JP2007525502A - Novel crystalline forms of conazoles and methods for their production and use - Google Patents

Abstract

  The present invention provides novel soluble conazole crystal forms (eg, itraconazole, posaconazole and saperconazole), including salts, co-crystals and related solvates, useful as pharmaceuticals. The present invention also provides pharmaceutical compositions comprising these conazole crystal forms and methods for their production. Also provided are methods of using such compositions for the treatment or prevention of systemic and topical fungi, yeast, and dermatophyte infections.

Description

Related applications

  This application is based on US Patent Provisional Application No. 60 / 451,213 filed on Feb. 28, 2003, US Provisional Application No. 60 / 487,064 filed on Jul. 11, 2003, 2003. Application PCT / US03 / 27772 filed on September 4, US Patent Application No. 10 / 660,202 filed on September 11, 2003, Application PCT / US03 filed on March 3, 2003 No. 066662, U.S. Provisional Application No. 60 / 508,208 filed on October 2, 2003, U.S. Provisional Application No. 60 / 542,752 filed on Feb. 6, 2004, April 2003. U.S. Provisional Application No. 60 / 463,962, filed on May 18, US Patent Application No. 10 / 449,307, filed May 30, 2003, March 18, 2003 U.S. Provisional Application No. 60 / 456,027, U.S. Patent Application No. 10 / 601,092 filed on June 20, 2003, PCT / US03 filed on Jun. 20, 2003 And 19574, and a continuation-in-part of application PCT / US04 / 006288, filed February 26, 2004, claiming the rights of application PCT / US03 / 41273, filed December 24, 2003.

  This application also includes US Provisional Application No. 60 / 590,590, filed June 23, 2004, Application PCT / US04 / 006288, filed February 26, 2004, September 11, 2004. No. 10 / 660,200, filed on Sep. 4, 2003, PCT / US03 / 27772, filed on Jul. 11, 2003, US Provisional Application No. 60/487, filed Jul. 11, 2003. No. 1064/307, filed on May 30, 2003, PCT / US03 / 17184 filed on May 30, 2003, filed April 18, 2003 U.S. Provisional Application No. 60 / 463,962, filed Feb. 28, 2003 U.S. Provisional Application No. 60 / 451,213, Jan. 31, 2003 US Provisional Application No. 60 / 444,315, filed on Jan. 10, 2003, U.S. Provisional Application No. 60 / 439,282, filed on Jan. 10, 2003, and U.S. Application filed on May 31, 2002. Application No. XX / XXX, XXX, filed Aug. 26, 2004, claiming the rights of patent provisional application 60 / 384,152 (“New crystalline forms of conazoles and methods for their production and use”) Of the inventor J. Remenar et al).

  The U.S. Patent Application No. XX / XXX, XXX filed on Aug. 26, 2004 is a U.S. Provisional Application No. 60 / 384,152 filed May 31, 2002, Jan. 10, 2003. U.S. Provisional Application No. 60 / 439,282, filed Jan. 31, 2003, and U.S. Provisional Application No. 60 / 444,315, filed Jan. 31, 2003, and filed Apr. 18, 2003 This is a continuation-in-part of US patent application Ser. No. 10 / 449,307 filed on May 30, 2003, claiming the rights of US Provisional Patent Application No. 60 / 463,962.

  The U.S. Patent Application No. XX / XXX, XXX, filed on August 26, 2004, is a U.S. Provisional Application No. 10 / 449,307, filed May 30, 2003, May 31, 2002. U.S. Provisional Application No. 60 / 384,152 filed on the same day, U.S. Provisional Application No. 60 / 439,282 filed on Jan. 10, 2003, U.S. Application filed on Jan. 31, 2003 Patent Provisional Application No. 60 / 444,315 and Application PCT filed May 30, 2003 claiming the rights of US Provisional Application No. 60 / 463,962 filed April 18, 2003 / US03 / 17184, part continuation application.

The U.S. Patent Application No. XX / XXX, XXX, filed August 26, 2004,
US Provisional Application No. 10 / 378,956 filed on March 3, 2003, US Provisional Application No. 60 / 463,962 filed on April 18, 2003, February 28, 2003 No. 60 / 451,213 filed on Sep. 4, 2003, and U.S. Provisional Application No. 60 / 487,064 filed July 11, 2003, on September 4, 2003 It is also a partial continuation application of PCT / US03 / 27772 for which it was filed. No. 10 / 378,956, filed Mar. 3, 2003, claims the rights of US Provisional Application No. 60 / 360,768, filed Mar. 1, 2002.

  The application XX / XXX, XXX filed on August 26, 2004 was filed on September 11, 2003, claiming the rights of PCT / US03 / 27772, filed September 4, 2003. It is also a continuation-in-part of US Patent Application No. 10 / 660,202. US patent application Ser. No. 10 / 660,202 filed on Sep. 11, 2003 is related to US Provisional Application No. 60 / 406,974 filed Aug. 30, 2002, May 15, 2002. September 3, 2002 claiming the rights of US Provisional Application No. 60 / 380,288 filed on the same day and US Provisional Application No. 60 / 356,764 filed February 15, 2002 US patent application Ser. No. 10 / 232,589, filed on Nov. 18, 2002, which is a continuation of US patent application Ser. No. 10 / 295,995, filed on August 8, 2003. We also claim the rights of US patent application Ser. No. 10 / 637,829 filed in No. 10 / 660,202, filed Sep. 11, 2003, is US Provisional Application No. 60 / 463,962, filed Jan. 31, 2003, filed Apr. 18, 2003. U.S. Provisional Application No. 60 / 444,315, filed on Jan. 10, 2003, U.S. Provisional Application No. 60 / 439,282, filed Jan. 10, 2003, and filed May 31, 2002 It is also a continuation-in-part of US patent application Ser. No. 10 / 449,307 filed on May 30, 2003, claiming the rights of US Provisional Patent Application No. 60 / 384,152. The US Patent Application No. 10 / 660,202, filed on September 11, 2003, is also a continuation-in-part of US Patent Application No. 10 / 601,092, filed on June 20, 2003. . No. 10 / 660,202, filed on Sep. 11, 2003, is US Provisional Application No. 60 / 451,213, filed Feb. 28, 2003, Apr. 18, 2003. We also claim the rights of US Provisional Application No. 60 / 463,962, filed on the same day, and US Provisional Application No. 60 / 487,064, filed June 11, 2003.

  The U.S. Patent Application No. XX / XXX, XXX filed on Aug. 26, 2004 is a provisional application No. 60 / 451,213 filed Feb. 28, 2003, Jul. 11, 2003. U.S. Provisional Application No. 60 / 487,064, filed on Sep. 4, 2003, PCT / US03 / 27772, filed Sep. 4, 2003, U.S. Patent Application No. 10 /, filed Sep. 11, 2003, No. 660,202, application PCT / US03 / 06662, filed March 3, 2003, US Provisional Application No. 60 / 508,208, filed October 2, 2003, February 6, 2004. US Provisional Application No. 60 / 542,752, filed on April 18, 2003, US Provisional Application No. 60 / 463,962 filed on April 18, 2003, filed May 30, 2003 U.S. Patent Application No. 10 / 449,307, U.S. Provisional Application No. 60 / 456,027, filed Mar. 18, 2003, U.S. Patent Application No. 10 filed on Jun. 20, 2003. No./601,009, application PCT / US03 / 19574, filed Jun. 20, 2003, and application PCT / US03 / 41273, filed Dec. 24, 2003. It is also a continuation-in-part of application PCT / US04 / 006288 filed on the day.

The application XX / XXX, XXX filed on August 26, 2004 is filed with US Provisional Application No. 60 / 590,590, filed July 23, 2004, on May 31, 2002. U.S. Provisional Application No. 60 / 384,152, U.S. Provisional Application No. 60 / 439,282, filed Jan. 10, 2003, U.S. Provisional Application, filed Jan. 31, 2003 Application No. 60 / 444,315, U.S. Provisional Application No. 60 / 463,962, filed Apr. 18, 2003, U.S. Provisional Application No. 60/451, filed Feb. 28, 2003. 213 and U.S. Provisional Application No. 60 / 487,064 filed Jul. 11, 2003.

  This application also claims the rights of US Provisional Application No. 60 / 569,036, filed May 7, 2004.

  All of the above applications are incorporated herein by reference.

FIELD OF THE INVENTION The present invention relates to novel soluble sapaconazole and cis-itraconazole crystal forms, including salts, co-crystals and polymorphs, which are useful as pharmaceuticals. provide. The present invention also provides pharmaceutical compositions comprising these saperconazole and cis-itraconazole crystal forms and methods for their production. Also provided are methods of using such compositions for the treatment or prevention of systemic and topical fungi, yeast, and dermatophyte infections. In a preferred embodiment, the present invention comprises (a) an organic salt comprising a reaction product of sappaconazole and an inorganic or organic acid, or (b) comprising a reaction product of sappaconazole and an inorganic or organic acid. A novel soluble crystalline line comprising co-crystals is provided.

  In a preferred embodiment of the invention, the novel soluble crystalline forms of saperconazole and cis-itraconazole are characterized by a powder X-ray diffraction pattern displayed by a 2-theta angle.

Background of the Invention Systemic fungal and mold diseases (systemic mycosis) are typical chronic symptoms that progress very slowly. These diseases are often caused by fungi that are not pathogenic and are either universally alive in the patient's body or are opportunistically found in the environment. Systemic fungus and mold disease was relatively rare in countries with mild climates, but there is now an increased incidence of many life-threatening systemic fungus and mold infections, which is a major threat to hypersensitive patients is there. Hypersensitivity patients include immunocompromised patients, especially those already hospitalized, as well as HIV infection, ion radiation, corticosteroids, immunosuppressants, invasive surgical techniques, long-term exposure to antimicrobial agents, etc. Or includes a patient weakened by a disease or condition such as cancer, leukemia, emphysema, bronchiectasis, diabetes mellitus, burns and the like. Symptoms manifested by these fungal / mold diseases are generally not strong and can include chills, fever, weight loss, loss of appetite, malaise, and depression.

  The most common systemic fungal / fungal infections in humans are blastosis, candidiasis, aspergillosis, histoplasmosis, coccidioidomycosis, paracoccidioidomycosis, and cryptococcosis.

Fungal and mold diseases are often restricted to typical anatomical sites, and many are associated with primary points in the lung, and more specific manifestations of specific fungal and mold infections when the infection spreads from the primary site There is. For example, blastosis is primarily associated with the lungs and sometimes spreads to the skin. Similarly, 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, and spleen. Other infectious diseases such as paracoccidioidomycosis and candidiasis are expressed in different ways and can be expressed in several forms that affect the internal organs, lymph nodes, skin, and mucous membranes depending on the pathogenesis. Diagnosis of specific fungal / fungal diseases can be by isolating pathogenic fungi / fungi from various specimens such as sputum, urine, blood, or bone marrow, or proof of tissue invasion in certain fungi / fungi types Can be performed.

