RU2575768C2 - Formulations of intravenous solutions of posaconazole stabilised by substituted beta-cyclodextrine - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to aqueous solutions applicable as pharmaceutical compositions of posaconazole for intravenous administration. These compositions contain a solvent, such as modified β-cyclodextrine in acidified solution, as well as a chelating agent, such as disodium edentate (ethylene diamine tetraacetate). The clinical trials have shown that a dose of the selected composition making 200 mg of posaconasole enables achieving the acceptable pharmacokinetic properties.

EFFECT: prepared pharmaceutical composition possesses physical and chemical stability.

21 cl, 8 dwg, 11 tbl

Description

FIELD OF THE INVENTION

The present invention relates to aqueous pharmaceutical compositions of posaconazole and a complexing agent. Such pharmaceutical compositions provide sufficient solubility of posaconazole, which leads to an increased shelf life of the drug and a reduced likelihood of precipitation during injection into a vein or cannula for intravenous drip.

The invention also relates to methods for treating and / or preventing mycoses using said pharmaceutical compositions.

BACKGROUND OF THE INVENTION

In US patent No. 5703079 and 5661151 (see column 69, example 24) describe posaconazole, a broad-spectrum antifungal agent, the structure of which is illustrated below:

US Pat. No. 6,958,337 describes crystalline forms of posaconazole. U.S. Patent Application 20060160823 describes a composition containing an injection suspension. Posaconazole in solid dosage form (capsule / tablet) is described in US Pat. Nos. 5,972,381 and 5,834,472.

Posaconazole is commercially available as an oral suspension (40 mg / ml) under the trademark NOXAFIL ™ in the United States by Merck (formerly Schering Corporation, Kenilworth, H J.). NOXAFIL ™ (posaconazole) is indicated for the prevention of invasive infections of Aspergillus and Candida in patients 13 years of age and older who are at high risk of developing these infections due to greatly reduced immunity, such as hematopoietic stem cell transplant recipients (HSCT) with graft versus graft versus host ”(GVHD) or patients with hemoblastoses with prolonged neutropenia due to chemotherapy. NOXAFIL ™ (posaconazole) is also indicated for the treatment of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and / or fluconazole.

Posaconazole is a weakly basic and slightly soluble in water drug that has poor bioavailability and variable absorption. Posaconazole has a solubility of less than 1 μg / ml in neutral and basic aqueous solutions. Although solubility increases in an acidic environment (for example, 3 μg / ml at pH 3 and 0.8 mg / ml at pH 1), a more dramatic increase in solubility would be required to achieve an estimated daily intravenous dose of more than 100 mg.

Thus, it would be desirable to have an intravenous solution available to patients to increase the bioavailability of posaconazole. An injection formulation would also allow administration of the formulation to patients who cannot be given oral dosage forms, as is the case for patients who have difficulty swallowing or who are unconscious. Undoubtedly, any such intravenous composition should demonstrate chemical and physical stability over the shelf life of the drug.

SUMMARY OF THE INVENTION

In some embodiments, the invention relates to a pharmaceutical composition for intravenous administration comprising:

posaconazole or a pharmaceutically acceptable salt thereof; and modified β-cyclodextrin,

in an aqueous solution, where the pH of said composition is between about 2.0 and about 3.5.

In further embodiments, said modified β-cyclodextrin comprises sulfobutyl ether-β-cyclodextrin.

In further embodiments, the composition further comprises a chelating agent.

In further embodiments, said pharmaceutical composition comprises a posaconazole free base, said modified β-cyclodextrin comprises sulfobutyl ether-β-cyclodextrin, said chelating agent comprises EDTA, and wherein said pH is between about 2.3 and about 3.0.

In further embodiments, the concentration of the posaconazole free base is between about 14 and about 22 mg / ml, the concentration of sulfobutyl ether-β-cyclodextrin is between about 350 and about 450 mg / ml, and the concentration of EDTA is between about 0.1 and about 0, 3 mg / ml.

In additional embodiments, the implementation of the concentration of the free base of posaconazole is approximately 18 mg / ml, the concentration of sulfobutyl ether-β-cyclodextrin is approximately 400 mg / ml, and the concentration of EDTA is approximately 0.2 mg / ml

In further embodiments, as a result of administering a dose of said composition that delivers 200 mg of posaconazole to a patient, C _max is between about 1176 and about 18375 ng / ml, and AUC _last is between about 21600 and about 33750 h * ng / ml.

In further embodiments, as a result of administering a dose of said composition that delivers 200 mg of posaconazole to a patient, C _max is approximately 1470 ng / ml and AUC _last is approximately 27,000 h * ng / ml.

In additional embodiments, said pharmaceutical composition for intravenous administration contains components and amounts of each of the components, as follows:

Components amount Posaconazole from about 5 to about 25 mg / ml Captisol® (sulfobutyl ether-β-cyclodextrin) from about 25 mm to about 200 mm Disodium edetate (EDTA) from about 0.1 to about 1.0 mg / ml 1N hydrochloric acid an amount sufficient to bring to a pH of from about 2.0 to about 3.0 1N sodium hydroxide an amount sufficient to bring to a pH of from about 2.0 to about 3.0 Water in a quantity sufficient for 1 ml

In further embodiments, said pharmaceutical composition comprises components and amounts of each of the components, as follows:

Components amount Posaconazole approximately 18 mg / ml Captisol® (sulfobutyl ether-β-cyclodextrin) approximately 400 mg / ml (185 mm) Disodium edetate (EDTA) approximately 0.2 mg / ml 1N hydrochloric acid an amount sufficient to bring to a pH of approximately 2.6 1N sodium hydroxide an amount sufficient to bring to a pH of approximately 2.6 Water in a quantity sufficient for 1 ml

In further embodiments, the invention relates to a method for treating or preventing an infection in an animal in need thereof, which comprises administering to said animal an effective amount of any of the pharmaceutical compositions described above.

In further embodiments, the infection is caused by a fungus or parasite.

In further embodiments, the infection is one or more selected from the group consisting of: oropharyngeal or esophageal candidiasis; refractory oropharyngeal and esophageal candidiasis; invasive aspergillosis, candidiasis, fusariosis, stsedosporioza, infections caused by dimorphic fungi, zygomycosis and invasive infections caused by rare mold and yeast fungi; invasive mycoses in patients refractory to other types of therapy or not tolerating them, candidiasis, invasive mold infections in patients who have undergone intensive chemotherapy and / or radiation therapy for hemablastoses, preparation for bone marrow or peripheral stem cell transplantation, and in patients receiving combination immunosuppressive therapy for the treatment of acute or chronic transplant versus host disease or its prevention during transplantation of parenchymal organs; Chagas disease and leishmaniasis.

