EP1718640A1 - Nouvelles formes cristallines de conazoles et procedes de preparation et d'utilisation de celles-ci - Google Patents

Nouvelles formes cristallines de conazoles et procedes de preparation et d'utilisation de celles-ci

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Publication number
EP1718640A1
EP1718640A1 EP04782868A EP04782868A EP1718640A1 EP 1718640 A1 EP1718640 A1 EP 1718640A1 EP 04782868 A EP04782868 A EP 04782868A EP 04782868 A EP04782868 A EP 04782868A EP 1718640 A1 EP1718640 A1 EP 1718640A1
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EP
European Patent Office
Prior art keywords
ray diffraction
diffraction pattern
pattern comprises
crystal
degrees
Prior art date
Legal status (The legal status 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 status listed.)
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EP04782868A
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German (de)
English (en)
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EP1718640A4 (fr
Inventor
Julius Remenar
Michael Macphee
Matthew Peterson
Sherry L. Morissette
Orn Almarsson
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Transform Pharmaceuticals Inc
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Transform Pharmaceuticals Inc
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Priority claimed from PCT/US2004/006288 external-priority patent/WO2004078163A2/fr
Priority claimed from US10/926,842 external-priority patent/US7446107B2/en
Application filed by Transform Pharmaceuticals Inc filed Critical Transform Pharmaceuticals Inc
Publication of EP1718640A1 publication Critical patent/EP1718640A1/fr
Publication of EP1718640A4 publication Critical patent/EP1718640A4/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • 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

Definitions

  • XX/XXX,XXX, filed August 26, 2004 is also a continuation-in-part of PCT/US03/17184, filed May 30, 2003, which claims the benefit of U.S. Application No. 10/449,307, filed May 30, 2003, U.S. Provisional Application No. 60/384,152, filed May 31, 2002, U.S. Provisional Application No. 60/439,282, filed January 10, 2003, U.S. Provisional Application No. 60/444,315, filed January 31, 2003, and U.S. Provisional Application No. 60/463,962, filed April 18, 2003. Said U.S. Application No.
  • XX/XXX,XXX, filed August 26, 2004 is also a continuation-in-part of PCT/US 03/27772, filed September 4, 2003, which claims the benefit of U.S. Application No. 10/378,956, filed March 3, 2003, U.S. Provisional Application No. 60/463,962, filed April 18, 2003, U.S. Provisional Application No. 60/451,213, filed February 28, 2003, and U.S. Provisional Application No. 60/487,064, filed July 11, 2003.
  • Said U.S. Application No. 10/378,956, filed March 3, 2003 claims the benefit of U.S. Provisional Application No. 60/360,768, filed March 1, 2002.
  • XX/XXX,XXX, filed August 26, 2004 is also a continuation-in-part of U.S. Application No. 10/660,202, filed September 11, 2003, which claims the benefit of PCT/US03/27772, filed September 4, 2003.
  • Said U.S. Application No. 10/660,202, filed September 11, 2003 also claims the benefit of U.S. Application No. 10/637,829, filed August 8, 2003, which is a divisional of U.S. Application No. 10/295,995, filed November 18, 2002, which is a continuation of U.S. Application No. 10/232,589, filed September 3, 2002, which claims the benefit of U.S. Provisional Application No. 60/406,974, filed August 30, 2002, U.S. Provisional Application No.
  • the invention provides novel soluble saperconazole and cz ' -v-itraconazole crystalline forms that include salts, co-crystals and polymorphs useful as pharmaceuticals.
  • the invention also provides pharmaceutical compositions comprising, and processes for making, these saperconazole and ct-j-intraconazole crystalline forms. Methods of using such compositions for the treatment or prevention of systemic and local fungal, yeast, and dermatophyte infections are also provided.
  • the invention provides novel soluble crystalline systems comprising (a) an organic salt comprising the reaction product of saperconazole and an organic or inorganic acid; or (b) a co-crystal comprising the reaction product of saperconazole and an organic or inorganic acid.
  • the novel soluble crystalline forms of saperconazole and c.-?-itraconazole are characterized by a powder X-ray diffraction pattern expressed in terms of 2 theta angles.
  • Systemic fungal diseases are typically chronic conditions that develop very slowly. These diseases are often induced by opportunistic causative fungi that are not normally pathogenic and commonly live in the patient's body or are commonly found in the environment. While systemic fungal diseases used to be relatively rare in temperate countries, there has been an increasing incidence of numerous life-threatening systemic fungal infections that now represent a major threat to susceptible patients.
  • Susceptible patients include immunocompromised patients, particularly those already hospitalized, and patients compromised by HIV infection, ionizing irradiation, corticosteroids, immunosuppressives, invasive surgical techniques, prolonged exposure to antimicrobial agents, and the like, or by diseases or conditions such as cancer, leukemia, emphysema, bronchiectasis, diabetes mellitus, burns, and the like.
  • the symptoms manifested by these fungal diseases are generally not intense, and may include chills, fever, weight loss, anorexia, malaise, and depression.
  • blastomycosis The most common systemic fungal infections in humans are blastomycosis, candidosis, aspergillosis, histoplasmosis, coccidioidomycosis, paracoccidioidomycosis, and cryptococcosis.
  • Fungal diseases are often confined to typical anatomic sites, and many involve a primary focus in the lung, with more characteristic manifestations of specific fungal infections appearing once the infection spreads from a primary site.
  • blastomycosis primarily involves the lungs, and occasionally spreads to the skin.
  • coccidioidomycosis occurs as an acute, benign, self- limiting respiratory disease, which can then progress to a chronic, often-fatal infection of the skin, lymph glands, liver, and spleen.
  • Other infectious diseases such as paracoccidioidomycosis and candidiasis present in different manners, and depending on the etiology, may exhibit several forms involving internal organs, the lymph nodes, skin, and mucous membranes.
  • Diagnosis of specific fungal diseases can be made by isolation of the causative fungus from various specimens, such as sputum, urine, blood, or the bone marrow, or with certain fungus types, through evidence of tissue invasion.
  • Yeast infections such as candidiasis and oral candidiasis (thrush) are usually localized to the skin and mucous membranes, with the symptoms varying depending on the site of infection. In many instances, such infections appear as erythematous, often itchy, exudative patches in the groin, axillas, umbilicus, between toes, and on finger-webs. Oral thrush involves an inflamed tongue or buccal mucosa, typically accompanied by white patches of exudate. Chronic mucocutaneous candidiasis is manifested in the form of red, pustular, crusted, thickened lesions on the forehead or nose.
  • Itraconazole is a broad-spectrum antifungal agent developed for oral, parenteral and topical use, and is disclosed in U.S. Pat. No. 4,267,179.
  • Itraconazole is a synthetic triazole derivative that disrupts the synthesis of ergosterol, the primary sterol of fungal cell membranes. This disruption appears to result in increased permeability and leakage of intracellular content, and at high concentration, cellular internal organelles involute, peroxisomes increase, and necrosis occurs.
  • itraconazole is defined as ( ⁇ )-l-5ec-butyl-4-[p-[4-[p-[[(2R*,4S*)-2-(2,4-dichlorophenyl)-2-(lH-l,2 ,4-triazol- 1 -ylmethyl)- 1 , 3 -dioxolan-4-yl]methoxy]phenyl] - 1 -piperazinyl]phenyl]- ⁇ 2 - l,2,4-triazolin-5-one, or alternatively, as 4-[4-[4-[4-[4- [[2-(2,4-dichlorophenyl)-2-(lH- l,2,4-triazol-l-ylmethyl)-l,3-dioxolan-4-yl ] methoxy]phenyl]-l-piperazinyl]phenyl]- 2,4-dihydro-2
  • ( ⁇ )C/s-Itraconazole comprises a mixture of only those isomers that describe a "cis" relationship in the dioxolane ring, i.e., the (1H-1, 2, 4-triazol-l -ylmethyl) moiety and the substituted phenoxy moiety are located on the same side of a plane defined by the 1, 3-dioxolane ring.
  • the first represented chiral center is at C-2 of the dioxolane ring
  • the second is at C-4 of the dioxolane ring
  • the third is in the -fee-butyl group.
  • ( ⁇ )cw-itraconazole is a mixture of (R,S,S), (R,S,R), (S,R,S) and (S,R,R) isomers.
  • the four possible stereoisomeric cis forms of itraconazole, and diastereomeric pairs thereof, are described in more detail in U.S. Pat. Nos. 5,474,997 and 5,998,413.
  • the individual stereoisomeric forms of c/s-itraconazole have antifungal properties, and contribute to the overall activity of ( ⁇ )cts-itraconazole.
  • SPORANOX ® has been approved for use as an antifungal agent for treating immunocompromised and non-immunocompromised patients having: blastomycosis (pulmonary and extrapulmonary); histoplasmosis, including chronic cavitary pulmonary disease and disseminated non-meningeal histoplasmosis; and aspergillosis.
  • blastomycosis pulmonary and extrapulmonary
  • histoplasmosis including chronic cavitary pulmonary disease and disseminated non-meningeal histoplasmosis
  • aspergillosis aspergillosis.
  • non-immunocompromised patients it has been approved for treatment of onychomycosis. See generally, Physician's Desk Reference, 56 th ed. (2002).
  • the compound has also been investigated for use in coccidioidomycosis, cryptococcosis, dermatophyte, and candidiasis infections.
  • Adverse effects associated with the administration of ( ⁇ )c/-?-itraconazole free base include nausea, vomiting, anorexia, headache, dizziness, hepatotoxicity, and inhibition of drug metabolism in the liver, leading to numerous, clinically significant, adverse drug interactions. See, Physician's Desk Reference, 56 th ed. (2002); Honig et ah, J. Clin. Pharmacol. 33_ ⁇ l201-1206 (1993) (terfenadine interaction); Gascon and Dayer, Ewr. J. Clin. Pharmacol., 41:573-578 (1991) (midazolam interaction); and Neuvonen et al, Clin. Pharmacol. Therap., 60:54-61 (1996) (lovastatin interaction).
  • the currently marketed SPORANOX ® solid dosage capsule form of itraconazole free base utilizes sugar-based beads coated with a hydrophilic polymer and an amorphous film of itraconazole. See Physicians Desk Reference, 56 th ed., pp.1800-1804 (2002); and U.S. Pat. No. 5,633,015.
  • This dosage form requires up to two capsules three times daily depending on the condition being treated. Even with the various formulation routes, the dosage amounts and dose frequency for itraconazole can be burdensome to patients.
  • Posaconazole and Saperconazole Chemistry and Uses Other related conazoles have also been discovered and used as antifungals. Two of these conazoles that are closely structurally related to itraconazole are Posaconazole and Saperconazole.
  • Posaconazole (CAS Registry Number: 171228-49- 2; CAS Name: 2,5-Anhydro-l,3,4-trideoxy-2-C-(2,4-difluorophenyl)-4-[[4-[4-[4-[l- [(lS,2S)-l-ethyl-2-hydroxypropyl]-l,5-dihydro-5-oxo-4H-l,2,4-triazol-4-yl]phenyl]- 1 -piperazinyl]phenoxy]methyl]- 1 -( IH- 1 ,2,4-triazol- 1 -yl)-D-tbreo-pentitol; Additional Names: (3R-cw)-4-
  • the invention provides novel soluble crystalline forms of conazoles including ct- traconazole, posaconazole or saperconazole comprising the reaction product of the conazole and an organic acid or an inorganic acid including salts, co-crystals, solvates, hydrates and multicomponent crystal systems having three or more components (including itraconazole).
  • the soluble crystalline form of the conazole comprises the reaction product of the conazole, e.g., cis- itraconazole, posaconazole or saperconazole, and a dicarboxylic acid or a carboxylic acid.
  • the invention provides soluble crystalline forms of an organic solvate of a conazole including cis-itraconazole, posaconazole or saperconazole salts, and crystalline forms of the acid salts of a conazole, such as cis-itraconazole, posaconazole or saperconazole HCI salt tartaric acid co-crystal.
  • the invention includes novel soluble conazole (e.g., cts-itraconazole, posaconazole or saperconazole) salts, co-crystals, solvates (including hydrates), and polymorphs.
  • the invention provides a soluble, multicomponent crystalline system comprising:
  • the multicomponent crystalline system is a co-crystal comprising a co-crystal former and a conazole.
  • the reaction product is a salt.
  • the reaction product is a co-crystal.
  • the first reaction product is a salt and the second reaction product is a co-crystal.
  • the system comprises a first reaction product, a second reaction product and a solvent.
  • the invention provides for a co-crystal comprising a co-crystal former and a conazole free base or a co-crystal former and a conazole salt. Either co-crystal form may further comprise a solvent as provided for herein.
  • the novel soluble crystalline form of cw-itraconazole is characterized by an endothermic transition temperature, a Raman spectrum, a crystal morphology or by selected peaks of a powder X-ray diffraction pattern expressed in terms of 2 theta angles, wherein the X- ray powder diffraction patterns comprise the 2 theta angle values listed herein.