  Many patients with severe fungal and mold infections are often comatose or have severe gastric paralysis, so such patients rarely accept oral medication. Or not at all possible. As a result, the use of insoluble or slightly soluble antibacterial fungi, such as itraconazole free base, which is difficult to administer intravenously to treat such patients is considerably hindered.

  Local or superficial fungal infections are caused by dermatophytes or fungi associated with the outer layers of the skin, nails, or hair. Such infections appear as mild inflammation and can spread gradually, causing alternating regression and appearance of exfoliating progressive lesions. Yeast infections, such as candidiasis and oral candidiasis (oral candidiasis), are usually localized to the skin and mucous membranes, and symptoms vary with the site of infection. In many cases, such infections appear as erythematous, often ugly exudative plaques on the groin, axilla, intraumbilical, toes, and scuffs. Oral candidiasis results in an inflamed tongue or buccal mucosa, typically with exudate white spots. Chronic mucocutaneous candidiasis appears in the form of a red, vesicular, thickened lesion on the forehead or nose.

Itraconazole Chemistry and Use Itraconazole is a wide range of antibacterial and fungal agents developed for oral, parenteral and topical use and is disclosed in US Pat. Itraconazole is a synthetic triazole derivative that disrupts the synthesis of ergosterol, the main sterol of fungal and mold cell membranes. This perturbation results in increased permeability and leakage of intracellular contents, and at high concentrations, the cell's internal organ cells disappear, peroxisomes increase, and necrosis occurs.

As shown in Non-Patent Document 1, itraconazole is (±) -1-sec-butyl-4- [p-4- [p-[[(2R ^* , 4S ^* )-2- (2,4 -Dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl] -Δ ² -1,2 , 4-triazolin-5-one or 4- [4- [4- [4-[[2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazole-1-). Ylmethyl) -1,3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl] -2,4-dihydro-2- (1-methylpropyl) -3H-1,2,4-triazoline- Defined as 5-on. There are three asymmetric carbons within itraconazole, one in the sec-butyl side chain on itraconazole and two in the dioxolane ring. As a result, eight possible stereoisomers of itraconazole, namely (R, R, R), (S, S, S), (R, R, S), (S, S, R), (R , S, S), (R, S, R), (S, R, S), and (S, R, R).

(±) cis-Itraconazole comprises a mixture of only isomers describing the “cis” relationship within the dioxolane ring, ie a (1H-1,2,4-triazol-1-ylmethyl) moiety and substituted The phenoxy moiety is placed on the same side of the plane defined by the 1,3-dioxolane ring. For convenience, the first displayed chiral center is at C-2 of the dioxolane ring, the second is at C-4 of the dioxolane ring, and the third is within the sec-butyl group. Therefore, (±) cis-itraconazole is (R, S, S), (R, S, R)
, (S, R, S) and (S, R, R) isomers.

  The four possible stereoisomeric cis forms of itraconazole, and their diastereomeric pairs are described in more detail in US Pat. In general, the individual stereoisomeric forms of cis-itraconazole have antibacterial and fungal properties and contribute to the overall activity of (±) cis-itraconazole.

  (±) cis-Itraconazole free base is very slightly soluble in water and therefore it is very difficult to produce an effective pharmaceutical composition containing it. In order to increase the solubility of itraconazole free base, complexes or co-formulations with cyclodextrins or their derivatives as described in Patent Literature 4, Patent Literature 3, and Patent Literature 5, and Patent Literature 6 Many means have been used, including coated beads as described.

  Another method for increasing the solubility of itraconazole is the two diastereomers ((R, S, S) and (R, S, R), as described in US Pat. The preparation of stereoisomers of cis-itraconazole, and in particular (2R, 4S) itraconazole, which may comprise a mixture of

Commercial Itraconazole (SPORANOX®) ⁽ ±) cis-Itraconazole, Janssen Pharmaceutical Products Products, LP, Chissville, NJ, USA ) Is the free base and is a racemic mixture of cis isomers within the dioxolane ring and has the structural formula (I):

Is displayed. Sporanox ^(R) was immunocompromised with blastomices (pulmonary and extrapulmonary); histoplasmosis, including chronic cavernous lung disease and disseminated non-meningeal histoplasmosis; and aspergillosis And approved for use as an antimicrobial / fungal agent to treat patients who are not immunocompromised. Furthermore, it was approved for the treatment of onychomycosis in patients who were not immunocompromised. See generally Non-Patent Document 2. This compound was also investigated for use in coccidioides, cryptocox, dermatophytes, and candida infections.

  Side effects associated with the administration of (±) cis-itraconazole free base are nausea, nausea, loss of appetite, headache, dizziness, hepatotoxicity, as well as drug metabolism in the liver resulting in many clinically significant malignant drug interactions. Includes suppression. See Non-patent document 2, Non-patent document 3 (terfenadine interaction), Non-patent document 4 (midazolam interaction), and Non-patent document 5 (lovastatin interaction). Reactions associated with hypersensitivity, such as urticaria and elevated serum liver enzymes, are also associated with drug administration. A more serious but less universal side effect is hepatotoxicity. For example, see Non-Patent Document 6.

  Moreover, as disclosed herein, cis-itaconazole free base is very slightly soluble in water. Therefore, because of its relative nonpolarity and insolubility, itraconazole free base also has two other drawbacks: it cannot be formulated into parenteral solutions, and it does not penetrate the blood-brain barrier efficiently. . The latter problem is exacerbated by drug interactions such as those observed between itraconazole free base and valproate, as described in Non-Patent Document 7, which is incorporated herein by reference. In another case of CNS fungus infection, the extreme of itraconazole free base to treat sequelae Aspergillus infection as described in Non-Patent Document 8, which is incorporated herein by reference. High doses were used. As a result, many therapeutic instructions that require rapid achievement of effective blood levels or reaching the CNS make treatment difficult or unattainable for treatment with itraconazole free base.

Furthermore, the occurrence of antibacterial / mold resistance (for example, Aspergillus fumigatus (Aspergillus as described in Non-Patent Document 9, which is incorporated herein by reference)
fumigatus)) is an additional challenge for the efficacy of itraconazole free base. For these resistant strains of fungi, molds, a high and relatively constant level of itraconazole free base must be produced in the target organ of the infected patient.

Over the years, many formulation schemes have been used to enhance itraconazole adsorption and bioavailability. For example, recently sold Itorakonazo free base of the solid dosage Supora Knox a capsule ^(R) utilizes the beads based sugar coated hydrophilic polymer and an amorphous film of itraconazole . See Non-Patent Document 10 and Patent Document 6. This dosage form requires up to 2 capsules 3 times a day depending on the condition to be treated.

  Even with various formulas, the dosage and frequency of itraconazole can be cumbersome for the patient. Furthermore, existing dosage forms of itraconazole show significant variability in bioavailability and adsorption, which also results from food effects. See Non-Patent Document 10. Therefore, adsorption to provide improvements over recent therapies, especially with respect to patient compliance, convenience, ease of consumption, and especially with immunocompromised multidrug patients (eg, AIDS or cancer patients) It is also desirable to increase bioavailability and reduce the number of pills per dose and reduce the frequency of doses (eg, twice per day to once per day).

The chemistry and use of posaconazole and saperconazole Other related conazoles have also been discovered and used as antibacterial and fungicides. Two of these conazoles that are structurally similar and related to itraconazole are posaconazole and saperconazole. Posaconazole (CAS registration number: 171228-49-2: CAS name: 2,5-anhydro-1,3,4-trideoxy-2-C- (2,4-difluorophenyl) -4-[[4- [4 -[4- [1-[(1S, 2S) -1-ethyl-2-hydroxypropyl] -1,5-dihydro-5-oxo-4H-1,2,4-triazol-4-yl] phenyl] -1-piperazinyl] phenoxy] methyl] -1- (1H-1,2,4-triazol-1-yl) -D-threo-pentitol: also known as: (3R-cis) -4- [4- [4 -[4- [5- (2,4-difluorophenyl) -5- (1,2,4-triazol-1-ylmethyl) tetrahydrofuran-3-ylmethoxyphenyl] piperazin-1-yl] phenyl] -2- [1 (S)- Chill -2 (S) - hydroxypropyl] -3,4-dihydro-2H-1,2,4-triazol-3-one) have the structural formula (II):

Is displayed.

Saperconazole (CAS registration number: 110588-57-3: CAS name: 4- [4- [4- [4-[[2- (2,4-difluorophenyl) -2- (1H-1,2, 4-triazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl] -2,4-dihydro-2- (1-methylpropyl) -3H-1, 2,4-triazol-3-one; also known as: (±) -1-sec-butyl-4- [p- [4- [p-[[(2R ^* , 4S ^* )-2- (2,4- Difluorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl] -Δ ² -1,2 , 4-triazolin-5-one) Formula (III):

Is displayed.
U.S. Pat. No. 4,267,179 US Pat. No. 5,474,997 US Pat. No. 5,998,413 US Pat. No. 4,764,604 US Pat. No. 5,707,975 US Pat. No. 5,633,015 USP Dictionary of Drug Names and USAN Physician's Disk Reference, 56th ed. (2002) Honig et al. , J .; Clin. Pharmacol. 33: 1201-1206 (1993) Gascon and Dayer, Eur. J. et al. Clin. Pharmacol. , 41: 573-578 (1991). Neuvonen et al. , Clin. Pharmacol. Therap. 60: 54-61 (1996). Lavrijsen et al. Lancet, 340: 251-252 (1992). Villa et al. Rev. Inst. Med. Top. , Sao Paulo, pp. 231-234 (Jul-Aug 2000) Imai et al. , Intern. Med. , 38 (10): 829-832 (1999) Danauui et al. , J .; Antimicrob. Chemother, 47: 333-340 (2001). Physicians Disk Reference, 56th ed. Pp. 1800-1804 (2002)

  Accordingly, there is a need for soluble forms of conazoles including cis-itraconazole, posaconazole and saperconazole that can be readily formulated for use in a variety of modes of administration, including parenteral and oral administration.

SUMMARY OF THE INVENTION The present invention provides a reaction product of conazole and organic or inorganic acids, including multi-component crystal systems having salts, co-crystals, solvates and three or more components (including itraconazole). Novel soluble crystalline forms of conazoles including cis-itraconazole, posaconazole or saperconazole comprising the product are provided. In one embodiment, the soluble crystalline form of conazole comprises a conazole, such as cis-itraconazole, posaconazole or sapaconazole, and a reaction product of a dicarboxylic acid or carboxylic acid. The present invention relates to organic solvates of conazole, including cis-itraconazole, posaconazole or saperconazole salts, and crystalline forms of acid salts of conazole, such as cis-itraconazole, posaconazole or saperconazole HCl salt tartaric acid co-crystals, I will provide a. The present invention includes novel soluble conazole (eg, cis-itraconazole, posaconazole or saperconazole) salts, co-crystals, solvates (including hydrates), and polymorphs.