In additional embodiments, after injecting said composition into an infusion bag, the composition and infusate were mixed and the resulting mixture was allowed to settle for up to 24 hours, no precipitate of posaconazole was visible.

In further embodiments, the method comprises administering to said animal a composition according to claim 1 in an amount sufficient to deliver a dose between about 180 and about 220 mg of posaconazole to said animal.

In further embodiments, the method comprises administering to said animal a composition according to claim 1 in an amount sufficient to deliver a dose of approximately 200 mg of posaconazole to said animal.

In further embodiments, administration is carried out once a day.

In additional embodiments, the administration is carried out twice a day.

In further embodiments, the method further comprises administering a second active ingredient selected from one or more of the group consisting of antifungal, antibacterial, antiviral, steroid, non-steroidal anti-inflammatory drugs, chemotherapeutic and antiemetic drugs.

In further embodiments, the antifungal drugs are selected from the group consisting of azoles, echinocandin, allylamine, polyene, flucytosine, benzoic acid, cyclopirox, 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborate, tolnaphthalate, undecylene acids, griseofulvin and haloprogin.

In further embodiments, the invention relates to a kit comprising:

small collapsing container;

infusion bag;

and composition

where the specified container contains this composition,

and said infusion bag contains a diluent selected from the group consisting of normal saline and 5% dextrose solution, and wherein said small collapsible container is placed directly inside said infusion bag suitable for said composition to be diluted by breaking said small collapsible container directly inside the diluent in the indicated infusion bag.

BRIEF DESCRIPTION OF THE DRAWINGS

In FIG. 1 shows the solubility of posaconazole as a function of the concentration of captisol® at various pH values.

In FIG. Figure 2 is a bar graph showing the solubility of posaconazole with various sulfobutyl ether-β-cyclodextrins (SBE-CyDs) at 100 mM and pH 4.5.

In FIG. Figure 3 shows the percentage of posaconazole (10 mg / ml) remaining in the solution over time in a 200 mM captisol® solution at pH 3.0.

In FIG. 4 shows the percentage of posaconazole (5 mg / ml) remaining in the solution over time in a 100 mM captisol® solution at pH 3.0.

In FIG. 5 shows the percentage of posaconazole (18 mg / ml) remaining in the solution over time in a 400 mg / ml captisol® solution at pH 2.6,

In FIG. Figure 6 shows the production process diagram for an industrial-scale installation series.

In FIG. 7 shows the profiles of the mean (± SD) plasma posaconazole concentration versus time after a single dose of 200 mg intravenous solution of posaconazole administered to healthy adult volunteers.

In FIG. Figure 8 summarizes the observed steady-state concentrations of posaconazole and the estimated concentration distribution for the intravenous solution of posaconazole.

DETAILED DESCRIPTION OF THE INVENTION

Various approaches have been taken to obtain a stable solution of posaconazole that is suitable for an intravenous formulation of sufficient bioavailability and other pharmaceutically desirable characteristics.

Intravenous solutions of posaconazole

It is known that cyclodextrins and their derivatives exhibit the property of increasing the aqueous solubility of certain compounds, as described in US Pat. No. 5,134,127. However, this document does not mention whether cyclodextrins can increase the solubility of posaconazole or other related azole compounds in water. Example 32 of US patent No. 7635773 proposes to report the stabilization of posaconazole sulfobutyl ether-β-cyclodextrin (SBE ₆₆ -β-CD), which was subjected to a single or double treatment with activated carbon.

Captisol® is a trademark for sulfobutyl ether-β-cyclodextrin presented below and marketed by CyDex Pharmaceuticals, Inc., Lenexa, KS. The chemical structure of captisol® is presented below:

Table 1 provides specific relevant information for Captisol®.

Table 1 Names Sulfobutyl ether-β-cyclodextrins, (SBE-β-CD) sodium salt Molecular mass 2163 g / mol
(solubility = 6.5) Solubility > 800 mg / ml in water CAS number 182410-00-0

This compound is used as a complexing agent to improve the solubility and / or stability of pharmaceutical compounds.

In order to evaluate the solubility range of posaconazole that could be achieved at acceptable pHs, a series of solutions with a fixed concentration of captisol® were prepared. When using an acidic solution of 20% captisol® (w / v), the solubility of posaconazole increased by more than 1000 times, and it was determined that a targeted concentration of 5 mg / ml could be achieved. Table 2 presents the solubilities of posaconazole in 20% captisol® solutions at various pH values.

table 2 pH Solubility of posaconazole (mg / ml) 3.0 8.7 3,1 7.8 * 3.2 6.9 3.4 5.2 3.6 4.0 3.8 3,1 * Calculated average value of the measured solubility at pH 3.0 and pH 3.2

The solubility of posaconazole was also evaluated in acidified solutions with various concentrations of captisol®. As shown in FIG. 1, the solubility of posaconazole increases with pH as does the concentration of captisol®. However, in FIG. 1 also shows that at each pH, an increase in the solubility of posaconazole occurs nonlinearly with respect to captisol®, and at pH 3.0 and 4.5 there is a greater than linear increase in the concentration of posaconazole. Thus, at some pH values at which the concentration of captisol® increases, the ratio of captisol® and dissolved posaconazole decreases. A composition based on this solubility effect could be developed, as a result of which the daily dose of captisol® could be reduced for the same daily dosage of posaconazole. For example, at pH 3.1, the solubility of posaconazole in 20% captisol® was calculated to be 7.8 mg / ml (see table 2), while in 40% captisol®, it was determined that the solubility was 22.5 mg / ml . In this case, the concentration of captisol® was increased by factor 2, while the solubility of posaconazole was increased by factor 2.9.

However, if the increasing concentration of captisol® produced more than a linear effect on the solubility of posaconazole, the opposite effect would also be expected, i.e. dilution of captisol® solutions containing posaconazole with or at approximately equilibrium solubility of posaconazole will precipitate posaconazole. This effect is significant in that the preferred method of delivering the composition of posaconazole is dilution with either normal saline or 5% dextrose followed by infusion. Surprisingly, however, upon subsequent dilution of the posaconazole / captisol® formulation, no precipitation was seen for at least 24 hours.

Hydrochloric acid was used as an oxidizing agent in posaconazole. However, in addition to the dissolution of posaconazole, several additional oxidizing agents were evaluated (i.e., citric, sulfuric, maleic, phosphoric, acetic, L-tartaric, D-tartaric, DL-tartaric, methanesulfonic, naphthalenesulfonic, p-toluenesulfonic, lactic, L- lactic, L-ascorbic and malic acid, as well as glycine hydrochloride). However, at the same pH when using these oxidizing agents, no improvement in solubility was noted.

In order to study additional compositional improvements, the effect of various cosolvents and nonionic surfactants on the solubility of posaconazole in a 100 mM captisol® solution was examined. Captisol® solutions were adjusted to pH 4.5 with HCl and an appropriate amount of cosolvents was added to them.

