WO2005117831A1 - Injectable pharmaceutical suspension comprising posaconazole - Google Patents

Injectable pharmaceutical suspension comprising posaconazole

Info

Publication number
WO2005117831A1
WO2005117831A1 PCT/US2005/018945 US2005018945W WO2005117831A1 WO 2005117831 A1 WO2005117831 A1 WO 2005117831A1 US 2005018945 W US2005018945 W US 2005018945W WO 2005117831 A1 WO2005117831 A1 WO 2005117831A1
Authority
WO
WIPO (PCT)
Prior art keywords
formulation
posaconazole
mean
plasma
hour
Prior art date
Application number
PCT/US2005/018945
Other languages
English (en)
French (fr)
Inventor
Leonore Witchey-Lakshmanan
Sydney Ugwu
Varda Sandweiss
Catherine Hardalo
Roberta S. Hare
Gopal Krishna
Zaiqi Wang
Marco Taglietti
Original Assignee
Schering Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=34971355&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2005117831(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Schering Corporation filed Critical Schering Corporation
Priority to MXPA06013886A priority Critical patent/MXPA06013886A/es
Priority to AU2005249502A priority patent/AU2005249502A1/en
Priority to JP2007515456A priority patent/JP2008501034A/ja
Priority to EP05755118A priority patent/EP1761247A1/en
Priority to BRPI0510417-3A priority patent/BRPI0510417A/pt
Priority to CA002567803A priority patent/CA2567803A1/en
Publication of WO2005117831A1 publication Critical patent/WO2005117831A1/en
Priority to IL179627A priority patent/IL179627A0/en
Priority to NO20066005A priority patent/NO20066005L/no

Links

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
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to formulations useful for treating infections.
  • these formulations include the active pharmaceutical ingredient posaconazole in an injectable suspension that is stable when subjected to terminal steam sterilization, and throughout
  • Posaconazole an anti-fungal agent, represented by the following chemical
  • posaconazole other formulations of posaconazole have been disclosed.
  • a solid (capsule/tablet) of posaconazole is disclosed in U.S. Patent Nos. 5,972,381 and 5,834,472.
  • a topical form of posaconazole e.g., a lotion, cream, ointment, or "lacquer nail polish” is contemplated based on other similar formulations, e.g., U.S. Patent No. 4,957,730 (PENLAC® available from Demiik®).
  • U.S. Patent No. 5,858,410 discloses pharmaceutical compositions containing particles of active agents of average diameter less than 5 microns, having been conrminuted, without prior conversion into a melt, by using a piston-gap homogenizer.
  • U.S. Patent Application No. 10/440,368 discloses the use of a phospholipid surface active agent to stabilize rnicroparticles of solid fenofibrate in an orally ad ⁇ rju ⁇ istered pharmaceutical composition.
  • Patent No. 5,091, 188 discloses the use of phospholipids, to prevent coalescence of i crocrystalline active agents in injectable pharmaceutical
  • compositions examples include lecithin,
  • phosphatidic acid phosphatidyl ethanolamine
  • cholesterol steaiylamine
  • glycolipids glycolipids and mono-glycerides.
  • the present invention provides formulations of posaconazole that are stable when subjected to terminal steam sterilization. These formulations are useful for the treatment of infections.
  • an aqueous injectable suspension of posaconazole that is homogenously suspended in vehicle with the aid of a phospholipid.
  • a thermoprotectant agent is employed to reduce autoclave-induced particle size growth, as well as a buffer system to stabilize the phospholipid during autoclaving.
  • the formulations provided remain stable after 20 minutes of autoclaving at 121°C and after subsequent storage at 4°C to 40°C for at least 6 months.
  • the present invention provides formulations comprising a suspension of posaconazole, stabilized by a phospholipid, in a mixture comprising a thermoprotectant, and a buffer system.
  • the formulation has been sterilized by autoclaving or by irradiation.
  • the buffer system comprises sodium phosphate, which may be provided as sodium phosphate monobasic monohydrate,
  • sodium phosphate dibasic anhydrous or the combination of the two.
  • the buffer system comprises an organic buffer.
  • the buffer system comprises at least one of histidine, citric acid, glycine, sodium citrate, arnrnoniu ⁇ i sulfate, or acetic acid.
  • the buffer system maintains a pH of about 3.0 to about 9.0.
  • the buffer system mamtains a pH of about 6.0 to about 8.0.
  • the buffer system mamtains a pH of about 6.4 to
  • the phospholipid comprises a natural
  • the phospholipid comprises a synthetic
  • the phospholipid comprises a natural phospholipid and a synthetic phospholipid.
  • the phospholipid comprises l-palmitoyl-2-oleoyl- sn-glycero-3-phosphocholine (POPC) .
  • POPC l-palmitoyl-2-oleoyl- sn-glycero-3-phosphocholine
  • thermoprotectant comprises trehalose.