In one aspect, the invention is a soluble multi-component crystalline system comprising (a) a reaction product of conazole and an organic or inorganic acid, and (b) one or more organic or inorganic solvents. The organic solvent is present in the system in a stoichiometric or non-stoichiometric ratio with respect to the second reaction product of the organic salt or conazole and the organic or inorganic acid.

  In another embodiment, the multi-component crystal system is a co-crystal comprising a co-crystal former and conazole.

  In another aspect, the reaction product is a salt.

  In another aspect, the reaction product is a co-crystal.

  In another embodiment, the first reaction product is a salt and the second reaction product is a co-crystal.

  In another embodiment, the system comprises a first reaction product, a second reaction product and a solvent.

  In another aspect, the present invention provides a co-crystal comprising a co-crystal former and a conazole free base or a co-crystal former and a conazole salt. Any co-crystal form may comprise a solvent as presented herein.

  Further, in a preferred embodiment of the invention, the novel soluble crystalline form of cis-itraconazole is characterized by an endothermic transition temperature, Raman spectrum, crystalline form or by a powder X-ray diffraction pattern displayed at 2 theta angles, where The X-ray powder diffraction pattern comprises the 2-theta angle values listed here.

  The present invention also provides pharmaceutical compositions comprising crystalline forms of conazole (eg, cis-itraconazole, posaconazole or saperconazole), including salts, co-crystals, solvates, and the like, and methods for their production. To do. Also provided are methods of using such compositions for the treatment or prevention of systemic and local fungi, molds, yeast, and dermatophyte infections.

  The compounds of the present invention are cis-itraconazole, posaconazole or saperconazole D, L and D, L-tartaric acid co-crystals, cis-itraconazole citrate, posaconazole or saperconazole, cis-itraconazole, posaconazole or saperconazole Fumaric acid co-crystal, cis-itraconazole, posaconazole or sapaconazole malonic acid co-crystal, cis-itraconazole, posaconazole or sapaconazole maleic acid co-crystal, cis-itraconazole, posaconazole or sapaconazole adipic acid co-crystal Cis-itraconazole, posaconazole or saperconazole dimesylate, cis-itraconazole, posaconazole or saperconazole succinic acid co-crystal, cis-ito sulfate Conazole, posaconazole or sapaconazole, cis-itraconazole benzenesulfonate, posaconazole or sapaconazole, cis-itraconazole, posaconazole or sapaconazole besylate, cis-itraconazole, posaconazole or sapaconazole di-HCl, cis-itraconazole, Posaconazole or saperconazole malic acid co-crystal, cis-itraconazole, posaconazole or saperconazole HCl salt D, L, or D, L-tartaric acid co-crystal, cis-itraconazole, posaconazole or saperconazole di-mesylate dioxane Solvates, cis-itraconazole, posaconazole or sapaconazole di-mesylate ethanol solvate, or cis-phosphate Conazole, including multi-component co-crystals of traconazole, posaconazole or saperconazole, and acid salts, cis-itraconazole, posaconazole or saperconazole salts, co-crystals, solvates, and hydrates of these compounds Including, but not limited to, a class of soluble crystalline forms. Preferred soluble crystalline forms of the conazoles of the present invention (eg, cis-itraconazole, posaconazole or saperconazole) include dicarboxylic acid salts, dicarboxylic acid co-crystals, and hydrochloride 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. Other preferred compounds of the invention include alcohol solvates (eg, ethanol, methanol, propylene glycol, propanol, etc.) or crystalline forms of dioxane solvate, or conazole (eg, cis-itraconazole, posaconazole or saperconazole) Co-crystals 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 oxalic acid co-crystal are included. In one embodiment, the co-crystal includes a co-crystal former and a conazole salt. In another embodiment, the co-crystal further comprises a solvent.

In another aspect, the present invention provides a soluble crystalline form or a soluble crystalline form of conazole having reduced food action. In specific embodiments, a control form (eg, itraconazole free base, a salt of itraconazole, or polymorphs, hydrates, solvates, or co-crystals thereof) or a control formulation (eg, Sporanox® ⁾ A soluble crystalline form or a soluble crystalline form of itraconazole having a reduced food action compared to

In another aspect, the present invention provides a method of reducing the food effect of conazole. There is provided a method of reducing the food effect of conazole comprising administering to a mammal a soluble crystalline form or a soluble crystalline form preparation of the present invention. For example, a method of reducing 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. Comprising. The reduction in food action discussed in the method above is a control form (eg, itraconazole free base, a salt of itraconazole, or polymorphs, hydrates, solvates, or co-crystals thereof) or a control formulation (eg, Can be measured in terms of the food effect observed from Sporanox ^(R) .

  The present invention further provides a therapeutically or prophylactically effective amount of conazole comprising a reaction product of conazole, such as cis-itraconazole, posaconazole or saperconazole, and an organic or inorganic acid, such as cis-itraconazole, Also provided are methods for treating or preventing local and systemic fungal, mold, yeast, and dermatophyte infections in patients by administration of posaconazole or soluble crystalline forms of saperconazole. The pharmaceutical dosage form of the present invention comprises a therapeutically or prophylactically effective amount of conazole comprising a conazole, such as cis-itraconazole, posaconazole or saperconazole, and a reaction product of an organic or inorganic acid ( For example cis-itraconazole, posaconazole or saperconazole).

BRIEF DESCRIPTION OF THE FIGURES FIG. 1 shows a diagram of a conazole co-crystal comprising a trimer composed of a co-crystal former sandwiched between two antiparallel conazole molecules.

  FIG. 2 shows a sphere and rod model of a single trimer homologue consisting of two cis-itraconazole molecules and an oxalic acid molecule.

  FIG. 3 shows a sphere and rod model of a single trimer homologue consisting of two posaconazole and oxalic acid molecules.

  FIG. 4 shows a sphere and rod model of a single trimer homologue consisting of two sappaconazole molecules and an oxalic acid molecule.

Figures 5 (a)-(b) show the following:
(A) PXRD diffractogram of cis-itraconazole HCl: DL-tartaric acid co-crystal,
(B) DSC thermogram of cis-itraconazole HCl: DL-tartaric acid co-crystal.

Figures 6 (a)-(b) show the following:
(A) PXRD diffractogram of cis-itraconazole HCl: D-tartaric acid co-crystal,
(B) DSC thermogram of cis-itraconazole HCl: D-tartaric acid co-crystal.

Figures 7 (a)-(b) show the following:
(A) PXRD diffractogram of cis-itraconazole HCl: L-tartaric acid co-crystal,
(B) DSC thermogram of cis-itraconazole HCl: L-tartaric acid co-crystal.

  FIG. 8—PXRD diffractogram of cis-Itraconazole (Form A).

  Figure 9-PXRD diffractogram of cis-Itraconazole (Form B).

  FIG. 10—PXRD diffractogram of cis-Itraconazole (Form C).

  Figure 11-PXRD diffractogram of cis-Itraconazole (Form D).

  FIG. 12—Comparison of PXRD diffractograms of forms A, B, C, and D of cis-itraconazole.

DETAILED DESCRIPTION OF THE INVENTION The following terms used herein have the following meanings:

  As used herein, the term “solvate” refers to a solute (either cis-itraconazole, posaconazole or saperconazole, or a salt, co-crystal, hydrate, or polyhydrate of cis-itraconazole, posaconazole or saperconazole. A variable stoichiometric complex produced by an organic solvent as defined herein including (form) and an alcohol, preferably methanol or ethanol, or dioxane.

  “Carboxylic acids” include formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, acrylic acid , Crotonic acid, benzoic acid, cinnamic acid, and salicylic acid. “Dicarboxylic acid” has the formula (II):

[Wherein R ₁ and R ₂ are each independently H, OH, Cl, Br, I, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted aryl, or R ₁ and R ₂ together represent a double bond]
As well as the stereochemically pure D or L salts of the compound of formula (II). Examples of dicarboxylic acids 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. Most preferably, the dicarboxylic acid of formula (II) is maleic acid or fumaric acid. It should be understood that other dicarboxylic acids such as malonic acid and adipic acid are separate embodiments of the present invention, but they fall outside the scope of formula (II).

  “Organic or inorganic acids” can be heated by reaction with carboxylic acids, dicarboxylic acids, hydrochloric acid, phosphoric acid, sulfuric acid, benzenesulfonic acid, methanesulfonic acid, and generally the free base cis-itraconazole, posaconazole or saperconazole. It includes, but is not limited to, any acidic species that will produce a mechanically stable crystalline (salt) form.

As used herein, the term “co-crystal” means a crystalline material composed of two or more unique solids at room temperature each having distinct physical characteristics such as structure, melting point and heat of fusion. However, as an exception, when specifically mentioned, the active pharmaceutical ingredient (API) can be a liquid at room temperature. The co-crystals of the present invention comprise a co-crystal former that is H-bonded to the API. The co-crystal former may be H-bonded directly to the API or may be H-bonded to another molecule that is bound to the API. Another molecule may be H-bound to the API or may be ionically or covalently bound to the API. Another molecule could 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. However, a co-crystal can include one or more solvate molecules in the crystal lattice. That is, co-crystal solvates, or co-crystals further comprising a solvent or compound that is liquid at room temperature, are encompassed by the present invention, but only one solid and one or more liquids ( Crystalline materials composed of (at room temperature) are not encompassed by the present invention, with the exception of the liquid APIs specifically mentioned above. The co-crystal can also be a co-crystal between the co-crystal former and the salt of the API, but the API and co-crystal former of the present invention are configured or bonded together by hydrogen bonding. There are other modes of molecular recognition including pi-stacking, guest-host complex formation and van der Waals interactions. Among the interactions listed above, hydrogen-bonding is the main interaction in the formation of co-crystals (and the necessary interaction according to the present invention), whereby non-covalent bonds are Formed between hydrogen bond donors and other hydrogen bond acceptors. Hydrogen bonding can result in several intramolecular structures. For example, hydrogen bonding can result in the formation of dimers, linear chains, or cyclic structures. These structures can further include extended (two-dimensional) hydrogen-bonded networks and isolated triplet elements. Another embodiment provides a co-crystal in which the co-crystal former is a second API. In another aspect, the co-crystal former is not an API. In another embodiment, the co-crystal comprises two co-crystal formers. For the purposes of the present invention, the chemical and physical properties of the API in co-crystal form may be comparable to a control compound that is the same API in different forms. Control compounds are in free form, ie more specifically free acid, free base, or zwitterion; salt, ie more specifically, for example, inorganic base addition salts such as sodium, potassium, lithium, calcium, magnesium, ammonium Aluminum salts or organic base addition salts, or inorganic acid addition salts such as HBr, HCl, sulfuric acid, nitric acid or phosphoric acid addition salts, or organic acid addition salts such as acetic acid, propionic acid, pyruvic acid, malic acid ), Succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, stearic acid or lactic acid addition salt; free form or salt anhydride or hydrate, ie More specifically, for example, hemihydrate, monohydrate, It may be specified as the dihydrate, trihydrate, tetrahydrate, pentahydrate, 1.5 hydrate, or free form or salt solvate. For example, a reference compound for an API in a salt form co-crystallized with a co-crystal former can be an API salt form. Similarly, the reference compound for the free acid API co-crystallized with the co-crystal former can be the free acid API. A control compound can also be specified as crystalline or amorphous.