An additional amount of posaconazole was added to the cyclodextrin / cosolvent solution adjusted to the desired pH, and the solutions were left to balance for three days. The contents of the tubes were centrifuged and the supernatant was evaluated for posaconazole.

Table 3 presents the effect of various cosolvents and several surfactants (0.1% 0.2% vol./about. Poloxamer F-68, tween 20 or tween 80) on the solubility of posaconazole. The tested surfactants did not increase the solubility of posaconazole, while the cosolvents decreased its solubility.

Table 3 Co-solvent Posaconazole (mg / ml) Control (100 mM Captisol®) 1.77 10% propylene glycol 0.41 10% PEG 400 1.28 10% PVP 0.64 0.1% poloxamer F-68 1,63 0.1% Tween 20 1.71 0.1% tween 80 1.74

The solubilities of posaconazole in each of several modified β- and γ-cyclodextrins were evaluated. The solubility of posaconazole was tested with three gamma cyclodextrins; SBE (5.2) -gamma, SBE (5.2) Et (3.9) -gamma, and SBE (5.2) Et (4.9) -gamma cyclodextrin, (CyDex, Inc.). At 100 mM cyclodextrin concentrations and a pH of 4.5, the highest solubility of posaconazole achieved was 0.189 mg / ml, about 8 times less than 1.51 mg / ml, achieved by captisol®, SBE (6.5) -β-cyclodextrin, in similar conditions (see Fig. 2).

On the other hand, some changes in β-cyclodextrin substitutions did not increase solubility. Using 100 mM cyclodextrin solutions at pH 4.5, the solubility of posaconazole in cyclodextrins SBE (4,6) -β, SBE (4,6) -Et (3,5) -β and SBE (4,6) -Et ( 8.5) -β relative to captisol®. The cyclodextrins SBE (4.6) -Et (3.5) -β and SBE (4.6) -Et (8.5) -β were dissolved 2.6 and 6.6 times more posaconazole (respectively) than captisol ® (see Fig. 2). However, comprehensive safety information on captisol® outweighed the potential benefits of greater solubility, and for this reason formulations with other sulfobutyl ether cyclodextrins were not further developed.

In conclusion, stability screening studies have also demonstrated that captisol® with posaconazole formulations undergo discoloration under accelerated testing conditions. Solutions of 10 mg / ml posaconazole in 40% captisol® at pH 3.0 were prepared both in the presence and in the absence of 1 mg / ml EDTA, and with or without nitrogen addition. After 20 days at 40 ° C, the solutions were evaluated for color changes by means of a calorimeter, where the color change was indicated by the value "b *" (solutions with a value of b * equal to 3 or higher turn yellow). As shown in table 4, the manifestation of color was minimized as EDTA, and the supply of a layer of nitrogen. However, in the solution containing EDTA, no further improvement was seen by turning on the supply of the nitrogen layer.

Table 4 Description EDTA Level N ₂ b * 10 mg / ml posaconazole, 200 mm captisol® 0.0 mg / ml No 4.17 10 mg / ml posaconazole, 200 mm captisol® 1.0 mg / ml No 1.49 10 mg / ml posaconazole, 200 mm captisol® 0.0 mg / ml Yes 2,33 10 mg / ml posaconazole, 200 mm captisol® 1.0 mg / ml Yes 1,67 Stability conditions: 40 ° C / 75% RH for 20 days

Based on these studies, as well as additional screening of the composition, EDTA was used in the current composition at a level of 0.2 mg / ml, which is suitable for parenteral administration. In addition, although posaconazole is stable in acidified captisol® solutions at room temperature and under accelerated testing conditions, as described below, a storage temperature of 5 ° C is assumed to further minimize yellow color.

A series of tests were performed to study the stability of posaconazole solutions for various compositions and pH. The accelerated stability of 10 mg / ml posaconazole in a 200 mM captisol® solution at pH 3.0 for three months was investigated. Posaconazole was added to a 200 mM Captisol® solution adjusted to the desired pH and stirred for 24 hours. Then the solution was filtered and placed under stable conditions at 4 ° C, 25 ° C / 60% RH and 40 ° C / 75% RH. The sample did not contain a chelating agent and was not sparged with nitrogen. The results are shown in FIG. 3. Temperature had a minimal effect on the degradation of posaconazole within three months. However, the solution turned pale yellow within two weeks and darkened over time. Thus, it was concluded that a chelating agent is important for preparing the compositions of the present invention.

A similar study over time of the stability of posaconazole (5 mg / ml) in a 100 mM solution of captisol® at pH 3.0 was carried out for three months. Posaconazole was added to a 100 mM captisol® solution adjusted to the desired pH and stirred for 24 hours. Then the solution was filtered and placed under stable conditions at 4 ° C, 25 ° C / 60% RH and 40 ° C / 75% RH. The sample did not contain a chelating agent and was not sparged with nitrogen. The results are shown in FIG. 4. The temperature had a minimal effect on the degradation of posaconazole over a three-month period. However, the solution turned pale yellow for two weeks and darkened over time.

The stability study of posaconazole (18 mg / ml) in a 400 mg / ml captisol® solution at pH 3.0 was also carried out over a nine-month period. The sample was produced using the most modern clinical production process. EDTA was dissolved in water for injection. Then, captisol® was dissolved in EDTA, and then the solution was acidified using HCl. Then, posaconazole was added and dissolved. As necessary, additional HCl was added to the solution to adjust to the desired pH. The solution was also sparged with nitrogen throughout the process.

Then the resulting solution was filtered under sterile conditions, poured into vials and placed in stable conditions under various storage conditions. As shown in FIG. 5, temperature had a minimal effect on the degradation of posaconazole over a nine-month period.

Several test formulations were also evaluated based on either HS 15 solutol (Macrogol® 15 hydroxystearate Ph. Eur.) Or cyclodextrins. It was found that these formulations have sufficient physical and chemical stability to support their further development, but, as described below, toxicological testing unexpectedly showed superior results for 40% of the composition of captisol®.

Got six experimental compositions shown in tables 5 and 6.

Table 5 presents the composition of the three compositions based on solutol® (Nos. 1-3), and table 6 presents the compositions of the other three compositions based on cyclodextrin (Nos. 4-6).

These six formulations were the subject of a toxicological screening study using a suspension formulation as a control. The compositions were administered to rats using intravenous infusion of 15 minutes for a two-week period. The dose of posaconazole for all animals was 10 mg / kg. In addition, before administering a dose, the hemolytic potential of each formulation was tested in vitro.

