1ml

In some embodiments, the formulation has a component 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 a component comprising:

ingredient  density Posaconazole  50 mg / ml POPC  40mg / ml Histidine  3mg / ml Citric Acid Monohydrate  0.24mg / ml Profile gallate  0.01mg / ml Butylated Hydroxytoluene  0.05mg / ml Trehalose  250 mg / ml Remaining adequate amount of water at pH about 6.4  1ml

In some embodiments, the formulation has a component comprising:

ingredient  density Posaconazole  50 mg / ml POPC  40mg / ml Histidine  3mg / ml Citric Acid Monohydrate  0.24mg / ml Alpha-D-Tocopherol  0.05mg / ml Trehalose  250 mg / ml Remaining appropriate amount of water at pH about 6.5  1ml

In some embodiments, the formulation has a weight ratio of phospholipid to posaconazole from about 60: 1 to about 1:10.

In some embodiments, the formulation has a weight ratio of phospholipid to posaconazole from about 1: 1 to about 1: 5.

In some embodiments, the formulation has a weight ratio of phospholipid to posaconazole from about 1: 1 to about 4: 5.

In some embodiments, the formulation has a weight ratio of heat protectant to posaconazole from about 300: 1 to about 1:10.

In some embodiments, the formulation has a weight ratio of heat protectant to posaconazole from about 1: 1 to about 6: 1.

In some embodiments, the formulation has a weight ratio of heat protectant to phospholipid from about 30: 1 to about 1: 6.

In some embodiments, the formulation has a weight ratio of heat protectant to phospholipid from about 5: 4 to about 30: 4.

In some embodiments, the invention includes a method of treating or preventing an infection in an animal in need thereof, comprising administering to the animal in need thereof an effective amount of the formulation. In some embodiments, the animal is a mammal, bird, fish or reptile.

In some embodiments, the animal is a mammal, including but not limited to humans.

In some embodiments, the infection is caused by fungi or parasites.

In some embodiments, the infection is selected from the group consisting of:

Oropharyngeal or esophageal candidiasis;

Refractory oropharyngeal or esophageal candidiasis;

Invasive aspergillosis, candidiasis, maldermal mycobacterium, scedosporiosis, infections caused by abnormal fungi, conjunctivitis, and invasive infections due to rare fungi and yeasts;

Invasive mycosis in patients refractory or resistant to other therapies;

Patients undergoing intensive chemotherapy and / or radiation therapy for hematologic malignancies, bone marrow or peripheral stem cell transplant conditioning conditions, and treatment of acute or chronic graft-versus-host disease or prevention of solid organ transplantation Candidiasis, invasive fungal infection in patients receiving combinatorial immunosuppressive therapy for;

Chagas disease; And

Leishmaniasis.

In some embodiments, the invention encompasses a method wherein said formulation is administered intravenously.

In some embodiments, the present invention provides a formulation wherein the formulation is intramuscular, subcutaneous, ocular, subconjunctival, intraocular, via anterior ocular injection, intravitreal, intraperitoneal, intramedural space, intracyst, intrathoracic, Intranasally, topically, through wound irrigation, intradermal, intrabuccally, abdominal, intra-articular, intra-ear, intrabronchial, intracapsular, intramedullary, intrapulmonary, inhaled, tracheal or Intrabronchial intubation, through direct intubation into the pulmonary, intramedullary, intratracheal, intrathoracic, thoracic canal perfusion, vaginal canal, dura, rectal, intracranial, intravascular, intraventricular, intraosseous, perfused bone Or through application as part of any mixture with cement for the prosthetic device.

In some embodiments, the formulation may comprise an antifungal agent such as azole; Amphotericin B; Deoxycholate amphotericin B; Flucitocin; Terbinafine; Antibacterial agents; Antiviral agents; Steroids; Nonsteroidal anti-inflammatory drugs ("NSAIDs"); Chemotherapy; And a second active ingredient selected from one or more groups consisting of anti-emetic agents.

In some embodiments, the invention provides antifungal agents, such as azoles; Amphotericin B; Deoxycholate amphotericin B; Flucitocin; Terbinafine; Antibacterial agents; Antiviral agents; steroid; Nonsteroidal anti-inflammatory drugs ("NSAIDs"); Chemotherapy; And administering a second active ingredient selected from one or more groups consisting of anti-emetic agents.

In some embodiments, the formulation is infused over about 1 hour to deliver 100 mg of Posaconazole, and if repeated at intervals of about 24 hours, an average of at least about 467 ng / ml of Posaconazole in a steady state Additionally providing a maximum plasma concentration (Cmax) and mean plasma area under the curve (AUC) value over a 24-hour period of Posaconazole of at least about 9840 ng / hr / ml at steady state. do.

In some embodiments, the formulation is infused over about 1 hour to deliver 200 mg of Posaconazole, and repeated at intervals of about 24 hours, the mean maximum plasma concentration of at least about 852 ng / ml Posaconazole at steady state ( Cmax) and mean plasma range (AUC) values under a 24 hour curve over Posaconazole of at least about 24,600 ng.hr/ml in steady state.

In some embodiments, the formulation further comprises an average plasma half-life in the range of about 14.9 to about 38.4 hours after administration of the dose of about 100 mg of posaconazole; And at least one of an average plasma steady state volume of about 200 to 500 L distribution.

In some embodiments, the formulation is infused over about 1 hour to deliver at least 200 mg of Posaconazole, and repeated at intervals of about 24 hours, at a steady state of mean maximum plasma concentration of at least about 1480 ng / ml Posaconazole (Cmax) and mean plasma range (AUC) values under the curve over 24 hours of Posaconazole of at least about 24,600 ng.hr/ml at steady state.

In some embodiments, the formulation further comprises an average plasma half-life in the range of about 18.7 to about 35.5 hours after administration of the dose of about 200 mg of posaconazole; And at least one of an average plasma steady state volume of about 200 to 500 L distribution.

In some embodiments, the formulation further comprises an average plasma half-life in the range of about 18.5 to about 51.4 hours after administration of the dose of about 400 mg of posaconazole; And at least one of an average plasma steady state volume of about 200 to 500 L distribution.

In some embodiments, the formulation further comprises an average plasma half-life in the range of about 27.2 to about 50.6 hours after administration of the dose of about 600 mg of posaconazole; And at least one of an average plasma steady state volume of about 200 to 500 L distribution.

In some embodiments, the formulation is further characterized as providing an average Posaconazole blood concentration profile that is substantially similar to that of FIG. 1 when infused over about 1 hour to deliver 25-600 mg of Posaconazole.

In some embodiments, the formulation is further characterized as providing an average Posaconazole plasma concentration profile that is substantially similar to that of FIG. 2 when infused over about 1 hour to deliver 25-600 mg of Posaconazole.

In some embodiments, the formulation provides a ratio of mean Posaconazole blood Cmax to mean Posaconazole plasma Cmax of about 1.5 when a single dose of the formulation is infused over about 1 hour to deliver 25-600 mg of Posaconazole. To about 3.8 as an additional feature.

In some embodiments, the formulation provides a ratio of mean Posaconazole blood Cmax to mean Posaconazole plasma Cmax of about 2.1 to about when a single dose of the formulation is infused over about 1 hour to deliver 25 mg of Posaconazole. Provided in 3.3 is an additional feature.

