Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/417—Imidazole-alkylamines, e.g. histamine, phentolamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4196—1,2,4-Triazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/10—Antimycotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2121/00—Preparations for use in therapy

Definitions

• the present invention is related generally to a treatment for systemic infections with yeast and mold organisms and specifically to a composition and method for parenteral administration of the general class of antiproliferative (antifungal) agents commonly referred to as azoles, and that contain itraconazole, posaconazole, voriconazole, fluconazole, ketoconazole and related compounds including, but not limited to mebendazole, in the treatment of such infections including, but not limited to fungal infections, that are sensitive to this general class of anti-infectious agents.
• DOSING The usual recommended dose varies between the different members of the azole family in a single dose or two to three divided daily doses. Capsules should be taken with a full meal because lipid-containing food improves absorption.
• ITZA and POSA are assumed to be rapidly absorbed from the intestinal tract.
• ITZA has an average bioavailability of approximately 50% while POSA has "variable" bioavailability depending on nutritional state, and a multitude of other factors that affect intestinal absorption (Ref 24, 29).
• intestinal absorption is highly variable, it is dependent on the intestinal microenvironment, on pH, the fat content of ingested food, and various other parameters that are only partly understood at this time (Ref 30).
• Ref 30 the degree of intestinal absorption
• detailed accurate data regarding intestinal absorption, as well as a thorough understanding of factors that determine this variable absorption are not available, neither are data regarding possible inter-individual variations in hepatic first-pass metabolism that further impact overall bioavailability. The impact of these factors cannot be assessed due to the absence of an IV reference formulation.
• Such findings should further encourage the development of parenteral solvent systems technology for dissolving and solubilizing the drugs, such that they can be administered in high-risk patients with high precision and complete dose assurance, yet without concern for hepatic first pass elimination and a continuous need for an established optimal nutritional state and intact intestinal function of the patients to facilitate the necessary reproducible intestinal absorption that will assure acceptable systemic drug bioavailability (Ref 31).
• parenteral administration forms would also allow a more thorough investigation of various administration schedules to further improve infection- control.
• Cremophor ELTM polyoxyethylated castor oil
• Cremophor ELTM polyoxyethylated castor oil
• Polysorbate 80 has also induced severe anaphylactic reactions (37). Therefore, the formulation of a solvent system that does not require the utilization of non-ionic surfactants is beneficial.
• the invention relates to pharmaceutical formulations, and more particular embodiments, to parenteral formulations of azole containing pharmaceutical agents such as itraconazole (ITZA) and related anti-infectious agents.
• Parenteral formulations of the invention are useful for the treatment and/or suppression of systemic infections with yeast, molds and other organisms that are sensitive to compounds that belong to this general class of drugs.
• the parenteral formulations avoid the undesirable, erratic bioavailability and unpredictable hepatic first pass extraction, of oral preparations and in view of being truly solubilized the agents are now free from the shortcomings experienced with the intravascular delivery of particulate matter, more commonly referred to as colloidal, or micro-particular suspensions, or microcrystalline suspensions of pharmaceutically active agents.
• the present invention provides pharmaceutically stable and parenterally acceptable novel formulations of azole compounds that can be utilized for the intravascular, or other systemic (or topical) treatment of infections caused by yeast, molds and other infectious agents in man and domestic animals.
• the formulations of the invention are based on the principle of cosolvency.
• Preferred cosolvent compositions of the invention are pharmaceutically acceptable, nontoxic, and stable for many hours at room temperature.
• Preferred formulations according to the invention can be mixed with clinically acceptable aqueous parenteral infusion fluids, such as normal saline or dextrose in water, as final diluent(s). Preferred formulations according to the invention retain full in vitro activity
• Formulations of the invention may be used intravascularly, using the intravenous route as the prototype administration form, and have been successfully used in intravascular administration in a mouse model to demonstrate that at clinically relevant doses the resulting plasma concentrations are in an active range based on comparisons with plasma concentrations obtained in clinical routine administration of orally available formulations as reflected in the published literature.
• Preliminary pharmacokinetics obtained in the mouse model with (a) preferred formulation(s) of the invention has yielded detectable (fungistatic) concentrations for at least one hour after administration of various members of the azole family.
• one embodiment of the invention is directed to an itraconazole- containing composition for parenteral use comprising itraconazole (ITZA) and a first solvent comprising (an) alcohol, such as benzyl alcohol and/or ethanol (EtOH), and an acid, such as HC1 or an organic acid, to obtain a low, stable pH (preferably in a range of from 1 to 5) and finally a polyethylene glycol (PEG), preferably polyethylene glycol-400 (PEG-400), to provide/simulate a non-polar/lipophilic milieu, wherein the composition is either essentially free of non-ionic surfactants or in which such surfactants are included in very low quantities that are not toxic, and further wherein the composition has less that 5% water, preferably less than 3% water and still more preferably less than 1% water or most preferably, essentially free of water.
• a first solvent comprising (an) alcohol, such as benzyl alcohol and/or ethanol (EtOH), and an acid, such as HC
• Non-ionic surfactants that are particularly undesirable due to their toxic effects include but are not limited to Cremophor ELTM, polysorbate 80, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, Brij 35, Brij 58, Brij 78, Brij 99, linear primary alcohol ethoxylates (such as NEODOL), Lubrol PX, Emulgen 913, nonoxynol-9, Triton X-100, polyoxyethylene-10-oleyl ether, polyoxyethylene-10-dodecyl ether, N,N-dimethyl- dodecylamine-N-oxide, and the like.
• Cremophor ELTM polysorbate 80, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, Brij 35, Brij 58, Brij 78, Brij 99, linear primary alcohol ethoxylates (such as NEODOL), Lubrol PX, Emulgen 913, nonoxynol-9, Triton
• the pharmaceutically active azole agent is dissolved in the composite solvent vehicle.
• the composition Prior to administration, the composition is preferably diluted with a secondary diluent comprising a readily available aqueous infusion fluid such as 0.9 % sodium chloride (NS), or 5% or 10% dextrose in water (D5W and D10W, respectively).