  • the invention also provides pharmaceutical compositions comprising, and processes for making, conazole (e.g., cis itraconazole posaconazole or saperconazole) crystalline forms including salts, co-crystals, solvates, etc.
  • Compounds of the invention include, but are not limited to, soluble crystalline forms of conazoles including: cw-itraconazole, posaconazole or saperconazole D, L, and D, L-tartaric acid co-crystal, cw-itraconazole, posaconazole or saperconazole citrate, c ⁇ -itraconazole, posaconazole or saperconazole fumaric acid co-crystal, cis- itraconazole, posaconazole or saperconazole malonic acid co-crystal, e ⁇ -itraconazole, posaconazole or saperconazole maleic acid co-crystal, cw-itraconazole, posaconazole or saperconazole adipic acid co-crystal, cww-itraconazole, posaconazole or saperconazole adipic acid co-crystal, c
  • Preferred soluble crystalline forms of conazoles include dicarboxylic acid salts, dicarboxylic acid co-crystals, and hydrochloric acid salt co-crystals.
  • Other preferred soluble crystalline forms of cis- itraconazole, posaconazole or saperconazole include hydrochloric acid, phosphoric acid, sulfuric acid or benzenesulfonic acid salts and co-crystals.
  • crystalline forms of an alcohol solvate e.g., ethanol, methanol, propylene glycol, propanol, etc.
  • dioxane solvate e.g., dioxane solvate
  • a conazole e.g., a cw-itraconazole, posaconazole or saperconazole
  • co-crystal such as tartaric acid co-crystal, fumaric acid co-crystal, malic acid co-crystal, maleic acid co-crystal, adipic acid co-crystal, di-mesylate, and succinic acid co-crystal.
  • the co-crystal comprises a co-crystal former and a conazole salt.
  • the co-crystal further comprises a solvent.
  • the present invention provides a soluble crystalline form or a formulation of a soluble crystalline form of a conazole with a decreased food effect.
  • a soluble crystalline form or a formulation of a soluble crystalline form of itraconazole is provided which has a decreased food effect with respect to that of a reference form (e.g., itraconazole free base, a salt of itraconazole, or a polymorph, hydrate solvate, or co-crystal thereof) or a reference formulation (e.g., Sporanox®).
  • the present invention provides a method for decreasing the food effect of a conazole.
  • a method for decreasing the food effect of a conazole comprising administering to a mammal a soluble crystalline form or a formulation of a soluble crystalline form of the present invention.
  • a method for decreasing the food effect of itraconazole comprises administering to a mammal a soluble crystalline form or a formulation of a soluble crystalline form of the present invention such as, but not limited to, itraconazole HCl:DL-tartaric acid co-crystal.
  • the decrease in food effect discussed in the above methods can be measured with respect to the food effect observed from a reference form (e.g., itraconazole free base, a salt of itraconazole, or a polymorph, hydrate solvate, or co-crystal thereof) or a reference formulation (e.g., Sporanox®).
  • a reference form e.g., itraconazole free base, a salt of itraconazole, or a polymorph, hydrate solvate, or co-crystal thereof
  • a reference formulation e.g., Sporanox®
  • the invention further provides methods of treating or preventing local and systemic fungal, yeast, and dermatophyte infections in a patient by administration of therapeutically or prophylactically effective amounts of soluble crystalline forms of a conazole such as ets-itraconazole, posaconazole or saperconazole, comprising the reaction product of a conazole such as czs-itraconazole, posaconazole or saperconazole, and an organic acid or an inorganic acid.
  • Pharmaceutical dosage forms of the invention comprise therapeutically or prophylactically effective amounts of soluble crystalline forms of a conazole (e.g., c/s-itraconazole, posaconazole or saperconazole) comprising the reaction product of cw-itraconazole, posaconazole or saperconazole and an organic acid or an inorganic acid.
  • a conazole e.g., c/s-itraconazole, posaconazole or saperconazole
  • an organic acid or an inorganic acid e.g., c/s-itraconazole, posaconazole or saperconazole
  • FIGURE 1 shows a schematic of a conazole co-crystal comprising a trimer consisting of a co-crystal former sandwiched between two antiparallel conazole molecules.
  • FIGURE 2 A ball and stick model of a single trimeric congener consisting of two cis- itraconazole molecules and a succinic acid molecule;
  • FIGURE 3 A ball and stick model of a single trimeric congener consisting of two posaconazole molecules and a succinic acid molecule;
  • FIGURE 4 A ball and stick model of a single trimeric congener consisting of two saperconazole molecules and a succinic acid molecule;
  • FIGURE 5 (a)-(b) illustrate the following:
  • FIGURE 6 (a)-(b) illustrate the following:
  • FIGURE 7 (a)-(b) illustrate the following:
  • FIGURE 8 PXRD diffractogram of c s-Itraconazole (Form A).
  • FIGURE 9 PXRD diffractogram of c/s-Itraconazole (Form B).
  • FIGURE 11 PXRD diffractogram of c ⁇ -Itraconazole (Form D).
  • FIGURE 12- Comparison of PXRD diffractograms of Forms A, B, C, and D of cis- itraconazole.
  • solvate is a complex of variable stoichiometry formed by a solute (either cts-itraconazole, posaconazole or saperconazole or salts, co-crystals, hydrates, or polymorphs of c ⁇ -itraconazole, posaconazole or saperconazole) and an organic solvent as defined herein, including an alcohol, preferably methanol or ethanol, or dioxane.
  • solute either cts-itraconazole, posaconazole or saperconazole or salts, co-crystals, hydrates, or polymorphs of c ⁇ -itraconazole, posaconazole or saperconazole
  • organic solvent as defined herein, including an alcohol, preferably methanol or ethanol, or dioxane.
  • Carboxylic acids include, but are not limited to, formic, acetic, propionic, butyric, isobutyric, valeric, isovaleric, pivalic, caproic, caprylic, capric, lauric, myristic, palmitic, stearic, acrylic, crotonic, benzoic, cinnamic, and salicylic acids.
  • Dicarboxylic acid means a compound of formula (II):
  • Ri and R 2 are each independently H, OH, CI, Br, I, substituted or unsubstimted C ⁇ . 6 alkyl, substituted or unsubstimted aryl or Ri and R 2 taken together represent a double bond as well as stereochemically pure D or L salts of a compound of formula (II).
  • the dicarboxylic acid of formula (II) include but are not limited to succinic acid, maleic acid, tartaric acid, malic acid or fumaric acid. Most preferably, the dicarboxylic acid of formula (II) is succinic acid, tartaric acid or malic acid. Least preferably, the dicarboxylic acid of formula (II) is maleic acid or fumaric acid.
  • dicarboxylic acids such as malonic acid and adipic acid are distinct embodiments of the invention although they fall outside the scope of formula (II).
  • Organic or inorganic acids include, but are not limited to, carboxylic acids, dicarboxylic acids, hydrochloric acid, phosphoric acid, sulfuric acid, benzenesulfonic acid, methanesulfonic acid, and, in general terms, any acidic species that will form a thermodynamically stable crystalline (salt) form upon reaction with the free base cis- itraconazole, posaconazole or saperconazole.
  • co-crystal as used herein means a crystalline material comprised of two or more unique solids at room temperature, each containing distinctive physical characteristics, such as strucmre, melting point and heats of fusion, with the exception that, if specifically stated, the active pharmaceutical ingredient (API) may be a liquid at room temperature.
  • the co-crystals of the present invention comprise a co-crystal former H-bonded to an API.
  • the co-crystal former may be H-bonded directly to the API or may be H-bonded to an additional molecule which is bound to the API.
  • the additional molecule may be H-bonded to the API or bound ionically or covalently to the API.
  • the additional molecule could also be a different API.
  • Solvates of API compounds that do not further comprise a co-crystal former are not co-crystals according to the present invention.
  • the co-crystals may however, include one or more solvate molecules in the crystalline lattice. That is, solvates of co-crystals, or a co-crystal further comprising a solvent or compound that is a liquid at room temperature, is included in the present invention, but crystalline material comprised of only one solid and one or more liquids (at room temperature) are not included in the present invention, with the previously noted exception of specifically stated liquid APIs.
  • the co-crystals may also be a co-crystal between a co-crystal former and a salt of an API, but the API and the co-crystal former of the present invention are constructed or bonded together through hydrogen bonds.
  • Other modes of molecular recognition may also be present including, pi-stacking, guest-host complexation and van der Waals interactions.
  • hydrogen-bonding is the dominant interaction in the formation of the co-crystal, (and a required interaction according to the present invention) whereby a non-covalent bond is formed between a hydrogen bond donor of one of the moieties and a hydrogen bond acceptor of the other. Hydrogen bonding can result in several different intermolecular configurations.
  • hydrogen bonds can result in the formation of dimers, linear chains, or cyclic structures. These configurations can further include extended (two- dimensional) hydrogen bond networks and isolated triads.
  • An alternative embodiment provides for a co-crystal wherein the co-crystal former is a second API. In another embodiment, the co-crystal former is not an API. In another embodiment the co-crystal comprises two co-crystal formers.
  • the chemical and physical properties of an API in the form of a co-crystal may be compared to a reference compound that is the same API in a different form.
  • the reference compound may be specified as a free form, or more specifically, a free acid, free base, or zwitterion; a salt, or more specifically for example, an inorganic base addition salt such as sodium, potassium, lithium, calcium, magnesium, ammonium, aluminum salts or organic base addition salts, or an inorganic acid addition salts such as HBr, HCI, sulfuric, nitric, or phosphoric acid addition salts or an organic acid addition salt such as acetic, propionic, pyruvic, malanic, succinic, malic, maleic, fumaric, tartaric, citric, benzoic, methanesulfonic, ethanesulforic, stearic or lactic acid addition salt; an anhydrate or hydrate of a free form or salt, or more specifically, for example, a hemihydrate, monohydrate, dihydrate, trihydrate, quadrahydrate, pentahydrate, sesquihydrate; or a solvate of a free form or salt.
  • the reference compound for an API in salt form co-crystallized with a co- crystal former can be the API salt form.
  • the reference compound for a free acid API co-crystallized with a co-crystal former can be the free acid API.
  • the reference compound may also be specified as crystalline or amorphous.
  • soluble crystalline forms or “soluble, multicomponent crystalline systems” encompass crystalline (or co-crystalline) species including salts, hydrates, solvates, multicomponent crystalline systems or crystalline polymorphs that are soluble in aqueous media at values greater than 5 mcg(microgram)/ml, more preferably greater than 10 mcg/ml, more preferably greater than 20 mcg/ml, more preferably greater than 30 meg /ml, more preferably greater than 40 meg /ml, more preferably greater than 50 meg /ml, and most preferably greater than 100 meg /ml in a solution with a pH of about 1.
  • Soluble multicomponent crystalline systems can comprise: (a) an organic compound (salt, co-crystal or a co-crystal of a salt and a second molecule) comprising the reaction product of c/s-itraconazole, posaconazole or saperconazole and an organic acid or an inorganic acid; and (b) one or more organic solvents, wherein the organic solvent is present in either a stoichiometric or non-stoichiometric ratio relative to the organic salt.
  • an organic compound salt, co-crystal or a co-crystal of a salt and a second molecule
  • Organic solvent includes, but not is limited to, 1, 4 dioxane ("dioxane”), 1,2-dichloroethane, dimethoxyethane, diethylene glycol dimethyl ether, tetrahydrofuran, diisopropyl ether, hydrocarbons such as hexane, heptane, cyclohexane, toluene or xylene, alcohols such as methanol, ethanol, 1 -propanol, 2- propanol, 1-butanol, 2-butanol, tert-butanol or ethylene glycol, ketones such as methyl ethyl ketone or isobutyl methyl ketone, amides such as dimethylformamide, dimethylacetamide or N-methylpyrrolidone, dimethoxyethane, tetrahydrofuran, dioxane, cyclohexane, toluene, xylene,
  • 1, 2-dichloroethane and ethanol are preferred organic solvents.
  • the term "anomer” as used herein means one of a pair of isomers of a cyclic compound resulting from creation of a new point of symmetry when a rearrangement of atoms occurs at an aldehyde or ketone position.
  • Alkyl means a straight chain or branched, saturated or unsaturated alkyl, cyclic or non-cyclic hydrocarbon having from 1 to 10 carbon atoms.
  • saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n- hexyl, and the like; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like.
  • Unsaturated alkyls contain at least one double or triple bond between adjacent carbon atoms (also referred to as an "alkenyl” or "alkynyl", respectively).
  • Representative straight chain and branched alkenyls include ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2- pentenyl, 3 -methyl- 1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, and the like; while representative straight chain and branched alkynyls include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-l butynyl, and the like.
  • saturated cyclic alkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; while unsaturated cyclic alkyls include cyclopentenyl and cyclohexenyl, and the like.