Table 5 IV solutions of posaconazole: based on solutol Components No.1:
30% solutol
(in real conditions - no dilution) mg / ml No.2:
30% solutol (1: 5 dilution NS ¹ )
mg / ml No.3:
75% solutol
(1: 5 dilution NS)
mg / ml Posaconazole 10 10 10 Solyutol HS 15 300 300 750 Ethanol 240 240 150 Polyethylene glycol 200 220 220 - Lactic acid fifty fifty - 0.9% saline q.s.ad - - 1 ml Water for injection q.s.ad 1 ml 1 ml - ¹ normal saline

Table 6 IV solutions of posaconazole: based on cyclodextrin Components No.4:
30% HPβCD ¹ (1: 5 dilution D5W ² ) mg / ml No.5:
20% captisol® (1: 2.5 dilution D5W) mg / ml No.6:
40% captisol® (1:10 dilution NS ³ ) mg / ml Posaconazole 10 5 twenty Captisol® - 200 400 HPβCD 200 - EDTA - 0.1 Wine acid 9 - - Hydrochloric acid - up to pH 3 up to pH 3 Sodium hydroxide up to pH 3.5 - - Water for injection q.s.ad 1 ml ml ml ¹ hydroxypropyl beta-cyclodextrin
² 5% dextrose
³ normal saline

One prototype (composition No. 1) was poured directly. However, the rest of the formulations were all diluted to a concentration of 2 mg posaconazole / ml before infusion.

The results of a toxicity screening study are summarized below.

A 30% solutol composition that was injected directly (formulation No. 1) caused hemolysis in in vitro screening and showed severe local intolerance, and hemolysis was shown in vivo. This study was stopped until completion and the animals were killed.

30% of the composition of solutol, which was diluted 1: 5 before infusion (composition No. 2), caused hemolysis in vitro, similar to hemolysis caused by composition No. 1. Based on this result, the animals were not dosed.

The 75% solutol composition, which was diluted 1: 5 before infusion (composition No. 3), showed some signs of in vitro hemolysis (time-dependent). In addition, clinical signs of local intolerance have been observed in some animals.

Similar results were observed for both 20% of the composition of HPβCD diluted 1: 5 before infusion (composition No. 4) and for 20% of the composition of captisol® diluted 1: 2.5 before infusion (composition No. 5). For both formulations, in vitro hemolysis testing showed no hemolysis, but mild effects on the renal tubule cells in rats were observed, and animal studies suggested that sterile dosage forms of HPβCD had significant toxicological potential.

40% of the composition of captisol® (composition No. 6) was diluted 1:10 before infusion. This composition did not cause hemolysis in vitro and did not show clinical signs of toxicity or effects on clinical pathological parameters.

Thus, only 40% of the composition of captisol® had no toxicological manifestations and, interestingly, this composition also had an advantage over 20% of the composition of captisol®. It is believed that the reason for this difference was that to obtain an equivalent dose of posaconazole, twice as much as 20% of the composition of captisol® was required than 40% of the composition.

The final composition based on a 40% captisol® solution included modifications to ensure the solubility of posaconazole for any potential compositional changes. For example, production requires both a targeted pH and an acceptable pH range, and the composition must be stable in all regulatory ranges. To meet these criteria, the concentration of posaconazole was slightly reduced, from 20 mg / ml to 18 mg / ml, and the pH was reduced from 3.0 to 2.6.

The clinical composition of the intravenous composition of posaconazole solution is presented in table 7.

Table 7 Components amount Range Posaconazole 18 mg / ml 5 to 25 mg / ml captisol® (sulfobutyl ether-β-cyclodextrin) 400 mg / ml (185 mm) 25 mM to 200 mM Sodium Edetate (EDTA) 0.2 mg / ml 0.1 to 1.0 mg / ml 1N hydrochloric acid Bringing pH (pH 2.6) PH 2.0 to 3.0 1N sodium hydroxide Bringing pH (pH 2.6) PH 2.0 to 3.0 Water in a quantity sufficient for 1 ml in a quantity sufficient for 1 ml

Conducted several studies of dilution of the composition, as described below.

A dilution study was performed to assess the similarity of sedimentation during dilution before administration to the patient. A ten percent excess of the required amount of posaconazole was weighed in an amber bottle. A solution of captisol® adjusted to the target pH using HCl was added to the vial. The vial was sealed and gently stirred at room temperature for 24 hours. After 24 hours, test vials were filtered through a Millipore PVDF Millex-GV® 0.22 micron filter. A portion of the filtered sample (10 ml) was added to a 100 ml pycnometer. The sample was diluted to 100 ml using either a 0.9% sodium chloride injection solution USP (normal saline) or a 5% USP injection dextrose solution ("D5W"). Samples were observed for 24 hours at 4 ° C and ambient temperature.

The results of using normal saline and D5W as diluents are summarized in Tables 8 and 9. A solid precipitate was visually observed in the following posaconazole formulations 24 hours after reconstitution with normal saline: 20 mg / ml of posaconazole in 200 mM captisol® at pH 3.3 mg / ml posaconazole in 100 mm captisol® at pH 4 and 5 mg / ml posaconazole in 150 mm or 200 mm captisol® at pH 4. All other diluted samples became transparent after 24 hours. A solid precipitate was visually observed in the following posaconazole formulations 24 hours after dilution with D5W: 5 mg / ml of posaconazole at pH 3, 10 mg / ml of posaconazole at pH 3, 20 mg / ml of posaconazole in 200 mm captisol® at pH 3, 3 mg / ml posaconazole in 100 or 200 mm captisol® at pH 4 and 5 mg / ml posaconazole in 150 mm captisol® at pH 4. All other diluted samples were clear after 24 hours. This experiment indicates that it is possible to obtain posaconazole formulations that do not precipitate upon dilution for administration to a patient.

Table 8 Dilution test in normal saline Originally 4 ° C (24 hours) Room temperature
(24 hours) Sample Organoleptic properties % posaconazole ^a Organoleptic properties % posaconazole ^a Organoleptic properties % posaconazole ^a Posaconazole 20 mg / ml 100 mM Captisol® at pH 2 Clear solution 100.00 Clear solution 102.52 Clear solution 102.59 Posaconazole 20 mg / ml 200 mM Captisol® at pH 2 Clear solution 100.00 Clear solution 102.37 Clear solution 99,99 Posaconazole 5 mg / ml 100 mM Captisol® at pH 3 Clear solution 100.00 Clear solution 100.29 Clear solution 100.26 Posaconazole 10 mg / ml 200 mM Captisol® at pH 3 Clear solution 100.00 Clear solution 103.18 Clear solution 102.1 Posaconazole 20 mg / ml 200 mM Captisol® at pH 3 Clear solution 100.00 Solid 102.75 Solid 101,20 Posaconazole 3 mg / ml 100 mM Captisol® at pH 4 Clear solution 100.00 Solid 101.56 Solid 99.33 Posaconazole 3 mg / ml 200 mM Captisol® at pH 4 Clear solution 100.00 Clear solution 100.93 Clear solution 100.27 Posaconazole 5 mg / ml 150 mM Captisol® at pH 4 Clear solution 100.00 Solid 101.22 Solid 99.94 Posaconazole 5 mg / ml 200 mM Captisol® at pH 4 Clear solution 100.00 Solid 101.30 Solid 99.59 a: Compared to the original value after dilution.