• a secondary diluent comprising a readily available aqueous infusion fluid such as 0.9 % sodium chloride (NS), or 5% or 10% dextrose in water (D5W and D10W, respectively).
• NS 0.9 % sodium chloride
• D5W and D10W dextrose in water
• novel solvent vehicles of the invention are not limited to ITZA and POSA, but may be used to facilitate parenteral administration of other water-insoluble drugs, preferentially members of the extended azole family.
• another embodiment of the invention includes a composition for parenteral use comprising: a water-insoluble, or poorly water-soluble / lipophilic pharmaceutically active agent; and a first solvent, the first solvent comprising (an) alcohol (such as benzyl alcohol, and/or acidified EtOH) and an acid to provide an acidic environment, and PEG, preferably PEG-400, to provide a non-proteic, lipophilic environment.
• the agent is dissolved in the first solvent.
• the composition optionally further comprises a second diluent comprising an aqueous infusion fluid to facilitate the subsequent systemic administration to a mammal, preferably a human or a (large) domestic animal.
• the invention also includes a method of preparing a poorly water-soluble / lipophilic, pharmaceutically active agent for parenteral use, comprising the steps of: providing a solution of a pharmaceutically active agent, that in itself is virtually water-insoluble, in a primary solvent ("stock-solution"); and diluting the pharmaceutically active agent in the secondary, clinically acceptable infusion fluid to produce a final clinical use-formulation.
• the primary solvent is prepared by combining PEG with an acidified alcohol such as EtOH and/or benzyl alcohol and the agent, such as ITZA or POSA, is dissolved therein.
• the method may further comprise the step of mixing the primary stock formulation with a second diluent, such as an aqueous infusion fluid to facilitate its clinical administration as a clinical treatment method for a systemic ailment (such as a fungal infection), anticipated to be sensitive to azole therapy.
• a second diluent such as an aqueous infusion fluid to facilitate its clinical administration as a clinical treatment method for a systemic ailment (such as a fungal infection), anticipated to be sensitive to azole therapy.
• the ratios of PEG to alcohol is in the range of 27 to 2, and more preferably between 12 and 8, and having a pH at around 1 to 5, more preferably 3 to 4.
• the invention also includes a method for treating a disease sensitive or responsive to azoles comprising: parenterally administering a therapeutically effective dissolved amount of ITZA, POSA or other azole containing pharmaceutical composition to the patient, the composition comprising: a pharmaceutically active azole derivative; a first solvent, the first solvent comprising an alcohol and an acid to provide a stable sub-physiological (low) pH,
• Still another embodiment of the invention is directed to a method for parenterally administering an azole to a mammal comprising: providing an aqueous formulation wherein a pharmaceutically active agent which in itself has very limited aqueous solubility.
• a pharmaceutically active agent which in itself has very limited aqueous solubility.
• the pharmaceutically active agent is dissolved in a stable fashion at clinically relevant concentrations to produce a primary composite solvent; dissolving the azole in the primary diluent to produce a stock formulation; mixing the stock formulation with a second diluent to form a clinically acceptable infusion fluid; and administering the infusion fluid to the mammal.
• the alcohol is EtOH or benzyl alcohol and the acid is HC1 and citric acid, acetic acid, or glutamic acid, while the lipophilic milieu is contributed by a PEG, such as PEG- 100, -200, -300, -400, -800 and the like.
• a PEG such as PEG- 100, -200, -300, -400, -800 and the like.
• Figures 1A-1E are graphs showing the stability of itraconazole at room temperature ( Figure 1A) and at 40°C (Figure IB) in the preferred primary solvent- formulation of benzyl alcohol-acidified EtOH/PEG-400 (i.e., prototype primary solvent vehicle H3) containing 4 mg/mL ITZA.
• Figure 1C shows the stability of itraconazole at room temperature in solvent H3/normal saline (1 : 1) (final concentration approximately 2.0 mg/ml) at room temperature. Different lots of itraconazole were solubilized and tested in repeated experiments where appropriate.
• the X-axis represents the time in days or hours in the respective figures, the Y- axis represents the actual drug concentration in mg/mL.
• Figures ID and IE shows ITZA stability in H3 variants H3D and H3G with 1 1.7% EtoH and devoid of benzyl alcohol.
• Figures ID and IE show the stability of ITZA in H3 variant solvents H3D and H3G, respectively, in the absence or presence of NS or D5W or D10W as final diluents.
• Figure 2 is an example of the standard curve for itraconazole concentration vs. area under the curve (AUC) (area under the curve, term used to denote the actual measured area of a peak in a chromatogram, and also for the area under the plasma concentration vs. time curve over several hours after administration of a drug to an animal or to a human, for the high-pressure liquid chromatography (HPLC) assay used in the stability studies.
• AUC area under the curve
• HPLC high-pressure liquid chromatography
• the X-axis shows concentration in mg/mL
• the Y-axis shows the AUC.
• Analogous standard curve(s) were prepared for the pharmacology studies.
• Figures 3A-3D depict chromatograms obtained from the HPLC assay in the solubility/ stability studies described under Example 1.
• Figure 3A blank sample, only solvent, no drug.
• Figure 3B ITZA-containing sample demonstrating the ITZA-specific peak with a retention time of approximately 4.7-5.5 min under the used conditions.
• Figures 3C and 3D show the analogous chromatographic data obtained with POSA, the retention time for POSA is 2.5-3 min.
• Figure 4 is a graph showing the hemolytic potential of the final use solvent formulation (prototype H3 acidified EtOH ⁇ benzyl alcohol/ PEG-400 solvent vehicle) in NS. Various combinations of Solven Blood were analyzed.
• Figure 5 is a photograph depicting the fungistatic activity of ITZA in the final use formulation against isolates of Aspergillus fumigatus and the accompanying Tables demonstrates the difference between different members of the azole family against various yeast and mold strains when solubilized in this solvent vehicle system.
• Figures 6A - 6F show chromatograms of plasma samples extracted as described under Example 3 and then subjected to HPLC analysis.
• Figure 6 A shows a blank plasma sample
• Figure 6B shows a plasma sample spiked with ITZA in the new prototype formulation
• Figure 6C shows a chromatogram from the pharmacology study, where mice were injected with itraconazole at an estimated 5 mg/kg in a total volume of about 100 ⁇ IV over 3-4 minutes. The sample was drawn 20 minutes after drug administration.