  • Cycloalkyls are also referred to herein as "carbocyclic" rings systems, and include bi- and tri-cyclic ring systems having from 8 to 14 carbon atoms such as a cycloalkyl (such as cyclopentane or cyclohexane) fused to one or more aromatic (such as phenyl) or non-aromatic (such as cyclohexane) carbocyclic rings.
  • aryl means a carbocyclic or heterocyclic aromatic group containing from 5 to 10 ring atoms.
  • the ring atoms of a carbocyclic aromatic group are all carbon atoms, and include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl.
  • a carbocyclic aromatic group can be unsubstituted or substituted.
  • the carbocyclic aromatic group is a phenyl group.
  • heterocyclic aromatic groups contains at least one heteroatom, preferably 1 to 3 heteroatoms, independently selected from nitrogen, oxygen, and sulfur.
  • heterocyclic aromatic groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3,)- and (l,2,4)-triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, furyl, phienyl, isoxazolyl, indolyl, oxetanyl, azepinyl, piperazinyl, morpholinyl, dioxanyl, thietanyl and oxazolyl.
  • a heterocyclic aromatic group can be unsubstimted or substituted.
  • a heterocyclic aromatic is a monocyclic ring, wherein the ring comprises 2 to 5 carbon atoms and 1 to 3 heteroatoms.
  • the terms "itraconazole” and "c/s-itraconazole” refer to ( ⁇ )c/s- 4-[4-[4-[4- [[2-(2,4-dichlorophenyl)-2-(lH-l,2,4-triazol-l-ylmethyl)-l,3-dioxolan-4- yl ] methoxy]phenyl]-l-piperazinyl]phenyl]- 2,4-dihydro-2-(l-methylpropyl)-3H- l,2,4-triazol-3-one, its four stereoisomers (+)-[2R-[2 ⁇ ,4 ⁇ ,4(R)]-4-[4-[4-[4- [[2-(2,4- dichlorophenyl)-2-( 1 H- 1 ,2,4-triazol- 1 -ylmethyl)- 1 ,3 -dioxolan-4-yl ] methoxy]phenyl]-
  • c/s-itraconazole, posaconazole or saperconazole tartaric acid co-crystal refers to novel soluble crystalline forms of c/s-itraconazole, posaconazole or saperconazole-DL-tartaric acid co-crystal, c/s-itraconazole, posaconazole or saperconazole-L-tartaric acid co-crystal, and c/s-itraconazole, posaconazole or saperconazole-D-tartaric acid co-crystal.
  • the other salts refer to racemic or "DL" salts unless otherwise indicated.
  • c/s-itraconazole, posaconazole or saperconazole- HC1 means the hydrochloric acid salt of novel soluble crystalline forms of c/s- itraconazole, posaconazole or saperconazole.
  • stereoisomer or “stereoisomeric form” means compounds having a stereoisomeric purity of at least 90%, and preferably at least 95% up to a stereoisomeric purity of 100% by weight, preferably compounds having a stereoisomeric purity of at least 97% up to a stereoisomeric purity of 100%, and more preferably having a stereoisomeric purity of at least 99% up to a stereoisomeric purity of 100% by weight, said weight percent based upon the total weight of the desired stereoisomers of the compound.
  • the term "diastereomeric pair" refers to a mixture of two stereoisomers of c/s-itraconazole, and in particular, either 1) a mixture of (+)-[2R- [2 ⁇ ,4 ⁇ ,4(R)]-4-[4-[4-[4- [[2-(2,4-dichlorophenyl)-2-(lH-l,2,4-triazol-l-ylmethyl)- l,3-dioxolan-4-yl ] methoxy]phenyl]-l-piperazinyl]phenyl]- 2,4-dihydro-2-(l- methylpropyl)-3H-l,2,4-triazol-3-one (the (R,S,R) stereoisomer) and (+)-[2R- [2 ⁇ ,4 ⁇ ,4(S)]-4-[4-[4-[4- [[2-(2,4-dichlorophenyl)-2-(lH-l)
  • the mixture is in the range of a 47:53 to a 53:47 mixture by weight, more preferably in the range of a 48:52 to a 52:48 mixture by weight, and most preferably the mixture is a 50:50 mixture by weight.
  • the term "adjunctively administered” refers to the administration of one or more compounds or active ingredients in addition to a pharmaceutically acceptable salt and co-crystal of c/s-itraconazole, posaconazole or saperconazole, or a hydrate, solvate or polymorph thereof, either simultaneously with the same or at intervals prior to, during, or following administration of the pharmaceutically acceptable salt of c/s-itraconazole, posaconazole or saperconazole to achieve the desired therapeutic or prophylactic effect.
  • the term "pharmaceutically acceptable salt” refers to a salt prepared from pharmacologically acceptable anions, such as hydrochloride, phosphate, formate, adipic acid co-crystal, succinic acid co-crystal, fumaric acid co- crystal, malic acid co-crystal, tartrate, malonic acid co-crystal, maleic acid co-crystal, mesylate and benzenesulfonate.
  • pharmacologically acceptable anions such as hydrochloride, phosphate, formate, adipic acid co-crystal, succinic acid co-crystal, fumaric acid co- crystal, malic acid co-crystal, tartrate, malonic acid co-crystal, maleic acid co-crystal, mesylate and benzenesulfonate.
  • anions are tartrate, benzenesulfonate, malic acid co-crystal and succinic acid co-crystal, and other co- crystals, hydrobromide, bitartrate, para-toluenesulfonate, glycolate, glucuronate, mucate, gentisate, isonicotinate, saccharate, acid phosphate, hydroiodide, nitrate, sulfate, bisulfate, acetate, propionate, camphorsulfonate, gluconate, isothionate, lactate, furoate, glutamate, ascorbate, benzoate, anthranilate, salicylate, phentylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, pantothenate, stearate, sulfanilate, alginate, p-toluenesulfonate, mes, hydro
  • Local and systemic fungal, yeast and dermatophyte infections include, but are not limited to blastomycosis, aspergillosis, histoplasmosis, onychomycosis, coccidioidomycosis, paracoccidioidomycosis, cryptococcosis, dermatophyte, and candidiasis infections.
  • the terms "itraconazole” and “c/s-itraconazole” are used interchangeably throughout this disclosure.
  • the term “conazole” refers to compounds comprising a substituted or unsubstimted 1, 2, 4-triazol group or a substituted or unsubstimted 1-H-in ⁇ idazole group. Conazoles can further be specified as having antifungal activity and useful as an active pharmaceutical ingredient. Conazoles can further be defined as comprising both a 1, 2, 4-triazol and a 1-H-imidazole group and, optionally, having antifungal activity.
  • compositions of the present invention include salts, co-crystals, multicomponent systems, solvates, hydrates and polymorphs of itraconazole, posaconazole, saperconazole and derivatives thereof:
  • This invention is concerned in past with IH-imidazoles and lH-l,2,4-tria.zoles having the formula
  • Q is N or CH
  • Ar is aryl
  • R is hydrogen or C ⁇ - 6 alkyl
  • Y-R 1 is a radical having the formula
  • R 1 is tetrahydrofuranylC ⁇ - 6 alkyl; or C ⁇ . 6 alkyl, C 3 . 6 cycloalkyl, arylCi- 6 alkyl or (C 3 - 6 cycloalkyl)C ⁇ -6 alkyl all substituted on the C ⁇ - 6 alkyl and/or C 3 . 6 cycloalkyl moiety with oxo, thioxo or with one or two radicals of formula —Z—R 1"3 ;
  • said Z being O or S
  • R Na being hydrogen, C ⁇ - 6 alkyl, aryl, C 3 - 6 cycloalkyl or tetrahydro 2H-pyran-2-yl;
  • R 1 is substimted with two --Z-R 1"a radicals
  • the two --R 1"3 radicals taken together, may form a bivalent radical of formula ⁇ CH 2 --, ⁇ CH(CH 3 ) ⁇ , ⁇ C(CH 3 ) 2 --, -CH 2 -CH 2 ⁇ , ⁇ CH(CH 3 )-CH 2 ⁇ or -CH 2 -CH 2 -CH 2 -;
  • X is O, S orNR 2 ;
  • R 2 being hydrogen or Ci- 6 alkyl
  • R 3 being hydrogen or Ci-e alkyl
  • A' and B' independently having the same meaning of A and B respectively, or A' and B', taken together, form a bivalent radical of formula
  • the nitrogen atom in the bivalent radical (c) is connected to NR 1 ; wherein one hydrogen in said radical (c) and up to two hydrogens in radical (d) may be replaced by a C ⁇ - 6 alkyl radical; provided that (i) when Y—R 1 is a radical of formula (a) wherein ⁇ A ⁇ B— is other than a bivalent radical of formula (c), then R 1 is other than C ⁇ -6 alkyl substimted with ⁇ - 6 alkyloxy; (ii) when Y--R 1 is a radical of formula (b) then R 1 is other than - 6 alkyl substituted with - 6 alkyloxy; wherein aryl is phenyl or substimted phenyl, said substituted phenyl having from 1 to 3 substituents each independently selected from the group consisting of halo, C ⁇ -6 alkyl, C ⁇ - 6 alkyloxy, nitro, amino and trifluoromethyl, provided that trinitrophenyl is excluded.
  • halo is generic to fluoro, chloro, bromo and iodo
  • C ⁇ . 6 alkyl is meant to include straight and branched hydrocarbon radicals having from 1 to 6 carbon atoms such as for example, methyl, ethyl, 1- methylethyl, 1,1-dimethylethyl, propyl, 1-methylpropyl, 2-methylpropyl, butyl, pentyl, hexyl and the like;
  • C 3 -6 cycloalkyl embraces cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • the compounds of formula (V) may contain in their structure a tautomeric system and consequently these compounds can be present in each of their tautomeric forms.
  • Compounds within the invention are those wherein Y--R 1 is a radical of formula (a) or (b), wherein X, A, B, A', B' and R 1 are as described hereinabove, provided that A' and B', taken together, do not form a radical of formula (c) or (d). More specifically, compounds within the invention are those compounds wherein Y-R 1 is a radical of formula (a). Further specific compounds within the invention are those compounds wherein
  • compounds within the invention are those wherein R 1 is C 3 - 6 cycloalkyl substimted with oxo or hydroxy, or C ⁇ - 6 alkyl or aryl - ⁇ alkyl both substituted on the C ⁇ - 6 alkyl moiety with oxo or with one or two hydroxy or C ⁇ - 6 alkyloxy radicals.
  • This invention is further concerned in part with IH-imidazoles and 1 H- 1,2,4- triazoles having the formula
  • Q isN or CH
  • R 4 is hydrogen, C ⁇ - 6 alkyl or arylC ⁇ -6 alkyl
  • R 5 is hydrogen, C ⁇ - 6 alkyl or arylC ⁇ - 6 alkyl
  • aryl is phenyl optionally substimted with up to 3 substituents each independently selected from halo, C ⁇ . 6 alkyl, C ⁇ - 6 alkyloxy and trifluoromethyl.
  • substituents each independently selected from halo, C ⁇ . 6 alkyl, C ⁇ - 6 alkyloxy and trifluoromethyl.
  • halo is generic to fluoro, chloro, bromo and iodo
  • C ⁇ -6 alkyl is meant to include straight and branched hydrocarbon radicals having from 1 to 6 carbon atoms such as for example, methyl, ethyl, propyl, 1-methylethyl, 1,1-dimethylethyl, 1-methylpropyl, 2-methylpropyl, butyl, pentyl, hexyl and the like.
  • the compounds of formula (VI) wherein R 4 is hydrogen contain in their strucmre a tautomeric system and consequently these compounds can be present in each of their tautomeric forms, both of which are intended to be included within the scope of the present invention.
  • Compounds within the present invention are those compounds of formula (VI) wherein R 4 and R 5 independently are hydrogen or C ⁇ - 6 alkyl. More specifically, compounds are the above compounds wherein R 5 is hydrogen and R 4 is C ⁇ -6 alkyl. More specifically, compounds are the above compounds wherein the substituents on the dioxolane moiety have a cis configuration.
  • a particular subgroup of the compounds of formula (VI) comprises the compounds above Q is nitrogen.
  • More specific compounds above are selected from the group consisting of cis- 4-[4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(lH-l,2,4-triazol-l-yl-methyl)-l ,3-dioxolan-4- yl]methoxy]phenyl]- 1 -piperazinyl]phenyl]-2,4-dihydro-2-(l -met hylpropyl)-3H- 1 ,2,4- triazol-3-one and cis-4-[4-[4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(lH-l,2,4-triazol-l- ylmethyl)-l, 3-dioxolan-4-yl]methoxy]phenyl]-l-piperazinyl]phenyl]-2-(l,2- dimethylpropyl )-2
  • the present invention provides compounds represented by formula VII
  • R 8 is a straight or branched chain (C 3 to C 8 ) alkyl group substimted by one or two hydroxy moieties or stereoisomers thereof or by one or two groups convertible in vivo into hydroxy moieties or an ester or ether thereof.