In some embodiments, the formulation provides a ratio of average Posaconazole blood Cmax to average Posaconazole plasma Cmax of about 1.9 to about when a single dose of the formulation is infused over about 1 hour to deliver 50 mg of Posaconazole. Provided in 3.8 as an additional feature.

In some embodiments, the formulation provides a ratio of mean Posaconazole blood Cmax to mean Posaconazole plasma Cmax of about 2.2 to about when a single dose of the formulation is infused over about 1 hour to deliver 100 mg of Posaconazole. Provided in 3.3 is an additional feature.

In some embodiments, the formulation provides a ratio of mean Posaconazole blood Cmax to mean Posaconazole plasma Cmax of about 1.5 to about when a single dose of the formulation is infused over about 1 hour to deliver 200 mg of Posaconazole. Provided in 3.2 is an additional feature.

In some embodiments, the formulation provides a ratio of mean Posaconazole blood Cmax to mean Posaconazole plasma Cmax of about 1.7 to about when a single dose of the formulation is infused over about 1 hour to deliver 400 mg of Posaconazole. Provided in 3.3 is an additional feature.

In some embodiments, the formulation provides a ratio of average Posaconazole blood Cmax to average Posaconazole plasma Cmax of about 1.9 to about when a single dose of the formulation is infused over about 1 hour to deliver 600 mg of Posaconazole. Provided as 3.1 is an additional feature.

In some embodiments, the formulation is injected over about 1 hour to deliver 25-600 mg of Posaconazole and at steady state when the formulation is repeated on a 24-hour basis, Mean Posaconazole Blood Cmax versus Average Posaconazole Plasma. It is further characterized by providing a ratio of Cmax of about 1.2 to about 2.5.

In some embodiments, the formulation is in steady state when the formulation is infused over about 1 hour to deliver 25 mg of Posaconazole and repeated on a 24-hour basis, of mean Posaconazole blood Cmax versus mean Posaconazole plasma Cmax. It is further characterized by providing a ratio of about 1.5 to about 2.3.

In some embodiments, the formulation is in steady state when the formulation is infused over about 1 hour to deliver 50 mg of Posaconazole and repeated on a 24-hour basis, of the mean Posaconazole blood Cmax versus the average Posaconazole plasma Cmax. It is further characterized by providing a ratio of about 1.5 to about 2.4.

In some embodiments, the formulation is in steady state when the formulation is infused over about 1 hour to deliver 100 mg of Posaconazole and repeated on a 24-hour basis, of the mean Posaconazole blood Cmax versus the average Posaconazole plasma Cmax. It is further characterized by providing a ratio of about 1.7 to about 2.5.

In some embodiments, the formulation injects the ratio of mean Posaconazole blood Cmax to mean Posaconazole plasma Cmax when the formulation is infused over about 1 hour to deliver 200 mg of Posaconazole and repeated on a 24-hour basis. And from 1.2 to about 2.0 is an additional feature.

In some embodiments, the formulation is in steady state when the formulation is infused over about 1 hour to deliver 400 mg of Posaconazole and repeated on a 24-hour basis, of the mean Posaconazole blood Cmax versus the average Posaconazole plasma Cmax. It is further characterized by providing a ratio of about 1.2 to about 2.2.

In some embodiments, the formulation is in steady state when the formulation is infused over about 1 hour to deliver 600 mg of Posaconazole and is repeated on a 24-hour basis, of the mean Posaconazole blood Cmax versus the average Posaconazole plasma Cmax. It is further characterized by providing a ratio of about 1.3 to about 1.7.

In some embodiments, water in the formulation is removed by lyophilization.

In some embodiments the treated animal is a human, but in other embodiments the treated animal is not a human.

In some embodiments, the formulation is one that is bioequivalent to the formulation described herein.

In some embodiments, the method further comprises administering a bolus loading dose of the formulation followed by an intravenous maintenance dose of the formulation.

In some embodiments, the method comprises administering an effective amount of Posaconazole to the animal when the formulation is infused over about 1 hour to deliver 100 mg of Posaconazole and delivered at intervals of about 24 hours, thereby maintaining the drug in a steady state. Providing an average maximum plasma concentration (Cmax) of Posaconazole of at least 467 ng / ml, and an average plasma range (AUC) value under the curve over 24 hours of Posaconazole of at least about 9840 ng / hr / ml at steady state. .

Brief description of the drawings

1 shows Posaconazole mean blood concentration-time profiles in healthy volunteers 1 hour after intravenous infusion of 25, 50, 100, 200, 400 and 600 mg of Posaconazole.

FIG. 2 shows Posaconazole mean blood concentration-time profiles in healthy volunteers 1 hour after intravenous infusion of 25, 50, 100, 200, 400 and 600 mg of Posaconazole.

FIG. 3 shows Posaconazole mean plasma and blood concentration-time profiles in healthy volunteers 1 hour after intravenous infusion of 25 mg of Posaconazole.

Figure 4 shows Posaconazole mean plasma and blood concentration-time profiles in healthy volunteers 1 hour after intravenous infusion of 600 mg of Posaconazole.

The present invention includes formulations suitable for parenteral administration, eg, by injection, to treat an infection. These formulations comprise a suspension of Posaconazole stabilized by phospholipids in a mixture comprising water, a heat protectant and a buffer system. Posaconazole is minimally soluble in water, so suspension formulation is advantageous. Phospholipids have been found to be effective surfactants for forming stable suspensions of Posaconazole in water or aqueous media.

These phospholipids can degrade when subjected to temperature excursions experienced during thermal sterilization (eg autoclaving), which is an essential step in ensuring the sterility of the injectable formulation. Thus, heat protectants are used to prevent aggregation and crystal growth of Posaconazole particles during autoclaving.

Parenteral buffer systems are typically designed to have a physiological pH of about 7.4. Phospholipids are known to be stable at pH in the range of about 6 to about 7. In addition, pH adjustment of injectable formulations may be necessary to achieve physiological compatibility and, for example, to minimize injection-site irritation. In addition, the rate of phospholipid hydrolysis may be temperature-sensitive. Thus, in the formulations of the present invention, the buffer system meets the physiological pH requirements and maintains the temperature / pH-dependent chemical stability of the phospholipids in the formulation during high temperature drop off (as experienced during autoclaving) and throughout shelf life. Is designed.

In accordance with the above, it has been found that POPC, a component that acts as a suspension stabilizer, is sensitive to autoclaving. Certain buffer systems have been found to control degradation of POPC-containing Posaconazole formulations during autoclaving. For example, such formulations have been found to be stable after 20 minutes of autoclaving at 121 ° C. In addition, these buffering systems stabilize these formulations during autoclaving followed by storage for at least 18 months at 4 ° C to 25 ° C. Similarly, other phospholipids similar to POPC can be used to stabilize the formulations described herein. For example, unsaturated phospholipids having an acyl chain length having an unsaturation degree of acyl chain of 1 to 4 in the range of C ₁₂ to C ₂₀ ; And saturated phospholipids with acyl chain lengths ranging from C ₁₂ to C ₁₈ are useful according to the invention. Examples of useful unsaturated phospholipids include:

1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine ("POPC")

l, 2-myristoleoyl-sn-glycero-3-phosphocholine

1,2-palmitoleoyl-sn-glycero-3-phosphocholine

1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC)

1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE)

1,2-Ninoleoyl-sn-glycero-3-phosphocholine and

l-oleoyl-2-myristoyl-sn-glycero-3-phosphocholine or combinations thereof.