• Figures 6D - 6F show chromatograms from the in vitro stability and in vivo experiments performed with POSA as an alternative azole.
• Figures 7 A and 7B are graphs showing the change in plasma concentration over time when 5 mg/kg ITZA (7 A), and 5 mg/kg POSA (7B), respectively, were injected into mice over 3-4 min.
• the X-axis shows the time after dose in minutes.
• the Y-axis shows the concentration of ITZA or POSA, calculated in ⁇ g/mL plasma.
• the graphs demonstrate that clinically relevant plasma concentrations can be achieved with these formulations when injected parenterally in the described setting.
• the present invention is directed to novel formulations containing anti-infectious agents, preferably belonging to the general class of compounds described as azoles, that may be administered parenterally.
• the invention provides for truly solubilized drugs in complex, pharmaceutically acceptable vehicles such that the dissolved drug(s) remain(s) physically and chemically stable for more than 24 hours at room temperature (RT).
• RT room temperature
• the invention allows for parenteral administration of the drugs in doses necessary to obtain significant, clinically relevant effects in humans and animals without undue toxicity from the proposed composite solvent vehicle(s).
• Preferred embodiments of the invention allow for the intravascular, or intracavitary, or intrathecal administration of ITZA and related azole agents, solubilized in alternative formulations to increase the clinical safety and efficacy of drug administration and to allow the exploration of additional, alternative, administration schedules. As a result, an improved control of infections that are sensitive to these agents may be achieved.
• ITZA as a representative example of orally administered antifungal agent(s), (tri)- azoles, has previously been extensively investigated in humans and domestic animals (Ref 1- 29, 32, 40-42); the(se) drug(s) has (have) well documented anti-infectious properties in both clinical and experimental settings.
• an acceptable parenteral formulation(s) of solubilized ITZA, POSA and other members of this diverse family of chemicals either referred to as tri-azoles, or simply azole compounds have not been consistently available, but parenteral administration has been accomplished by allowing the use of microcrystalline suspensions of these azoles.
• the variable and somewhat unreliable stability of such formulations have given varying, unpredictable results.
• voriconazole is currently commercially available as such a formulation, while ITZA was voluntarily
• Truly solubilized, parenteral formulations of ITZA and POSA would be useful as treatment of systemic infectious disorders in immunocompromised patients who for a multitude of reasons are unable to consistently take oral preparations, such as e.g. commonly experienced after (intensive) conventional chemotherapy for acute leukemia and other malignant diseases, and after (allogeneic) hematopoietic stem cell transplantation, where in the early post-transplant phase drug-related nausea, vomiting, diarrhea, and gastrointestinal mucositis, as well as administration of concomitant medications may impair oral drug bioavailability while later on the occurrence of intestinal graft- vs-host disease and its therapy may result in a similar situation.
• oral preparations such as e.g. commonly experienced after (intensive) conventional chemotherapy for acute leukemia and other malignant diseases, and after (allogeneic) hematopoietic stem cell transplantation, where in the early post-transplant phase drug-related nausea, vomiting, diarrhea, and gastrointestinal mucositis, as well as
• ITZA is a poorly water-soluble agent with exceedingly low solubility in physiologically acceptable aqueous solvents/infusion fluids that would be compatible with human administration.
• oral preparations capsules and an oral suspension
• microcrystalline suspension for IV use was withdrawn by its supplier shortly after FDA-approval due to its unpredictable pharmaceutical behavior.
• a truly solubilized form of ITZA has never been available, but only a colloidal, or microcrystalline suspension in hydroxypropyl- beta-cyclodextrin (Ref 42).
• the present invention uses a novel series of composite diluent vehicles to solubilize ITZA and POSA without affecting their anti- infectious activity.
• the preferred solvents are, in the proposed concentrations and total doses used, nontoxic and safe for human and other intravascular administration in mammalians, most preferably in humans and domestic animals.
• ITZA is dissolved using benzyl alcohol in combination with acidified ethanol and PEG400 as the primary vehicle or solvent.
• These solvents are further miscible in secondary/final aqueous diluents, e.g. the routinely available aqueous infusion fluids 0.9 % sodium chloride (NS), D5W, and D10W.
• aqueous infusion fluids 0.9 % sodium chloride (NS), D5W, and D10W.
• NS sodium chloride
• terminal diluents/infusion fluids are typical examples of vehicles routinely available in any hospital.
• ITZA and POSA Prior to IV administration, ITZA and POSA are dissolved at concentrations of about 3 - 6 mg/mL and then mixed with a secondary/final diluent to a use-concentration of approximately 1.5 - 3 mg/mL.
• ITZA is very lipophilic
• the use of an acidified alcohol/PEG400 solvent vehicle quickly dissolves it and immediately stabilizes the agent for further dilution in the secondary aqueous diluent, to be used in a similar volume.
• the stability of the formulation permits prolonged infusions without appreciable loss of drug activity due to physical precipitation or chemical degradation, as well as providing an opportunity to administer patients repeated
• the various described composite solvent vehicles were successfully used to dissolve ITZA at concentrations ranging from less than 2 mg/mL to at least 30 mg/mL.
• This broad range covers the administration of doses necessary to yield antifungal concentrations in vivo to treat infections sensitive to these drugs. Further, this range is sufficient to achieve effective plasma concentrations in patients suffering systemic mold and other infections as documented by previous investigations, utilizing the orally available counterparts of the respective drugs.
• 95368396.1 concentrations are maintained for at least one hour in the plasma in a mouse model after IV injection of 5 mg/kg body weight, which when combined with the known plasma half-life of approximately 10 - 11 hrs for ITZA and 25 - 35 hrs for POSA, respectively (Ref 24, 32, 42, 45), should assure the safe and effective treatment of infections with these agents.
• the preferred embodiment of the invention uses acidified ethanol and/or benzyl alcohol, and PEG, subsequently diluted with an aqueous secondary diluent such as an infusion solution prior to systemic administration, other non-toxic solvent vehicles that are safe for human administration may be used.