  • the phospholipid comprises l-palmitoyl-2-oleoyl- sn-glycero-3-phosphocholine (POPC)
  • the thermoprotectant comprises trehalose
  • the buffer system comprises sodium phosphate monobasic monohydrate, sodium phosphate dibasic anhydrous, or the combination of sodium phosphate monobasic monohydrate and sodium phosphate dibasic anhydrous.
  • the posaconazole has a particle size distribution whose median value is between about 1.0 and about 8.0 microns, with not more than about 3000 particles of 10 microns or greater size and not
  • the posaconazole has a particle size distribution whose median value is between about 1.0 and about 5.0 microns, with
  • the posaconazole has a particle size distribution
  • the formulation has ingredients comprising: Ingredient Concentration range Posaconazole about 50 mg/ml POPC about 40 mg/ml Sodium Phosphate, 0.345 mg/ml monobasic, monohydrate, USP Sodium Phosphate, dibasic, 1.065 anhydrous, USP Trehalose 250 mg/ml Water for Injection, USP q.s. 1 ml ad
  • the formulation has ingredients comprising: Ingredient Concentration range
  • POPC about 10 to about 60 mg/ml Sodium Phosphate, about 0.01 to about 0.6 monobasic, monohydrate, mg/ml
  • the formulation has ingredients comprising: Ingredient Concentration range Posaconazole about 40 to about 60 mg/ml POPC about 20 to about 50 mg/ml Trehalose about 100 to about 250 mg/ml Water for Injection, USP q.s. about 1 ml ad
  • the formulation has ingredients comprising: Ingredient Concentration Posaconazole 50 mg/ml
  • the formulation has ingredients further comprising an antioxidant.
  • the antioxidant comprises propyl gallate at a concentration of about 0.02 to about 0.005 mg/ml.
  • the antioxidant comprises butylated hydroxytoluene at a concentration of about 0.1 to about 0.02 mg/ml.
  • the antioxidant comprises alpha-D-tocopherol at a concentration of about 0.5 to about 0.01 mg/ml.
  • the formulation has ingredients comprising: Ingredient Concentration Posaconazole 50 mg/ml
  • the formulation has ingredients comprising: Ingredient Concentration Posaconazole 50 mg/ml POPC 40 mg/ml Histidine 3 mg/ml Citric acid monohydrate 0.24 mg/ml Alpha-D-tocopherol 0.05 mg/ml Trehalose 250 mg/ml Water q.s. ad 1 ml at a pH of about 6.5.
  • the formulation has a wt. ratio of phospholipid to posaconazole between about 60: 1 and about 1: 10. In some embodiments, the formulation has a wt. ratio of phospholipid to posaconazole between about 1: 1 and about 1:5.
  • the formulation has a wt. ratio of phospholipid to posaconazole between about 1: 1 and about 4:5.
  • the formulation has a the wt. ratio of thermoprotectant to posaconazole between about 300: 1 and about 1: 10.
  • the formulation has a wt. ratio of thermoprotectant to posaconazole between about 1 : 1 and about 6: 1.
  • the formulation has a wt. ratio of thermoprotectant to phospholipid between about 30: 1 and about 1 :6.
  • the formulation has a wt. ratio of thermoprotectant to phospholipid between about 5:4 and about 30:4.
  • the invention encompasses a method of treating or preventing an infection inan animal in need thereof which comprises
  • the anirnal is a mammal, a bird, a fish, or a reptile.
  • the animal is a mammal, including but not limited to a human.
  • the infection is caused by a fungus or a parasite.
  • the infection is selected from the group consisting of: oropharyngeal or esophageal candidiasis; refractory oropharyngeal and esophageal candidiasis; invasive aspergillosis, candidiasis, fusariosis, scedosporiosis, infections due to dimorphic fungi , zygomycosis, and invasive infections due to rare molds and yeasts; invasive mycoses in patients who are refractory to, or intolerant of, other therapies;
  • the invention encompasses a method wherein said formulation is ad ⁇ rinistered intravenously.
  • the invention encompasses a method wherein said formulation is administered intramuscularly, subcutaneously, ophthalmically, subconjuctivally, intraocularly, via anterior eye chamber injection, intravitreally, intraperitoneally, intrathecally, intracystically, intrapleurally, intranasally, topically, via wound irrigation, intradermally, intrabuccally, intra-abdominally, intra-articularly, intra-aurally, intrabronchially, intracapsularly, intra ⁇ ieningeally, intrapulrnonarilly, via inhalation, via endotracheal or endobronchial installation, via direct installation into pulmonary cavities, mtraspinally, intrasynovially, intrathoracically, via thoracostomy irrigation, vaginally, epidurally, rectally, intracisternally, intravascularly.intraventricularly, intraosseously, via irrigation of infected bone, or via application as part of any admixture with cement for pros
  • the formulation further comprises a second active
  • ingredient selected from one or more of the group consisting of:
  • antifungals such as azoles; amphotericin B; deoxycholate amphotericin
  • the invention encompasses a method further comprising administering a second active ingredient selected from one or
  • antifungals such as azoles
  • amphotericin a group consisting of: antifungals such as azoles; amphotericin
  • deoxycholate amphotericin B flucytosine; terbinafine; antibacterials; antivirals; steroids; nonsteroidal drugs ("NSAIDs”); chemotherapeutics; and, anti-emitics.