Examples of saturated phospholipids include:

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) or combinations thereof.

Unsaturated phospholipids are known to be oxidized. To prevent this oxidation, antioxidants can be used. In some embodiments, the antioxidant preferably comprises propyl gallate at a concentration of about 0.02 to about 0.005 mg / ml. In another embodiment, the antioxidant preferably comprises butylated hydroxytoluene at a concentration of about 0.1 to about 0.02 mg / ml. In a related embodiment, the antioxidant preferably comprises propyl gallate at a concentration of about 0.02 to about 0.005 mg / ml in combination with butylated hydroxytoluene at a concentration of about 0.1 to about 0.02 mg / ml. In still other embodiments, the antioxidant preferably comprises alpha-D-tocopherol at a concentration of about 0.5 to about 0.01 mg / ml.

The inventors have found certain ratios of ingredients that produce advantageous formulations. For example, the weight ratio of phospholipid to posaconazole is preferably from about 1: 0.1 to about 1:10, more preferably from about 1: 1 to about 1: 5, still more preferably from about 1: 1 to about 4: 5. The weight ratio of heat protectant to posaconazole is preferably from about 0.5: 1 to about 6: 1, more preferably from about 2: 1 to about 6: 1. The weight ratio of heat protectant to phospholipid is preferably from about 20: 1 to about 5: 4, more preferably from about 20: 4 to about 30: 4.

The formulations of the present invention comprise a suspension of solid particles of Posaconazole of a particular particle size distribution in aqueous phase. Particle size distributions present in suspended particles are important for physiological compatibility, injectability, physical stability of suspensions, re-suspension, and pharmacodynamic properties and biodistribution (ie sequestration in specific body tissues). . Because these properties are important for formulations delivered to patients, it is important to control the processes that contribute to changes in particle size distribution after differentiation.

This process involves flocculation during autoclaving and de-suspension due to temperature drop and / or agitation experienced during shipping and storage. This is the particle size distribution in formulations prepared for administration to patients that affect pharmacodynamic properties and bio-dispersion.

The inventors of the present invention find that for injectable formulations of Posaconazole, these properties have a median value of about 1.0 to about 8.0 microns, preferably about 1.0 to about 5.0 microns, more preferably about 1.2 to about 4.5 microns. It was measured that it was in an advantageous range. In each case, the particle size distribution indicates that up to about 3000 particles are at least 10 microns and up to about 300 particles are at least 25 microns in size.

In injectable formulations of the invention comprising POPC, it has been found to be useful to maintain a pH range of about 3.0 to about 9.0, preferably about 6.0 to about 8.0, and more preferably about 6.4 to about 7.6.

The inventors have found that certain organic buffers, such as histidine and citric acid, are more advantageous in controlling pH-related degradation of POPC in the formulation. The components used in the pH control system may also serve as components of the buffer system, after pH adjustment is achieved. Non-limiting examples of pH control system components that work in the process include sodium hydroxide, hydrochloric acid and phosphoric acid.

Anti-infective applications

The present invention includes methods for the prevention and treatment of various infections caused by a broad spectrum of infectious agents. The term "infection" refers to fungi, yeast and other infectious agents, such as Candida, dermatophytes, Dimorphics, Dematiaceous [e.g. alternaria ( Alternaria and Bipolaris], Aspergillus, Acremonium, Basidiomycetes, Bjerkandera, Coprinus, Paesillomai Paecilomyces, Microsporum, Trichophyton, Pseudallescheria, Schizophyllum, Cryptococcus, Histoplasma, Blastoma Blastomyces, Coccidioides, Fusarium, Exophiala, Zygomycocetes (e.g. Mucor, Rhizopus, and Rhizomucor], Kluyveromyces, Saccharomyces Saccharomyces, Yarrowia, Pichia, Epidermophyton, Paracoccidioides, Scedosporium, Apophysomyces, Curvularia, Penicillium, Fonsecaea, Wangiella, Sporrothrix, Pneumocystis, Trichosporon, Apsidia (Absidia), Cladophilalophora, Ramichloridium, Syncephalastrum, Madurella, Scytalidium, Leshmania, Protozoa, Bacteria, Gram negative, Gram positive, Legionella Borrelia, Mycoplasma, Treponema, Gardneralla, Trichomononas and Trypanosoma Include anaerobes, including It is not limited to this.

The present invention is intended to treat both opportunistic and non-opportunistic infections, where the term “opportunistic” as used herein refers to a disease only in a host whose resistance is reduced by, for example, chemotherapy or HIV. It indicates an infection caused by an organism that can cause it.

In particular, Posaconazole is useful in the prevention and / or treatment of the following disease states:

Early [first line] treatment of oropharyngeal or esophageal candidiasis;

Rescue therapy of azole-refractory oropharyngeal and esophageal candidiasis (eg, in patients who have failed oral fluconazole and / or itraconazole);

Invasive aspergillosis, candidiasis, maldermatosis, scedosporosis, abnormal fungi (e.g., Cryptococosis, coccidioidomycosis, paracoccidioidomycosis, histoplasmosis) , Early treatment of infections caused by Blastomycosis, conjunctival bacillus, and invasive infections caused by rare fungi and yeasts;

Remedies for invasive fungal disease in patients refractory or resistant to other therapies (eg, amphotericin B, lipid formulations of amphotericin B, caspofungin, boriconazole and / or itraconazole);

Patients undergoing intensive chemotherapy and / or radiation therapy for hematologic malignancies, bone marrow or peripheral stem cell transplant conditioning conditions, and treatment of acute or chronic graft-versus-host disease or solid organ transplantation Prevention of invasive candidiasis, invasive fungal infections (conjugation and aspergillosis) in high risk patients, including patients receiving combination immunosuppressive therapy for prophylaxis;

Chagas disease, including acute and chronic forms [T. Wave flagella due to T. cruzi]; And

Leishman's flagellitis, including visceral and topical forms.

administration

Immuno-suppressive therapies (eg chemotherapy, radiation therapy, myelotomy conditioned therapy) often result in one or more of the above mentioned infections. The present invention encompasses the administration of Posaconazole formulations added to immunosuppressive therapies, wherein the Posaconazole formulations act prophylactically in connection with opportunistic infections involving the aforementioned disease states.

The present invention includes various types of administration to any part, organ, epilepsy or cavity of the animal body that is a subject for infection. Non-limiting sets of examples of types in which the Posaconazole formulations of the invention can be administered are intravenous, intramuscular, subcutaneous, ocular, subconjunctival, intraocular, via anterior ocular injection, intravitreal, intraperitoneal Intramedullary, intramedullary, intracyst, intrathoracic, intranasal, topically, wound perfusion, intradermal, intranasal, abdominal, intraarticular, intraearm, intrabronchial, intracapsular, intramedullary, intrapulmonary, Through intubation, through tracheal or intrabronchial intubation, through intubation into the lung, spinal cord, endocardium, intrathoracic, thoracic canal perfusion, vaginal canal, dura, rectal, intracranial, intravascular, intraventricular, intraosseous , Through perfusion of infected bone, and through application as part of any mixture with cement for artificial instruments.