• EtOH One preferred solvent, EtOH, that has previously been used to solubilize various pharmacologically active agents for administration in man, is routinely used as an antidote for methanol poisoning (Ref 46). No serious clinical adverse effects have been experienced from the use of such a solvent in humans in the contemplated resulting doses and concentrations.
• HC1 as an acidifier one could also use an organic acid such as acetic acid to drastically change the pH and thereby allow solubilization of the pharmacologically active agent.
• compositions of the invention have a number of uses.
• preferred formulations of the invention are particularly useful in the treatment of fungal, yeast and mold infections in mammals, particularly Candida, Aspergillus or Mucorales infections.
• Certain infections, most notably those caused by Histoplasma Spp. and Aspergillus Spp. may be successfully controlled by ITZA, and in addition POSA has been of particular value in treatment of mucormycosis in immunocompromised patients.
• the benefits are also expected to include fewer clinical side effects than that experienced with the corresponding oral drug formulation, since intravascular administration gives complete control of the bioavailability with optimized pharmacokinetics of the drugs and therefore minimizes the risk for side effects due to unwanted drug-drug interactions and treatment-failure secondary to incomplete intestinal absorption as well as accidental overdosing in patients who have an unexpectedly high intestinal absorption paired with a low metabolic drug clearance.
• novel composite solvent vehicle(s) of the invention may also be used to investigate different administration schedules (e.g., prolonged IV infusions, and repeated IV dosing) to optimize treatment outcome for azole drug-based therapy. Further, the invention makes it possible to investigate the benefits of different dose schedules of the azole drug against various systemic (infectious) diseases without the confounding adverse effects from unpredictable intestinal drug absorption and hepatic first-pass effects that in an arbitrary fashion influence the metabolism of oral azoles.
• administration schedules e.g., prolonged IV infusions, and repeated IV dosing
• the stability of the new formulations makes them particularly suited for evaluating different administration schedules, including those of prolonged infusions and multiple dosing schedules, further realizing the outstanding therapeutic potential of azole drugs, particularly ITZA and POSA.
• the stable solubilization may also allow for intracavitary and/or intrathecal application of azole drugs as treatment of peritoneal, pleural and leptomeningeal spread of infection, although some caution has to be paid to the low pH of the infusate as well as to the (possible) content of benzyl alcohol which may contribute to meningeal inflammation that might alter a patient's seizure threshold.
• solvent vehicles of the invention are not limited to use with ITZA and POSA, and can be utilized in an analogous fashion to make parenteral solvent systems for other poorly water-soluble, biologically active agents, with particular emphasis on all other members of the general class of azole compounds.
• Exemplary antifungal azoles include a) imidazoles such as miconazole, ketoconazole, clotrimazole, econazole, omoconazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole, sulconazole and tioconazole, b) triazoles such as fluconazole, itraconazole, isavuconazole, ravuconazole, posaconazole, voriconazole, terconazole and c) thiazoles such as abafungin.
• imidazoles such as miconazole, ketoconazole, clotrimazole, econazole, omoconazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole, sulcon
• azole- containing antibiotics that can be solubilized with this technique.
• Other drugs that can be solubilized with this approach include, but are not limited to, hyperthyroid drugs such as carbimazole, cytotoxic agents such as epipodophyllotoxin derivatives, taxanes, bleomycin, anthracyclines, as well as platinum compounds and camptothecin analogs.
• the present invention provides a method to safely solubilize and administer many poorly water-soluble, pharmacologically active agents, in addition to ITZA and POSA as examples of the diverse members of the groups of pharmaceutically active chemicals referred to as azoles, or tri-azole compounds.
• one embodiment of the invention is directed to an azole-containing composition for parenteral use comprising the azole pharmaceutical and a first solvent comprising acidified EtOH and or benzyl alcohol as well as PEG such as PEG-400, wherein the composition is essentially free of non-ionic surfactants and comprises less than 5% water.
• the azole compositions will comprise less than 3% water, or less than 1% or, most preferably, will be essentially free of water.
• the azole drug is dissolved in the first composite solvent, and prior to administration, the composition is preferably mixed with a second diluent comprising an aqueous infusion fluid to allow for convenient clinical administration to a mammal, preferably a domestic large animal and most preferably a human.
• the alcohol such as EtOH or benzyl alcohol comprises between 1 and 25% of the first solvent and the acid comprises between 1 and 10% of the first solvent, such that a subphysiological pH is obtained in the solvent, preferably a pH of less than 4; finally the PEG more preferably comprises between 10 and 90% (v/v) of the first composite solvent.
• the invention is not limited to acidified EtOH and/or benzyl alcohol with PEG.
• Other solvents, such as organic acids may be used to substantially alter the pH.
• Useful infusion fluids include, but are not limited to, normal saline and dextrose in water.
• the infusion fluid may be a lipid-based infusion emulsion fluid such as those used for parenteral nutrition.
• the composition Prior to dilution with the infusion fluid, the composition preferably comprises between 1 and 30 mg/mL of the azole drug and, more preferably, comprises between 2 mg/mL and 6 mg/mL of the agent.
• the undiluted composition is stable for at least 24 hours and even more preferred stable for more than 3 days at room temperature (RT).
• the secondary diluent is an aqueous infusion fluid, e.g. normal saline and the final composition comprises between 1 mg/mL and 5 mg/mL of ITZA after mixing in the secondary, terminal, diluent.
• This diluted composition is stable for at least 12 hours, but preferably for more than 24 hours at RT.
• novel solvent vehicles of the invention are not limited to ITZA, but may also be used to facilitate parenteral administration of other drugs with poor aqueous solubility, including, preferably, other members of the general family of compounds commonly referred to as azoles, or tri-azole compounds, although they will also include other pharmaceutically active, poorly water-soluble agents.