Table 9 Dilution Study in D5W Originally 4 ° C (24 hours) Room temperature
(24 hours) Sample Organoleptic properties % posaconazole ^a Organoleptic properties % Of posaconazole ^and Organoleptic properties % posaconazole ^a Posaconazole 20 mg / ml 100 mM Captisol® at pH 2 Clear solution 100.00 Clear solution 99.35 Clear solution 101.19 Posaconazole 20 mg / ml 200 mM Captisol® at pH 2 Clear solution 100.00 Clear solution 99.01 Clear solution 97.21 Posaconazole 5 mg / ml 100 mM Captisol® at pH 3 Clear solution 100.00 Solid 100,99 Solid 100.05 Posaconazole 10 mg / ml 200 mM Captisol® at pH 3 Clear solution 100.00 Solid 99.90 Solid 99.05 Posaconazole 20 mg / ml 200 mM Captisol® at pH 3 Clear solution 100.00 Solid 100.39 Solid 101.05 Posaconazole 3 mg / ml 100 mM Captisol® at pH 4 Clear solution 100.00 Solid 100.72 Solid 99.72 Posaconazole 3 mg / ml 200 mM Captisol® at pH 4 Clear solution 100.00 Solid 101.12 Solid 100.69 Posaconazole 5 mg / ml 150 mM Captisol® at pH 4 Clear solution 100.00 Solid 101.13 Solid 100.01 Posaconazole 5 mg / ml 200 mM Captisol® at pH 4 Clear solution 100.00 Clear solution 101.63 Clear solution 102.53 a: Compared to the original value after dilution.

To assess the deposition potential during infusion of the diluted solution into a vein, a dynamic deposition study was performed using the method of Yalkowsky et al. (J.L. H. Johnson, Y. He, S.H. Yalkowsky, Validation of an in Vitro Model for Prediction of In Vivo Phlebitis, AAPS, 2002, poster # 14919) with minor modifications. Sorenson's isotonic phosphate buffer (ISPB) flow rate was 5 ml / min, which is comparable to the speed of blood flow in the human body in easily accessible veins.

A peristaltic pump (Master Flex® model 7518-10) provided a flow of the aqueous phase at a rate of 5 ml / min through a flexible tube (Cole-Parmer's L / S 14 Silicone (Platinum), which had an inner diameter of 1.6 mm), then through UV flow cell. The aqueous phase served as a blood substitute and consisted of Sorenson's isotonic phosphate buffer (ISPB) at pH 7.4. The sample solution was injected into the cuvette through a needle introducing a 30 cm upflow of the flow cell. A syringe pump was used to control the rate of sample injection. The injection rate ranged from 0.05 to 10 ml / min. The appearance of a precipitate was detected by a Beckman DU-7 spectrophotometer at 540 nm. This study was carried out at room temperature. The filtered prototype was diluted 1:10 with normal saline or D5W before injection.

The results of a dynamic sedimentation study for samples injected at 1.0 ml / min are illustrated in Table 10. The results of a dynamic sedimentation study suggest that various formulations can be prepared and diluted without precipitation. Less precipitation was also noted in samples introduced at a rate of less than 1.0 ml / min.

Table 10 pH 2 pH 3 pH 4 200 mM captisol® Posaconazole 20 mg / ml Precipitation ^a Can not be
received Cannot be received Posaconazole 10 mg / ml Transparent ^b Transparent ^b Cannot be received Posaconazole
5 mg / ml Transparent ^b Transparent ^b Transparent ^b Posaconazole
3 mg / ml Transparent ^b Transparent ^b Transparent ^b 150 mM Captisol® Posaconazole 20 mg / ml Precipitation ^a Cannot be received Cannot be received Posaconazole 10 mg / ml Not tested Not tested Cannot be received Posaconazole 5 mg / ml Transparent ^b Transparent ^b Cannot be received Posaconazole 3 mg / ml transparent ^b Transparent ^b transparent ^b 100 mm captisol Posaconazole 20 mg / ml Precipitation ^a Cannot be received Cannot be received Posaconazole 10 mg / ml Precipitation ^a Cannot be received Cannot be received Posaconazole 8 mg / ml Transparent ^b Transparent ^b Cannot be received Posaconazole 5 mg / ml Transparent ^b Transparent ^b Cannot be received Posaconazole 3 mg / ml Transparent ^b Transparent ^b Cannot be received but. Precipitation after dynamic in vitro administration
b. No precipitation after dynamic in vitro administration

Production methods

The clinical intravenous composition of posaconazole can be obtained in the following ways:

posaconazole can be obtained by the methods described in examples 24 and 32 of US patent No. 5661151 and W095 / 17407.

An intravenous solution concentrate can be prepared according to the following procedure:

load the initial volume of water for injection (WFI) into the tank.

Add EDTA to WFI in the tank and mix until dissolved.

Add SBE-β-cyclodextrin to WFI in the tank and mix until dissolved.

Filter the appropriate volume of EDTA + SBE-β-cyclodextrin solution through a clarification filter into the main mixing tank. The total filtered volume of the EDTA + SBE-β-cyclodextrin solution depends on the mixing efficiency of the equipment used during mixing.

Add 1N HCl to the tank to oxidize the filtered solution.

Add posaconazole to the filtered solution. During mixing by means of equipment that provides sufficient shaking, posaconazole can be loaded in powder form. When mixing with equipment that provides limited shaking, pre-wet posaconazole in WFI in a separate tank in the ratio of one part posaconazole to five parts water (1: 5 ratio) and mix until a homogeneous suspension is obtained.

Add a pre-moistened suspension of posaconazole to the main tank and mix until dissolved.

Add an additional 1N HCl or 1N NaOH to adjust the pH to a suitable level.

Add enough water for injection to get the final batch volume and mix until a homogeneous solution is obtained.

Filter the pharmaceutical composition under sterile conditions through a 0.22 μm filter. Place the filtered product in 6RDIN glass vials. Close and close with a crimp cover.

The solution was sparged with nitrogen during the mixing process.

During the development of the manufacturing process, various processes were evaluated, including the optimization of posaconazole: WFI ratio, changing the order of addition of excipients, and at the same time adding powdered excipients. Based on research on the development of the drug, the production method described above in detail provides an optimal solution production process.