  • the formulation is further characterized by providing a mean maximum plasma concentration (Cmax) of posaconazole of at least about 467 ng/ml at steady state, and a mean plasma Area Under the Curve over 24 hours (AUC) value of posaconazole of at least
  • the formulation is further characterized by providing a mean maximum plasma concentration (Cmax) of posaconazole of at least about 852 ng/ml at steady state, and a mean plasma Area
  • the formulation is further characterized by
  • posaconazole at least one of: a mean plasma half-life in a range of about
  • the formulation is further characterized by providing a mean maximum plasma concentration (Cmax) of posaconazole of at least about 1480 ng/ml at steady state, and a mean plasma Area Under the Curve over 24 hours (AUC) value of posaconazole of at least
  • the formulation is further characterized as providing, after administration of a dosage of about 200 mg of said posaconazole, at least one of: a mean plasma half-life of about 18.7 to
  • the formulation is further characterized as
  • posaconazole at least one of: a mean plasma half-life of about 18.5 to about 51.4 hours; and a mean plasma steady state volume of distribution of about 200-500 L.
  • the formulation is further characterized as providing, after adriiinistration of a dosage of about 600 mg of said posaconazole, at least one of: a mean plasma half-life of about 27.2 to about 50.6 hours; and a mean plasma steady state volume of distribution of about 200-500 L.
  • the formulation is further characterized as providing a mean posaconazole blood concentration profile substantially similar to that of Figure 1 , when said formulation is infused over about 1 hour to deliver 25-600 mg of posaconazole.
  • the formulation is further characterized as providing a mean posaconazole plasma concentration profile substantially similar to that of Figure 2, when said formulation is infused over about 1 hour to deliver 25-600 mg of posaconazole.
  • the formulation is further characterized as
  • the formulation is further characterized as providing a ratio of mean posaconazole blood Cmax to mean posaconazole
  • the formulation is further characterized as providing a ratio of mean posaconazole blood Cmax to mean posaconazole plasma Cmax of between about 1.9 and about 3.8, when a single dose of said formulation is infused over about 1 hour to deliver 50 mg of posaconazole.
  • the formulation is further characterized as providing a mean posaconazole blood Cmax to mean posaconazole plasma Cmax of between about 2.2 and about 3.3, when a single dose of said formulation is infused over about 1 hour to deliver 100 mg of posaconazole.
  • the formulation is further characterized as
  • the formulation is further characterized as
  • said formulation is infused over about 1 hour to deliver 400 mg of posaconazole.
  • the formulation is further characterized as providing a ratio of mean posaconazole blood Cmax to mean posaconazole plasma Cmax of between about 1.9 and about 3.1, when a single dose of said formulation is infused over about 1 hour to deliver 600 mg of posaconazole.
  • the formulation is further characterized as providing a ratio of mean posaconazole blood Cmax to mean posaconazole plasma Cm x of between about 1.2 and about 2.5, at steady state when said formulation is infused over about 1 hour to deliver 25-600 mg of posaconazole, and repeated on a 24-hour basis.
  • the formulation is further characterized as
  • the formulation is further characterized as providing a ratio of mean posaconazole blood Cmax to mean posaconazole
  • plasma Cmax of between about 1.5 and about 2.4 at steady state when said formulation is infused over about 1 hour to deliver 50 mg of posaconazole, and repeated on a 24-hour basis.
  • the formulation is further characterized as providing a ratio of mean posaconazole blood Cmax to mean posaconazole plasma Cmax of between about 1.7 and about 2.5, at steady state when said formulation is infused over about 1 hour to deliver 100 mg of posaconazole, and repeated on a 24-hour basis.
  • the formulation is further characterized as providing a ratio of mean posaconazole blood Cmax to mean posaconazole plasma Cmax of between about 1.2 and about 2.0, at steady state when said formulation is infused over about 1 hour to deliver 200 mg of posaconazole, and repeated on a 24-hour basis.
  • the formulation is further characterized as
  • the formulation is further characterized as providing a ratio of mean posaconazole blood Cmax to mean posaconazole
  • plasma Cmax of between about 1.3 and about 1.7 at steady state when said formulation is infused over about 1 hour to deliver 600 mg of posaconazole, and repeated on a 24-hour basis.
  • the water in the formulation has been removed by lyophilization.
  • the anirnal treated is human, while in other embodiments the animal treated is non-human.
  • the formulation is one that is bioequivalent to a formulation disclosed herein.
  • the method further comprises ad ⁇ iimstering a bolus loading dose of said formulation and then admimstering an intravenous maintenance dose of said formulation.