• drugs include, but are not limited to, cytotoxic agents such as epipodophyllotoxin derivatives, taxanes, bleomycin, anthracyclines, as well as platinum compounds. They also include antibiotics, such as poorly water-soluble polyenes (e.g. , Amphotericin B and Natamycin) and other antifungal agents such as members
• echinocandins as well as antibacterial agents, (e.g., polymyxin B and colistin), anti-viral agents including, but not limited to, nucleoside analogs commonly used to treat infections such as hepatitis and retro virus-infections. Further, they include tranquilizing, and hypnotic/anesthetic drugs such as benzodiazepines, propofol, and anti-psychotic agents.
• antibacterial agents e.g., polymyxin B and colistin
• anti-viral agents including, but not limited to, nucleoside analogs commonly used to treat infections such as hepatitis and retro virus-infections.
• nucleoside analogs commonly used to treat infections such as hepatitis and retro virus-infections.
• they include tranquilizing, and hypnotic/anesthetic drugs such as benzodiazepines, propofol, and anti-psychotic agents.
• another embodiment of the invention includes a composition for parenteral use comprising: a water-insoluble or poorly water- soluble/lipophilic, pharmaceutically active agent and a first solvent, the first solvent comprising an acidified alcohol, a pH-lowering agent (acid), as well as polyethylene-glycol (PEG, preferably with an average molecular weight of 400 Daltons), that will contribute a lipophilic microenvironment.
• the pharmaceutically active agent is dissolved in the first composite solvent vehicle.
• the composition optionally further comprises a secondary diluent such as an aqueous infusion fluid, which will make it amenable to administration to a mammal (preferably a human or domestic animal) through an indwelling catheter.
• the invention also includes a method of preparing a poorly water-soluble / lipophilic, pharmaceutically active agent for parenteral use comprising the steps of: 1) providing a composite solvent system based on the principle of cosolvency, and 2) dissolving the pharmaceutically active agent in the primary solvent vehicle to produce a stock formulation.
• the primary alcohol is EtOH
• the pH-lowering component is (an) acid, such as hydrochloric acid and/or citric acid, which is further compounded with PEG
• the pharmaceutically-active agent is ITZA, POSA or an alternative, later generation representative of the (tri-) azole family.
• the method may further comprise the step of mixing the stock formulation with a second aqueous diluent, such as an aqueous infusion fluid to facilitate safe and convenient clinical drug administration.
• a second aqueous diluent such as an aqueous infusion fluid
• EtOH and benzyl alcohol other alcohols, and weaker (e.g. organic) acids such as acetic acid may be used to form the primary solvent without departing from the spirit and scope of the invention.
• the invention also includes a method for treating a disease that is sensitive, or responsive, to azole-containing antifungal (e.g., ITZA/POSA) treatment comprising: parenterally administering the therapeutically effective amount of a fully solubilized azole drug composition systemically to a mammal, the composition comprising: an azole drug such as ITZA or POSA; a first solvent, the first solvent comprising an acidified alcohol and PEG, wherein the drug is dissolved in this composite solvent vehicle; and a secondary diluent, the second diluent comprising a clinically acceptable aqueous infusion fluid that will make it
• ITZA/POSA azole-containing antifungal
• Diseases that may be treated include, but are not limited to, fungal infections that include those caused by either yeast- or mold-species, Histoplasma spp., and neoplastic disease such as leukemia, lymphoma, Hodgkin's disease, a myeloproliferative or myelodysplasia disorder, or an autoimmune disease and an organ-transplant rejection.
• the composition is administered intravascularly, however it is conceivable that the agent may also be administered intrathecally, intrapleurally, or intraperitoneally, among other routes.
• the composition may also be applied topically, such as in the treatment of a (localized) dermal or vaginal infection.
• the patient can be any animal. More preferably, the animal is a mammal, and most preferably, a human.
• terapéuticaally effective amount means that a sufficient amount of the composition is added to achieve a desired therapeutic effect preferably starting with the first dose, or alternatively, such that a therapeutically desirable effect can be achieved after a suitable phase of repeated (systemic) administrations.
• the actual amount used will vary based on numerous factors, such as the type of disease, the age, sex, health, species and weight of the patient, and the use and length of use, as well as other factors known to those of skill in the art.
• Still another embodiment of the invention is directed to a method for parenterally administering an azole drug such as ITZA or POSA to a patient comprising: 1) providing a composite first solvent based on the principle of cosolvency; 2) dissolving the ITZA or POSA in the primary solvent vehicle to produce a stock formulation; 3) mixing the stock formulation with a second diluent to form an infusion fluid; and 4) administering the infusion fluid to the patient.
• the composite first solvent vehicle is comprised of an acidified alcohol, more preferably it is EtOH mixed with HCl and/or citric acid, and the second component is PEG400.
• Example 1 Itraconazole Formulations Acceptable for Parenteral Administration.
• This example demonstrates the successful design of stable formulations of ITZA, using solvent vehicles that are nontoxic and suitable for parenteral administration.
• the necessary solubility/stability was calculated, and preparations were evaluated with high- pressure liquid chromatographic (HPLC) technique.
• HPLC high- pressure liquid chromatographic
• Propylene glycol, cremophor EL, Tween 80, 6N hydrochloric acid, 2M citric acid and benzyl alcohol were obtained from Sigma (St. Louis, MO).
• Polyethylene glycol 400, 2-hydroxypropyl-beta-cyclodextrin, dextrose and acetic acid were purchased from Fisher (Pittsburgh, PA).
• Ethanol was from Decon Labs. Inc. (King of Prussia, PA) and intralipid was from Fresenius Kabi (Uppsala, Sweden).
• the HPLC system included: an analytical column (Nova-pak CI 8 with 4- ⁇ beads; 150 mm x 3.9 mm; Waters Corp., Milford, MA), an autosampler (model Waters 717 plus autosampler, a pump (model Waters 600E system controller) set to deliver 1 mL/min and an UV detector (model WatersTM 486 Tunable Absorbance detector) set at 261 nm for ITZA and POSA, 273 nm for MBZSA, 230 nm for KZSA and 259 nm for FZSA.
• an analytical column Nova-pak CI 8 with 4- ⁇ beads; 150 mm x 3.9 mm; Waters Corp., Milford, MA
• an autosampler model Waters 717 plus autosampler
• a pump model Waters 600E system controller
• UV detector model WatersTM 486 Tunable Absorbance detector
• the mobile phase for ITZA, KZSA and MBZSA was a mixture of 60% acetonitrile in H 2 0 plus 0.05% diethylamine, sparge at 60% with helium as the degassing agent.