Co-formulations comprising a combination of Posaconazole and one or more other active ingredients are also within the scope of the present invention. Non-limiting examples of such active ingredients include antifungal agents such as echinocandins (including caspofungin, mycapfungin and anidolapundin) and azoles (including barrioconazole, itraconazole, fluconazole, ketoconazole, labuconazole); Amphotericin B; Deoxycholate amphotericin B; And terbinafine.

In addition, antibacterial, antiviral, steroid or nonsteroidal anti-inflammatory drugs ("NSAIDs"); Chemotherapy; And / or combinations with anti-emetic agents are within the scope of the present invention. Similarly, unlike a single formulation, simultaneous administration of posaconazole and one or more of the above active ingredients is also within the scope of the present invention.

Also within the scope of the invention are various dosage regimens, each consisting of a number of doses and a period of administration. Preferred dosages include once every 12, 24, 36 and 48 hours. Preferred administration periods are in the range of 30 minutes to 4 hours, more preferably in the range of 1 to 2 hours. Also within the scope of the preferred administration is a range of ratios and varying doses of the cyclic dose, and the cyclic load dose, or some of the cyclic load doses, with therapeutic plasma concentration ranges similar or greater than those described in Table 14 below. A combination of intravenous infusion maintenance doses.

As used herein, the following terms will have the following definitions.

As used herein, the phrase “phospholipid” means a lipid compound that, upon hydrolysis, produces phosphoric acid, alcohols, fatty acids and nitrogenous bases. Examples thereof include natural salts and synthetic phospholipids, which include lecithin, cephalin, sphingomyelin and 1-palitoyl-2-oleoyl-sn-glycero-3-phosphocholine ("POPC"). .

As used herein, the phrase “natural phospholipids” refers to phospholipids that exist naturally or originate from natural sources. Non-limiting examples of natural phospholipids include egg phospholipids, soybean phospholipids and animal tissue phospholipids. Combinations of one or more natural phospholipids are also within the scope of the present invention.

As used herein, the phrase “synthetic phospholipid” means artificial 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), l, 2-dilauryl-sn-glycero-3-phosphocholine (DLPC), l, 2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), l, 2 -Dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-stearoyl-sn-glycero-3-phosphocholine (DSPC). Combinations of one or more synthetic phospholipids are also within the scope of the present invention.

As used herein, the phrase “buffer system” refers to a buffer comprising one or more components that maintain 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 above-mentioned components are understood to include salts, hydrates and solvates thereof. Thus, for example, phosphoric acid includes sodium or potassium phosphate salts, among other salts. Preferred buffer systems include sodium phosphate monobasic, sodium phosphate dibasic or combinations thereof. More preferred buffer systems include sodium phosphate monobasic monohydrate, sodium phosphate dibasic anhydride, or combinations thereof. As used herein, the phrase “organic buffer” refers to a buffer comprising one or more organic compounds. 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 interferes with oxidation. Exemplary antioxidants include propyl gallate, butylated hydroxytoluene and alpha-D-tocopherol.

As used herein, the phrase "central particle size" refers to the 50th percentile by volume-weight as determined by Malvern ^® , Sympatec ^® , or Horibe ^® laser diffraction particle size analysis. Particle size within 50 ^th percentile). Particle sizes are typically specified up to 24 months throughout shelf life and at the end of shelf life, when prepared, refrigerated or kept at room temperature. Particle size is also measured and maintained when the formulation is diluted to large parenteral volumes, for example with 5% dextrose or water for injection.

As used herein, the phrase “initial median particle size” refers to a particle size present within one week after a specified time point. For example, the initial median particle size after autoclaving refers to the median particle size present within one week after autoclaving is complete.

As used herein, the term “autoclaving” refers to sterilization by the final steam sterilization method. For example, autoclaving for 20 minutes at 121 ° C. is sufficient to sterilize the Posaconazole formulations described herein.

As used herein, the phrase “heat protectant” refers to an agent that stabilizes phospholipids during temperature escape. In the present invention, heat protectants are used to preserve the phospholipids necessary to control crystal growth and aggregation of Posaconazole particles during autoclaving. Heat protectors are typically soluble polyhydroxyl compounds. Trehalose, for example, is a heat protectant that can be used 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 that is chemically converted by metabolic or chemical processes upon administration to a subject to produce Posaconazole, or a salt and / or solvate thereof.

As used herein, the term “solvate” refers to the physical association between a compound and one or more solvent molecules. This physical association includes varying degrees of ionic and / or covalent bonds, such as hydrogen bonds. In certain instances, solvates may be separated, for example when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. The term “solvate” includes both solution-phase and separable solvates. Non-limiting examples of suitable solvates include hydrates, ethanolates and methanolates.

As used herein, the term "injectable" means taken for parenteral administration.

As used herein, the term “fungus” refers to one of various morphological forms of yeast and fungi, fungi, candida, dematophytes, dimorphix, demathiaseus (eg alternaria and bipolaris). ), Aspergillus, Acremonium, Basidiomycetes, Bjercandera, Coprinus, Paesilomyses, Microsporium, Trichophyton, Schdaleceria, Skijopilum, Crypcococcus, Heath Toplasma, blastomais, coccidioides, fusarium, exopiala, zygomycocetes (e.g. mucor, lycopus, and lyzomucor), Kluyveromyces, saccharomyces, Yarrowia, Pichia, Epidermophyton, Paracoccidioides, Skedosporium, Apopisomyses, Kurbularia, Penicillium, Ponsecaea, Wanggiela, Sporotrix, Pneumotistis, Tricosphoron, apsidia, cle Includes Dopi Allophora, Lamichloride, Cinsepalastrum, Madhurella, Scythalidium, Leshumania, Protozoa, Bacteria, Gram-Negative, Gram-positive, Mycoplasma, Treponema, Gardnerala and Trichomonas do.

As used herein, the term "dematiaseous" means dark candida and / or hyphae, and includes non-limiting examples of alternaria and bipolaris.

As used herein, the term “zaigomycocete” refers to a class of fungi characterized by sexual reproduction that forms conjunctival spores and asexual reproduction by means of immobilized spores called spore cysts or conidia. Examples include Mucor, Rifupus and Litomucor.

As used herein, the term “anaerobes” means microorganisms that survive and grow in the absence of oxygen, and include, but are not limited to, Legionella Borrelia, Mycoplasma, Treponema, Gardnerala and Trichomonas. do.

As used herein, the term "parasite" refers to an organism that survives in, or survives in, and attracts nourishment from nourishment. Parasites include, among others, Rischman's flagellar and wave flagella.

As used herein, the term “antifungal” means an agent that is active against one or more fungi and includes echinocandins, such as caspofungin, mycapfungin and anidulafungin.

As used herein, the term “azole” means divinyleneimine and includes voriconazole, itraconazole, fluconazole, ketoconazole, labuconazole.