Industrial production

The production process using three tanks was used for 200 l of industrial-scale batches. To ensure uniform mixing, suspension mixers were used to facilitate the dissolution of captisol and posaconazole. Nitrogen sparging was used during the mixing process. In FIG. 6 is a flowchart for pilot batches of industrial scale, the process of which is summarized below:

EDTA and captisol are dissolved in nitrogen sparged water for injection (WFI) in a first tank. The EDTA + captisol solution is then filtered through a 0.22 μm membrane clarifying filter into a mixing tank for the pharmaceutical product.

In the reservoir for mixing the pharmaceutical product, the filtered EDTA + captisol solution is acidified with hydrochloric acid and API is added to the acidified solution. The solution was stirred until the API dissolved. The pH is then adjusted to 2.6 using hydrochloric acid and / or sodium hydroxide as necessary and the product is brought to its final volume.

The pharmaceutical product is then filtered through a 0.22 μm membrane filter, reducing the total number of microbes, into the receiving tank. From the receiving tank, the solution is sterilized through a 0.22 μm in-line sterilizing filter and filled under sterile conditions and sealed in sterile pyrogen-free glass vials in the class A packaging area.

Diluted IV infusion (mixture)

Diluted intravenous solution (mixture) for infusion can be obtained in accordance with the following procedure:

the following concentrations and dose ranges limit the lower and upper levels in the study of single increasing doses defined in the clinical protocol.

Lower dose, 150 mg (1 mg / ml mixture):

balance the temperature of the posaconazole injection solution, 18 mg / ml pharmaceutical product, with room temperature. Carefully flip the pharmaceutical vial ten times.

Remove the appropriate volume of diluent (0.9% NaCl or 5% dextrose) from the mixture bag so that 142 ml of diluent is left in the bag.

Remove 8.4 ml of posaconazole injection, 18 mg / ml, using an appropriate syringe, and inject all this amount of pharmaceutical product into an IV bag. Shuffle the contents of the bag with ten gentle turns.

High dosage, 450 mg (3 mg / ml mixture):

balance the temperature of the posaconazole injection solution, 18 mg / ml pharmaceutical product, with room temperature. Carefully flip the pharmaceutical vial ten times.

Remove the appropriate volume of diluent (0.9% NaCl or 5% dextrose) from the mixture bag so that 125 ml of the diluent remains in the bag.

Remove 25 ml of posaconazole injection, 18 mg / ml, using a syringe of the appropriate size and inject the entire amount of the pharmaceutical product into the IV bag. Shuffle the contents of the bag with ten gentle turns.

Tests in healthy individuals

To assess the pharmacokinetics, safety, and tolerability of the intravenous solution of posaconazole when a single dose and multiple doses were administered, a one-center, randomized, blind, placebo-controlled study of a single administration of Phase 1 was conducted for an expert (within the dose level). The first group received a single dose of posaconazole 200 mg. Intravenous posaconazole was mixed in 150 ml of 5% dextrose to provide a final concentration of approximately 1.33 mg / ml of posaconazole in a 200 mg dose and poured into the peripheral vein in the arm for 90 minutes. Although the introduction of a central catheter is generally recommended for infusions of low pH formulations, the lack of signal in non-clinical toxicology studies has supported the use of intravenous posaconazole via peripheral catheters in this study.

A group of 12 individuals (9 active substance and 3 dextrose-based placebo) received a single infusion of an intravenous solution of posaconazole on 1 day. Six out of 9 individuals underwent a post-infusion local reaction, manifested in the form of erythema, induction and soreness. One individual had a hemorrhage, resulting in swelling on the arm. These phenomena were reported between 4 and 24 hours after infusion. Local intolerance appears to have arisen as a result of irritation caused by a low pH infusate, slowly introduced through peripheral catheters. The observed local intolerance accelerated the termination of this test in healthy volunteers who received intravenous posaconazole via peripheral infusion. Alternative infusion strategies (fast or slow infusion through peripheral catheters) will be investigated in healthy volunteers. Low pH formulations tolerate better if infused through central catheters. Therefore, they developed a strategy to continue this program on patients with central catheters.

The pharmacokinetic profile of intravenous posaconazole was typical of an intravenous drug (see FIG. 7) with low variability. The average T _max value was 1 hour, the average C _{max was} 1470 ng / ml, the average AUC (0-24) 13500 h · ng / ml, (calculated by C _avg 563 ng / ml), and the variability of all parameters was about 25% or less.

Table 11 presents the average (CV%) pharmacokinetic parameters of posaconazole in plasma after administration of a single dose, 200 mg of intravenous solution of posaconazole, to healthy adult volunteers (all patients are included).

Table 11 Treatment Day C _max (ng / ml) T _maxa (h) AUC _tf (h * ng / ml) AUC (I) (h * ng / ml) t _1/2 (h) Vd / F (L) C _avg ^b (ng / ml) POS IV solution (200 mg; treatment A: n = 9) one 1470 (24) 1.00 (1.00 - 4.00) 27000 (23) 28100 (26) 24.3 (22) 254 (17) 1170 (26) (range: 904-1900) IV = intravenously, C _max = maximum observed plasma concentration; T _max = time to C _max ; AUC _tf = area under the curve from the initial point in time to the last measurable sample; AUC (I) = area under the plasma concentration-time curve from time 0 to infinity; t _1/2 = terminal elimination half-life, Vd / F = apparent distribution volume; C _avg = predicted mean steady state concentration.
a: Medium (minimum, maximum),
b: Values for C _{avg are} projected without adjustment for possible time dependencies.

The observed pharmacokinetic parameters were C _max and T _max . Individual plasma concentration data were used to calculate the following pharmacokinetic parameters: AUC (tf), AUC (I), t _1/2 , Vd / F and C _avg · The reaction rate constant of the final phase (k) was calculated as the negative value of the slope of the linear the final logarithmic portion of the plasma concentration-time curve using linear regression. t _{1/2 was} calculated as t _1/2 = ln (2) / K. AUC (tf) was calculated using the linear trapezoidal method and extrapolated to infinity, AUC (I), as described below: AUC (I) = AUC (tf) / Cest _tf / K, where Cest _tf is the calculated concentration corresponding to the time of the last a measurable sample, determined from linear regression of the final section.

As presented in table 11, it is assumed that the range of C _avg after administration of a single dose of 200 mg will be from about 900 to about 1900 ng / ml, which coincides with the target C _avg , tending to overlap with the value for the oral suspension of posaconazole. Thus, the most appropriate dose is 200 mg QD, provided that the pharmacokinetic data provided for the patients are not different from those of healthy volunteers and no non-linearity is observed as a result of multiple doses.

In FIG. Figure 8 presents the generalized results of the observed sustained effects of posaconazole and the predicted distribution of the effects of the intravenous solution of posaconazole. Each rectangle displays the distance from the 25th to the 75th percentile, the line inside the rectangle displays the average value, the "mustache" displays the 10th and 90th percentiles, and the points outside the "mustache" display sharply deviating values; sharply deviating values are not presented for the predicted distribution of exposure.