  • the method comprises admimstering to said animal an effective amount of posaconazole to provide a mean maximum
  • Cmax plasma concentration of posaconazole of at least about 467 ng/ml
  • FIG. 1 shows posaconazole mean blood concentration-time profiles in healthy volunteers after 1 hr intravenous infusions of 25, 50, 100, 200,
  • FIG. 2 shows posaconazole mean plasma concentration-time profiles in healthy volunteers after 1 hr intravenous infusions of 25, 50, 100, 200,
  • FIG. 3 shows posaconazole mean plasma and blood concentration-time profiles in healthy volunteers after 1 hr intravenous infusion of 25 mg posaconazole.
  • FIG. 4 shows posaconazole mean plasma and blood concentration- time profiles in healthy volunteers after 1 hr intravenous infusion of 600 mg posaconazole.
  • the present invention encompasses formulations suitable for parenteral
  • adrrrinistration e.g., by injection, for treating an infection.
  • formulations comprise a suspension of posaconazole, stabilized by a phospholipid, in a mixture comprising water, a thermoprotectant, and a l
  • posaconazole Since posaconazole is minimally soluble in water, a suspension formulation is advantageous. Phospholipids have been found to be effective surfactants in forming stable suspensions of posaconazole
  • thermoprotectant is used to prevent agglomeration and crystal growth of the posaconazole particles during autoclaving.
  • Parenteral buffer systems are typically designed to be at physiological pH of about 7.4.
  • Phospholipids are known to be stable at a pH range of about 6 to about 7.
  • pH adjustment of injectable formulations can be necessary to achieve physiological compatibility, and thus, for example, to minimize injection-site irritation.
  • the rate of phospholipid hydrolysis can be temperature-sensitive.
  • the buffer systems are designed to meet physiological pH requirements, and to maintain the temperature/pH-
  • buffer systems were found to control degradation of POPC-contarning posaconazole formulations during autoclaving. For example, such formulations were found to be stable after 20 minutes of autoclaving at 121°C. In addition, these buffer systems stabilize such formulations during storage at 4°C to 25°C for at least 18 months following autoclaving.
  • other phospholipids that are similar to POPC could be used to stabilize the formulations disclosed herein.
  • unsaturated phospholipids with an acyl chain length ranging from C 1 2 to C20 wherein the degree of unsaturation of the acyl chain ranges from 1 to 4; as weE as saturated phospholipids with an acyl chain length ranging from C12 to Ci8 are useful according to the present invention.
  • useful unsaturated phospholipids include: 1 -palrmtoyl-2-oleoyl-sn-glycero-3-phosphocholine ("POPC") ,
  • DOPC 1,2-Dioleoyl-sn-Glycero-3-Phosphocholine
  • DOPE 1,2-Dioleoyl-sn-Glycero-3-Phosphoethanolamine
  • saturated phospholipids include:
  • DMPC 1,2-Di ⁇ yristoyl-sn-Glycero-3-Phosphocholine
  • the antioxidant comprises propyl gallate, preferably at a concentration of about 0.02 to about 0.005 mg/ml.
  • the antioxidant comprises butylated hydroxytoluene, preferably at a concentration of about 0.1 to about 0.02 mg/ml.
  • the antioxidant comprises propyl gallate, preferably at a concentration of about 0.02 to about 0.005 mg/ml, in combination with butylated hydroxytoluene, preferably at a concentration of about 0.1 to about 0.02 mg/ml.
  • the antioxidant comprises alpha-D-tocopherol, preferably at a concentration of about 0.5 to about 0.01 mg/ml.
  • phospholipid to posaconazole is preferably between about 1:0.1 and about
  • thermoprotectant to posaconazole is preferably between about 0.5: 1 and about 6: 1, more preferably, between about 2: 1 and about 6: 1.
  • thermoprotectant to phospholipid is preferably, between about
  • the formulations of the present invention comprise a suspension of solid particles of posaconazole of specific particle size distribution in an aqueous phase.
  • the particle size distribution displayed in the suspended particles is critical for physiological compatibility, syringeability, physical stability of the suspension, re-suspendability, and for pharmacokinetic characteristics and bio- distribution [le., sequestration within specific bodily tissues). Since these characteristics are critical to the formulation as delivered to the patient, it is important that processes that contribute to changes in particle size distribution after rnicronization are controlled.
  • Such processes can include agglomeration during autoclaving, and de- suspension due to temperature excursions and/or agitation experienced during shipping and storage. It is the particle size distribution in the
  • the inventors of the present invention have deterrnined that for injectable formulations of posaconazole, these characteristics are brought within
  • the particle size distributions display not more
  • pH adjustment system components that function in this way include
  • the present invention encompasses methods of prevention and treatment
  • infection is understood to include, but not be limited to, those having the following properties: characteristics: characteristics: characteristics: characteristics: characteristics: characteristics: characteristics: characteristics; and
  • Schizophyllum Crytococcus, Histoplasma, Blastomyces, Coccidioides, Fusarium, Exophiala, Zygomycocetes ⁇ e.g., Mucor, Rhizopus, and Rhizomucor), Kluyveromyces, Saccharomyces, Yarrowia, Pichia, Epidermophyton, Paracoccidioides, Scedosporium, Apophysomyces, Curvularia, Penicilliurn, Fonsecaea, Wangiella, Sporothrix, Pneumocystis, Trichosporon, Absidia, Cladophialophora, Rarnichloridiurn, Syncephalastrum, Madurella, Scytalidium, Leshmania, protozoa, bacteria, gram negatives, gram positives, anaerobes, including Legionella Borrelia, Mycoplasma, Treponema, Gardneralla, Trichomononas and Trypan
  • the present invention is intended to treat both opportunistic and non- opportunistic infections, where the term "opportunistic" as used herein denotes those infections caused by organisms capable of causing a disease only in a host whose resistance is lowered, e.g., by chemotherapy or H.I.V.