  • ester or ether thereof.
  • the ester or ether is a group convertible in vivo into OH e.g. a polyether ester, phosphate ester or an amino acid ester.
  • a compound represent by the formula VI
  • the novel soluble crystalline forms of c/s- itraconazole, posaconazole or saperconazole have a solubility greater than 5 mcg/ml, more preferably greater than 10 mcg/ml, more preferably greater than 20 mcg/ml, more preferably greater than 30 mcg/ml, more preferably greater than 40 mcg/ml, more preferably greater than 50 mcg/ml, more preferably greater than 100 mcg/ml, more preferably greater than 1 mg/ml, and more preferably greater than 10 mg/ml in a solution with a pH of about 1.
  • Preferred novel soluble crystalline forms of c/s-itraconazole, posaconazole or saperconazole of the invention include dicarboxylic acid co-crystals of c/s- itraconazole, posaconazole or saperconazole such as c/s-itraconazole, posaconazole or saperconazole di-mesylate, c/s-itraconazole, posaconazole or saperconazole tartaric acid co-crystal, c/s-itraconazole, posaconazole or saperconazole fumaric acid co- crystal, itraconazole, posaconazole or saperconazolemalonic acid co-crystal, itraconazole, posaconazole or saperconazolemaleic acid co-crystal, itraconazole, posaconazole or saperconazoleadipic acid co-crystal, c/s-
  • Dicarboxylic acid salts and co-crystals of c/s-itraconazole, posaconazole or saperconazole include, but are not limited to, c/s- itraconazole, posaconazole or saperconazole tartrate, c/s-itraconazole, posaconazole or saperconazole succinic acid co-crystal, c/s-itraconazole, posaconazole or saperconazole di-mesylate and c/s-itraconazole, posaconazole or saperconazole malic acid co-crystal.
  • dicarboxylic acid salts and co-crystals of c/s-itraconazole, posaconazole or saperconazole are c/s-itraconazole, posaconazole or saperconazole fumaric acid co-crystal, c/s-itraconazole, posaconazole or saperconazole malonic acid co-crystal, c/s-itraconazole, posaconazole or saperconazole adipic acid co-crystal and c/s-itraconazole, posaconazole or saperconazole maleic acid co-crystal.
  • a co-crystal form of an API is particularly advantageous where the original API, such as the conazoles including c/s-itraconazole, posaconazole or saperconazole is insoluble or sparingly soluble in water.
  • the co-crystal properties conferred upon the API are also useful because the bioavailability of the API can be improved and the plasma concentration and/or serum concentration of the API can be improved. This is particularly advantageous for orally-administrable formulations.
  • the dose response of the API can be improved, for example by increasing the maximum attainable response and/or increasing the potency of the API by increasing the biological activity per dosing equivalent.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a co-crystal of a conazole including c/s-itraconazole, posaconazole or saperconazole and a co-crystal forming compound, such that the conazole and co-crystal forming compound are capable of co-crystallizing from a solution phase under crystallization conditions or from the solid-state through grinding or heating.
  • the conazole has at least one functional group selected from ether, thioether, alcohol, thiol, aldehyde, ketone, thioketone, nitrate ester, phosphate ester, thiophosphate ester, ester, thioester, sulfate ester, carboxylic acid, phosphonic acid, phosphinic acid, sulfonic acid, amide, primary amine, secondary amine, ammonia, tertiary amine, sp2 amine, thiocyanate, cyanamide, oxime, nitrile diazo, organohalide, nitro, s-heterocyclic ring, thiophene, n-heterocyclic ring, pyrrole, o-heterocyclic ring, furan, epoxide, peroxide, hydroxamic acid, imidazole, pyridine and the co-crystal forming compound has at least one functional group selected from
  • the co-crystals of the present invention are formed where the conazole and co-crystal forming compound are bonded together through a hydrogen bonds. Other non-covalent interactions, including ⁇ -stacking and van-der-waals interactions, may also be present.
  • there is a need to contact the conazole with the co-crystal forming compound This may involve grinding the two solids together or melting one or both components and allowing them to recrystallize. This may also involve either solubilising the conazole and adding the co-crystal forming compound, or solubilising the co-crystal forming compound and adding the conazole.
  • the conazole may be solubilised in the co- crystal forming compound.
  • Crystallisation conditions are applied to the conazole and co-crystal forming compound. This may entail altering a property of the solution, such as pH or temperature and may require concentration of solute, usually by removal of the solvent, typically by drying the solution. Solvent removal results in the concentration of conazole increasing over time so as to facilitate crystallisation. Once the solid phase comprising any crystals is formed, this may be tested as described herein.
  • the co-crystals obtained as a result of such process steps may be readily incorporated into a pharmaceutical composition by conventional means.
  • compositions in general are discussed in further detail below and may further comprise a pharmaceutically-acceptable diluent, excipient or carrier.
  • the present invention provides a process for the production of a pharmaceutical composition, which process comprises: (1) providing a conazole; (2) providing a co-crystal forming compound which has at least one functional group selected from amine, amide, pyridine, imidazole, indole, pyrrolidine, carboxyl, carboxyl, hydroxyl, phenol, sulfone, sulfonyl, mercapto and methyl thio; (3) grinding, heating or contacting in solution the conazole with the co- crystal forming compound under crystallization conditions, and (4) isolating co-crystals formed thereby; and (5) incorporating the co-crystals into a pharmaceutical composition.
  • the present invention provides a process for the production of a pharmaceutical composition, which comprises: (1) grinding, heating or contacting in solution a conazole with a co-crystal forming compound, under crystallization conditions, so as to form a solid phase; (2) isolating co-crystals comprising the conazole and the co-crystal forming compound.
  • Assaying the solid phase for the presence of co-crystals of the conazole and the co-crystal forming compound may be carried out by conventional methods known in the art. For example, it is convenient and routine to use powder X-ray diffraction techniques to assess the presence of the co-crystals.
  • Other techniques used in an analogous fashion, include differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and Raman spectroscopy. Single crystal X-ray diffraction is especially useful in identifying co-crystal structures.
  • the present invention therefore provides a process of screening for co-crystal compounds, which comprises: (1) providing (/) a conazole compound, and (ii) a co-crystal forming compound; (2) screening for co-crystals of conazoles with co-crystal forming compounds by subjecting each combination of conazole and co-crystal forming compound to a step comprising: (a) grinding, heating or contacting in solution the conazole with the co- crystal forming compound under crystallization conditions so as to form a solid phase; (b) isolating co-crystals comprising the conazole and the co-crystal forming compound.
  • An alternative embodiment is drawn to a process of screening for co-crystal compounds, which comprises: (1) providing (/) a conazole or a plurality of different conazoles, and (ii) a co-crystal forming compound or a plurality of different co-crystal forming compounds, wherein at least one of the conazole and the co-crystal forming compound is provided as a plurality thereof; (2) screening for co-crystals of conazoles with co-crystal forming compounds by subjecting each combination of conazole and co-crystal forming compound to a step comprising (a) grinding, heating or contacting in solution the conazole with the co- crystal forming compound under crystallization conditions so as to form a solid phase; (b) isolating co-crystals comprising the conazole and the co-crystal forming compound.
  • the present invention provides a process for modulating the solubility of a conazole, which process comprises: (1) grinding, heating or contacting in solution the conazole with a co- crystal forming compound under crystallization conditions, so as to form a co-crystal of the conazole and the co-crystal forming compound; (2) isolating co-crystals comprising the conazole and the co-crystal forming compound.
  • the solubility of the conazole is modulated such that the aqueous solubility is increased.
  • Solubility of conazoles may be measured by any conventional means such as spectroscopic determination of the amount of conazole in a saturated solution of the conazole, such as UV-spectroscopy, IR-spectroscopy, Raman spectroscopy, quantitative mass spectroscopy or gass chromatography.
  • the conazole may have low aqueous solubility.
  • low aqueous solubility in the present application refers to a compound having a solubility in water which is less than or equal to lOmg/ml, when measured at 37°C, and preferably less than or equal to 5mg/ml or lmg/ml.
  • Low aqueous solubility can further be specifically defined as less than or equal to 900, 800, 700, 600, 500, 400, 300, 200 150 100, 90, 80, 70, 60, 50, 40, 30, 20 micrograms/ml, or further 10, 5 or 1 micrograms/ml.
  • solubility can be increased 2, 3, 4, 5, 7, 10, 15, 20, 25, 50, 75, 100, 200, 300, 500, 750, 1000, 5000, or 10,000 times when compared to crystalline free base, by making a co-crystal of the free form or salt.
  • aqueous solubility can be measured in simulated gastric fluid (SGF) or simulated intestinal fluid (SIF) rather than water (Dressman JB, et al., Pharm Res. (1998) Jan; 15(1): 11-22 incorporated by reference in its entirety).
  • SIF is 0.68% monobasic potassium phosphate, 1% pancreatin, and sodium hydroxide where the pH of the final solution is 7.5.
  • the pH may also be specified as 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.5, 4, 4.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, or 12.
  • Examples of embodiments includes: co-crystal compositions with an aqueous solubility, at 37 degrees C and a pH of 7.0, that is increased at least 5 fold over the crystalline free form and co-crystal compositions with a solubility in SGF that is increased at least 5 fold over the crystalline free form.
  • Dissolution Modulation In another aspect of the present invention, the dissolution profile of the conazole is modulated whereby the aqueous dissolution rate or the dissolution rate in simulated gastric fluid or in simulated intestinal fluid, or in a solvent or plurality of solvents is increased or decreased.
  • Dissolution rate is the rate at which conazole solids dissolve in a dissolution media. Conazoles that are not dissolved before they are removed from intestinal absorption site are considered useless. Therefore, the rate of dissolution has a major impact on the performance of conazoles that are poorly soluble. Because of this factor, the dissolution rate of conazoles in solid dosage forms is an important, routine, quality control parameter used in the conazole manufacturing process.
  • Dissolution rate K S (C 3 -C) where K is dissolution rate constant, S is the surface area, C s is the apparent solubility, and C is the concentration of conazole in the dissolution media.
  • the dissolution rate of conazoles may be measured by conventional means known in the art.
  • the increase in the dissolution rate of a co-crystal, as compared to the crystalline free form, may be specified, such as by 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100%, or by 2, 3, 4, 5 ,6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 75, 100, 125, 150, 175, 200 fold greater than the free form or salt form in the same solution. Conditions under which the dissolution rate is measured is the same as discussed above The increase in dissolution may be further specified by the time the composition remains supersaturated.
  • Examples of above embodiments includes: co-crystal compositions with an dissolution rate, at 37 degrees C and a pH of 7.0, that is increased at least 5 fold over the crystalline free form and co-crystal compositions with a dissolution rate in SGF that is increased at least 5 fold over the crystalline free form.
  • Bioavailability Modulation The methods of the present invention are used to make a pharmaceutical conazole formulation with greater solubility, dissolution, and bioavailability, AUC, reduced time to T max , the time to reach peak blood serum levels, and higher C maX; , the maximum blood serum concentration, when compared to the neutral form or salt alone.
  • AUC is the area under the plot of plasma concentration of conazole (not logarithm of the concentration) against time after conazole administration. The area is conveniently determined by the "trapezoidal rule": the data points are connected by straight line segments, perpendiculars are erected from the abscissa to each data point, and the sum of the areas of the triangles and trapezoids so constructed is computed.
  • the AUC from t n to infinite time is estimated by C n /k e i.
  • the AUC is of particular use in estimating bioavailability of conazoles, and in estimating total clearance of conazoles (Cl ⁇ ).
  • AUC F • D/Cl ⁇ , where F is the availability of the conazole.
  • the present invention provides a process for modulating the bioavailability of a conazole when administered in its normal and effective dose range, whereby the AUC is increased, the time to T max is reduced, or Cmax is increased, which process comprises: (1) grinding, heating or contacting in solution the conazole with a co- crystal forming compound under crystallization conditions, so as to form a co-crystal of the conazole and the co-crystal forming compound; (2) isolating co-crystals comprising the conazole and the co-crystal forming compound.
  • Examples of the above embodiments includes: co-crystal compositions with a time to T max that is reduced by at least 10% as compared to the free crystalline form, co-crystal compositions with a time to T max that is reduced by at least 20% over the free crystalline form, co-crystal compositions with a time to T ma ⁇ that is reduced by at least 40% over the free crystalline form, co-crystal compositions with a time to T max that is reduced by at least 50% over the free crystalline form, co-crystal compositions with a T max that is reduced by at least 60% over the free crystalline form, co-crystal compositions with a T max that is reduced by at least 70% over the free crystalline form, co-crystal compositions with a T ma ⁇ that is reduced by at least 80% over the free crystalline form, co-crystal compositions with a C max that is increased by at least 20% over the free crystalline form, co-crystal compositions with a C max that is increased by at least 30% over the free
  • the present invention provides a process for improving the dose response of a conazole, which process comprises: (1) contacting in solution a conazole with a co-crystal forming compound under crystallization conditions, so as to form a co-crystal of the conazole and the co- crystal forming compound; (2) isolating co-crystals comprising the conazole and the co-crystal forming compound.