Thus, in some embodiments, the composition is one that delivers 200 mg of posaconazole to a patient, where administration of such a dose results in a C _{max of} approximately 1470 ng / ml and an AUC _{last of} approximately 27,000 h * ng / ml.

Bioequivalent doses and compositions are within the scope of the invention. For systemically absorbable drugs, bioavailability is usually defined as representing the relevant pharmacokinetic parameters (e.g., C _max and AUC) between 80% and 125% of the reference drug. Thus, in some embodiments, the composition is one that delivers 200 mg of posaconazole to a patient, where administration of such a dose results in a C _{max of} about 1176 to about 18375 ng / ml and a AUC _{last of} about 21600 to about 33750 h * ng / ml.

METHODS OF TREATMENT

Antibacterial use

The present invention relates to methods for the prevention and treatment of a number of infections caused by a wide range of pathogens. The term "infection" is intended to include, but is not limited to, 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, Rhiachromis, Rhyme, Ichomopus, Richia, Ichomopus, Ricia, Romycebris, Ichomopus, Romycetomyceus, Romycetomyceus, Romycetomycetis Paracoccidioides, Scedosporium, Apophysomyces, Curvularia, Penicillium, Fonsecaea, Wangiella, Sporothrix, Pneumocystis, Trichosporon, Cladophialophora, Ramichloridium, Syncephalastru m, Madurella, Scytalidium or protozoa such as Leshmania, Trichomononas and Trypanosoma.

The present invention is intended for the treatment of both opportunistic and non-opportunistic infections, where the term “opportunistic”, as used herein, refers to infections caused by organisms that can cause disease only in the host whose resistance is reduced, for example, due to chemotherapy or HIV. Posaconazole can be used to treat the progression of invasive mycoses, including prophylactic, empirical, preventive, primary and refractory treatments.

Specifically, posaconazole is used to prevent and / or treat the following painful conditions: starting therapy (first line) of oropharyngeal or esophageal candidiasis; conservative treatment of azole-resistant oropharyngeal and esophageal candidiasis (for example, in patients who are not affected by oral fluconazole and / or intraconazole); starting therapy for invasive aspergillosis, candidiasis, fusarium, stsodosporioza, infections caused by dimorphic fungi (for example, cryptococcosis, coccidioidomycosis, paracoccidioidomycosis, histoplasmosis, blastomycosis), zygomycosis and invasive fungi, caused by invasive fungi, conservative therapy of invasive mycoses in patients who are refractory or who have intolerance to other types of therapy (for example, amphotericin B, lipid formulations of amphotericin B, fluconazole, caspofungin, micafungin, anidulafungin, voriconazole and / or intraconazole); prevention of invasive candidiasis, invasive mold infections (including zygomycosis and aspergillosis) in patients at high risk, including patients who have undergone intensive chemotherapy and / or radiation therapy for hemablastoses, a course of treatment that prepares for bone marrow or peripheral stem cell transplantation, and patients receiving combination immunosuppressive therapy for the treatment of acute or chronic transplant versus host reactions or prevention of transplantation of solid organ anov; Shaggas's disease (trypanosomiasis caused by T. cruzi), including acute and chronic forms; and leishmaniasis, including visceral and localized forms.

In some embodiments, the invention provides a method of treating or preventing an infection in an animal in need thereof, which comprises administering to said animal an effective amount of the composition. 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 invention provides a method wherein said composition is administered intravenously.

Drug administration

Immunosuppressive therapy (e.g., chemotherapy, radiation therapy, a course of treatment that prepares for the separation of myelocyte germs of hematopoietic cells) often leads to one or more of the above infections. The present invention relates to the administration of the composition of posaconazole in addition to immunosuppressive therapy, wherein the composition of posaconazole acts prophylactically against opportunistic infections, including the aforementioned disease states.

The present invention relates to a number of methods of introducing into any part, organ, interstitium of an animal body cavity that is susceptible to infection. A non-limiting number of examples of methods by which the posaconazole formulations of the present invention can be administered include: intravenous, intramuscular, by inhalation, or intravascular.

Co-composition or co-administration, including 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: antifungal agents such as echinocandins (including caspofungin, micafungin and anidulafungin) and azoles; amphotericin B; amphotericin B deoxycholate; flucytosine; and terbinafine.

In addition, the scope of the present invention includes combinations with antibacterial, antiviral, steroidal or non-steroidal anti-inflammatory drugs (“NSAIDs”), chemotherapeutic and / or antiemetic drugs. Similarly, co-administration of posaconazole with at least one of the aforementioned active ingredients, in addition to being included in a single composition, is also included in the scope of the present invention.

In certain embodiments, the pharmaceutical compositions described herein can be administered to a patient in need thereof in a dose of 100 mg to 400 mg every 12 to 24 hours. In some such embodiments, the implementation of the dose may contain at least one intravenous dosage form.

In certain embodiments, the pharmaceutical compositions described herein can be administered to a patient in need thereof in a dose of 100 mg to 400 mg every 12 to 24 hours. In some preferred embodiments, the composition is administered in an amount sufficient to deliver a dose of from about 180 to about 220 mg of posaconazole to the patient. In some more preferred embodiments, the dose is about 200 mg of posaconazole. The introduction can be carried out once a day or twice a day.

The pharmaceutical compositions of the present invention are administered to a patient in accordance with a dosage regimen. It should be understood that the specific dosage regimen for any particular patient depends on a number of factors, including type, age, body weight, body surface area, height, general health, gender, diet, time of administration, rate of excretion, drug combination, specific disease the treatment from which the patient receives, the severity of the condition, the renal and hepatic functions of the patient, the specific active ingredient used and the opinion of the attending physician.

Other features and embodiments of the invention will become apparent in the following examples, which are given more to illustrate the invention than to limit its intended scope.

Definitions

Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patents, and other documents referenced herein are hereby incorporated by reference in their entireties.

As used herein, the phrase “parenteral small dosage preparation” refers to a single or multiple injection of a small dosage, labeled as or indeed containing 100 ml or less.

As used herein, the term “injectable” means adapted for parenteral administration.

As used herein, the term "fungus" includes, but is not limited to, one of the diverse morphological forms of yeast and mold fungi. Fungi include organisms in the following groups or genera: Candida, dermatophytes, Dimorphics, Dematiaceous (e.g., Alternaria and Bipolaris), Aspergillus, Acremonium, Basidiomycetes, Bjerkandera, Coprinus, Paecilomyces, Microsporum, Trichophyton, Pseudallescheria, Schizoplasma, Schizoptoma, Schizoptoma, Schizoptoma Coccidioides, Fusarium, Exophiala, Zygomycocetes (e.g., Absidia, Mucor, Rhizopus, and Rhizomucor), Kluyveromyces, Saccharomyces, Yarrowia, Pichia, Epidermophyton, Paracoccidiophi, Peciophi phiocioci phi phiocifioecida, Scedosporium, Apophysophi phi phiocifiocifica, Curved , Ramichloridium, Syncephalastrum, Madurella, Scytalidium or protozoa such as Leshmania, Trichomononas and Trypanosoma.