A “soluble crystal form” or “soluble multicomponent crystal system” is greater than 5 mcg (micrograms) / ml, more preferably greater than 10 mcg (micrograms) / ml, more preferably 20 mcg (micrograms) in an aqueous medium. / Ml, more preferably greater than 30 mcg (microgram) / ml, more preferably greater than 40 mcg (microgram) / ml, more preferably greater than 50 mcg (microgram) / ml, and most preferably 100 mcg ( Includes salts, hydrates, solvates, multicomponent crystal systems or crystalline polymorphs that are soluble in values in solution having a pH of about 1 greater than microgram) / ml. The soluble multicomponent crystal system comprises (a) an organic compound comprising a reaction product of cis-itraconazole, posaconazole or sapaconazole and an organic or inorganic acid (salt, co-crystal or co-crystal of a salt and a second molecule) And (b) the organic solvent may comprise one or more organic solvents present in a stoichiometric or non-stoichiometric ratio with respect to the organic salt.

  “Organic solvent” refers 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, For example 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, alcohols Such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, including tert- butanol and mixtures thereof, but not limited to. 1,2-dichloroethane and ethanol are preferred organic solvents.

  The term “anomer” as used herein refers to one of the isomeric pairs of cyclic compounds that result from the creation of a new symmetry point when an atom rearrangement occurs at the aldehyde or ketone position.

  “Alkyl” means a straight or branched, saturated or unsaturated alkyl, cyclic or acyclic hydrocarbon having 1 to 10 carbon atoms. Representative saturated linear alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl and the like, and saturated branched alkyls are isopropyl, sec-butyl, isobutyl, Includes tert-butyl, isopentyl and the like. Unsaturated alkyls contain at least one double or triple bond between adjacent carbon atoms (also referred to as “alkenyl” or “alkynyl”, respectively). Representative linear and branched alkenyls are ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2- Representative linear and branched alkynyls, including butenyl, 2,3-dimethyl-2-butenyl and the like are acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl and the like are included. Representative saturated cyclic alkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, and unsaturated cyclic alkyls include cyclopentenyl, cyclohexenyl, and the like. Cycloalkyls are also referred to herein as “carbocyclic” ring systems, and C 8-14 bi- and tri-ring systems such as one or more aromatic (eg phenyl) or non-aromatic. Includes cycloalkyl (eg cyclopentane or cyclohexane) fused to a carbocyclic ring (eg cyclohexane).

The term “aryl” as used herein means a carbocyclic or heterocyclic aromatic group containing from 5 to 10 ring atoms. The ring atoms of carbocyclic aromatic groups are all carbon atoms and are phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, and benzo-fused carbocyclic moieties such as 5, 6, 7, 8 -Including but not limited to tetrahydronaphthyl. A carbocyclic aromatic group may be unsubstituted or substituted. Preferably, the carbocyclic aromatic group is a phenyl group. The ring atoms of the heterocyclic aromatic group contain at least one heteroatom, preferably 1 to 3 heteroatoms, independently selected from nitrogen, oxygen, and sulfur. Illustrative examples of heterocyclic aromatic groups are pyridinyl, pyridazinyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3,)-and (1,2,4) -triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, Including, but not limited to, furyl, thienyl, isoxazolyl, thiazolyl, furyl, fienyl, isoxazolyl, indolyl, oxetanyl, azepinyl, piperazinyl, morpholinyl, dioxanyl, thietanyl and oxazolyl. Heteroaromatic groups can be unsubstituted or substituted. Preferably, the heteroaromatic is a monocyclic ring, wherein the ring comprises 2 to 5 carbon atoms and 1 to 3 heteroatoms.

  The term “substituted” as used herein refers to any of the above groups (ie, aryl or alkyl) in which at least one hydrogen atom has been replaced with a substituent. In the case of a keto substituent (“C (═O)”), two hydrogen atoms are replaced. Substituents include halogen, hydroxy, alkyl, aryl, arylalkyl, heterocycle or heterocyclealkyl.

  As used herein, the terms “itraconazole” and “cis-itraconazole” refer to (±) cis-4- [4- [4- [4-[[2- (2,4-dichlorophenyl) -2- (1H— 1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl] -2,4-dihydro-2- (1-methylpropyl)- 3H-1,2,4-triazol-3-one, its four stereoisomers (+)-[2R- [2α, 4α, 4 (R)]-4- [4- [4- [ 4-[[2- (2,4-Dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl ] Phenyl] -2,4-dihydro-2- ( -Methylpropyl) -3H-1,2,4-triazol-3-one (also referred to as (R, S, R) stereoisomer), (+)-[2R- [2α, 4α, 4 (S)] -4- [4- [4- [4-[[2- (2,4-Dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolane-4- Yl] methoxy] phenyl] -1-piperazinyl] phenyl] -2,4-dihydro-2- (1-methylpropyl) -3H-1,2,4-triazol-3-one ((R, S, S) (Also referred to as stereoisomers), (−)-[2S- [2α, 4α, 4 (R)]-4- [4- [4- [4-[[2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy] Phenyl] -1-piperazinyl] phenyl] -2,4-dihydro-2- (1-methylpropyl) -3H-1,2,4-triazol-3-one ((S, R, R) stereoisomer) And) (-)-[2S- [2α, 4α, 4 (S)]-4- [4- [4- [4-[[2- (2,4-dichlorophenyl) -2- (1H- 1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl] -2,4-dihydro-2- (1-methylpropyl)- Unless otherwise noted, 3H-1,2,4-triazol-3-one (also referred to as (S, R, S) stereoisomer), as well as their diastereomeric pairs, is referred to.

  The term “cis-itraconazole, posaconazole or saperconazole tartrate co-crystal” as used herein refers to cis-itraconazole, posaconazole or saperconazole-DL-tartaric acid co-crystal, cis-itraconazole, posaconazole or saperconazole— Refers to a novel soluble crystalline form of L-tartaric acid co-crystals and cis-itraconazole, posaconazole or saperconazole-D-tartaric acid co-crystals. Similarly, unless otherwise specified, other salts refer to racemic or “DL” salts.

  The term “cis-itraconazole, posaconazole or saperconazole-HCl” as used herein refers to a novel soluble crystalline form of hydrochloride salt of cis-itraconazole, posaconazole or saperconazole.

  The term “stereoisomer” or “stereoisomeric form” as used herein is a compound having a stereoisomer purity of at least 90% by weight, and preferably at least 95% by weight, up to 100% by weight stereoisomer purity. And a compound having a stereoisomer purity of at least 97% by weight to a stereoisomer purity of 100% by weight, and more preferably at least 99% by weight to a stereoisomer purity of 100% by weight. The weight percent is based on the total weight of the desired stereoisomer of the compound.

  The term “diastereomeric pair” as used herein refers to a mixture of two stereoisomers of cis-itraconazole, and in particular 1) (+)-[2R- [2α, 4α, 4 (R)] — 4- [4- [4- [4-[[2- (2,4-Dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-yl] ] Methoxy] phenyl] -1-piperazinyl] phenyl] -2,4-dihydro-2- (1-methylpropyl) -3H-1,2,4-triazol-3-one ((R, S, R) steric Isomer)) and (+)-[2R- [2α, 4α, 4 (S)]-4- [4- [4- [4-[[2- (2,4-dichlorophenyl) -2- (1H- 1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-yl] meth Ci] phenyl] -1-piperazinyl] phenyl] -2,4-dihydro-2- (1-methylpropyl) -3H-1,2,4-triazol-3-one ((R, S, S) stereoisomerism Or 2) (-)-[2S- [2α, 4α, 4 (R)]-4- [4- [4- [4-[[2- (2,4-dichlorophenyl) -2] -(1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl] -2,4-dihydro-2- (1- Methylpropyl) -3H-1,2,4-triazol-3-one ((S, R, R) stereoisomer), and (-)-[2S- [2α, 4α, 4 (S)]-4 -[4- [4- [4-[[2- (2,4-dichlorophenyl) -2- (1H-1,2,4) Triazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl] -2,4-dihydro-2- (1-methylpropyl) -3H-1,2, Refers to any mixture of 4-triazol-3-one ((S, R, S) stereoisomer). In a preferred embodiment, the mixture is within a mixing range of 47:53 to 53:47 by weight, more preferably within a mixing range of 48:52 to 52:48 by weight, and most preferably a 50:50 mixture by weight. .

  The term “administered simultaneously” as used herein refers to pharmaceutically acceptable salts of cis-itraconazole, posaconazole or saperconazole, or hydrates, solvates or polymorphs thereof, Administration of one or more compounds or active ingredients at the same time or before, during or after administration of cis-itraconazole, posaconazole or saperconazole.

  As used herein, the term “pharmaceutically acceptable salt” refers to pharmacologically acceptable anions such as hydrochloride, phosphate, formate, adipic acid co-crystal, oxalic acid co-crystal, fumarate. Refers to salts made from acid co-crystal, malic acid co-crystal, tartrate, malonic acid co-crystal, maleic acid co-crystal, mesylate and benzene sulfonate. Particularly preferred anions are tartrate, benzenesulfonate, malate co-crystal and oxalate co-crystal, and other co-crystals, hydrobromide, ditartrate, para-toluenesulfonate, glycol Acid salt, glucuronic acid salt, mucoic acid salt, gentisic acid salt, isonicotinic acid salt, saccharic acid salt, phosphate, hydrochloride, nitrate, sulfate, hydrogensulfate, acetate, propionate, camphorsulfonate , Gluconate, Isothionate, Lactate, Folate, Glutamate, Ascorbate, Benzoate, Anthranilate, Salicylate, Fentyl acetate, Mandelate, Embonate (pamoate), Methanesulfone Acid salt, ethanesulfonate, pantothenate, stearate, sulfanilate, alginate, p-toluenesulfonate, Acrylate, and galacturonic acid salt.

  As used herein, the term “a method of treating or preventing local and systemic fungal, mold, yeast and dermatophyte infections” refers to local and systemic fungal, mold, yeast and dermatophyte infections or Meaning prevention or recovery from one or more of those symptoms. Local and systemic fungi / fungi, yeast and dermatophyte infections are Blast myces, Aspergillus, histoplasma, nail fungus, coccidioides, paracoccidioides, cryptococcus, dermatophytes, and candida infections.

  The terms “itraconazole” and “cis-itraconazole” are used interchangeably throughout this disclosure.