  • posaconazole is useful in the prevention and/or treatment
  • Initial (first line) treatment of oropharyngeal or esophageal candidiasis Salvage therapy of azole-refractory oropharyngeal and esophageal candidiasis (e.g., in patients who have failed oral fluconazole and/ or itraconazole);
  • Salvage therapy for invasive mycoses in patients who are refractory to or intolerant of other therapies e.g., amphotericin B, lipid formulations of amphotericin B, caspofungin, voriconazole and/or itraconazole;
  • Chagas disease (Trypanosorniasis due to T. cruzi) including acute and
  • Irr ⁇ nuno-suppressant therapy ⁇ e.g., chemotherapy, radiation therapy,
  • the present invention encompasses the administration of a posaconazole formulation adjunctive to imrnuno- suppressant therapy, wherein the posaconazole formulation functions prophylactically with regard to opportunistic infections including the
  • the present invention encompasses a variety of modes of administration to any part, organ, interstice or cavity ofan animal's body that is subject to an infection.
  • a non-lir ting set of examples of modes by which the posaconasole formulations of the present invention may be adrninistered includes: intravenously, intramuscularly, subcutaneously, ophthalmically, subconjuctivally, intraocularly, via anterior eye chamber injection, intravitreally, intraperitoneally, intrathecally, intracystically, intrapleurally, intranasally, topically, via wound irrigation, intradermally, intrabuccally, intra-abdominally, intra-articularly, intra-aurally,
  • inhalation via endotracheal or endobronchial installation, via direct installation into pulmonary cavities, intraspinally, rntrasynovially, intrathoracically, via thoracostomy irrigation, vaginally, epidurally, rectally, intracisternally, intravascularly.intraventricularly, intraosseously, via irrigation of infected bone, and via application as part
  • Co-formulations comprising combinations of posaconazole and at least one other active ingredient are also within the scope of the present invention.
  • active ingredients include: antifungals such as echinocandins (including caspofungin, ⁇ iicafungin, and anidulafungin) and azoles (including voriconazole, itraconazole, fluconazole, ketoconazole, ravuconazole); amphotericin B; deoxycholate amphotericin B; flucytosine; and terbinafine.
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • chemotherapeutics chemotherapeutics
  • anti-emitics co-administradministered with at least one of the above active ingredients, aside from within a single formulation, is also within the scope of the present invention.
  • regimens each consisting of a frequency of dosing and a duration of administration.
  • Preferred frequencies of dosing include once every 12, 24,
  • bolus dosing at various rates and various doses, and combinations of a bolus loading dose, or several bolus loading doses, with an intravenous infusion
  • phospholipid refers to a lipid compound that yields on hydrolysis phosphoric acid, an alcohol, fatty acid and a nitrogenous base.
  • examples include natural and synthetic phoshpholipids, which include lecithin, cephalin, sphingornyelin and 1- pahnitoyl-2-oleoyl-sn-glycero-3-phosphocholine (“POPC”) .
  • POPC pahnitoyl-2-oleoyl-sn-glycero-3-phosphocholine
  • natural phospholipid refers to a phospholipid occurring in nature, or derived from a natural source.
  • Non- lirniting examples of natural phospholipids include egg phospholipids, soy
  • synthetic phospholipid refers to a man-made
  • Non-limiting examples of synthetic phospholipids include
  • POPC l-paln ⁇ itoyl-2-oleoyl-sn-glycero-3-phosphocholine
  • DOPC 1,2-oleoyl-sn- glycero-3-phosphocholine
  • DLPC DLPC
  • DLPC DLPC
  • DMPC l,2-Dipalmitoyl-sn-Glycero-3-Phosphocholine
  • DSPC 1,2- Stearoyl-sn-Glycero-3-Phosphocholine
  • buffer system refers to a buffer comprising one or more components that maintains a particular pH range.
  • suitable buffer systems include: phosphoric acid; glycine; sodium citrate; histidine; citric acid; acetic acid; tromethamine; ammonium sulfate; and combinations thereof.
  • the aforementioned components are understood to include the salts, hydrates and solvates thereof.
  • phosphoric acid includes the sodium phosphate or potassium phosphate salts, among other salts.
  • Preferred buffer systems include sodium phosphate monobasic, sodium phosphate dibasic, or a combination thereof. More preferred buffer systems include sodium phosphate monobasic monohydrate, sodium phosphate dibasic
  • organic buffer refers to a buffer comprising at least one organic compound.