  • Dose response is the quantitative relationship between the magnitude of response and the dose inducing the response and may be measured by conventional means known in the art.
  • the curve relating effect (as the dependent variable) to dose (as the independent variable) for a conazole-cell system is the "dose-response curve".
  • the dose-response curve is the measured response to a conazole plotted against the dose of the conazole (mg/kg) given.
  • the dose response curve can also be a curve of AUC against the dose of the conazole given.
  • the present invention provides a process for improving the stability of a conazole in its free form or a salt thereof, which process comprises:
  • compositions of the present invention including the conazole or active pharmaceutical ingredient (conazole) and formulations comprising the conazole, are suitably stable for pharmaceutical use.
  • the conazole or formulations thereof of the present invention are stable such that when stored at 30 deg. C for 2 years, less than 0.2% of any one degradant is formed.
  • degradant refers herein to product(s) of a single type of chemical reaction. For example, if a hydrolysis event occurs that cleaves a molecule into two products, for the purpose of the present invention, it would be considered a single degradant.
  • RH relative humidity
  • the relative humidity (RH) may be specified as ambient (RH), 75% (RH), or as any single integer between 1 to 99%.
  • the present invention provides a process for making co- crystals of unsaltable conazoles which process comprises
  • Difficult to salt compounds include bases with a pKa ⁇ 3 or acids with a pKa > 10. Zwitterions are also difficult to salt or unsaltable compounds.
  • the present invention provides a method for decreasing the hygroscopicity of a conazole, which method comprises
  • An aspect of the present invention provides a pharmaceutical composition comprising a co-crystal of a conazole that is less hygroscopic than amorphous or crystalline, free form or salt (including metal salts such as sodium, potassium, lithium, calcium, magnesium).
  • Hygroscopicity can be assessed by dynamic vapor sorption analysis, in which 5-50 mg of the compound is suspended from a Cahn microbalance.
  • the compound being analyzed should be placed in a non-hygroscopic pan and its weight should be measured relative to an empty pan composed of identical material and having nearly identical size, shape, and weight. Ideally, platinum pans should be used.
  • the pans should be suspended in a chamber through which a gas, such as air or nitrogen, having a controlled and known percent relative humidity (%RH) is flowed until eqilibrium criteria are met.
  • a gas such as air or nitrogen
  • Typical equilibrium criteria include weight changes of less than 0.01 % change over 3 minutes at constant humidity and temperature.
  • the relative humidity should be measured for samples dried under dry nitrogen to constant weight ( ⁇ 0.01 % change in 3 minutes) at 40 degrees C unless doing so would de- solvate or otherwise convert the material to an amorphous compound.
  • the hygroscopicity of a dried compound can be assessed by increasing the RH from 5 to 95 % in increments of 5 % RH and then decreasing the RH from 95 to 5 % in 5 % increments to generate a moisture sorption isotherm.
  • the sample weight should be allowed to equilibrate between each change in %RH. If the compound deliquesces or becomes amorphous between above 75 % RH, but below 95 % RH, the experiment should be repeated with a fresh sample and the relative humidity range for the cycling should be narrowed to 5-75 % RH or 10-75 % RH instead of 5-95 %RH.
  • Hygroscopicity can be defined using various parameters.
  • a non-hygroscopic molecule should not gain or lose more than 1.0%, or more preferably, 0.5 % weight at 25degrees C when cycled between 10 and 75 % RH (relative humidity at 25 degrees C).
  • the non-hygroscopic molecule more preferably should not gain or lose more than 1.0%, or more preferably, 0.5 % weight when cycled between 5 and 95 %RH at 25 degrees C, or more than 0.25 % of its weight between 10 and 75 % RH. Most preferably, a non-hygroscopic molecule will not gain or lose more than 0.25 % of its weight when cycled between 5 and 95 % RH.
  • hygroscopicity can be defined using the parameters of Callaghan et al., Equilibrium moisture content of pharmaceutical excipients, in Conazole Dev. Ind. Pharm., Vol. 8, pp. 335-369 (1982). Callaghan et al. classified the degree of hygroscopicity into four classes.
  • Class 1 Non-hygroscopic Essentially no moisture increases occur at relative humidities below 90%.
  • Class 2 Slightly hygroscopic Essentially no moisture increases occur at relative humidities below 80%.
  • Class 3 Moderately hygroscopic Moisture content does not increase more than 5% after storage for 1 week at relative humidities below 60%.
  • Class 4 Very hygroscopic Moisture content increase may occur at relative humidities as low as 40 to 50%.
  • hygroscopicity can be defined using the parameters of the European Pharmacopoeia Technical Guide (1999, p. 86) which has defined hygrospocity, based on the static method, after storage at 25°C for 24 h at 80 percent RH: Slightly hygroscopic: Increase in mass is less than 2 percent m/m and equal to or greater than 0.2 percent m/m. Hygroscopic: Increase in mass is less than 15 percent m/m and equal to or greater than 0.2 percent m/m. Very Hygroscopic: Increase in mass is equal to or greater than 15 percent m/m. Deliquescent: Sufficient water is absorbed to form a liquid.
  • Co-crystals of the present invention can be set forth as being in Class 1, Class 2, or Class 3, or as being Slightly hygroscopic, Hygroscopic, or Very Hygroscopic. Co-crystals of the present invention can also be set forth based on their ability to reduce hygroscopicity. Thus, preferred co-crystals of the present invention are less hygroscopic than the conazole.
  • the reference compound can be specified as the conazole in free form (free acid, free base, hydrate, solvate, etc.) or salt (e.g., metal salt such as sodium, potassium, lithium, calcium, or magnesium).
  • co-crystals that do not gain or lose more than 1.0% weight at 25 degrees C when cycled between 10 and 75 % RH, wherein the reference compound gains or loses more than 1.0% weight under the same conditions.
  • co-crystals that do not gain or lose more than 0.5% weight at 25 degrees C when cycled between 10 and 75 % RH, wherein the reference compound gains or loses more than 0.5% or more than 1.0% weight under the same conditions.
  • co-crystals that do not gain or lose more than 0.5% weight at 25 degrees C when cycled between 5 and 95 % RH, wherein the reference compound gains or loses more than 0.5% or more than 1.0% weight under the same conditions.
  • co-crystals that do not gain or lose more than 0.25% weight at 25 degrees C when cycled between 5 and 95 % RH, wherein the reference compound gains or loses more than 0.5% or more than 1.0% weight under the same conditions.
  • co-crystals that have a hygroscopicity (according to Callaghan et al.) that is at least one class lower than the reference compound or at least two classes lower than the reference compound.
  • a Class 1 co-crystals of a Class 2 reference compound a Class 2 co- crystals of a Class 3 reference compound, a Class 3 co-crystals of a Class 4 reference compound, a Class 1 co-crystals of a Class 3 reference compound, a Class 1 co- crystals of a Class 4 reference compound, or a Class 2 co-crystals of a Class 4 reference compound.
  • co-crystals that have a hygroscopicity (according to the European Pharmacopoeia Technical Guide) that is at least one class lower than the reference compound or at least two classes lower than the reference compound.
  • Non-limiting examples include; a slightly hygroscopic co- crystals of a hygroscopic reference compound, a hygroscopic co-crystals of a very hygroscopic reference compound, a very hygroscopic co-crystals of a deliquescent reference compound, a slightly hygroscopic co-crystals of a very hygroscopic reference compound, a slightly hygroscopic co-crystals of a deliquescent reference compound, a hygroscopic co-crystals of a deliquescent reference compound.
  • the present invention demonstrates that crystalline phases can be engineered by combining molecules selected to match hydrogen bond donors with acceptors and by considering structural complementarities.
  • the present invention further shows that supramolecular synthesis can be applied to active pharmaceutical ingredients using organic acid and base combinations with pK a differences that are inconsistent with salt formation in water (given the pK a value of 3.7 for the piperazine of itraconazole, conventional wisdom would limit a salt screen to those strong acids having dissociation constants below 1.7).
  • An aspect of the present invention includes co-crystals comprising or consisting of hydrogen-bonded trimers consisting of two molecules of c/s- itraconazole (or two molecules of posaconazole or two molecules of saperconazole) and one molecule of a dicarboxylic acid (e.g., succinic acid).
  • Preferred dicarboxylic acid co-crystals of c/s-itraconazole, posaconazole or saperconazole have a crystal strucmre as shown in Figure 1.
  • the drug molecule (see Figure 1) is composed of a three ring backbone (A-C), a triazole ring (D), a spacer group (E) and a terminating group (F).
  • the trimer has two drug molecules oriented anti-parallel to each other with a second molecule, a dicarboxylic acid, (G) templating or filling the void between the two drug molecules.
  • the distance between the carboxylic acid oxygen (-O(H)), one of the possible function groups of molecule G, and the tirazole nitrogen (-N-), D can be between 3.4 and 1.8 angstroms, more preferably between 3.2 and 2.3 angstroms, still more preferably between 3.0 and 2.5 angstroms and more preferable still between 2.8 and 2.6 angstroms.
  • the distance between the two drug molecules that make up the trimer as measured by the distance between a nitrogen atom in ring A of one molecule and ring A of the second molecule can be between about 7.5 and about 6.4 angstroms, more preferably between about 7.0 and about 6.6 angstroms and still more preferably about 6.8 angstroms.
  • the distance between the two triazole rings (D) in the trimer, as measured by the shortest distance between two nitrogen atoms, with one each separate molecule, can be between about 12.5 and about 8.0 angstroms, more prefereably between about 11 and about 10.6 angstroms and still more preferably about 10.8 angstroms.
  • the trimer can also, in some cases, be defined further by being oriented around a center of inversion located at the center of molecule G.
  • the dicarboxylic acid that is used to fill the pocket of the trimer can be for example, fumaric acid, succinic acid, tartaric acid, DL- tartaric acid, D-tartaric acid, L-tartaric acid, meso-tartaric acid, d-malic acid, L-malic acid, DL-malic acid, malonic, glutaric acid, adipic acid or acetic acid.
  • the crystal strucmre of one congener ( Figure 2 for itraconazole; (actual), Figure 3 for posaconazole (proposed) and Figure 4 for saperconazole (proposed)) reveals an unanticipated and specific interaction between the triazole of the conazole and the diacid in the solid state (the solid grey atoms are ca bon, the open atoms are hydrogens, the small dots (or light gray) are nitrogen atoms the large dots (black and white) are oxygen and the other atoms (hatched) are either chlorine or fluorine, depending on the compound.
  • compositions of the invention comprise a therapeutically effective amount of an acid salt, co-crystal, solvate, hydrate, or multicomponent crystalline system such as c/s-itraconazole, posaconazole or saperconazole HCI salt tartaric acid co-crystal, or a soluble, multicomponent crystalline system comprising c/s-itraconazole, posaconazole or saperconazole di- mesylate and ethanol, or a soluble, multicomponen't crystalline system comprising c/s- itraconazole, posaconazole or saperconazole di-mesylate and dioxane.
  • an acid salt such as c/s-itraconazole, posaconazole or saperconazole HCI salt tartaric acid co-crystal, or a soluble, multicomponent crystalline system comprising c/s-itraconazole, posaconazole or saperconazole
  • the present invention provides a soluble crystalline form or a formulation of a soluble crystalline form of a conazole with a decreased food effect.
  • a soluble crystalline form or a formulation of a soluble crystalline form of itraconazole is provided which has a decreased food effect with respect to that of a reference form (e.g., itracoxiazole free base, a salt of itraconazole, or a polymorph, hydrate solvate, or co-crystal thereof) or a reference formulation (e.g., Sporanox®).
  • a reference form e.g., itracoxiazole free base, a salt of itraconazole, or a polymorph, hydrate solvate, or co-crystal thereof
  • a reference formulation e.g., Sporanox®
  • the present invention provides a method for decreasing the food effect of a conazole.
  • a method for decreasing the food effect of a conazole comprising administering to a mammal a soluble crystalline form or a formulation of a soluble crystalline form of the present invention.
  • a method for decreasing the food effect o-f itraconazole comprises administering to a mammal a soluble crystalline fo:rm or a formulation of a soluble crystalline form of the present invention such as, but not limited to, itraconazole HCl:DL-tartaric acid co-crystal.
  • the decrease in food effect discussed in the above methods can be measured with respect to the food effect observed from a reference form (e.g., itraconazole free base, a salt of itraconazole, or a polymorph, hydrate solvate, or co-crystal thereof) or a reference formulation (e.g., Sporanox®).