  The term “conazole” refers to a compound comprising a substituted or unsubstituted 1,2,4-triazole group or a substituted or unsubstituted 1-H-imidazole group. Conazoles can be further identified as having antibacterial / fungal activity and are useful as active pharmaceutical ingredients. Conazoles comprise 1,2,4-triazole and 1-H-imidazole groups and can optionally be further defined as having antimicrobial / fungal activity. Even more specific compounds of the invention include the salts, co-crystals, multicomponent systems, solvates, hydrates and polymorphs of itraconazole, posaconazole, saperconazole and their derivatives.

Itraconazole This invention is a partial formula

[Where:
Q is N or CH;
Ar is aryl,
R is hydrogen or C _1-6 alkyl and Y—R ¹ is of the formula

A group or formula having

A group having
Wherein R ¹ is tetrahydrofuranyl C _1-6 alkyl, or C _1-6 alkyl and / or C _3-6 cycloalkyl moiety with oxo, thioxo or 1 or 2 of the formula -ZR ^1-a C _1-6 alkyl, C _3-6 cycloalkyl, aryl C _1-6 alkyl or (C _3-6 cycloalkyl) C _1-6 alkyl, all substituted with groups,
Z is O or S;
R ^1-a is hydrogen, C _1-6 alkyl, aryl, C _3-6 cycloalkyl or tetrahydro 2H-pyran-2-yl;
Alternatively, when R ¹ is substituted with two —Z—R ^1-a groups, the two —R ^1-a groups together form a group —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 - can form a divalent group,
X is O, S or NR ² ;
R ² is hydrogen or C _1-6 alkyl;
A is methylene optionally substituted with up to two groups selected from the group consisting of> C═O, NR ³ or optionally C _1-6 alkyl and aryl;
R ³ is hydrogen or C _1-6 alkyl;
B is methylene optionally substituted with> C═O or optionally up to 2 groups selected from the group consisting of C _1-6 alkyl and C _1-6 alkyloxy;
Alternatively, A and B are taken together to form the formula —N═CH—;
A divalent group of
A ′ and B ′ independently have the same meaning of A and B, respectively, or A ′ and B ′ taken together are of the formula —N═CH—; formula (c) or —CH═CH— Formula (d)
A divalent group of
Wherein the nitrogen atom in the divalent group (c) is bonded to NR ¹ , wherein one hydrogen in the group (c) and up to two hydrogens in the group (d) are C _1-6 alkyl Provided that (i) Y—R ¹ is a group of the formula (a) in which —A—B— is other than the divalent group of the group (c), R ¹ is other than _{C 1-6} alkyl substituted with _{C 1-6} alkyloxy,
If (ii) ^{Y-R 1} is a group of formula (b), ^{R 1} is other than _{C 1-6} alkyl substituted with _{C 1-6} alkyloxy,
Where aryl is phenyl or substituted phenyl, each substituted phenyl being independently selected from the group consisting of halo, C _1-6 alkyl, C _1-6 alkyloxy, nitro, amino and trifluoromethyl. With 1 to 3 substituents, except for trinitrophenyl]
Of 1H-imidazoles and 1H-1,2,4-triazoles and their stereochemically isomeric forms.

In the above definition, the term “halo” generically refers to fluoro, chloro, bromo and iodo, and the term “C _1-6 alkyl” refers to straight and branched hydrocarbon groups having 1 to 6 carbon atoms, For example, it is meant to include methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, 1-methylpropyl, 2-methylpropyl, butyl, pentyl, hexyl and the like, and “C _3-6 cyclo “Alkyl” includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

  The compounds of formula (V) can contain tautomeric systems in their structure, and as a result they can exist in each of their tautomeric forms.

The compounds within the present invention are as described above for X, A, B, A ′, B ′ and R ¹ provided that A ′ and B ′ together form the formula (c) or ( Y—R ¹ which does not form the group of d) is a group of the formula (a) or (b).

More specifically, the compounds within the present invention are those in which Y—R ¹ is a group of formula (a).

Another specific compound within the invention is methylene wherein X is O and A and B are independently> C═O or optionally up to 2 C _1-6 alkyl groups Or A and B together form a divalent group of formula (c) in which the hydrogen atom may be substituted by a C _1-6 alkyl group, and R ¹ is tetrahydrofuranyl C _{1- 6} alkyl, or C _3-6 cycloalkyl substituted with oxo or hydroxy, or C both substituted with oxo on the C _1-6 alkyl moiety or with one or two formulas —O—R ^1-a _1-6 alkyl or C _1-6 alkylaryl, or when R ¹ is substituted with two —O—R ^1-a groups, the two —R ^1-a groups together The formula —C (CH ₃ ) ₂ — or —C It is a compound that can form a divalent group of H ₂ —.

More specifically, the compounds within the present invention are C _3-6 cycloalkyl, wherein R ¹ is substituted with oxo or hydroxy, or both oxo on the C _1-6 alkyl moiety or 1 or 2 hydroxy or Those that are C _1-6 alkyl or C _1-6 alkylaryl substituted with C _1-6 alkyloxy.

More specifically, the compounds within this invention are phenyl where Ar is substituted with two halos,
R is hydrogen, A is C (CH ₃ ) ₂ or CH ₂ , B is CH ₂ or> C═O, or A and B are taken together to replace a hydrogen atom with a methyl group A compound that forms an optional group (c) and wherein R ¹ is C6 alkyl substituted with oxo or hydroxy.

Sappaconazole The present invention is further divided into formulas

[Where:
Q is N or CH;
R ⁴ is hydrogen, C _1-6 alkyl or aryl C _1-6 alkyl, and R ⁵ is hydrogen, C _1-6 alkyl or aryl C _1-6 alkyl;
Where aryl is phenyl optionally substituted with up to three substituents each independently selected from halo, C _1-6 alkyl, C _1-6 alkyloxy and trifluoromethyl]
Of 1H-imidazoles and 1H-1,2,4-triazoles and their stereochemically isomeric forms.

In the above definition, the term “halo” generically refers to fluoro, chloro, bromo and iodo, and the term “C _1-6 alkyl” refers to straight and branched hydrocarbon groups having 1 to 6 carbon atoms, for example, It is meant to include methyl, ethyl, propyl, 1-methylethyl, 1,1-dimethylethyl, 1-methylpropyl, 2-methylpropyl, butyl, pentyl, hexyl and the like.

Compounds of formula (VI) in which R ⁴ is hydrogen can contain tautomeric systems in their structure and as a result these compounds exist in each of their tautomeric forms Both of which are intended to be included within the scope of the present invention.

Compounds within the invention are compounds of formula (VI) wherein R ⁴ and R ⁵ are independently hydrogen or C _1-6 alkyl.

More specifically, the compounds are those described above wherein R ⁵ is hydrogen and R ⁴ is C _1-6 alkyl.

  More specifically, the compound is a compound as described above wherein the substituent on the dioxolane moiety has a cis structure.

  A special subgroup of formula (VI) are the above compounds wherein Q is nitrogen.

  The more specific compound is cis-4- [4- [4- [4-[[2- (2,4-difluorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl). ) -1,3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl] -2,4-dihydro-2- (1-methylpropyl) -3H-1,2,4-triazole-3 -ON and cis-4- [4- [4- [4-[[2- (2,4-difluorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3 -Dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl] -2- (1,2-dimethylpropyl) -2,4-dihydro-3H-1,2,4-triazol-3-one Selected from the group consisting of

Posaconazole The present invention is of formula VII

[Wherein P is independently both F or both Cl, or one X is independently F and the other is independently Cl;
R ⁸ is a linear or branched (C ₃ -C ₈ ) substituted by 1 or 2 hydroxy moieties or by 1 or 2 groups convertible in vivo to hydroxy moieties or esters or ethers thereof An alkyl group]
Or a stereoisomer thereof.

  In one aspect of the invention, Formula VII

[Wherein P is independently both F or both Cl, or one P is independently F and the other is independently Cl;
R ⁹ is H or (C ₁ -C ₃ ) alkyl and R ¹⁰ is (C ₁ -C ₃ ) alkyl substituted by one hydroxy moiety or by a group convertible to a hydroxy moiety in vivo; And the asterisk ( ^* ) has R or S absolute configuration]
A compound represented by is provided, its ester or ether.

  In another aspect, the present invention provides Formula V

[Wherein R ¹¹ is

Is]
Provides a compound represented by

  In one aspect, the ester or ether is a group that can be converted to OH in vivo, such as a polyether ester, phosphate ester or amino acid ester.

  In another aspect of the invention, Formula VI

[Wherein R ¹³ = − ^* CH (C ₂ H ₅ ) CH (R ₁₂ ) CH ₃ or — ^* CH (CH ₃ ) CH (R ₁₂ ) CH ₃ , where R ¹³ is OH, or OH in vivo Is a group convertible to
A compound represented by is provided.

  In some embodiments, the novel soluble crystalline form of cis-itraconazole, posaconazole or saperconazole is greater than 5 mcg / ml, more preferably greater than 10 mcg / ml, more preferably 20 mcg / ml in a solution having a pH of about 1. Greater than, 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, and more preferably greater than 10 mg / ml Have

  Preferred novel soluble crystalline forms of cis-itraconazole, posaconazole or saperconazole of the present invention are dicarboxylic acid co-crystals of cis-itraconazole, posaconazole or saperconazole, such as cis-itraconazole, posaconazole or saperconazole di-mesylate, Cis-itraconazole, posaconazole or sapaconazole tartaric acid co-crystal, cis-itraconazole, posaconazole or sapaconazole fumarate co-crystal, cis-itraconazole, posaconazole or saperconazole malonic acid co-crystal, cis-itraconazole, posaconazole or Sappaconazole maleic acid co-crystal, cis-itraconazole, posaconazole or saperconazole adipic acid co-crystal, cis-i Includes laconazole, posaconazole or saperconazole 1-malic acid co-crystals and cis-itraconazole, posaconazole or sapaconazole succinic acid co-crystals and their salts, co-crystals, hydrates, solvates or polymorphs To do. Cis-Itraconazole, posaconazole or saperconazole dicarboxylates and co-crystals are cis-itraconazole, posaconazole or saperconazole tartrate, cis-itraconazole, posaconazole or saperconazole succinic acid co-crystal, cis-itraconazole, posaconazole Or including, but not limited to, saperconazole di-mesylate and cis-itraconazole, posaconazole or saperconazole malic acid co-crystals. Cis-itraconazole, posaconazole or other dicarboxylic acid salts and co-crystals of cis-itraconazole, posaconazole or sapaconazole fumarate co-crystal, cis-itraconazole, posaconazole or sapaconazole malonic acid co-crystal Cis-itraconazole, posaconazole or saperconazole adipic acid co-crystal and cis-itraconazole, posaconazole or saperconazole maleic acid co-crystal.