• the mobile phase for FZSA was 30%) acetonitrile in H 2 0 plus 0.05%> diethylamine.
• a volume of 10-30 was injected into HPLC for quantitation of ITZA and its analogues.
• ITZA and its analogues were dissolved in various solvents incubated at 37°C for 30 minutes, cooled down to room temperature, centrifuged at 14,000 rpm for 1 min. The supernatant was analyzed using HPLC to determine the maximum solubility of ITZA and its azole analogues.
• ITZA (4 mg/ml) dissolved in solvent H3 (2.36 mg/ml citric acid, 3.42 % benzyl alcohol, 68.5 % PEG400, 26.55 % ethanol and 0.059 N hydrochloric acid) was stored either at room temperature for 2 months or 40°C for 1 month.
• solvent H3 (2.36 mg/ml citric acid, 3.42 % benzyl alcohol, 68.5 % PEG400, 26.55 % ethanol and 0.059 N hydrochloric acid
• ITZA and its analogues in solvent H3 or solvent H3/saline (1 : 1) were incubated at room temperature and analyzed after 0, 2, 4, 6, 8 and 24 hours.
• a composite benzyl alcohol/EtOH/HCl/PEG/ITZA solution as referenced in these Examples was prepared as follows.
• H3D and H3G Azole solubilities in H3-Variant vehicles without benzyl alcohol
• KZSA Ketoconazole
• POSA Posaconazole
• Itraconazole was preferably dissolved in a composite solvent at low, subphysiological pH, necessitating the inclusion of an acidic alcohol component in the solvent vehicle.
• the preferred composite solvent vehicles should allow a final dilution step with a clinically acceptable infusion fluid, including but not limited to, normal saline or dextrose in water.
• Table 3A sets forth the results of the stability studies at room temperature, and Table 3B lists the results of the stability at 40°C.
• Table 4 shows results obtained for the stability of Itraconazole in solvent H3/normal saline (1 :1) (final concentration approximately 2.0 mg/mL) at room temperature (RT) and, again, the data is shown graphically in Figure 1C.
• Table 5 shows the compositions of different solvent H3 variants.
• Table 7A sets forth the azole solubility and stability in H3 variants, i.e. different composite solvent vehicles with varying amounts of EtOH, in the absence of benzyl alcohol.
• Figure 7A shows the stability of ITZA in H3D with 17.7% EtOH in the absence of benzyl alcohol
• Table 7B shows ITZA stability in H3 variant H3G, with 11.7% EtOH, and void of benzyl alcohol.
• the Tables 7A and 7B show data compiled graphically in Figures ID and IE.
• Table 8 shows the analysis of a standard curve for ITZA for the stability experiments above, and the data are set forth graphically in Figure 2.
• ITZA solubility range for ITZA was calculated by extrapolation from doses known to have significant anti-fungal efficacy in man. Such clinical studies have been conducted using the FDA-approved oral preparation.
• the utilized ITZA treatment schedules typically prescribe an oral dose in the range of 200-500 mg once or twice daily until desired anti-fungal effect is obtained. Commonly an initial loading dose, or pulses, of higher doses may be administered two-three times daily for several days, followed by a lower daily maintenance dose (Ref 29, 42).
• the clinically most effective/optimal ITZA dose schedule is not known, but based on an apparent terminal half-life of about 10-12 hours it has been commonly assumed that once or twice daily (maintenance) dose administration is sufficient to achieve desired antifungal effects.
• any attmempt(s) to speed up the saturation of tissue levels of POSA by increasing the dose intensity will only be partially successful because of its unpredictable bioavailability, in the range of 50-60%, and an apparent saturation of intestinal drug absorption with increasing dose intensity (Ref 29).
• a solvent system was discovered that provides a stock formulation that at 2-6 mg/mL, is stable (>90%) for at least three days (72 hours) at RT, and when diluted with an equal amount of a secondary aqueous diluent, such as normal saline (NS) or dextrose in water as
• a secondary aqueous diluent such as normal saline (NS) or dextrose in water as
• the resulting use-formulation is stable at 2 mg/mL for at least 24 hours at RT.
• a stock formulation of ITZA in the range of 2-10 mg/mL in our preferred composite solvent vehicles H3, variants of which are described, could be appropriately diluted in a similar volume of NS or other routinely available infusion fluid to achieve the desired final use-concentration.
• the clinician could then elect to infuse ITZA over either short or prolonged time periods without having to exchange bags of infusate that might be needed if the formulation had more limited physical stability and/or were subject to chemical degradation.
• pharmacy "service hours" are limited to the regular day-time service, since the final use-formulation can be prepared during the day-shift, and because of its extended stability in solution this would still conveniently allow for night-time administration.
• ITZA solubility of ITZA was determined in several individual vehicles. Briefly, a known amount of ITZA drug, formulated as a powder (Sigma Inc., St Louis, MO), was equilibrated in the respective solvent at RT over 1-4 hours. An aliquot was removed, filtered, and prepared for HPLC to determine maximum solubility at room temperature. Based on the ITZA solubility in each vehicle, different solvents were mixed according to the cosolvency principle in an attempt to arrive at an enhanced stable solubility.
• H3 The preferred solvent vehicles, jointly referred to as "H3", were composed based on acidified alcohol and PEG400.
• the addition of acidified alcohol was intended to achieve a significant lowering of the pH to below normal physiological levels, contributing to keep the drug solubilized in an acidified, lipophilic infusate (the latter further accounted for by the addition of PEG400).
• These composite solvent vehicles allowed a stable solubility of ITZA at concentrations readily acceptable for infusion of doses previously shown to have significant antifungal/antimicrobial activity when repeated doses were administered in humans and domestic animals (Ref 10, 27, 29, 40-42, 45), and the drug was demonstrated to remain stable in solution for at least 24 hours at RT (Fig- 1).