As used herein, the term “mean maximum concentration (Cmax), when accompanied by the term“ steady state ”, refers to a sufficient number of repeated doses of a formulation that produces a maximum blood or plasma concentration that is substantially equivalent to one other value. It means the average maximum concentration value occurring after. Thus, the subsequent maximum concentration values no longer occur, but are each peak that achieves substantially the same maximum value one time before and the next.

As used herein, the term “animal” is understood to include humans, non-human mammals, fish, birds, and reptiles.

As used herein, the term "biological equivalent" is understood to have the meaning assigned to that term by the U.S. Food & Drug Administration. "Bioequivalence is significant in the proportion and extent to which the active ingredient or active moiety in a pharmaceutical equivalent or pharmaceutical substitute is useful at the site of drug action when administered at the same molar dose under similar conditions in a properly designed study. It means no difference. " 21 CFR 320.l (e). Methods for measuring biological equivalents are described 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].

The following non-limiting examples illustrate certain aspects of the present invention.

Exemplary formulations of Posaconazole associated with POPC and trehalose using various buffer systems are detailed in Tables 1-3 below. These formulations provide a range for buffer systems that maintain specific pH ranges.

Exemplary Posaconazole formulations for each of the buffer systems described in Tables 1-3 are provided in Examples 1-3, respectively.

Example 1

Important: In Example 1 the pH is 7.4.

Example 2

Important: In Example 2, the pH is 6.4.

Example 3

Of course, in Example 3 the pH is 6.6.

In addition, exemplary Posaconazole formulations comprising antioxidants are described in Examples 4-6.

Example 4

Important: In Example 4 the pH is 7.4.

Example 5

Important: The pH in Example 5 is 6.4.

Example 6

Important: In Example 6 the pH is 6.5.

Example 7 is a preferred embodiment of the present invention.

Example 7

In Example 7, the pH is 7.2.

Below is an exemplary placebo formulation with a pH of 6.4. This exemplary placebo formulation was used in the comparative stability data described below.

Comparative stability Data  Research

The stability of POPC in Examples 1-3 was compared with the exemplary placebo described above both before and after autoclaving at 121 ° C. for 20 minutes. In addition, Posaconazole stability, particle size, pH, and physical observations were examined for each formulation before and after autoclaving. Each formulation also contains 4 ° C., 25 ° C. and 40 ° C. (ie 4 ° C. ± 2 ° C. at 60% ± 5% relative humidity; 25 ° C. ± 2 ° C. at 60% ± 5% relative humidity; and 40 at ambient relative humidity). After an additional storage period of 1 month, 3 months and 6 months after autoclave sterilization at 1 ° C. ± 2 ° C., respectively. Note that particle size was measured using Malvern laser diffraction particle size analysis technology. Particle size is characterized by values for the median ("50 ^th percentile") and the maximum ("100 th percentile"). Stability data from these comparative studies are aggregated as follows for the formulations reflected in Examples 1-6 shown in Tables 4-9, respectively.

Posaconazole's activity against a broad spectrum of infectious agents was tested in vitro. Tables 10 and 11 show a subset of the results of these in vitro tests, indicating that Posaconazole is most active against some of these infectious agents.

Within each dosing group, subjects were randomized on day 1 according to a computer-generated schedule provided by the Schering-Plough Research Institute.

Healthy adults males or females aged 18 to 45 years with a body mass index (BMI) of 19 to 27 were suitable for inclusion in groups 1 to 4 of the study. Healthy adults males or females with a BMI of 19 to 27 and weighing> 60 kg were suitable for inclusion in groups 5 and 6 of the study.

POS IV (50 mg / mL) was diluted in 5% dextrose (D ₅ W) in water in an IV bag. Subjects designated active drugs were administered intravenously over 1 hour in 100 mL volumes of the following single dose: group 1, 25 mg; Group 2, 50 mg; Group 3, 100 mg; Group 4, 200 mg; Group 5, 400 mg; Group 6, 125 mL volume: A single dose of 600 mg was administered intravenously over 1 hour and 15 minutes.

Blood samples (10 mL each) were measured immediately prior to administration (0 h) and 0.25, 0.5, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, Collected at 12, 14, 16, 24, 48, 72, 96 and 120 hours, and at subsequent visits on day 14. Blood samples were collected into two tubes containing ethylenediaminetetraacetate salt (EDTA), each tube containing 4 mL to 5 mL of blood, one for the determination of Posaconazole in whole blood and the other. Is for the determination of Posaconazole in plasma. For measurement of Posaconazole in plasma, blood tubes (4 mL to 5 mL) were collected for 10 minutes at approximately 4 ° C. and 1500 g and then centrifuged within approximately 15 minutes to completely separate red blood cells from plasma. All blood and plasma samples were immediately frozen above −20 ° C. and kept frozen until analysis. Blood and plasma concentrations of Posaconazole were measured using confirmed high performance liquid chromatography-mass spectrometry (LC-MS / MS) analysis. The appropriate lower limit of the assay (LLOQ) was 5.0 ng / mL and the calibration range was 5 to 5000 ng / mL.

The following pharmacodynamic parameters were measured: maximum plasma concentration (Cmax); Time of maximum plasma concentration (Tmax); Range below plasma concentration (AUC [I]) for time curves to infinity; Range below plasma concentration (AUC [tf]) for time curve to final measurable sampling time; The final phase half life (t _1/2); Total body clearance (CL); And volume of distribution (Vdss) at steady-state.

Posaconazole blood and plasma concentrations above LLOQ were used for non-differentiated pharmacodynamic analysis. Pharsight ^® Knowledgebase Server ^® : Pharmacokinetic analysis using version 2.0.1 (PKS) and WinNonlin version 4.0.1 (Pharsight Corporation, Cary, NC) It was. Cmax and Tmax are the observed values. The final phase ratio constant [k] was calculated as the negative of the slope of the logarithmic linear end of the serum concentration-time curve using linear regression. The final phase half-life, t _1/2 was calculated as 0.693 / k.

The range under the blood concentration concentration-time curve from 0 hours to the time of the final applicable sample was calculated using the linear trapezoidal rule. The AUC (tf) was then extrapolated to infinity (I) as follows:

AUC (I) = AUC (tf) + Ces (tf) / k

Where Ces (tf) is the assessment concentration measured from the linear regression method at the final measurable sampling time, tf.

Total sieve clearance, CL, was calculated from the following equation:

CL = Dose / AUC (I)

The apparent volume of distribution, Vdss, at steady-state was calculated as follows:

Vdss = CL x MRT

Here, MRT is the average residence time (adjusted during injection) measured from the instantaneous analysis.

The single dose plasma concentrations observed were used for pharmacodynamic modeling and stimulation and steady-state concentrations were planned for once daily (QD) dosage regimens. Nonparametric superposition methods were used for stimulation under pharmacodynamic modeling and estimation of linear pharmacodynamics (see Gibaldi M, Perrier D., Pharmacokinetics, 2nd ed., New York: Marcel Dekker, Inc., 1982: 409-). 17).