If the API and the selected co-crystallizing compound are capable of forming a co-crystal, the resulting co-crystal is the free form (eg, free base, ion, hydrate, solvate, etc.) of the API. Or compared to its acid salt, especially solubility, dissolution, bioavailability, stability, C _max , T _max , processability, longer lasting treatment plasma concentration, hygroscopicity, crystallinity of amorphous compounds, morphology variety Gives improved properties of the API with respect to reductions in properties (including polymorphic and crystalline properties), changes in morphology and crystalline properties, and the like. For example, particularly advantageous are co-crystal forms of API in which the conazoles, including the original API, such as cis-itraconazole, posaconazole or saperconazole, are insoluble or slightly soluble in water. In addition, the co-crystal properties provided by the API are also useful because the bioavailability of the API can be improved and the plasma and / or serum concentration of the API can be improved. This is particularly advantageous for orally administrable formulations. In addition, the API dose response can be improved by increasing the maximum response that can be obtained by increasing the biological activity per dose equivalent and / or increasing the potency of the API.

  Accordingly, in one aspect, the present invention provides cis-itraconazole, posaconazole or saperconazole such that conazole and co-crystallizing compounds can be co-crystallized from solution phase under crystallization conditions or from the solid state by grinding or heating. A pharmaceutical composition comprising a co-crystal of conazole and a co-crystallizing compound is provided. In another aspect, conazole is 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, organic halide, nitro, s-heterocyclic ring, thiophene, n-heterocycle Having at least one functional group selected from the formula ring, pyrrole, o-heterocyclic ring, furan, epoxide, peroxide, hydroxamic acid, imidazole, pyridine and co-crystallizing compounds are amines, amides, Pyridine, imidazole, indole, pyrrolidine, carbo Conazole and co-crystallizing compounds can be co-crystallized from the solution phase under crystallization conditions because they have at least one functional group selected from benzene, carboxyl, hydroxyl, phenol, sulfone, sulfonyl, mercapto and methylthio is there.

  A co-crystal of the invention is produced in which conazole and the co-crystallizing compound are bonded together by hydrogen bonding. There may also be other non-covalent interactions including π-stacking and van der Waals interactions.

  In each process according to the invention, it is necessary to contact the conazole with the co-crystallizing compound. This involves grinding the two solids together or melting one or both components and recrystallizing them. This can also involve dissolving the conazole and adding the co-crystal forming compound or dissolving the co-crystal forming compound and adding the conazole. In a preferred arrangement, conazole can be dissolved in the co-crystallizing compound. Crystallization conditions apply to conazole and co-crystallizing compounds. This sets changes in the properties of the solution, such as pH or temperature, and may typically require concentration of the solute, typically by removal of the solvent by drying the solution. Solvent removal increases the concentration of conazole over time to promote crystallization. Once a solid phase comprising crystals has formed, it can be tested as described herein.

  The co-crystals obtained as a result of such process steps can be easily added to the pharmaceutical composition by conventional means. The pharmaceutical composition is generally discussed in more detail below and may further comprise a pharmaceutically acceptable diluent, excipient or carrier.

In another aspect, the present invention provides (1) preparing conazole,
(2) preparing a co-crystal-forming compound having at least one functional group selected from amine, amide, pyridine, imidazole, indole, pyrrolidine, carbonyl, carboxyl, hydroxyl, phenol, sulfone, sulfonyl, mercapto and methylthio. ,
(3) triturating conazole with the co-crystallizing compound in solution under crystallization conditions, heating or contacting, and (4) isolating the co-crystal formed thereby and (5) co-crystal Is provided in the pharmaceutical composition. A method for producing a pharmaceutical composition is provided.

In yet another aspect, the present invention provides (1) grinding conazole with a co-crystallizing compound in solution under crystallization conditions, heating or contacting to form a solid phase,
(2) A method for producing a pharmaceutical composition comprising isolating a co-crystal comprising conazole and a co-crystallizing compound.

  Evaluation of the solid phase for the presence of co-crystals of conazole and co-crystallizing compounds can be performed by conventional methods known in the art. For example, it is convenient and conventional to use powder X-ray diffraction techniques to assess the presence of co-crystals. This can be done by comparing the diffraction of conazole, crystal-forming compound and putative co-crystal to prove whether a true co-crystal was produced or not. Other techniques used in a similar manner include differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and Raman spectroscopy. Single crystal X-ray diffraction is particularly useful in identifying co-crystal structures.

In another aspect, the present invention thus provides (1) (i) a conazole compound, and (ii) a co-crystallizing compound,
(2) each combination of conazole and co-crystallizing compound is (a) ground in solution with conazole together with the co-crystallizing compound, heated or contacted to form a solid phase,
(B) screening the co-crystal of conazole and the co-crystallizing compound by subjecting to a step comprising isolating the co-crystal comprising conazole and the co-crystallizing compound. A screening method for co-crystal compounds is provided.

Another aspect is:
(1) (i) 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 conazole and the co-crystal-forming compound is prepared Prepare as multiple of
(2) each combination of conazole and co-crystallizing compound is (a) ground in solution with conazole together with the co-crystallizing compound, heated or contacted to form a solid phase,
(B) screening the co-crystal of conazole and the co-crystallizing compound by subjecting to a step comprising isolating the co-crystal comprising conazole and the co-crystallizing compound. A screening method for co-crystal compounds.

Solubility adjustment :
In another aspect, the present invention provides: (1) Grinding conazole with a co-crystallizing compound in solution under crystallization conditions, heating or contacting to form a co-crystal of conazole and the co-crystallizing compound. Cough,
(2) A method for adjusting the solubility of conazole, comprising isolating a co-crystal comprising conazole and a co-crystal-forming compound.

In one embodiment, the solubility of conazole is adjusted to increase water solubility. The solubility of conazoles is determined by any conventional means such as spectroscopic measurement of the amount of conazole in a saturated solution of conazole, such as UV-spectroscopy, IR-spectroscopy, Raman spectroscopy, quantitative mass spectrometry or gas chromatography. Can be measured.

  In another aspect of the invention, conazole can have a low water solubility. Typically, low water solubility in this application refers to a compound having a solubility in water of less than or equal to 10 mg / ml and preferably less than or equal to 1 mg / ml as measured at 37 ° C. More specifically, “low water solubility” is 900, 800, 700, 600, 500, 400, 300, 200, 150, 100, 90, 80, 70, 60, 50, 40, 30, 20 microgram / ml. Or 10, 5 or 1 microgram / ml, lower or equal. As an embodiment of the present invention, the solubility is 2, 3, 4, 5, 7, 10, 15, 20, 25, 50, 75 compared to the crystalline free base by preparing a co-crystal of the free form or salt. , 100, 200, 300, 500, 750, 1000, 5000, or 10,000 times. Furthermore, water solubility can also be measured in simulated gastric fluid (SGF) or simulated intestinal fluid (SIF) rather than water (Dressman JB, et al., Pharm Res., Incorporated herein by reference). 1998) Jan; 15 (1): 11-222). The SGF of the present invention (undiluted) is prepared by combining 1 g / L Triton X-100 and 2 g / L NaCl in water and adjusting the pH with 20 mM HCl to give a final pH = 1.7. It was manufactured by obtaining a solution having SIF is 0.68% monobasic potassium phosphate, 1% pancreatin, and sodium hydroxide, where the pH of the final solution is 7.5. The pH is 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 it can be specified as 12.

  Examples of embodiments are co-crystal compositions having an aqueous solubility that is at least 5-fold increased from the crystalline free form at 37 ° C. and a pH of 7.0, and in SGF at least 5-fold increased from the crystalline free base. Co-crystal compositions having solubility are included.

Dissolution adjustment :
In another aspect of the invention, the dissolution characteristics of conazole are adjusted, thereby increasing or decreasing the water dissolution rate or dissolution rate in simulated gastric fluid or simulated intestinal fluid or solvent or solvents. The dissolution rate is the rate at which the conazole solid dissolves in the dissolution medium. Conazole that does not dissolve before it is removed from the intestinal absorption site is considered useless. Thus, dissolution rate has a significant impact on the performance of conazoles that are hardly soluble. Because of this factor, the dissolution rate of conazoles in solid dosage forms is an important universal quality control parameter used in the conazole manufacturing process.
Dissolution rate = KS (C _s -C)
Where K is the dissolution rate constant, S is the surface area, C _s is the apparent solubility, and C is the concentration of conazole in the dissolution medium.

  The dissolution rate of conazoles can be measured by conventional means known in the art.

  The increase in the dissolution rate of the co-crystal compared to the crystalline free form is, for example, to 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100%, or the free form or salt in the same solution 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 75, 100, 125, 150, 175, 200 times the form it can. The conditions for measuring the dissolution rate are the same as discussed above. The increase in dissolution can also be specified by the time that the composition remains supersaturated.

  Examples of the above embodiments are co-crystal compositions having an aqueous solubility that is at least 5-fold increased from the crystalline free form at 37 ° C. and a pH of 7.0, and SGF that is at least 5-fold increased from the crystalline free base. Includes co-crystal compositions having moderate solubility.

Bioavailability adjustment :
Using the method of the present invention, compared to neutral form or salt alone, greater solubility, dissolution, and bioavailability, AUC, reduced time to T _max, which is the time to reach peak serum levels, and A pharmaceutical conazole formulation with a higher maximum serum concentration, C _max , is produced.

AUC is the area under the plot of plasma concentration of conazole (not logarithm of concentration) versus time after administration of conazole. This area is simply measured by the “trapezoidal rule”, the data points are connected by straight line segments, the perpendicular is upright from the abscissa to each data point, and the total area of the triangle and trapezoid thus constructed is Calculated. If it is not 0 _{(C n} at time _{t n)} last measured concentration, AUC from _{t n} to infinity time is estimated by _C n _{/ k el.}

AUC has special application in estimating the bioavailability of conazoles and estimating the total clearance of conazole (Cl _T ). After a single intravenous dose, AUC = D / Cl _T , or AUC = C ₀ / k _{el for a} single compartment system following primary elimination kinetics. For non-venous regimes, AUC = C ₀ / k _{el for} such systems, where F is the bioavailability of conazole.

Thus, in another aspect, the present invention provides: (1) Grinding conazole with a co-crystallizing compound in solution under crystallization conditions, heating or contacting; To produce crystals,
(2) adjusting the bioavailability of conazole when administered within its normal and effective dosage range comprising isolating a co-crystal comprising conazole and a co-crystallizing compound. , Thereby increasing AUC, reducing the time to T _max , or providing a method for increasing C _max .