  • a reference form e.g., itraconazole free base, a salt of itraconazole, or a polymorph, hydrate solvate, or co-crystal thereof
  • a reference formulation e.g., Sporanox®
  • a further embodiment of the invention encompasses a method of treating or preventing local or systemic fungal, yeast, and dermatophyte infections in a patient which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a pharmaceutically acceptable soluble crystalline form of a conazole (including c/s-itraconazole, posaconazole or saperconazole), including salts, co-crystals, salt co-crystals and hydrates, solvates or polymorphs thereof.
  • a conazole including c/s-itraconazole, posaconazole or saperconazole
  • the invention includes a method for treating or preventing local and systemic fungal, yeast, and dermatophyte infections in a patient comprising administering to a patient in need of such treatment or prevention, a therapeutically or prophylactically effective amount of a composition of the present invention including a salt or co-crystal of c/s-itraconazole, posaconazole or saperconazole such as c/s-itraconazole, posaconazole or saperconazole di-mesylate, c/s-itraconazole, posaconazole or saperconazole tartaric acid co-crystal, c/s- itraconazole, posaconazole or saperconazole fumaric acid co-crystal, c/s-itraconazole, posaconazole or saperconazole malonic acid co-crystal, c/s-itraconazole, posaconazole or saperconazole mal
  • the invention further encompasses the use of a dicarboxylic acid salt or co- crystal of c/s-itraconazole, posaconazole or saperconazole.
  • Methods of treatment include administration of pharmaceutical compositions of the invention comprising a therapeutically effective amount of an acid salt c/s-itraconazole, posaconazole or saperconazole HCI salt tartaric acid co-crystal, or a soluble, multicomponent crystalline system comprising c/s-itraconazole, posaconazole or saperconazole di- mesylate and ethanol, or a soluble, multicomponent crystalline system comprising c/s- itraconazole, posaconazole or saperconazole di-mesylate and dioxane.
  • Pharmaceutical dosage forms of the invention comprise a therapeutically or prophylactically effective amount of a novel soluble crystalline form of c/s- itraconazole, posaconazole or saperconazole, including hydrates, solvates or polymorphs thereof. These dosage forms also comprise a soluble, multicomponent crystalline system comprising c/s-itraconazole, posaconazole or saperconazole organic salt and an organic solvent. These compositions can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. Oral pharmaceutical compositions and dosage forms are a preferred dosage form.
  • the oral dosage form is a solid dosage form, such as a tablet, a caplet, a hard gelatin capsule, a starch capsule, a hydroxypropyl methylcellulose (“HPMC”) capsule, or a soft elastic gelatin capsule.
  • Other preferred dosage forms include an intradermal dosage form, an intramuscular dosage form, a subcutaneous dosage form, and an intravenous dosage form.
  • compositions and dosage forms of the invention comprise an active ingredient as disclosed herein, e.g., an acid salt c/s-itraconazole, posaconazole or saperconazole HCI salt tartaric acid co-crystal or a soluble, multicomponent crystalline system comprising c/s-itraconazole, posaconazole or saperconazole organic salt and an organic solvent.
  • Pharmaceutical compositions and unit dosage forms of the invention typically also comprise one or more pharmaceutically acceptable excipients or diluents.
  • the pharmaceutical compositions and unit dosage forms of the invention typically also comprise one or more pharmaceutically acceptable excipients or diluents, wherein at least one of the pharmaceutically acceptable excipients or diluents is an antioxidant.
  • Pharmaceutical unit dosage forms of this invention are suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., intramuscular, subcutaneous, intravenous, intraarterial, or bolus injection), topical, or transdermal administration to a patient.
  • dosage forms include, but are not limited to: tablets; caplets; capsules, such as hard gelatin capsules, starch capsules, hydroxypropyl methylcellulose ("HPMC") capsules, and soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; cataplasms (poultices); pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage
  • composition, shape, and type of dosage forms of the invention will typically vary depending on their use.
  • a dosage form used in the acute treatment of a disease or disorder may contain larger amounts of the active ingredient than a dosage form used in the chronic treatment of the same disease or disorder.
  • a parenteral dosage form may contain smaller amounts of the active ingredient than an oral dosage form used to treat the same disease or disorder.
  • Typical pharmaceutical compositions and dosage forms comprise one or more excipients.
  • Suitable excipients are well known to those skilled in the art of pharmacy, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a patient.
  • oral dosage forms such as tablets or capsules may contain excipients not suited for use in parenteral dosage forms.
  • pharmaceutical compositions or dosage forms may contain one or more compounds that reduce or alter the rate by which the active ingredient will decompose.
  • antioxidants include, but are not limited to, antioxidants, pH buffers, or salt buffers.
  • One or more antioxidants can be used in pharmaceutical compositions and dosage forms to deter radical oxidation of the active ingredient, wherein such antioxidants include, but are not limited to, ascorbic acid, phenolic antioxidants including, but not limited to, butylated hydroxyanisole (BHA) and propyl gallate, and chelators including, but not limited to citrate, EDTA, and DTPA.
  • BHA butylated hydroxyanisole
  • chelators including, but not limited to citrate, EDTA, and DTPA.
  • a combination of phenolic antioxidants and chelators can be used.
  • dosage forms of the invention comprise a pharmaceutically acceptable salt and co- crystal of c/s-itraconazole, posaconazole or saperconazole or its stereoisomers, selected from the group consisting of c/s-itraconazole, posaconazole or saperconazole malic acid co-crystal and c/s-itraconazole, posaconazole or saperconazole-HCl, and pharmaceutically acceptable hydrates, solvates, polymorphs, and co-crystals thereof, in an amount of from about 10 mg to about 1000 mg, preferably in an amount of from about 25 mg to about 500 mg, more preferably in an amount of from 40 mg to 400 mg, and most preferably in an amount of from about 50 mg to about 200 mg.
  • compositions of the invention that are suitable for oral administration can be presented as discrete dosage forms, such as, but not limited to, tablets (including without limitation scored or coated tablets), pills, caplets, capsules (including without limitation hard gelatin capsules, starch capsules, HPMC capsules, and soft elastic gelatin capsules), chewable tablets, powder packets, sachets, troches, wafers, aerosol sprays, or liquids, such as but not limited to, syrups, elixirs, solutions or suspensions in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil emulsion.
  • tablets including without limitation scored or coated tablets
  • pills including without limitation hard gelatin capsules, starch capsules, HPMC capsules, and soft elastic gelatin capsules
  • chewable tablets powder packets, sachets, troches, wafers, aerosol sprays, or liquids, such as but not limited to, syrups, elixirs, solutions
  • compositions contain a predetermined amount of the active ingredient, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19th ed., Mack Publishing, Easton PA (1995).
  • Typical oral dosage forms of the invention are prepared by combining the active ingredient in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients can take a wide variety of forms depending on the form of the composition desired for administration.
  • excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.
  • excipients suitable for use in solid oral dosage forms include, but are not limited to, starches, sugars, microcrystalline cellulose, kaolin, diluents, granulating agents, lubricants, binders, stabilizers, and disintegrating agents. Due to their ease of administration, tablets, caplets, and capsules (such as hard gelatin, HPMC, or starch capsules) represent the most advantageous solid oral dosage unit forms, in which case solid pharmaceutical excipients are used.
  • tablets or caplets can be coated by standard aqueous or nonaqueous techniques.
  • These dosage forms can be prepared by any of the methods of pharmacy.
  • pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredient(s) with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.
  • a tablet can be prepared by compression or molding.
  • Compressed tablets can be prepared by compressing in a suitable machine the active ingredient(s) in a free-flowing form, such as a powder or granules, optionally mixed with one or more excipients.
  • Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • excipients that can be used in oral dosage forms of the invention include, but are not limited to, binders, stabilizers, fillers, disintegrants, and lubricants.
  • Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.
  • natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl
  • Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, and AVICEL-PH-105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA, U.S.A.), and mixtures thereof.
  • An exemplary suitable binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC-581.
  • Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103TM and Starch 1500 LM.
  • fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • the binder or filler in pharmaceutical compositions of the invention is typically present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.
  • Disintegrants can be used in the pharmaceutical compositions and dosage forms to provide tablets or caplets that disintegrate when exposed to an aqueous environment.
  • Tablets or caplets that contain too much disintegrant may disintegrate in storage, while those that contain too little may be insufficient for disintegration to occur and may thus alter the rate and extent of release of the active ingredient(s) from the dosage form.
  • a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) should be used to form solid oral dosage forms of the invention.
  • the amount of disintegrant used varies based upon the type of formulation and mode of administration, and is readily discernible to those of ordinary skill in the art.
  • Typical pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of disintegrant, preferably from about 1 to about 5 weight percent of disintegrant.
  • Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, clays, other algins, other celluloses, gums, and mixtures thereof.
  • Antioxidants can be used in the pharmaceutical compositions and dosage forms to deter degradation or radical oxidation of the active ingredient.
  • antioxidants include, but are not limited to, ascorbic acid, phenolic antioxidants including, but not limited to, butylated hydroxyanisole (BHA) and propyl gallate, and chelators including, but not limited to, citrate, EDTA, and DTPA, or combinations thereof.
  • BHA butylated hydroxyanisole
  • chelators including, but not limited to, citrate, EDTA, and DTPA, or combinations thereof.
  • Lubricants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.
  • Additional lubricants include, for example, a syloid silica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, MD), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Piano, TX), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA), and mixtures thereof. If used at all, lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.
  • Other oral dosage forms for pharmaceutical compositions of the invention are soft elastic gelatin capsules. Soft elastic gelatin capsule unit dosage forms can be made using conventional methods well known in the art. See, e.g., Ebert, Pharm.
  • soft elastic gelatin capsules also known as "soft gels" have an elastic or soft, globular or oval shaped gelatin shell that is typically a bit thicker than that of hard gelatin capsules, wherein a plasticizing agent, e.g., glycerin, sorbitol, or a similar polyol, is added to a gelatin.
  • a plasticizing agent e.g., glycerin, sorbitol, or a similar polyol
  • the type of gelatin, as well as the amounts of plasticizer and water, can be used to vary the hardness of the capsule shell.
  • the soft gelatin shells may contain a preservative, such as methyl- and propylparabens and sorbic acid, to prevent the growth of fungi.
  • the active ingredient may be dissolved or suspended in a liquid vehicle or carrier, such as vegetable or mineral oils, glycols, such as polyethylene glycol and propylene glycol, triglycerides, surfactants, such as polysorbates, or a combination thereof.
  • a liquid vehicle or carrier such as vegetable or mineral oils, glycols, such as polyethylene glycol and propylene glycol, triglycerides, surfactants, such as polysorbates, or a combination thereof.
  • Active ingredients of the invention can be administered by controlled or delayed release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,566; each of which is incorporated herein by reference in its entirety.
  • Such dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof, to provide the desired release profile in varying proportions.
  • Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients of the invention.
  • the invention thus encompasses single unit dosage forms suitable for oral administration such as, but not limited to, tablets, pills, capsules, gelcaps, and caplets, that are adapted for controlled- release.
  • controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts.
  • the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the disease or condition in a minimum amount of time.
  • Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance.
  • controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects.
  • Controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body.
  • Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or can also be stimulated by compounds.
  • controlled-release pharmaceutical products can be designed to also initially release one or more additional active ingredients (such as a metabolic inhibitor) that can effect characteristics of the other active ingredient (such as c/s- itraconazole, posaconazole or saperconazole malic acid co-crystal and c/s- itraconazole, posaconazole or saperconazole-HCl, or a hydrate, solvate, polymorph, or co-crystal thereof).
  • a metabolic inhibitor such as a CYP3A4 inhibitor can be used to inhibit first-pass hepatic metabolism of the active ingredient.
  • Topical dosage forms of the invention include, but are not limited to, creams, lotions, ointments, gels, shampoos, sprays, aerosols, solutions, emulsions, and other forms know to one of skill in the art. See, e.g., Remington 's Pharmaceutical Sciences, 18 th ed., Mack Publishing, Easton, PA (1990); and Introduction to Pharmaceutical Dosage Forms, 4 th ed., Lea & Febiger, Philadelphia, PA (1985).
  • viscous to semi-solid or solid forms comprising a carrier or one or more excipients compatible with topical application and having a dynamic viscosity preferably greater than water are typically employed.
  • Suitable formulations include, without limitation, solutions, suspensions, emulsions, creams, ointments, powders, liniments, salves, and the like, which are, if desired, sterilized or mixed with auxiliary agents (e.g., preservatives, stabilizers, wetting agents, buffers, or salts) for influencing various properties, such as, for example, osmotic pressure.
  • auxiliary agents e.g., preservatives, stabilizers, wetting agents, buffers, or salts
  • suitable topical dosage forms include sprayable aerosol preparations wherein the active ingredient, preferably in combination with a solid or liquid inert carrier, is packaged in a mixture with a pressurized volatile (e.g., a gaseous propellant, such as freon), or in a squeeze bottle.
  • a pressurized volatile e.g., a gaseous propellant, such as freon
  • Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms if desired. Examples of such additional ingredients are well known in the art. See, e.g., Remington's Pharmaceutical Sciences, 18 th ed., Mack Publishing, Easton, PA (1990).