After the infusion of POS IV stopped, Posaconazole plasma concentrations descended abnormally sharply and subsequently increased by the surprisingly slow late phase (see FIGS. 1-4). This pharmacodynamic profile is believed to be irregular and unique among known azoles. Moreover, this pharmacodynamic pattern was also observed after intravenous administration of Posaconazole in the animals. This is an indicator of the rapid distribution of Posaconazole to the liver and spleen and subsequent slow release from these tissues. Thus, as can be seen from the literature regarding other pharmaceutically active agents (Townsend RW, 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 can be initially blocked through absorption through the reticuloendothelial system ("RES") in tissues such as the liver and spleen. Although not intended to be limited to any single mechanism of action, the resulting high concentrations of Posaconazole in these tissues due to drug containment may contribute to enhanced anti-infective activity as these tissues are often sites of infection. It is believed to be present.

In order to measure target administration for intravenous administration, it is essential to measure the average C _avg and the average C _max . Previous studies in orally administered Posaconazole are beneficial in this regard. Table 14 shows the pharmacodynamic data obtained from this oral administration, arranged by quartile based on the observed range of Posaconazole plasma concentration values. For each quartile, the rate of response to aspergillosis is shown.

The table indicates that the target mean C _max for a reaction rate of 50% or higher should be 467-1480 ng / mL, or higher. Pharmacodynamic modeling and steady-state planning based on the pharmacodynamic results of QD POS IV dosing regimens yielded a planned Posaconazole mean C _max of 714 at a 100 mg POS IV QD dose. ng / mL (see Table 17, 100 mg dose), which value exceeds 467 ng / mL, the minimum clinically relevant mean plasma C _max . The data in Table 17 suggest that there is a dose of 50-100 mg that will result in a minimum clinically relevant mean plasma Cmax of about 467. However, in late disease states, it is desirable to treat patients at the maximum tolerated dose. Thus, in order to plan a dose of 100 mg to achieve the minimum clinically relevant mean plasma C _max , it may be desirable to give the subject a higher dose, eg, 200 mg, 400 mg or 600 mg, to tolerate resistance. have.

After intravenous administration of the POS IV formulation, Posaconazole was slowly removed from the serum with an average final half-life of 21-39 hours. The half-life is higher at higher doses compared to that in the lower dose group (see Tables 15 and 16), with doses ranging from about 15 hours to 400 mg (when using a 100 mg dose). In the case of use), the range was about 51 hours. Longer half-lives may be desirable as they contribute to better antifungal activity by providing sustained high plasma concentrations of the antifungal agent over the entire dosing interval. Systemic clearance was shown to decrease with increasing dose and ranged from 13 to 6 L / hour (see Tables 15 and 16). The average distribution volume was high (326-408L) to exceed the total water volume in the body of about 40L. This suggests excessive tissue distribution and penetration into tissue, a feature that is believed to contribute to improving anti-infective activity. The range for the data for Vdss was 219 to 516L. This is consistent with the coefficient of change of the data, which suggests that the volume distribution can range from 200 to 500L.

Preferred ratios of blood to plasma Posaconazole C _max and AUC values are shown in Tables 18 and 19. Overall Posaconazole Exposure (AUC) is higher in plasma compared to that in blood (see Tables 18 and 19-AUC ratios). However, Posaconazole concentration is higher in the blood than in plasma during infusion and is approximately up to 1 hour post-infusion (see Figures 3 and 4; Tables 19 and 19, C _max ratio). This unique difference between blood and plasma concentrations can contribute to the preferential blockade of Posaconazole in the liver and spleen, as noted above. The coefficient of change in this data indicates that the ratio of blood to plasma Posaconazole C _max can range from 1.8 to 3.5 for a single dose injected over an hour to deliver 25 to 600 mg of Posaconazole. Suggest. The coefficient of change in the data indicates that the ratio of blood to plasma Posaconazole C _max is 1.0 at steady state when injecting Posaconazole over about 1 hour and delivering 25 to 600 mg of Posaconazole over a 24-hour cycle. It is suggested that it can have a range of 2.3. Different ratios than shown in Table 18 can provide different distribution properties that can lead to differences in anti-infective activity.

Average (n = 9) Posaconazole plasma pharmacodynamic parameters in subjects after a single-dose 1 hour IV infusion of Posaconazole IV formulation

It is to be understood that all formulations which are biologically equivalent to those described herein are also within the scope of the present invention.

The 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 be 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 documents are cited herein, the entire contents of which are hereby incorporated by reference.

Claims (80)