An example of the above embodiment is a co-crystal composition having a time to T _max reduced by at least 10% compared to the free form, a co-crystal composition having a time to T _max reduced by at least 20% compared to the free form. A crystal composition, a co-crystal composition having a time to T _max reduced by at least 40% compared to the free form, a co-crystal having a time to T _max reduced by at least 50% compared to the free form Composition, co-crystal composition having time to T _max reduced by at least 60% compared to free form, co-crystal composition having time to T _max reduced by at least 70% compared to free form co has a time to T _max that is reduced at least 80% compared to the free form - crystalline composition, having a C _max that is increased by at least 20% over the free form Co - compared crystal composition, a free form - crystalline composition, co has a C _max that is increased by at least 30% compared to the free form - crystalline composition, co with C _max that is increased by at least 40% over the free form A co-crystal composition having a C _max increased by at least 50%, a co-crystal composition having a C _max increased by at least 60% compared to the free form, having a C _max increased by at least 70% compared to the free form Co-crystal composition, co-crystal composition having C _max increased by at least 80% compared to free form, co-crystal composition having AUC increased by at least 10% compared to free form, compared to free form Co-crystal composition having an AUC increased by at least 20%, co-crystal composition having an AUC increased by at least 30% compared to the free form, free A co-crystal composition having an AUC increased by at least 40% compared to the form, a co-crystal composition having an AUC increased by at least 50% compared to the free form, and an AUC increased by at least 60% compared to the free form Co-crystal compositions, co-crystal compositions having an AUC increased by at least 70% compared to the free form, or co-crystal compositions having an AUC increased by at least 80% compared to the free form.

Dose response adjustment :
In another aspect, the present invention provides (1) grinding conazole with a co-crystallizing compound in solution under crystallization conditions, heating or contacting to form a co-crystal of conazole and the co-crystallizing compound. Cough,
(2) A method for improving the dose response of conazole, comprising isolating a co-crystal comprising conazole and a co-crystallizing compound.

  The dose response is a quantitative relationship between the extent of the response and the dose that elicits the response and can be measured by conventional means known in the art. The curve associated with the effect (as a dependent variable) on the dose (as an independent variable) for the Conazole-cell line is the [Dose-Response Curve]. Typically, a dose-response curve is the measured response to conazole plotted against the specified conazole dose (mg / kg). The dose response curve may also be an AUC curve for a specified conazole dose.

Increased stability :
In yet another aspect of the present invention, the present invention provides (1) grinding conazole with a co-crystallizing compound in solution under crystallization conditions, heating or contacting to form a co-form of the conazole and the co-crystallizing compound. -Produce crystals,
(2) A method for improving the stability of conazole in its free form or salt thereof comprising isolating a co-crystal comprising conazole and a co-crystallizing compound.

  In a preferred embodiment, a composition of the invention comprising a conazole or an active pharmaceutical ingredient (conazole) and a formulation comprising conazole are of suitable stability for pharmaceutical use. Preferably, the conazoles or formulations thereof of the present invention are so stable that less than 0.2% of any degradant is produced when stored at 30 ° C. for 2 years. The term degradation material here refers to one or more products of a single type of chemical reaction. For example, if a hydrolysis phenomenon occurs that splits the molecule into two products, it will be considered a single degradation material for the purposes of the present invention. More preferably, less than 0.2% of either degradation material is produced when stored at 40 ° C. for 2 years. Alternatively, either 0.2% or 0.15% or less than 0.1% degradation product is produced when stored at 30 ° C for 3 months, or stored at 40 ° C for 3 months When produced, either one of 0.2% or 0.15% or less than 0.1% of the degradation material is formed. Additionally or alternatively, either one of the 0.2% or 0.15% or less than 0.1% degradation material is produced when stored at 60 ° C. for 4 weeks. Relative humidity (RH) can also be specified as ambient (RH), 75% (RH), or any single integer between 1-99%.

Compounds that are difficult or impossible to produce :
In yet another aspect, the present invention provides (1) grinding conazole with a co-crystallizing compound in solution under crystallization conditions, heating or contacting to form a co-crystal of conazole and the co-crystallizing compound. Generated,
(2) A method for producing a co-crystal of unstable conazoles comprising isolating a co-crystal comprising conazole and a co-crystal-forming compound.

  Compounds that are difficult to form include bases with pKa <3 or acids with pKa> 10. Zwitterions are also compounds that are difficult or impossible to produce salts.

Hygroscopic reduction :
In yet another aspect, the present invention provides (1) grinding conazole with a co-crystallizing compound in solution under crystallization conditions, heating or contacting,
(2) forming a co-crystal of conazole and a co-crystal-forming compound;
(3) A method is provided for reducing the hygroscopicity of conazole, comprising isolating a co-crystal comprising conazole and a co-crystallizing compound.

  One aspect of the present invention comprises conazole co-crystals that are less hygroscopic than amorphous or crystalline free forms or salts (including metal salts such as sodium, potassium, lithium, calcium, magnesium). A pharmaceutical composition is provided. Hygroscopicity can be assessed by dynamic vapor adsorption analysis, where 5-50 mg of compound is suspended from the Khan microbalance. The compound to be analyzed should be placed in a non-hygroscopic bread and its weight should be measured against an empty bread composed of the same substance and having approximately the same size, shape and weight . The pan should be suspended in the room, and a gas having a known relative% relative humidity (% RH) adjusted in it, for example air or nitrogen, is allowed to flow until an equilibrium standard is reached. A typical equilibrium criterion includes a change in weight of less than 0.01% over 3 minutes at a constant humidity and temperature. For samples that have been dried to a constant weight (<0.01% change within 3 minutes) at 40 ° C. under dry nitrogen, the relative humidity is solvated or otherwise amorphous. It should be measured under conditions that do not convert it to a compound. In one aspect, the dried compound was prepared by increasing the RH from 5% to 95% in 5% RH increments and then reducing the RH from 95 to 5% in 5% increments to produce a moisture adsorption isotherm. The hygroscopicity of can be evaluated. If the compound deliquesces or becomes amorphous while above 75% RH but below 95% RH, the experiment should be repeated with a new sample and the relative humidity range for the cycle is 5-95. It should narrow to 5-75% RH or 10-75% RH instead of% RH. If the sample cannot be dried prior to testing due to lack of form stability, the sample should be tested using two full humidity cycles, either 10-75% RH or 5-95% RH And if there is significant weight loss at the end of the first cycle, the results of the second cycle should be used.

  Hygroscopicity can be defined using various parameters. For purposes of the present invention, non-hygroscopic molecules are 1.0 wt%, or more preferably 0.5 wt% when cycled between 10 and 75% RH (relative humidity at 25 ° C). Do not increase or lose more. Non-hygroscopic molecules are more preferably 1.0% by weight when circulating between 10 and 75% RH at 25 ° C., or more preferably 0.5% by weight, or between 10 and 75% RH. Do not increase or lose 0.25%, more of the weight. Most preferably, non-hygroscopic molecules should not increase or lose more than 0.25% of their weight when circulated between 5 and 95% RH.

Alternatively, for the purposes of the present invention, hygroscopicity is described by Callaghan et al. , Equilibrium moisture content of pharmaceutical students, in Console Dev. Ind. Pharm. , Vol. 8, pp. 335-369 (1982). Callaghan et al. Classified moisture absorption into 4 types.
Category 1: Non-hygroscopicity No inherent increase in moisture at relative humidity below 90% Category 2: Slightly hygroscopic No inherent increase in moisture at relative humidity below 80% Category 3: Medium hygroscopic 60 Moisture content does not increase more than 5% after 1 week of storage at a relative humidity lower than% Category 4: Extremely hygroscopic An increase in water content can occur at relative humidity as low as 40-50%

  Alternatively, for the purposes of the present invention, hygroscopicity is from European Pharmacopoeia Technical Guide (1999, p. 86), which defines wettability based on static methods after storage at 80% RH for 24 hours at 25 ° C. Can be defined using parameters.

  Slightly hygroscopic: the increase in mass is less than 2% m / m and equal to or greater than 0.2% m / m.

  Hygroscopic: the increase in mass is less than 15% m / m and equal to or greater than 0.2% m / m.

  Very hygroscopic: the increase in mass is equal to or greater than 15% m / m.

  Deliquescent: Sufficient water is absorbed to form a liquid.

  The co-crystals of the present invention can be shown as being of type 1, type 2, or type 3, or as being slightly hygroscopic, hygroscopic, or very hygroscopic. The co-crystals of the present invention can also be shown on the basis of their ability to reduce hygroscopicity. Therefore, the preferred co-crystals of the present invention are less hygroscopic than conazole. A control compound can be identified as a free form (free acid, free base, hydrate, solvate, etc.) or a salt (eg, a metal salt such as sodium, potassium, lithium, calcium or magnesium) of conazole. In addition, co-crystals that do not increase or lose more than 1.0% by weight at 25 ° C. when cycled between 10-75% RH are also encompassed by the present invention, while the control compound is 1. Increase or lose more than 0% by weight. In addition, co-crystals that do not increase or lose more than 0.5% by weight at 25 ° C. when cycled between 10-75% RH are also encompassed by the present invention, while the control compound is 0.1% under the same conditions. Increase or lose more than 5% by weight or more than 1.0% by weight. In addition, co-crystals that do not increase or lose more than 1.0% by weight at 25 ° C. when cycled between 5-95% RH are also encompassed by the present invention, while the control compound is 1. Increase or lose more than 0% by weight. Furthermore, co-crystals that do not increase or lose more than 0.5% by weight at 25 ° C. when cycled between 5 and 95% RH are also encompassed by the present invention, while the control compound is 0.1% under the same conditions. Increase or lose more than 5% by weight or more than 1.0% by weight. In addition, co-crystals that do not increase or lose more than 0.25% by weight at 25 ° C. when cycled between 5 and 95% RH are also encompassed by the present invention, while the control compound is 0.1% under the same conditions. Increase or lose more than 5% by weight or more than 1.0% by weight.

  Further included are co-crystals having a hygroscopicity (according to Callaghan et al.) That is at least one class or at least two classes lower than the control compound. Group 2 control compound group 1 co-crystal, group 3 control compound group 2 co-crystal, group 4 control compound group 3 co-crystal, group 3 control compound group 1 co-crystal, group 4 control compound group One co-crystal, or a group 2 co-crystal of a group 4 control compound is included.

  Further included are co-crystals having a hygroscopicity (according to European Pharmacopoeia Technical Guide) that is at least one class or at least two classes lower than the control compound. Non-limiting examples are a hygroscopic co-crystal of a hygroscopic control compound, a hygroscopic co-crystal of a very hygroscopic control compound, a highly hygroscopic co-crystal of a deliquescent control compound, a very hygroscopic A slightly hygroscopic co-crystal of the sexual control compound, a slightly hygroscopic co-crystal of the deliquescence control compound, and a hygroscopic co-crystal of the deliquescence control compound.

In one aspect, the present invention shows that the crystalline phase can be treated by combining molecules selected to be compatible with the hydrogen bond donor with the acceptor and considering structural complementarity. The present invention further regard also shown (itraconazole piperazine can be applied to active pharmaceutical ingredients supramolecular synthesized using organic acids and bases combined with a pK _a differences that are inconsistent with salt formation in water 3.7 of if pK a _a, conventional knowledge in the strong acid having a lower dissociation constant than 1.7 would limit the salt screen).