  • Parenteral dosage forms can be administered to patients by various routes, including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Since administration of parenteral dosage forms typically bypasses the patient's natural defenses against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions. Suitable vehicles that can be used to provide parenteral dosage forms of the invention are well known to those skilled in the art.
  • Examples include, without limitation: sterile water; Water for Injection USP; saline solution; glucose solution; aqueous vehicles such as but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and propylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • the solutions are preferably isotonic and have a physiological pH.
  • Compounds that increase the solubility the active ingredient(s) disclosed herein can also be incorporated into the parenteral dosage forms of the invention.
  • Transdermal and mucosal dosage forms of the invention include, but are not limited to, ophthalmic solutions, patches, sprays, aerosols, creams, lotions, suppositories, ointments, gels, solutions, emulsions, suspensions, or other forms know th to one of skill in the art. See, e.g. , Remington 's Pharmaceutical Sciences, 18 ed., Mack Publishing, Easton, PA (1990); and Introduction to Pharmaceutical Dosage Forms, 4 th ed., Lea & Febiger, Philadelphia, PA (1985).
  • Dosage forms suitable for treating mucosal tissues within the oral cavity can be formulated as mouthwashes, as oral gels, or as buccal patches.
  • transdermal dosage forms include "reservoir type” or “matrix type” patches, which can be applied to the skin and worn for a specific period of time to permit the penetration of a desired amount of active ingredient.
  • Suitable excipients e.g., carriers and diluents
  • other materials that can be used to provide transdermal and mucosal dosage forms encompassed by this invention are well known to those skilled in the pharmaceutical arts, and depend on the particular tissue or organ to which a given pharmaceutical composition or dosage form will be applied.
  • excipients include, but are not limited to water, acetone, ethanol, ethylene glycol, propylene glycol, butane- 1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof, to form dosage forms that are non-toxic and pharmaceutically acceptable.
  • additional components may be used prior to, in conjunction with, or subsequent to treatment with active ingredients of the invention.
  • penetration enhancers can be used to assist in delivering the active ingredients to or across the tissue.
  • Suitable penetration enhancers include, but are not limited to: acetone; various alcohols such as ethanol, oleyl, an tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; and various water-soluble or insoluble sugar esters such as TWEEN 80 (polysorbate 80) and SPAN 60 (sorbitan monostearate).
  • the pH of a pharmaceutical composition or dosage form, or of the tissue to which the pharmaceutical composition or dosage form is applied may also be adjusted to improve delivery of the active ingredient(s).
  • a solvent carrier its ionic strength, or tonicity
  • Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of the active ingredient(s) so as to improve delivery.
  • stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a delivery- enhancing or penetration-enhancing agent.
  • Different hydrates, solvates, polymorphs, or co-crystals of the active ingredient can be used to further adjust the properties of the resulting composition.
  • compositions and dosage forms thereof possess potent activity against and are useful for treating or preventing local and systemic fungal, yeast, and dermatophyte infections.
  • pharmaceutically acceptable soluble crystalline form of c/s-itraconazole, posaconazole or saperconazole, and pharmaceutical compositions and dosage forms thereof can be used to treat or prevent blastomycosis, aspergillosis, histoplasmosis, onychomycosis, coccidioidomycosis, paracoccidioidomycosis, cryptococcosis, dermatophyte, and candidiasis infections.
  • the magnimde of a prophylactic or therapeutic dose of each active ingredient in the acute or chronic management of a disease or disorder will vary with the disease or disorder itself, the specific active ingredients, and the route of administration.
  • the dose, dose frequency, or both may also vary according to age, body weight, response, the past medical history of the patient, and consideration of whether the patient is or will be concurrently or concomitantly taking other dmgs or pharmaceuticals.
  • Suitable dosing regimens can be readily selected by the skilled artisan with due consideration of such factors by following, for example, dosages and dose regimens reported in the literature and recommended in the Physician's Desk Reference ® (56 th ed., 2002) for itraconazole or saperconazole; which can be extended for determining dosing of posaconazole.
  • the magnitude of a prophylactic or therapeutic dose of the active ingredient used in an embodiment of the invention will be that which is safe and effective (e.g., has received regulatory approval).
  • the active ingredient e.g., soluble crystalline forms of c/s-itraconazole, posaconazole or saperconazole di-mesylate, c/s- itraconazole, posaconazole or saperconazole tartrate, c/s-itraconazole, posaconazole or saperconazole fumaric acid co-crystal, c/s-itraconazole, posaconazole or saperconazole malonic acid co-crystal, c/s-itraconazole, posaconazole or saperconazole maleic acid co-crystal, c/s-itraconazole, posaconazole or saperconazole adipic acid co-crystal,
  • the dosage amounts can be administered in single or divided doses.
  • the dosage amounts and frequencies provided above are encompassed by the terms “therapeutically effective”, “prophylactically effective”, and “therapeutically or prophylactically effective” as used herein.
  • the suitability of a particular route of administration employed for a particular active ingredient will depend on the active ingredient itself (e.g., whether it can be administered orally without decomposing prior to entering the blood stream) and the disease or disorder to be treated or prevented.
  • topical administration is typically preferred for treating or preventing local diseases or disorders of the skin
  • oral or parenteral administration is typically preferred for systemic diseases or disorders, or diseases or disorders within the body of the patient.
  • oral or parenteral administration may be preferred for the treatment or prevention of acute diseases or disorders
  • transdermal or subcutaneous routes of administration may be employed for treatment or prevention of a chronic disease or disorder.
  • Soluble crystalline form of c/s-itraconazole, posaconazole or saperconazole can be made using various methods known to those skilled in the art. For example, methods for the chemical synthesis of ( ⁇ )c/s-itraconazole are described in U.S. Pat. No. 4,267,179 and Heeres, J. et al, J. Med. Chem., 27:894-900 (1984), both of which are incorporated by reference herein in their entirety.
  • the four individual stereoisomeric forms of the compounds of formula (I), or diastereomeric pairs or mixtures thereof, can be prepared and purified using various methods known to those skilled in the art, such as those described in U.S. Pat. No.
  • Salts and co-crystals of c/s-itraconazole, posaconazole or saperconazole include without limitation, pharmaceutically acceptable salts prepared by treating c/s- itraconazole, posaconazole or saperconazole free base with appropriate acids, such as organic or inorganic acids, including without limitation, malic acid, hydrochloric acid, sulfuric acid, fumaric acid, phosphoric acid, tartaric acid, maleic acid, malonic acid, adipic acid, benzenesulfonic acid, and the like.
  • the process for forming a salt or co-crystal can be carried out in a solvent system in which both reactants (i.e., a conazole such as c/s-itraconazole, posaconazole or saperconazole free base and the respective acid) are sufficiently soluble.
  • a solvent or solvent mixmre in which the resulting salt and co-crystal is only slightly soluble or not soluble at all is used.
  • a solvent in which the desired salt and co-crystal is very soluble can be used, and then an anti-solvent (or a solvent in which the resulting salt is poorly soluble) is added to the solution.
  • salt formation or crystallization includes concentrating the salt and co-crystal solution (e.g., by heating, under reduced pressure if necessary, or by slowly evaporating the solvent, for example, at room temperature), or seeding with the addition of seed crystals, or setting up water activity required for hydrate formation.
  • c/s-itraconazole, posaconazole or saperconazole and a dicarboxylic acid e.g., a dicarboxylic acid of formula (IV)
  • THF e.g., a dicarboxylic acid of formula (IV)
  • the samples were examined by powder x-ray diffraction (PXRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and/or the hygroscopicity of the samples were determined, as set forth below.
  • PXRD powder x-ray diffraction
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • Thermogravimetic analysis of each sample was performed using a Q500 Thermogravimetric Analyzer (TA Instruments, New Castle, DE, U.S.A.), which uses as its control software Advantage for QW-Series, version 1.0.0.78, Thermal Advantage Release 2.0 ( ⁇ 2001 TA Instruments- Water LLC), with the following components: QDdv.exe version 1.0.0.78 build 78.2; RHBASE.DLL version 1.0.0.78 build 78.2; RHCOMM.DLL version 1.0.0.78 build 78.0; RHDLL.DLL version 1.0.0.78 build 78.1; an TGA.DLL version 1.0.0.78 build 78.1.
  • the analysis software used was Universal Analysis 2000 for Windows 95/95/2000/NT, version 3.
  • thermogravimetric analysis comprised transferring an aliquot of a sample into a platinum sample pan (Pan part # 952019.906; (TA Instruments, New Castle, DE USA)). The pan was placed on the loading platform and was then automatically loaded into the Q500 Thermogravimetric Analyzer using the control software.
  • Thermograms were obtained by individually heating the sample at 10°C/minute across a temperature range (generally from 25°C to 300°C) under flowing dry nitrogen (compressed nitrogen, grade 4.8 (BOC Gases, Murray Hill, NJ USA)), with a sample purge flow rate of 60 mL/minute and a balance purge flow rate of 40 mL/minute. Thermal transitions (e.g., weight changes) were viewed and analyzed using the analysis software provided with the instrument.
  • DSC analysis of each sample was performed using a Q1000 Differential Scanning Calorimeter (TA Instruments, New Castle, DE, U.S.A.), which uses Advantage for QW-Series, version 1.0.0.78, Thermal Advantage Release 2.0 ( ⁇ 2001 TA Instruments- Water LLC), with the following components: QDdv.exe version 1.0.0.78 build 78.2; RHBASE.DLL version 1.0.0.78 build 78.2; RHCOMM.DLL version 1.0.0.78 build 78.0; RHDLL.DLL version 1.0.0.78 build 78.1; an TGA.DLL version 1.0.0.78 build 78.1.
  • the analysis software used was Universal Analysis 2000 for Windows 95/95/2000/NT, version 3.
  • the sample pan was loaded into the Q1000 Differential Sanning Calorimeter, which is equipped with an autosampler, and a thermogram was obtained by individually heating the same using the control software at a rate of 10°C/minute from T m ⁇ n (typically 30°C) to T ma ⁇ (typically 300°C) using an empty aluminum pan as a reference.
  • Dry nitrogen compressed nitrogen, grade 4.8 (BOC Gases, Murray Hill, NJ USA)
  • the precipitate can be amorphous or crystalline.
  • the loaded capillary tube was mounted in a holder that was placed and fitted into the x-y stage.
  • a diffractogram was acquired using control software (RINT Rapid Control Software, Rigaku Rapid/XRD, version 1.0.0 ( ⁇ 1999 Rigaku Co.)) under ambient conditions at a power setting of 46 kV at 40 mA in transmission mode, while oscillating about the omega-axis from 0-5 degrees at 1 degree/second, and spinning about the phi-axis over 360 degrees at 2 degrees/second.
  • the exposure time was 15 minutes unless otherwise specified.
  • the diffractogram obtained was integrated of 2-theta from 2-60 degrees and chi (1 segment) from 0-36 degrees at a step size of 0.02 degrees using the cyllnt utility in the RINT Rapid display software (RINT Rapid display software, version 1.18 (Rigaku/MSC)) provided by Rigaku with the instrument.
  • the dark counts value was set to 8 as per the system calibration by Rigaku. No normalization or omega, chi or phi offsets were used for the integration.
  • the relative intensity of peaks in a diffractogram were determined by visual comparison of the peaks in the diffractogram.
  • the relative intensity of the peaks is not necessarily a limitation of the PXRD pattern because peak intensity can vary from sample to sample due to crystalline impurities.
  • angles of each peak can vary by about +/-0.1 degrees.
  • the entire pattern or most of the pattern peaks may also shift by about +/-0.1 degree due to differences in calibration, settings, and other variations from instrument to instrument and operator to operator.
  • the relative intensity is designated as strong (S), medium (M), and weak (W).
  • the hygroscopicity profiles for a sample from each of vials 1-5, as well as c/s- itraconazole free base, were determined by exposing a sample from each of vials 1-5 to four different environments of varying relative humidity (namely, 0%, 30%, 57%, and 75%), and incubating the samples in that environment for about 8 hours at room temperature (20-25 °C).
  • the humidity chambers consisted of desiccators with desiccants/salt baths in the bottom, above which the open vials containing samples were suspended.
  • Solid phosphorous pentoxide was used to achieve ⁇ 0 % relative humidity
  • saturated aqueous magnesium bromide solution was used to provide ⁇ 30 % relative humidity
  • saturated aqueous sodium bromide solution was used to provide ⁇ 57 % relative humidity
  • saturated aqueous sodium chloride solution was used to provide ⁇ 75 % relative humidity.
  • the relative hygroscopicity of each sample was determined using methods well known to one skilled in the pharmaceutical arts as reported in "Pharmaceutical Preformulation & Formulation: A Practical Guide From Candidate Drug Selection to Commercial Dosage Form," Ed. Mark Gibson, published by IHS Health Group Co, p. 49 (2001), which is incorporated herein by reference in its entirety.