A formulation comprising a suspension of Posaconazole stabilized by phospholipids in a mixture comprising water, a heat protectant and a buffer system. The formulation of claim 1, wherein water is removed by lyophilization. The formulation of claim 1, wherein the formulation is sterilized by autoclaving. The formulation of claim 1, wherein the formulation is sterilized by radiation. The formulation of claim 1, wherein the buffer system comprises sodium phosphate. The formulation of claim 1, wherein the buffer system comprises an organic buffer. The formulation of claim 1, wherein the buffer system comprises one or more of one or more of histidine, citric acid, glycine, sodium citrate, ammonium sulfate, or acetic acid. The formulation of claim 1, wherein the buffer system maintains a pH of about 3.0 to about 9.0. The formulation of claim 1, wherein the buffer system maintains a pH of about 6.0 to about 8.0. The formulation of claim 1, wherein the buffer system maintains a pH of about 6.4 to about 7.6. The formulation of claim 1, wherein the phospholipid comprises natural phospholipid. The formulation of claim 1, wherein the phospholipid comprises synthetic phospholipid. The formulation of claim 1, wherein the phospholipid comprises natural and synthetic phospholipids. The formulation of claim 1, wherein the phospholipid comprises 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC). The formulation of claim 1, wherein the heat protectant comprises trehalose. The phospholipid of claim 1, wherein the phospholipid comprises 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), the heat protectant comprises trehalose, and the buffer system is sodium phosphate Formulations comprising a. The method of claim 1, wherein the posaconazole has a particle size distribution with a median value of about 1.0 to about 8.0 microns, and about 300 particles having a size of at least 10 microns or less and 25 particles having a size of at least 25 microns. Formulation below. The method of claim 1, wherein the Posaconazole has a particle size distribution with a median value of about 1.0 to about 5.0 microns, wherein about 300 particles are at least about 10 microns in size and at least 25 microns in size. Formulation below. The method of claim 1, wherein the Posaconazole has a particle size distribution with a median value of about 1.2 to about 4.5 microns, wherein about 300 particles are at least about 10 microns in size and at least 25 microns in size. Formulation below. The formulation of claim 16, wherein the component comprises: ingredient  Concentration range Posaconazole  About 50mg / ml POPC   About 40mg / ml Sodium Phosphate, Monobasic, Monohydrate, USP  0.345mg / ml Sodium Phosphate, Dibasic, Anhydride, USP  1.065 Trehalose  250 mg / ml Remaining amount of infusion water, USP   1ml The formulation of claim 16, wherein the component comprises: ingredient  Concentration range Posaconazole  About 1 to about 100 mg / ml POPC  About 10 to about 60 mg / ml Sodium Phosphate, Monobasic, Monohydrate, USP  About 0.01 to about 0.6 mg / ml Sodium Phosphate, Dibasic, Anhydride, USP  About 0.04 to about 1.5 mg / ml Trehalose  About 10 to about 300 mg / ml Remaining amount of infusion water, USP   1 ml The formulation of claim 16, wherein the component comprises: 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 Remaining amount of infusion water, USP   1 ml The formulation of claim 7 wherein the component comprises: ingredient  density Posaconazole  50 mg / ml POPC  40mg / ml Histidine  3mg / ml Citric Acid Monohydrate  0.24mg / ml Trehalose  250 mg / ml Remaining adequate amount of water at pH about 6.4  1ml The formulation of claim 1, further comprising an antioxidant. The formulation of claim 24, wherein the antioxidant comprises propyl gallate at a concentration of about 0.02 to about 0.005 mg / ml. The formulation of claim 24, wherein the antioxidant comprises butylated hydroxytoluene at a concentration of about 0.1 to about 0.02 mg / ml. The formulation of claim 24, wherein the antioxidant comprises alpha-D-tocopherol at a concentration of about 0.5 to about 0.01 mg / ml. The formulation of claim 24, wherein the component comprises: ingredient  density Posaconazole  50 mg / ml POPC  40mg / ml Histidine  3mg / ml Citric Acid Monohydrate  0.24mg / ml Profile gallate  0.01mg / ml Butylated Hydroxytoluene  0.05mg / ml Trehalose  250 mg / ml Remaining adequate amount of water at pH about 6.4  1ml The formulation of claim 24, wherein the component comprises: ingredient  density Posaconazole  50 mg / ml POPC  40mg / ml Histidine  3mg / ml Citric Acid Monohydrate  0.24mg / ml Alpha-D-Tocopherol  0.05mg / ml Trehalose  250 mg / ml Remaining appropriate amount of water at pH about 6.5  1ml The formulation of claim 1, wherein the weight ratio of phospholipid to posaconazole is from about 60: 1 to about 1:10. The formulation of claim 1, wherein the weight ratio of phospholipid to posaconazole is about 1: 1 to about 1: 5. The formulation of claim 1, wherein the weight ratio of phospholipid to posaconazole is about 1: 1 to about 4: 5. The formulation of claim 1, wherein the weight ratio of heat protectant to posaconazole is about 300: 1 to about 1:10. The formulation of claim 1, wherein the weight ratio of heat protectant to posaconazole is from about 1: 1 to about 6: 1. The formulation of claim 1, wherein the weight ratio of heat protectant to phospholipid is from about 30: 1 to about 1: 6. The formulation of claim 1, wherein the weight ratio of heat protectant to phospholipid is from about 5: 4 to about 30: 4. A method for treating or preventing an infection in an animal comprising administering to the animal in need thereof an effective amount of a formulation according to claim 20. The method of claim 37, wherein the infection is caused by fungi or parasites. The method of claim 37, wherein the infection is one or more infections selected from the group consisting of: Oropharyngeal or esophageal candidiasis; Refractory oropharyngeal and esophageal candidiasis; Invasive aspergillosis, candidiasis, maldermal mycobacterium, scedosporiosis, infections caused by abnormal fungi, conjunctivitis, and invasive infections due to rare fungi and yeasts; Invasive mycosis in patients refractory or resistant to other therapies; Hematologic malignancy, bone marrow or peripheral stem cell transplantation Patients undergoing intensive chemotherapy and / or radiation therapy for conditioning regimens, and treatment of acute or chronic graft-versus-host disease or solid organ transplantation Candidiasis, invasive fungal infections in patients undergoing combination immunosuppressive therapy for the prevention of; Chagas disease; And Leishmaniasis. An animal in need of such treatment, comprising administering to the animal in need thereof an effective amount of a formulation according to any one of claims 1, 21, 22, 23, 28 and 29. How to treat or prevent an infection. 41. The method of claim 40, wherein the infection is caused by fungi or parasites. The method of claim 40, wherein the infection is one or more infections selected from the group consisting of: Oropharyngeal or esophageal candidiasis; Refractory oropharyngeal and esophageal candidiasis; Invasive aspergillosis, candidiasis, maldermal mycobacterium, scedosporiosis, infections caused by abnormal fungi, conjunctivitis, and invasive infections due to rare fungi and yeasts; Invasive mycosis in patients refractory or resistant to other therapies; For patients undergoing intensive chemotherapy and / or radiation therapy for hematologic malignancies, bone marrow or peripheral stem cell transplant conditioned therapy, and for the treatment of acute or chronic graft-versus-host disease or for the prevention of solid organ transplantation Candidiasis, chipping fungal infections in patients receiving combination immunosuppressive therapy; Chagas disease; And Leishmaniasis. The method of claim 37, wherein the formulation is administered intravenously. 38. The method of claim 37, wherein the formulation is intramuscular, subcutaneous, ocular, subconjunctival, intraocular, via anterior ocular injection, intravitreal, intraperitoneal, intramedullary space, intracyst, intrathoracic, intranasal, Locally, through wound perfusion, intradermal, intraoral, abdominal, intraarticular, intra ear, intrabronchial, intracapsular, intramedural, intrapulmonary, inhaled, through tracheal or intrabronchial intubation, intrapulmonary, spinal cavity Through direct intubation into the endometrium, intravaginal membrane, thoracic tube, thoracic canal perfusion, vaginal canal, dura, rectal, intracranial, intravascular, intraventricular, intraosseous, perfusion of infected bone, or with any cement for artificial instruments Administered via application as part of a mixture. The method of claim 40, wherein the formulation is administered intravenously. The formulation of claim 40 wherein the formulation is intramuscular, subcutaneous, ocular, subconjunctival, intraocular, via anterior ocular injection, intravitreal, intraperitoneal, intramedullary space, intracyst, intrathoracic, intranasal, Locally, through wound perfusion, intradermal, intraoral, abdominal, intraarticular, intra ear, intrabronchial, intracapsular, intramedural, intrapulmonary, inhaled, through tracheal or intrabronchial intubation, intrapulmonary, spinal cavity Through direct intubation into the endometrium, intravaginal membrane, thoracic tube, thoracic canal perfusion, vaginal canal, dura, rectal, intracranial, intravascular, intraventricular, intraosseous, perfusion of infected bone, or with any cement for artificial instruments Administered via application as part of a mixture. The method of claim 20, further comprising: an antifungal agent; Amphotericin B; Deoxycholate amphotericin B; Flucitocin; Terbinafine; Antibacterial agents; Antiviral agents; steroid; Nonsteroidal anti-inflammatory drugs ("NSAIDs"); Chemotherapy; And a second active ingredient selected from one or more of the group consisting of anti-vomiting agents. 