  • suitable organic buffers include: glycine;. sodium citrate; histidine; citric acid; acetic acid; and combinations thereof.
  • antioxidant refers to an agent that hinders
  • antioxidants include propyl gallate, butylated hydroxytoluene, and alpha-D-tocopherol.
  • the phrase "median particle size” refers to the particle size present in the volume-weighted 50 th percentile, as ascertained by Malvern®, Sympatec®, or Horibe® laser diffraction particle size analysis. Particle sizes are measured throughout, and at the term ation of, the shelf life, typically up to 24 months after manufacture, when held at either refrigerated or room temperatures. Particle sizes are also measured and maintained when the formulation is diluted into large volume parenterals, e.g., 5% dextrose or water for injection.
  • the phrase "initial median particle size” refers to the particle size present within 1 week after a specified timepornt.
  • the initial median particle size after autoclaving refers to the median particle size present within 1 week after autoclaving has been
  • autoclaving refers to sterilization by the
  • terminal steam sterilization method For example, autoclaving for 20
  • thermoprotectant refers to an agent that
  • thermoprotectant is used to preserve the
  • Thermoprotectants are typically water soluble polyhydroxyl compounds.
  • trehalose is a thermoprotectant agent that may be used in conjunction with posaconazole.
  • Others include maltose, sorbitol, dextrose, sucrose, lactose and mannitol.
  • prodrug refers to a compound that is a drug precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield posaconazole or a salt and/or solvate thereof.
  • solvate refers to a physical association between a compound with one or more solvent molecules. This physical association involves varying degrees of ionic and/or covalent bonding,
  • solvate encompasses both solution-phase and isolatable solvates.
  • suitable solvates include hydrates, ethanolates, and
  • injectable means adapted to parenteral ad ⁇ iinistration.
  • fungus means one of the diverse morphologic forms of yeasts and molds.
  • Fungi include Candida, dermatophytes, Dirnorphics, Dematiaceous ⁇ e.g., Alternaria and Bipolaris), Aspergillus, Acremonium, Basidiomycetes, Bjerkandera, Coprinus, Paecilomyces, Microsporum, Trichophyton, Pseudallescheria, Schizophyllurn, Crytococcus, Histoplasma, Blastomyces, Coccidioides, Fusarium, Exophiala, Zygomycocetes ⁇ e.g., Mucor, Rhizopus, and Rhizomucor), rvluyveromyces, Saccharomyces, Yarrowia, Pichia, Epidermophyton, Paracoccidioides, Scedosporium, Apophysomyces, Curvularia, Periicillium, Fonsecae
  • hyphae and includes as non-limiting examples Alternaria and Bipolaris.
  • Zygomycocete means a class of fungi characterized by sexual reproduction resulting in the formation of
  • zygospore and asexual reproduction by means of nonmotile spores called sporangiospores or conidia, and includes as non-liiniting examples Mucor, Rhizopus, and Rhizomucor.
  • anaerobe means a rnicroorganisrn that can live and grow in the absence of oxygen, and includes as non-limiting examples Legionella Borrelia, Mycoplasma, Treponema, Gardneralla, and Trichomononas .
  • parasite means an organism that lives on or in another and draws its nourishment therefrom. Parasites include Leshmania and Trypansoma, among others.
  • antifungal means an agent having activity against one or more fungi, and includes echinocandins such as caspofungin, micafungin, and anidulafungin.
  • azole means divtayleriimine, and includes voriconazole, itraconazole, fluconazole, ketoconazole, ravuconazole:
  • anirnal is understood to include humans, non- human mammals, fish, birds and reptiles.
  • bioequivalent is understood as having that meaning assigned to the term by the U.S. Food & Drug Administration. "Bioequivalence means the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when adrninistered at the same molar dose under similar conditions in an appropriately designed study.” 21 CFR 320.1(e). Methodologies for determiriing bioequivalence are given in "Guidance for Industry: Statistical Approaches to Establishing Bioequivalence," U.S. Department of Health and Human Services, Food and Drug Adrmnistration, Center for Drug Evaluation and Research
  • exemplary posaconazole formulations that include antioxidant are described in Examples 4-6.
  • the pH is 6.4 in Example 5.
  • the pH is 6.5 in Example 6.
  • Example 7 is a preferred embodiment of the present invention. Exam le 7
  • Example 7 The pH is 7.2 in Example 7.
  • the following is an exemplary placebo formulation wherein the pH is 6.4.
  • POS IV posaconazole intravenous drug product formulation
  • POS IV 50 mg/mL was diluted in 5% dextrose in water (D5W) in IV bags.
  • Subjects assigned to active drug received in a 100-mL volume one of the following single doses administered intravenously over 1 hour: Group 1 ,
  • Group 6 a 125-mL volume a single dose of 600 mg administered intravenously over 1 hour and 15 minutes.