  • samples exhibiting greater than 0.2% and less than 2% weight loss after incubation in 75% relative humidity at 25°C for 8 hours are categorized as slightly hygroscopic.
  • Samples exhibiting greater than 2% and less than 15% weight loss after incubation in 75% relative humidity at 25°C for 8 hours are categorized as hygroscopic.
  • samples exhibiting weight loss greater than or equal to 15% after incubation in 75% relative humidity at 25°C for 8 hours are categorized as very hygroscopic.
  • the solid was collected by filtration and washed with cold absolute ethanol (15 mL). The white solid was dried in a vacuum oven overnight at 80°C. The crystalline substance was found to be a DL-tartaric acid co-crystal of itraconazole hydrochloride.
  • the solid was characterized by PXRD and DSC, as shown in figures 5(a) and 5(b), respectively.
  • the c/s-itraconazole HCl:DL-tartaric acid co-crystal can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 5(a) including, but not limited to, 3.72, 10.94, 13.90, 14.19, 16.61, 17.71, 19.01, 19.76, 21.29, 21.91, 24.10, and 24.89 degrees 2-theta (Rigaku, data as collected).
  • the DSC thermogram of the c/s-itraconazole HCl:DL-tartaric acid co-crystal showed an endothermic transition at about 161 degrees C, as shown in Figure 5(b).
  • the solid was collected by filtration and washed with cold absolute ethanol (15 mL). The white solid was dried in a vacuum oven overnight at 80°C. The crystalline substance was found to be a D-tartaric acid co-crystal of itraconazole hydrochloride.
  • the solid was characterized by PXRD and DSC, as shown in figures 6(a) and 6(b), respectively.
  • the c/s-itraconazole HCl:D-tartaric acid co-crystal can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 6(a) including, but not limited to, 3.72, 10.92, 13.89, 14.17, 16.61, 17.67, 19.00, 19.75, 21.29, 21.95, 24.05, and 24.87 degrees 2-theta (Rigaku, data as collected).
  • the DSC thermogram of the c/s-itraconazole HCl:DL-tartaric acid co-crystal showed an endothermic transition at about 161 degrees C, as shown in Figure 6(b).
  • the solid was collected by filtration and washed with cold absolute ethanol (15 mL). The white solid was dried in a vacuum oven overnight at 80°C. The crystalline substance was found to be an L-tartaric acid co-crystal of itraconazole hydrochloride.
  • the solid was characterized by PXRD and DSC, as shown in figures 7(a) and 7(b), respectively.
  • the c/s-itraconazole HCl:L-tartaric acid co-crystal can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 7(a) including, but not limited to, 3.74, 10.92, 14.00, 16.69, 17.66, 19.06, 19.86, 21.42, 21.96, 24.07, and 24.84 degrees 2-theta (Rigaku, data as collected).
  • the DSC thermogram of the c/s-itraconazole HCI: DL-tartaric acid co-crystal showed an endothermic transition at about 162 degrees C, as shown in Figure 7(b).
  • Co-crystals of a salt of c/s-itraconazole exhibited decreased hygroscopicity over that of the c/s-itraconazole salt.
  • the DL-tartaric acid co-crystal has the lowest hygroscopicity of the three co- crystals.
  • a di-HCl c/s-itraconazole salt in the D- and L-tartaric acid co-crystal samples.
  • the stability of the c/s-itraconazole HCl:DL-tartaric acid co-crystal is higher under certain solvent conditions than that in a co-crystal with the free base, such as c/s-itraconazole:succinic acid.
  • the c/s-itraconazole HChDL-tartaric acid co- crystal is stable over time in solvent while the c/s-itraconazole:succinic acid co-crystal can dissociate into free base and succinic acid.
  • Formulation Ml Preparation- Itraconazole HChDL-Tartaric Acid Co-crystal 367.0 mg of hydroxypropyl cellulose 100,000 (HPC) was weighed into a glass mortar. 366.3 mg of itraconazole HChDL-tartaric acid co-crystal was added to the mortar. The components were ground using a pestle and mixed with a spatula until the powder appeared well mixed and uniform in appearance. 736.9 mg of d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS) was added to a vial and heated to 60 degrees C to melt. The blended powder of co-crystal and HPC was added to the molten TPGS and mixed by both vortexing and stirring with a spatula until uniform. The formulation was left to cool to room temperature resulting in a waxy, white solid.
  • HPC hydroxypropyl cellulose 100,000
  • the resultant formulation was labeled Ml.
  • Pentagastrin was administered subcutaneously to each dog at a dose volume of 0.1 mL/kg in an attempt to stimulate gastric secretion.
  • Pentagastrin was prepared as a solution in dimethylsulfoxide (DMSO) and hydroxypropyl beta-cyclodextrin (HPCD in water) on the day of dose administration at a concentration of 1.5 mg/mL.
  • DMSO dimethylsulfoxide
  • HPCD hydroxypropyl beta-cyclodextrin
  • the area under the plasma concentration versus time curve from time zero to the last quantifiable concentration (AUCn-t) was calculated by the linear trapezoidal method.
  • AUCo- ⁇ the area under the plasma concentration versus time curve from time zero to infinity, was calculated as the sum of AUCo- t plus the ratio of the last plasma concentration to K e ⁇ .
  • the apparent systemic clearance (CL/F) was determined by dividing the dose by the area under the curve from time zero to infinity. Values below the limit of quantification were assigned a value of zero for pharmacokinetic analysis.
  • Table 1 shows the results of an in vivo study of the pharmacokinetic parameters of itraconazole in plasma following a single oral administration of Sporanox® or formulation Ml to male beagle dogs.
  • AUCo- ⁇ The area under the plasma concentration versus time curve from time zero to infinity (ng'hr/mL)
  • AUC o- t The area under the plasma concentration versus time curve from time zero to 24 hr post-dose (ng'hr/mL)
  • C max The highest observable concentration (ng/mL) fe: Terminal phase half-life (hr)
  • CL/F Clearance (mL/hr»kg)
  • Tma X Time to Cmax (hr) Untruncated values were used for calculation purposes
  • the Ml formulation is shown, in Table 1, to have a decreased sensitivity to the pH increase in the stomach when compared to Sporanox®.
  • Table 2 shows the concentrations of hydroxy-itraconazole metabolite in plasma (ng/mL) following the above single oral administration of Sporanox® (2.5 mg itraconazole/kg) to male beagle dogs (pentagastrin administration).
  • Table 3 shows the concentrations of hydroxy-itraconazole metabolite in plasma (ng/mL) following the above single oral administration of formulation Ml (2.5 mg itraconazole/kg) to male beagle dogs (pentagastrin administration).
  • the formulation was pressed into pellets using a Stokes Tablet Press (DT Industries model 511). Pellets were pressed to a diameter of 2.38 mm, and a height of 1.30 mm at an average applied pressure of 14000 psi. The average pellet mass was 5.8 mg.
  • the resultant formulation was labeled J12A.
  • Pentagastrin was prepared as a solution in dimethylsulfoxyde (DMSO) and hydroxypropyl beta-cyclodextrin (HPCD in water) on the day of dose administration at a concentration of 1.5 mg/mL.
  • DMSO dimethylsulfoxyde
  • HPCD hydroxypropyl beta-cyclodextrin
  • dogs received one capsule of J12A orally at a target dose of itraconazole of 2.5 mg/kg.
  • blood samples were collected from each animal by jugular venipuncture at selected time-points.
  • Table 4 shows the concentrations of itraconazole and hydroxy-itraconazole in plasma (ng/mL) following a single oral administration (2.5 mg/kg) of J12A to male beagle dogs.
  • Table 5 shows the mean pharmacokinetic parameters of itraconazole in plasma following a single oral administration of J12A (2.5 mg itraconazole/kg) to male beagle dogs.
  • AUC 0 . ⁇ The area under the plasma concentration versus time curve from time zero to infinity (ng « hr/mL)
  • AUC o- t The area under the plasma concentration versus time curve from time zero to 24 hr post-dose (ng'hr/mL)
  • C max The highest observable concentration (ng/mL)
  • T max Time to Cmax (hr) t : Terminal phase half-life (hr)
  • Table 6 shows the mean pharmacokinetic parameters of hydroxy-itraconazole in plasma following a single oral administration of J12A (2.5 mg itraconazole/kg) to -male beagle dogs.
  • Form A can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in the PXRD diffractogr- m in Figure 8 including, but not limited to, 4.57, 8.67, 10.72, 14.41, 16.55, 17.48, 17.96, 19.32, 20.33, 22.41, 23.43, 25.29, and 27.06 degrees 2-theta.
  • Forms B, C, and D have been characterized via PXRD. The characterization data and the methods of making are described below for each of these forms.
  • c/s-Itraconazole Form B was obtained from crystallized c/s-itraconazole recovered from dissolution testing of a formulation of c/s-itraconazole HChDL-tartaric acid co- crystal.
  • the formulation contained 25 % c/s-itraconazole:DL-tartaric acid co-crysrtal, 25 % poloxamer 407, 25 % PEG 6000, 20 % Avicel, and 5 % HPMC 5 cps.
  • the formulation was dry blended in a mortar and pestle. About 100 mg of the formulation was loaded into a gelatin capsule and the capsule was dropped into approximately 10 mL of simulated gastric fluid (SGF) at pH 2.0 and 37 degrees C.
  • SGF simulated gastric fluid
  • Form B can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in the PXRD diffractogram in Figure 9 including, but not limited to, 7.23, 8.60, 10.61, 11.02, 12.17, 13.45, 14.11, 16.51, 17.55, 18.48, 19.06, 19.77, 20.36, 21.69, 23.34, 25.18, and 26.99 degrees 2- theta.
  • c/s-Itraconazole Form C was obtained from crystallized c/s-itraconazole recovered from dissolution testing of a formulation of c/s-itraconazole HChDL-tartaric acid co- crystal.
  • the formulation contained 25 % c/s-itraconazole:DL-tartaric acid co-crystal, 25 % vitamin-E TPGS, 25 % PEG 20000, and 25 % HPMC 5 cps.
  • the formulation was dry blended in a mortar and pestle. About 100 mg of the formulation was loaded into a gelatin capsule and the capsule was dropped into approximately 10 mL of simulated gastric fluid (SGF) at pH 2.0 and 37 degrees C.
  • SGF simulated gastric fluid
  • Form C can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in the PXRD diffractogram in Figure 10 including, but not limited to, 7.22, 8.68, 11.08, 14.10, 15.75, 16.42, 17.58, 18.47, 18.88, 19.77, 21.71, and 22.94 degrees 2-theta.
  • c/s-Itraconazole Form D was obtained from crystallized c/s-itraconazole recovered from dissolution testing of a formulation of c/s-itraconazole HChDL-tartaric acid co- crystal.
  • the formulation contained 25 % c/s-itraconazole:DL-tartaric acid co-crystal, 25 % vitamin-E TPGS, 25 % PEG 20000, and 25 % HPMC 5 cps.
  • the formulation was dry blended in a mortar and pestle. About 100 mg of the formulation was loaded into a gelatin capsule and the capsule was dropped into approximately 10 mL of simulated gastric fluid (SGF) at pH 2.0 and 37 degrees C.
  • SGF simulated gastric fluid
  • Form D can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in the PXRD diffractogram in Figure 11 including, but not limited to, 5.97, 7.22, 8.74, 11.09, 14.09, 15.77, 16.46, 17.60, 18.50, 18.93, 19.77, 21.71, 22.97, 23.90, and 26.97 degrees 2-theta.
  • Figure 12 shows a comparison of the four PXRD diffractograms of c/s-itraconazole Forms A, B, C, and D.

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Abstract

L'invention concerne de nouvelles formes cristallines de conazole soluble (par ex. de l'itraconazole, du posaconazole et du saperconazole) notamment des sels, des cocristaux et des solvates associés utiles en tant que produits pharmaceutiques. L'invention concerne également des compositions pharmaceutiques contenant ces formes cristallines de conazole et des procédés de préparation de celles-ci. L'invention concerne enfin des procédés d'utilisation de ces compositions dans le traitement ou la prévention d'infections locales fongiques, d'infections aux levures, et d'infections dermatophytes.
EP04782868A 2004-02-26 2004-09-01 Nouvelles formes cristallines de conazoles et procedes de preparation et d'utilisation de celles-ci Withdrawn EP1718640A4 (fr)

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PCT/US2004/006288 WO2004078163A2 (fr) 2003-02-28 2004-02-26 Compositions pharmaceutiques a base d'un co-cristal
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US10/926,842 US7446107B2 (en) 2002-02-15 2004-08-26 Crystalline forms of conazoles and methods of making and using the same
PCT/US2004/028456 WO2005092884A1 (fr) 2004-02-26 2004-09-01 Nouvelles formes cristallines de conazoles et procedes de preparation et d'utilisation de celles-ci

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EP1718640A4 (fr) 2008-01-09
JP2007525502A (ja) 2007-09-06

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