As used herein, the term "Dematiaceous" ("dark") means dark-colored spore and / or hyphae and includes, but are not limited to: Alternaria and Bipolaris. Pheogyphomycosis is an example of a “dark” fungal infection.

As used herein, the term "parasite" means an organism that lives on or in another organism and draws its nutrients from it. Parasites include Leishmania, Trypanosoma and Trichomonas, among others.

As used herein, the term “AUC” is the area under the plasma concentration-time curve from zero time to a specific sampling time period. For example, AUC (4 hours) means the area under the plasma concentration-time curve from time zero to 4 hours.

The term “patient” refers to an animal, including a mammal (eg, a human).

The term “pharmaceutically acceptable excipient” refers to a non-toxic excipient that can be administered to a patient together with weakly basic and poorly water-soluble azoles, as described herein, which does not impair their pharmacological activity.

The term “treatment” or “therapy” is intended to mean prophylactic use to prevent disease or to alleviate or partially relieve symptoms of a stated condition, disease, or disorder in a mammal, such as a human.

The term "pharmacokinetics" refers to the process by which a drug is absorbed, distributed, metabolized and removed by the body. Pharmacokinetic parameters include, but are not limited to, “maximum plasma concentration” or “C _max ”, “area under the plasma concentration-time curve” or “AUC”, and “time to C _max ” or “T _max ”.

As used herein, the term "t _1/2 " refers to the half-life of a drug.

The present invention is not limited in scope to the specific embodiments described herein. Moreover, 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.

Claims (21)

1. A pharmaceutical composition for intravenous administration comprising:
posaconazole or a pharmaceutically acceptable salt thereof; and
modified β-cyclodextrin, which contains sulfobutyl ether-β-cyclodextrin and a chelating agent;
in an aqueous solution, where the pH of the composition is from 2.0 to 3.5,
where the concentration of said posaconazole or a pharmaceutically acceptable salt thereof is between about 14 and about 22 mg / ml, and the concentration of said modified β-cyclodextrin is from about 350 to about 450 mg / ml. 2. The composition of claim 1, wherein said pharmaceutical composition comprises a free posaconazole base and said chelating agent contains EDTA. 3. The composition of claim 2, wherein the concentration of said EDTA is between about 0.1 and about 0.3 mg / ml. 4. The composition of claim 2, wherein the concentration of said free posaconazole free base is about 18 mg / ml, the concentration of said sulfobutyl ether-β-cyclodextrin is about 400 mg / ml, and the concentration of said EDTA is about 0.2 mg / ml. 5. The composition of claim 1, wherein, as a result of administering a dose of said composition that delivers 200 mg of posaconazole to a patient, C _max is between about 1176 and about 18375 ng / ml and AUC _last is between about 21600 and about 33750 h * ng / ml . 6. The composition of claim 1, wherein, as a result of administering a dose of said composition that delivers 200 mg of posaconazole to a patient, C _max is approximately 1470 ng / ml and AUC _last is approximately 27000 h * ng / ml. 7. The pharmaceutical composition according to claim 1, wherein after the composition is introduced into the infusion bag, the composition and the infusion are mixed, and after the resulting mixture is left to stand for 24 hours, no posaconazole precipitate is visible. 8. The composition of claim 1, wherein the modified β-cyclodextrin contains β-cyclodextrin sulfobutyl ether having a degree of substitution of 6.5 and a molecular weight of 2163 g / mol. 9. A pharmaceutical composition for intravenous administration containing the components and amounts of each component, as described below:

10. The pharmaceutical composition according to claim 9, containing components and amounts of each component, as described below:

11. The pharmaceutical composition according to any one of paragraphs. 1-10, containing from 100 mg to 400 mg of posaconazole. 12. The pharmaceutical composition for intravenous administration according to any one of paragraphs. 1-10, containing from 100 mg to 400 mg of posaconazole, which further comprises a diluent. 13. The pharmaceutical composition for intravenous administration according to any one of paragraphs. 1-10, containing from 100 mg to 400 mg of posaconazole, which further comprises a diluent selected from physiological saline and 5% dextrose solution. 14. A method of treating or preventing an infection in a patient in need thereof, comprising administering to said patient an effective amount of a pharmaceutical composition according to any one of claims. 1-13. 15. The method of claim 14, wherein said infection is caused by a fungus or parasite. 16. The method according to p. 14 for the prevention of invasive infections of Aspergillus or Candida. 17. The method according to p. 14, where the specified infection is one or more selected from the group consisting of: oropharyngeal or esophageal candidiasis; refractory oropharyngeal or esophageal candidiasis; invasive aspergillosis, candidiasis, fusarium infection, stsedosporiosis, infections caused by dimorphic fungi, zygomycosis and invasive infections caused by rare mold and yeast fungi; invasive mycoses in patients who are refractory to, or who do not tolerate other types of therapy; candidiasis, invasive mold infections in patients who underwent intensive chemotherapy and / or radiation therapy for hemoblastoses, a course of treatment that prepares for bone marrow or peripheral stem cell transplantation, and in patients receiving combination immunosuppressive therapy for the treatment of acute and chronic graft versus host reactions "Or transplantation of parenchymal organs; Chagas disease; and leishmaniasis. 18. The method according to p. 14, where the specified introduction occurs once a day or twice a day. 19. The method of claim 14, further comprising administering a second active component selected from one or more of the group consisting of antifungal agents, antibacterial agents, antiviral agents, steroids, non-steroidal anti-inflammatory drugs, chemotherapeutic and antiemetic drugs. 20. The method of claim 14, further comprising administering antifungal agents selected from the group consisting of azoles, echinocandin, allylamine, fulnine, flucytosine, benzoic acid, cyclopirox, 1,3-dihydro-5-fluoro-1-hydroxy-2 , 1-benzoxaborate, tolnaftate, undecylenic acid, griseofulvin and haloprogin. 21. A kit for treating or preventing an infection in a patient, comprising:
small collapsing container;
infusion bag;
and a composition according to any one of paragraphs. 1-13,
where the specified container contains a composition according to any one of paragraphs. 1-13,
and where the specified infusion bag contains a diluent selected from the group consisting of normal saline and 5% dextrose solution,
and wherein said small collapsible container is placed directly inside said infusion bag in an appropriate manner to allow dilution of said composition by breaking said small collapsible container directly inside the diluent in said infusion bag.

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