• the HPLC system was modified form Woestenberghs et al (Ref 52). Briefly, it utilized a CI 8 Nova-Pak analytical column with an average of 4- ⁇ bead size; 150 mm x 3.9 mm (Waters, Milford, MA), equipped with Waters 717 plus autosampler, a pump model 600E system controller (Waters), set to a flow rate of 1.0 ml/min.
• the detector was a Waters
• Ketoconazole A 1.0 230
• HPLC assay provides an accurate and sensitive detection system for low concentrations of ITZA (azole compounds) in solution, both protein-free mixtures and protein-containing fluids (such as clinically obtained samples, e.g. blood plasma), utilizing fluorescence detection in the UV spectrum.
• ITZA azole compounds
• POSA protein-free mixtures and protein-containing fluids
• a wavelength of 261 was chosen, based on the inherent absorption and emission maxima of the ITZA molecule. This was varied as to which particular azole analog was examined (Table 9).
• All chemicals were HPLC grade unless otherwise indicated. The mobile phase flow rate was 1.0 ml/min.
• the analytic system was based on previously established extraction and HPLC experience with ITZA as described by (Ref 52).
• FIGs. 3A and 3B Examples of authentic ITZA chromatograms from the HPLC assay are shown in Figs. 3A and 3B.
• Figure 3 depicts two chromatograms obtained from the HPLC assay in the (protein-free) stability studies.
• the injected sample volume was 10 ⁇ .
• the HPLC conditions are described above.
• the drug analyzed was from the stability study, where ITZA was dissolved in the prototype H3 solvent vehicles (a), and further diluted using NS as the final diluent (b).
• the HPLC retention time under the above conditions utilizing the C18 Nova-Pak column was 4.7-5.5 min.
• the assay was linear from 0.1 ⁇ g/mL to 100 ⁇ g/mL in protein- free solutions, i.e.
• Figure 2 is the standard curve of ITZA concentration vs. area under the curve (AUC) (area under the curve, term used to denote the actual measured area of a peak in a chromatogram, and also for the area under the plasma concentration vs. time curve over several hours after administration of a drug to an animal or human being) for the high-pressure liquid chromatography (HPLC) assay used in the stability studies.
• AUC area under the curve
• HPLC high-pressure liquid chromatography
• the X-axis shows concentration in ⁇ g/ml
• the Y-axis shows the AUC.
• An analogous standard curve was prepared for the pharmacology study, see also below.
• the corresponding chromatograms obtained with POSA in the stability study are shown in Figs 3 d, when using the composite H3G solvent vehicle.
• the solubility in composite solvent vehicles was investigated, as based on the cosolveny principle. Based on these experiments we concluded that the solvent base preferably may contain up to 5% benzyl alcohol, and that an acidified nonaqueous, lipophilic, environment can be optimally created using the (clinically acceptable) cosolvents EtOH and PEG(-400) mixed with citric acid and HC1 to create a low, subphysiological, pH necessary to maintain ITZA in solution when the secondary aqueous
• a preferred primary solvent vehicle for the continued investigations was composed of EtOH (6 - 27 %, v/v), HC1 (0.059 N), and Citric acid (1-5 %) ibenzyl alcohol (0-5 %, v/v), with PEG400, (10-90 %, v/v).
• ITZA was dissolved at a final stock concentration of 2 - 6 mg/mL in benzyl alcohol with acidified EtOH/PEG-400 (prototype ITZA stock solvent vehicle) and incubated at RT and at 40°C.
• the resulting ITZA concentrations were measured by HPLC in samples taken immediately after solubilization, then hourly for 8 hours, and then at gradually increasing time intervals for up to several days (weeks), depending on the initial rate of solubilization/degradation in the respective solvent system.
• the ITZA solubility differed markedly between different primary solvents. A solubility in excess of 100 mg/mL was reached using benzyl alcohol and glacial acetic acid.
• the ITZA "stock" concentration in these composite solvents would be kept at a minimum of 2-6 mg/mL, with maintained stability and allowing for administration of a clinically active drug dose without resulting high doses of EtOH, PEG-400 or benzyl alcohol after dilution to a desired final use-concentration of 1.5 - 3 mg/mL (Fig. 1, Fig. 3).
• the hemolytic potential for the final use-formulation would be minimal, yet it should also provide negligible amounts of EtOH to the recipient.
• the patient's total doses of the various cosolvents would clearly be within acceptable limits.
• the cells were pelleted at 10,000 x g in an Eppendorf micro-centrifuge, and after washing twice in NS, the pellet was resuspended and lysed using distilled water.
• the release of hemoglobin in the supernatant ⁇ i.e., hemolysis) was determined spectrophotometrically at a wavelength of 550 nm.
• Maximum lysis was measured against a reference erythrocyte solution that had been lysed by hypotonic shock.
• the hemolytic potential of the preferred stock- and final use-formulation was then evaluated as described. The results were plotted as the fraction of intact
• erythrocytes versus concentration (total volume percent) of the solvent vehicle.
• the total volume percent was defined as the volume percent of the solvent system in the mixture after addition of the erythrocyte suspension. This was done to simulate the dilution of the drug formulation in the blood stream after parenteral administration.
• Intact, healthy erythrocytes were defined as those capable of retaining their hemoglobin intracellularly after mixture with the solvent vehicle (Ref 53).
• FIG. 4 is a graph showing the hemolytic potential of the final use formulation (- ⁇ -).
• the X-axis shows the solvent system as a fraction of the total volume tested
• the Y-axis shows the percent hemolysis.
• the preferred H3 solvent using acidified EtOH ⁇ benzyl alcohol with PEG400/NS complete (final-use) vehicle had very low hemolytic potential and should be completely safe for mammalian (preferably human) intravascular (and intracavitary, e.g. intraperitoneal or intrapleural, and intrathecal) administration.
• Candida cruzei ATCC strain 6258
• ITZA(ref 2) is a second batch of ITZA dissolved in the basic test vehicle
• ITZA* is a control lot of ITZA dissolved in DMSO as a positive control
• Tested drug range 75 ⁇ g/mL to 0.07 ⁇ g/mL
• Drug dilution range 75 ⁇ g/mL to 0.07 ⁇ g/mL.