  • EDTA ethylenediaminetetraacetate salt
  • posaconazole in plasma, the tube of blood (4 mL to 5 mL) was centrifuged within approximately 15 minutes of collection at approximately 4°C and IS Og for 10 minutes to completely separate red blood cells from plasma. All blood and plasma samples were immediately frozen to at least -20°C and maintained in the frozen state until assayed.
  • the blood and plasma concentrations of posaconazole were determined using validated high performance liquid chromatographic-mass spectrometric (LC-MS/MS) assays.
  • the lower limit of quantitation (LLOQ) of this assay was 5.0 ng/mL and the calbration range was 5 to 5000 ng/mL.
  • the terminal phase rate constant (k) was calculated as the negative of the slope of the log-linear terminal portion of the serum concentration-time curve using linear regression.
  • the terminal phase half-life, t ⁇ / 2 was calculated as 0.693/k.
  • AUC(tf) The area under the serum concentration-time curve from time 0 to the time of final quantifiable sample [AUC(tf)] was calculated using the linear trapezoidal rule. AUC(tf) was then extrapolated to irifinity (I) as follows:
  • AUC(I) AUC(tf) + Ces(tf)/k where Ces(tf) is the estimated concentration determined from linear regression at final measurable sampling time, tf.
  • Vdss CL x MRT where MRT is the mean residence time (adjusted for infusion duration)
  • posaconazole plasma concentrations declined unusually rapidly, and then, surprisingly, increased subsequently, followed by a slow declining terminal phase (see Figures 1-4).
  • This pharmacokinetic profile is believed to be atypical and unique among known azoles.
  • this pharmacokinetic pattern was also observed after the intravenous adrrunistration of posaconazole in animals. It is indicative of a rapid distribution of posaconazole to the liver and spleen and subsequent slow release from these tissues. Therefore, as noted in the literature with respect to another pharmaceutically active agent (Townsend RW, Zutshi A, Bekersky I., "Biodistribution of 4-
  • POS IV may be
  • RES reticuloendothelial system
  • Table 14 displays pharmacokinetic data resulting from such oral ad ⁇ iinistration, arranged by quartile based on the observed range of posaconazole plasma concentration values. For each quartile, the response rate for apergillosis is displayed.
  • the table shows that the target mean Cmax for a response rate of at least 50% should be in the range of 467 to 1480 ng/mL, or higher.
  • the pharmacokinetic modeling and steady-state projection based on the pharmacokinetic results of POS IV once-a-day (QD) dosing regimen show that the projected posaconazole mean Cmax at a 100 mg POS IV QD dose
  • posaconazole was slowly eliminated from plasma with an average terminal half-life of 21 to 39 hours.
  • the half-life was higher at the higher dose compared to that at lower dose groups (see Tables 15 and 16), in a range of about 15 hours (with a lOOmg dose) to about 51 hours (with a 400mg dose).
  • a long half- life is desirable as it provides the sustained and high plasma
  • Vdss extensive tissue distribution and penetration into the tissues, a characteristic that likely contributes to enhanced anti-infective activity.
  • the range in the data for Vdss was from 219 to 516L. This is consistent
  • volume distribution could have a range of 200 to 500 L.
  • the preferable ratios of blood to plasma posaconazole Cmax and AUC values are shown in Tables 18 and 19.
  • Overall posaconazole exposure (AUC) was higher in plasma compared to that in blood ⁇ see Tables 18 and 19 - AUC ratio).
  • the posaconazole concentrations were greater in blood than in plasma during the infusion and approximately up to 1 hr post-infusion (see Figures 3 and 4; Tables 18 and 19, Cmax ratio).
  • the coefficient of variation of the data suggests that the ratio of blood to plasma posaconazole Cmax could have a range of 1.8 to 3.5 for single dose infused over 1 hour to deliver 25-600 mg of posaconazole.