30. The method of any one of claims 1, 21, 22, 23, 28 and 29, comprising: an antifungal agent; Amphotericin B; Deoxycholate amphotericin B; Flucitocin; Terbinafine; Antibacterial agents; Antiviral agents; steroid; Nonsteroidal anti-inflammatory drugs ("NSAIDs"); Chemotherapy; And a second active ingredient selected from one or more of the group consisting of anti-vomiting agents. 38. The method of claim 37, further comprising: an antifungal agent; Amphotericin B; Deoxycholate amphotericin B; Flucitocin; Terbinafine; Antibacterial agents; Antiviral agents; steroid; Nonsteroidal anti-inflammatory drugs ("NSAIDs"); Chemotherapy; And administering a second active ingredient selected from one or more of the group consisting of anti-vomiting agents. 41. The method of claim 40, further comprising: an antifungal agent; Amphotericin B; Deoxycholate amphotericin B; Flucitocin; Terbinafine; Antibacterial agents; Antiviral agents; steroid; Nonsteroidal anti-inflammatory drugs ("NSAIDs"); Chemotherapy; And administering a second active ingredient selected from one or more of the group consisting of anti-vomiting agents. The method of claim 1, wherein when the formulation is infused over about 1 hour to deliver 100 mg of Posaconazole and repeated at about 24 hour intervals, at least about 467 ng / ml of Posaconazole in steady-state. Further comprising providing an average maximum plasma concentration (C _max ) and an average plasma range (AUC) over a 24-hour curve of Posaconazole of at least about 9840 ng.hr/ml in steady state. The mean maximum plasma concentration of posaconazole of at least about 852 ng / ml in steady state when the formulation is infused over about 1 hour to deliver 200 mg of Posaconazole and is repeated at intervals of about 24 hours. C _max ), and a formulation characterized by providing an average plasma range (AUC) over a 24-hour curve of Posaconazole of at least about 24,600 ng.hr/ml at steady state. The average maximum plasma concentration of posaconazole of at least about 1480 ng / ml in steady state when the formulation is infused over about 1 hour and delivered at intervals of about 24 hours to deliver 200 mg or more of Posaconazole. C _max ), and a formulation characterized by providing an average plasma range (AUC) over a 24-hour curve of Posaconazole of at least about 24,600 ng.hr/ml at steady state. The method of claim 1, wherein after administration of a dose of about 100 mg of Posaconazole, the mean plasma half-life in the range of about 14.9 to about 38.4 hours; And at least one of an average plasma steady state volume in a distribution of about 200 to 500 L. 2. The method of claim 1, further comprising: an average plasma half life in the range of about 18.7 to about 35.5 hours after administration of a dose of about 200 mg of posaconazole; And at least one of an average plasma steady state volume in a distribution of about 200 to 500 L. 2. The method of claim 1, further comprising: an average plasma half-life in the range of about 18.5 to about 51.4 hours after administration of a dose of about 400 mg of posaconazole; And at least one of an average plasma steady state volume in a distribution of about 200 to 500 L. 2. The method of claim 1, further comprising: an average plasma half-life in the range of about 27.2 to about 50.6 hours after administration of a dose of about 600 mg of posaconazole; And at least one of an average plasma steady state volume in a distribution of about 200 to 500 L. 2. The formulation of claim 1, further comprising providing an average Posaconazole plasma concentration profile substantially similar to that of FIG. 1 when infused over about 1 hour to deliver 25-600 mg of Posaconazole. The formulation of claim 1, further comprising providing an average Posaconazole plasma concentration profile substantially similar to that of FIG. 2 when infused over about 1 hour to deliver 25-600 mg of Posaconazole. The method of claim 1, wherein when a single dose of the formulation is infused over about 1 hour to deliver 25-600 mg of Posaconazole, the ratio of mean Posaconazole blood C _max to mean Posaconazole plasma C _max is about 1.5 to Formulations further characterized as providing about 3.8. The method of claim 1, wherein the ratio of mean Posaconazole blood C _max to mean Posaconazole plasma C _max is about 2.1 to about 3.3 when a single dose of the formulation is infused over about 1 hour to deliver 25 mg of Posaconazole. Formulations further comprising providing. The method of claim 1, wherein the ratio of mean Posaconazole blood C _max to mean Posaconazole plasma C _max is about 1.9 to about 3.8 when a single dose of the formulation is infused over about 1 hour to deliver 50 mg of Posaconazole. Formulations further comprising providing. The method of claim 1, wherein the ratio of mean Posaconazole blood C _max to mean Posaconazole plasma C _max is about 2.2 to about 3.3 when a single dose of the formulation is infused over about 1 hour to deliver 100 mg of Posaconazole. Formulations further comprising providing. The method of claim 1, wherein the ratio of mean Posaconazole blood C _max to mean Posaconazole plasma C _max is about 1.5 to about 3.2 when a single dose of the formulation is infused over about 1 hour to deliver 200 mg of Posaconazole. Formulations further comprising providing. The ratio of mean Posaconazole blood C _max to mean Posaconazole plasma C _max when the single dose of the formulation is infused over about 1 hour to deliver 400 mg of Posaconazole, according to claim 1. Formulations further comprising providing. The ratio of average Posaconazole blood C _max to average Posaconazole plasma C _max when the single dose of the formulation is infused over about 1 hour to deliver 600 mg of Posaconazole, according to claim 1. Formulations further comprising providing. The ratio of mean Posaconazole blood C _max to mean Posaconazole plasma C _{max when} the formulation is infused over about 1 hour and repeated on a 24-hour basis to deliver 25-600 mg of Posaconazole. Formulations further characterized as providing from about 1.2 to about 2.5. The ratio of mean Posaconazole blood C _max to mean Posaconazole plasma C _{max when} the formulation is infused over about 1 hour and repeated on a 24 hour basis to deliver 25 mg of Posaconazole. Formulations further characterized as providing from 1.5 to about 2.3. The ratio of mean Posaconazole blood C _max to mean Posaconazole plasma C _max of claim 1 when the formulation is infused over about 1 hour to deliver 50 mg of Posaconazole and repeated on a 24-hour basis. To about 2.4, wherein the formulation is further characterized. The ratio of mean Posaconazole blood C _max to mean Posaconazole plasma C _max of claim 1, wherein the formulation is infused over about 1 hour to deliver 100 mg of Posaconazole and repeated on a 24-hour basis. To about 2.5 to a dosage form further characterized. The ratio of mean Posaconazole blood C _max to mean Posaconazole plasma C _max of claim 1.2 when the formulation is infused over about 1 hour to deliver 200 mg of Posaconazole and repeated on a 24-hour basis. To about 2.0, wherein the formulation is further characterized. The ratio of mean Posaconazole blood C _max to mean Posaconazole plasma C _max according to claim 1, wherein the formulation is injected over about 1 hour to deliver 400 mg of Posaconazole and repeated on a 24-hour basis. Formulations further characterized as providing from 1.2 to about 2.2. The ratio of mean Posaconazole blood C _max to mean Posaconazole plasma C _max of claim 1, wherein the formulation is infused over about 1 hour to deliver 600 mg of Posaconazole and repeated on a 24-hour basis. To about 1.7, further comprising a formulation. The method of claim 37, wherein the animal is a human. The method of claim 37, wherein the animal is not a human dl. The method of claim 40, wherein the animal is a human. The method of claim 40, wherein the animal is not a human. The method of claim 1 further comprising being bioequivalent with the formulation according to claim 1, 20, 21, 22, 23, 28 and 29. Formulation characterized by the above. The method of claim 37, further comprising administering an intravenous maintenance dose of the formulation after administering a bolus loading dose of the formulation. If the formulation is infused over about 1 hour to deliver 100 mg of Posaconazole and repeated at intervals of about 24 hours, an effective amount of Posaconazole is administered to animals in need of treatment or prevention of infection at about 467 ng / providing an average maximum plasma concentration (C _max ) of at least ml of Posaconazole (C _max ) and an average plasma range (AUC) under the curve over 24 hours of Posaconazole of at least about 9840 ng.hr/ml at steady state. How to treat or prevent an infection in an animal.

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