• susceptibility tests were set-up using a standardized methodology (CLSI M38A standard). Drugs were diluted into RPMI-Mops medium (Yeast One Broth (Sensititer, product Y3462, Trek Diagnostic Systems, Cleveland, OH) Sensititer Lot number 151416SA- expiration date 2011-01). Two different strains of yeast were tested, the standardized evaluation / read out was performed at 24 hours after the start of each culture. The tests were repeated twice and all MIC (minimum inhibitory concentration) values are reported as an average of the three experiments.
• ITZA in a preferred variant composite solvent vehicles of H3 and mixed with blood or plasma may be recovered as native drug using quantitative extraction technology and HPLC assay, and that the ITZA and POSA concentrations remain in the fungi-toxic range for in excess of one hour after IV administration of a dose of 5 mg/kg. It further indicates that the plasma pharmacokinetics after parenteral administration of ITZA and POSA in a preferred formulation in mice conforms to what can be expected based on the published pharmacology of oral ITZA and POSA. The estimated half-life of about 30 min of ITZA in our preliminary in vivo experiments appears significantly shorter than the 10+ hours reported for use of oral ITZA (Ref 42, 45).
• the 30 min half-life after a single IV dose reflects the initial blood-to-tissue distribution half-life, which is significantly shorter than the expected terminal elimination half-life (Ref 52).
• oral drug administration may lead to slow intestinal absorption over many hours, such that the resulting observed plasma- concentration elimination curve/half-life reflects the net effects of absorption from gut to blood plus distribution from blood to tissues and finally metabolic degradation, all of which is additionally confounded by first-pass elimination of drug that passes through the portal vein to the liver before it reaches the systemic circulation.
• the ITZA dose of 5 mg/kg BW was determined to be a suitable test dose that could be administered to the mice as a slow (3-4 min) IV bolus injection without requiring sedation, but could be performed with only minimal physical restraint of the animals in a standard funnel-type cage.
• the ITZA was formulated in the H3 solvent system described above as the preferred solvent to a stock concentration of 4 - 5 mg/mL and then diluted with NS (ratio 1 : 1) so the intended dose (5.0 mg/kg BW) could be injected in a tail vein in a total volume of approximately 100 ⁇ ..
• the ITZA concentrations of the final use-formulation were confirmed by HPLC prior to all drug administrations. No sedative premedication was used for the mice
• Fig. 6 This figure shows chromatograms of plasma samples extracted as described under Example 3 and then subjected to HPLC.
• Figure 6a shows a blank plasma sample
• Figure 6b shows a plasma sample spiked with ITZA in the preferred composite solvent formulation (H3) to 9 g/ml
• figure 6c shows a chromatogram from the pharmacology study, where a mouse was injected with ITZA at 5 mg/kg.
• Fig 6d shows a blank mouse plasma sample
• Fig 6e shows a plasma sample spiked with POSA in the preferred composite solvent vehicle H3 G to 5 ⁇ g/mL
• Fig 6f shows an actual chromatogram from a mouse plasma sample drawn 20 min after injection of POSA at 5 mg/kg in the in vivo experiment described above.
• the ITZA retention time in this system was 4.7 -5.5 min, and the POSA retention time was 2.4-3 min when using the C18 Nova-Pak column (see Example 1).
• the recovery of ITZA with the described technique was approximately 90 % from human plasma spiked in vitro with 9 g/mL of drug.
• the assay was linear after drug extraction from human plasma samples spiked in the concentration range from 0.1 ⁇ g/mL to 100 ⁇ g/mL. The limiting
• FIG. 7A and 7B are graphs showing the change in plasma concentration over time, up to one hour, when 5 mg/kg of ITZA and POSA were injected in mice.
• the X-axis shows the time after dose in minutes.
• the Y-axis shows the azole concentration per ⁇ g/mL plasma.
• the apparent in vivo half-life of ITZA and POSA are in the range of 30 minutes and 6-7 hours, respectively under the conditions used with this formulation.
• the data prove that the novel pharmaceutically acceptable, stable formulations of ITZA, POSA and other chemically related azole compounds can be used for intravascular administration in treatment of infections caused by microorganisms that are sensitive to these agents.
• the reformulated azoles retain their antimicrobial activity, which is
• the novel solvent systems improve not only the clinical safety of azole-based antimicrobial (-infectious) therapy, but also to make it possible to further optimize the use of these important drugs in the treatment of fungal and other infections in immunocompromised patients that may have suboptimal bioavailability of orally administered drugs due to intestinal compromise and an accompanying inability to maintain proper oral nutrition.
• Embodiments of the invention may also be used when treating patients with anti-cancer chemotherapy who are at increased risk for systemic fungal infections, such as those undergoing conditioning treatment preceding hemopoietic stem cell transplantation.
• All of the compositions and/or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred
• Singh N Limaye AP, Forrest G, Safdar N, Munoz P, Pursell K, Houston S, Rosso F, Montoya JG, Patton P, Del Busto R, Aguado JM, Fisher RA, Klintmalm GB, Miller R, Wagener MM, Lewis RE, Kontoyiannis DP, Husain S. Combination of voriconazole and caspofungin as primary therapy for invasive aspergillosis in solid organ transplant recipients: a prospective, multicenter, observational study. Transplantation. 2006;81(3):320-326.
• Robertson R Common poisonings. In: Wyngarden JB, and Smith LH (Eds.) Cecil. Textbook of Medicine. WB Saunders Company, Philadelphia, PA. 1988. Pp. 140-145.
• AUC - area under the curve term used to denote the actual measured surface area of a peak in a chromatogram, and also for the area under the plasma concentration vs. time curve over several hours after administration of a drug to an animal or human being as a measure of total systemic drug exposure.
• the soybean lipid emulsion was freeze-dried before use as a solvent in the ensuing studies and is referred to as "lipid" in this text.
• PBS - Phosphate-buffered saline (Dulbecco's formulation, pH 7.4).
• PEG - and PEG-400/PEG400 - Polyethylene glycol-400 (i.e. with an average molecular weight of 400 Daltons)
• RPMI-Mops Standardized tissue culture medium buffered with Mops buffer (3-(N-morpholino)propanesulfonic acid, pH 7.2).

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