  • the coefficient of variation of the data suggests that
  • the ratio of blood to plasma posaconazole Cmax could have a range of 1.0 to 2.3 at steady state when posaconazole is infused over about 1 hour

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WO2006130177A1 (en) * 2005-05-27 2006-12-07 Schering Corporation Particulate-stabilized injectable pharmaceutical compositions of posaconazole
WO2007131253A2 (de) * 2006-05-12 2007-11-22 Pharmacon-Forschung Und Beratung Gmbh Verwendung von kombinationspräparaten, umfassend antimykotika
EP2130540A1 (en) 2008-06-02 2009-12-09 Sandoz AG Pharmaceutical compositions containing a crystalline form of posaconazole
EP2141159A1 (en) 2008-07-03 2010-01-06 Sandoz AG A Crystalline form of posaconazole
WO2011003992A1 (en) 2009-07-09 2011-01-13 Sandoz Ag A crystalline form of posaconazole
WO2011144653A1 (en) 2010-05-19 2011-11-24 Sandoz Ag Process for the preparation of chiral triazolones
WO2012005973A1 (en) 2010-06-29 2012-01-12 Schering Corporation Posaconazole intravenous solution formulations stabilized by substituted beta-cyclodextrin
US9073904B2 (en) 2010-05-19 2015-07-07 Sandoz Ag Preparation of posaconazole intermediates
US9199919B2 (en) 2010-05-19 2015-12-01 Sandoz Ag Process for the preparation of chiral hydrazides
US9206146B2 (en) 2010-05-19 2015-12-08 Sandoz Ag Purification of posaconazole and of posaconazole intermediates
US9493428B2 (en) 2011-06-16 2016-11-15 Sandoz Ag Process for the preparation of a chiral compound
CN113933131A (zh) * 2021-09-24 2022-01-14 合肥天一生物技术研究所有限责任公司 一种阴道微生物荧光染色液

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WO2006130177A1 (en) * 2005-05-27 2006-12-07 Schering Corporation Particulate-stabilized injectable pharmaceutical compositions of posaconazole
EP3192507A1 (de) 2006-05-12 2017-07-19 Christian Noe Verwendung von kombinationspräparaten, umfassend antimykotika
US8815925B2 (en) 2006-05-12 2014-08-26 Christian Noe Use of combination preparations comprising antifungal agents
NO342103B1 (no) * 2006-05-12 2018-03-26 Christian Noe Kombinasjonslegemiddel som inneholder et antimykotiskt middel og et ikke-steroid, antiinflammatorisk middel, for anvendelse ved topisk behandling av Candida-mykoser
WO2007131253A2 (de) * 2006-05-12 2007-11-22 Pharmacon-Forschung Und Beratung Gmbh Verwendung von kombinationspräparaten, umfassend antimykotika
WO2007131253A3 (de) * 2006-05-12 2008-11-27 Pharmacon Forschung & Beratung Gmbh Verwendung von kombinationspräparaten, umfassend antimykotika
US8552042B2 (en) 2006-05-12 2013-10-08 Christian Noe Use of combination preparations comprising antifungal agents
US8563555B2 (en) 2008-06-02 2013-10-22 Sandoz Ag Pharmaceutical compositions containing a crystalline form of posaconazole
WO2009147075A3 (en) * 2008-06-02 2010-01-28 Sandoz Ag Pharmaceutical compositions containing a crystalline form of posaconazole
CN102046172B (zh) * 2008-06-02 2013-06-19 桑多斯股份公司 包含泊沙康唑晶体形式的药物组合物
EP2130540A1 (en) 2008-06-02 2009-12-09 Sandoz AG Pharmaceutical compositions containing a crystalline form of posaconazole
EP2141159A1 (en) 2008-07-03 2010-01-06 Sandoz AG A Crystalline form of posaconazole
US8435998B2 (en) 2008-07-03 2013-05-07 Sandoz Ag Crystalline form of posaconazole
WO2011003992A1 (en) 2009-07-09 2011-01-13 Sandoz Ag A crystalline form of posaconazole
WO2011144653A1 (en) 2010-05-19 2011-11-24 Sandoz Ag Process for the preparation of chiral triazolones
US9073904B2 (en) 2010-05-19 2015-07-07 Sandoz Ag Preparation of posaconazole intermediates
US9199919B2 (en) 2010-05-19 2015-12-01 Sandoz Ag Process for the preparation of chiral hydrazides
US9206146B2 (en) 2010-05-19 2015-12-08 Sandoz Ag Purification of posaconazole and of posaconazole intermediates
US9040539B2 (en) 2010-05-19 2015-05-26 Sandoz Ag Process for the preparation of chiral triazolones
KR101834024B1 (ko) * 2010-06-29 2018-03-02 머크 샤프 앤드 돔 코포레이션 치환된 베타―시클로덱스트린에 의해 안정화된 포사코나졸 정맥내 용액 제제
US9358297B2 (en) 2010-06-29 2016-06-07 Merck Sharp & Dohme Corp. Posaconazole intravenous solution formulations stabilized by substituted β-cyclodextrin
EP2588116A1 (en) 2010-06-29 2013-05-08 Merck Sharp & Dohme Corp. Posaconazole intravenous solution formulations stabilized by substituted beta-cyclodextrin
WO2012005973A1 (en) 2010-06-29 2012-01-12 Schering Corporation Posaconazole intravenous solution formulations stabilized by substituted beta-cyclodextrin
EP3391890B1 (en) 2010-06-29 2021-08-25 Merck Sharp & Dohme Corp. Posaconazole intravenous solution formulations stabilized by substituted beta-cyclodextrin
EP3391890A1 (en) * 2010-06-29 2018-10-24 Merck Sharp & Dohme Corp. Posaconazole intravenous solution formulations stabilized by substituted beta-cyclodextrin
US9493428B2 (en) 2011-06-16 2016-11-15 Sandoz Ag Process for the preparation of a chiral compound
CN113933131A (zh) * 2021-09-24 2022-01-14 合肥天一生物技术研究所有限责任公司 一种阴道微生物荧光染色液
CN113933131B (zh) * 2021-09-24 2024-01-26 合肥天一生物技术研究所有限责任公司 一种阴道微生物荧光染色液

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