  One aspect of the present invention is a hydrogen-comprising two molecules of cis-itraconazole (or two molecules of posaconazole or two molecules of sapaconazole) and one molecule of a dicarboxylic acid (eg, oxalic acid). Co-crystals comprising or consisting of bound trimers are included. A preferred dicarboxylic acid co-crystal of cis-itraconazole, posaconazole or saperconazole has the crystal structure shown in FIG. The chemical molecule (see FIG. 1) is composed of three ring skeletons (AC), a triazole ring (D), a spacer group (E), and a terminal group (F). The trimer has two drug molecules oriented antiparallel to each other with dicarboxylic acid (G), a second molecule that templates or fills the void between the two drug molecules. D, which is the distance between the carboxylate oxygen (—O (H)), one of the possible functional groups of molecule G, and the triazole nitrogen (—N—) is between 3.4 and 1.8 angstroms, More preferably between 3.2 and 2.3 angstroms, even more preferably between 3.0 and 2.5 angstroms and even more preferably between 2.8 and 2.6 angstroms. The distance between the two molecules constituting the trimer is about 7.5 to about 7.5, as measured by the distance between the nitrogen atom in ring A of one molecule and ring A of the second molecule. It can be between 6.4 angstroms, preferably between about 7.0 and about 6.6 angstroms, and even more preferably about 6.8 angstroms. The distance (D) between the two triazole rings in the trimer and the separate molecule is about 12.5 to about 8.0 Angstroms as measured by the shortest distance between the two nitrogen atoms. Between, more preferably between about 11 and about 10.6 angstroms and even more preferably at 10.8 angstroms. Trimers can also be further defined by orientation around the center of inversion located in the center of molecule G in some cases. The dicarboxylic acids (succinic acid in the model shown) used to fill the trimer wells are for example fumaric acid, succinic acid, tartaric acid, DL-tartaric acid, D-tartaric acid, L-tartaric acid, meso-tartaric acid, It can be d-malic acid, L-malic acid, DL-malic acid, malonic acid, glutaric acid, adipic acid or acetic acid. The crystal structure of one congener (Figure 2 for itraconazole (actual), Figure 3 for posaconazole (proposed) and Figure 4 for saperconazole (proposed)) is the conjecture between the triazole and diacid of conazole in the solid state. Show outer and specific interactions (filled gray atoms are carbon, colorless atoms are hydrogen, small dots (or light gray) are nitrogen atoms, large dots (black and white) are oxygen And the other atom (thin line) is chlorine or fluorine depending on the compound).

  Particularly preferred pharmaceutical compositions of the invention are therapeutically effective amounts of acid salts, co-crystals, solvates, hydrates, or multi-component crystal systems such as cis-itraconazole, posaconazole or saperconazole HCl. Salt-tartaric acid co-crystal, or a soluble multi-component crystal system comprising cis-itraconazole, posaconazole or sapaconazole dimesylate and ethanol, or cis-itraconazole, posaconazole or saperconazole dimesylate and dioxane A soluble multi-component crystal system.

In another aspect, the present invention provides a soluble crystalline form or a soluble crystalline form of conazole having reduced food action. In a specific embodiment, the control mode (e.g., itraconazole free base, itraconazole salts, their polymorphs, hydrates, solvates or co - crystal) or control formulation (e.g., Supora Knox ^(R)) A soluble crystalline form or formulation of a soluble crystalline form of itraconazole having a reduced food effect compared to

In another aspect, the present invention provides a method of reducing the food effect of conazole. There is provided a method of reducing the food effect of conazole comprising administering to a mammal a soluble crystalline form or a soluble crystalline form preparation of the present invention. For example, how to reduce the food action of itraconazole. Administration of a soluble crystalline form or a soluble crystalline form preparation of the present invention to a mammal, such as but not limited to itraconazole HCl: DL-tartaric acid co-crystals. The reduction in food action discussed in the above method is a control form (eg, itraconazole free base, a salt of itraconazole, their polymorphs, hydrates, solvates, or co-crystals) or a control formulation (eg, It can be measured relative to the food effect observed from Sporanox ^(R) ).

  Another aspect of the invention is to provide a therapeutically or prophylactically effective amount of a salt, co-crystal, salt co-crystal and hydrate, solvate or polymorph in a patient in need of treatment or prevention. Local or systemic fungi in a patient, comprising administering a pharmaceutically acceptable soluble crystalline form of conazole (including cis-itraconazole, posaconazole or saperconazole), Methods for treating or preventing yeast and dermatophyte infections are included. More specifically, the present invention relates to salts or co-crystals of cis-itraconazole, posaconazole or saperconazole, such as cis-itraconazole, posaconazole or saperconazole di-mesylate, cis-itraconazole, posaconazole or sapaconazole tartrate. Crystal, cis-itraconazole, posaconazole or sapaconazole fumarate co-crystal, cis-itraconazole, posaconazole or sapaconazole malonic acid co-crystal, cis-itraconazole, posaconazole or sapaconazole maleic acid co-crystal, cis- Itraconazole, posaconazole or saperconazole adipic acid co-crystal, cis-itraconazole, posaconazole or saperconazole malic acid co-crystal or cis Local or systemic fungal, mold, yeast and dermatophyte infections in a patient comprising administering a composition of the invention comprising itraconazole, posaconazole or sapaconazole succinate co-crystals Includes methods of treating or preventing.

  The invention further encompasses the use of cis-itraconazole, posaconazole or saperconazole dicarboxylates or co-crystals. The method of treatment comprises a therapeutically effective amount of the acid salts cis-itraconazole, posaconazole or sapaconazole HCl tartrate co-crystal, or cis-itraconazole, posaconazole or sapaconazole di-mesylate and ethanol. Administration of a pharmaceutical composition of the invention comprising a soluble multi-component crystal system comprising: or a soluble multi-component crystal system comprising cis-itraconazole, posaconazole or saperconazole di-mesylate and dioxane. Become.

Pharmaceutical Compositions and Dosage Forms Pharmaceutical dosage forms of the present invention comprise a therapeutically or prophylactically effective amount of cis-itraconazole, posaconazole or hydrate, solvate or polymorph It comprises a novel soluble crystalline form of saperconazole. These dosage forms also comprise a soluble multi-component crystal system comprising cis-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 receiver. Oral pharmaceutical compositions and dosage forms are preferred dosage forms. Preferably, the oral dosage form is a solid dosage form such as a tablet, caplet, hard gelatin capsule, starch capsule, hydroxypropyl methylcellulose (“HPMC”) capsule, or soft elastic gelatin capsule. Other preferred dosage forms include intradermal dosage forms, intramuscular dosage forms, subcutaneous dosage forms, and intravenous dosage forms.

The pharmaceutical compositions and dosage forms of the present invention are active ingredients disclosed herein, for example the acid salts cis-itraconazole, posaconazole or saperconazole HCl salt tartaric acid co-crystals or cis-itraconazole, posaconazole or saperco. A soluble multi-component crystal system comprising a nazole organic salt and an organic solvent. The pharmaceutical compositions and unit dosage forms of the present invention typically also comprise one or more pharmaceutically acceptable excipients or diluents. In one embodiment, the pharmaceutical compositions and unit dosage forms of the present invention typically also comprise one or more pharmaceutically acceptable excipients or diluents, where the pharmaceutical One type of pharmaceutically acceptable excipient or diluent is an antioxidant.

  The pharmaceutical unit dosage forms of the present invention can be oral, mucosal (eg, nasal, sublingual, vaginal, buccal, or rectal), parenteral (eg, intramuscular, subcutaneous, intravenous, intraarterial) to the patient. Or large pill injection), topical or transdermal administration. Examples of dosage forms are tablets, caplets, capsules such as hard gelatin capsules, starch capsules, hydroxypropyl methylcellulose (“HPMC”) capsules, and soft elastic gelatin capsules; cachets; lozenges; lozenges Dispersant; Suppository; Ointment; Patch (Poultice); Paste; Powder; Application; Cream; Plaster; Liquid; Patch; Aerosol (for example, nasal spray or inhalant); Gels; liquids suitable for oral or mucosal administration to patients, including suspensions (eg, aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, and elixirs Dosage forms; liquid dosage forms suitable for parenteral administration to patients; as well as liquid drugs suitable for parenteral administration to patients Bactericidal solid which can be reconstituted to give an amount form (e.g., crystalline or amorphous solids) including, but not limited to.

  The composition, shape, and type of dosage forms of the invention will typically vary depending on their use. For example, a dosage form used in the acute treatment of a disease or disorder may contain a greater amount of the active ingredient than a dosage form used in the chronic treatment of the same disease or disorder. Similarly, parenteral dosage forms may contain less active ingredient than oral dosage forms used to treat the same disease or disorder. These and other ways in which specific dosage forms encompassed by this invention may vary from one another will be readily apparent to those skilled in the art. For example, 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 pharmaceutical compositions and dosage forms comprise one or more excipients. Suitable excipients are known to those skilled in the pharmaceutical arts, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for addition into a pharmaceutical composition or dosage form includes various factors known in the art, including but not limited to methods of administering the dosage form to a patient. Depends on. For example, oral dosage forms such as tablets or capsules may contain excipients that are not suitable for use in parenteral dosage forms. In addition, the pharmaceutical composition or dosage form may contain one or more compounds that reduce or alter the rate at which the active ingredient degrades. Such compounds, referred to herein as “stabilizers” 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 prevent radical oxidation of the active ingredient, where such antioxidants are ascorbic acid, butylated Including, but not limited to, phenolic antioxidants, including, but not limited to, conjugated hydroxyanisole (BHA) and propyl gallate and citrates, EDTA, and DTPA It is not limited to. Preferably, a combination of a phenolic antioxidant and a chelating agent can be used if it is known that radical oxidation of the active ingredient occurs.

  As with the amount and type of excipient, the amount and specific type of active ingredient in the dosage form can vary depending on factors including, but not limited to, the manner in which it is administered to the patient. However, typical dosage forms of the present invention are pharmaceutically selected from the group consisting of cis-itraconazole, posaconazole or sapaconazole malic acid co-crystals and cis-itraconazole, posaconazole or sapaconazole-HCl. Acceptable salts and co-crystals, and pharmaceutically acceptable hydrates, solvates, polymorphs, and co-crystals thereof in an amount of about 10 mg to about 1000 mg, preferably about 25 mg to In an amount of about 500 mg, more preferably in an amount of 40 mg to 400 mg, and most preferably in an amount of about 50 mg to about 200 mg.

Oral dosage forms Pharmaceutical compositions of the present invention suitable for oral administration include tablets (including but not limited to stamped or coated tablets), pills, caplets, capsules (hard gelatin capsules, starches) Capsules, HPMC capsules, and soft elastic gelatin capsules), chewable tablets, powder packets, sachets, troches, top furs, aerosol sprays, separate dosages including but not limited to It may be realized as a form or as a liquid including but not limited to syrups, elixirs, solutions or suspensions in aqueous liquids, non-aqueous liquids, oil-in-water emulsions, or water-in-oil emulsions. Such compositions contain a predetermined amount of active ingredient and can be prepared by pharmaceutical methods 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).

  A typical dosage form of the present invention is manufactured by combining the active ingredients in intimate mixing with at least one excipient according to conventional pharmaceutical blending techniques. Excipients can take a wide variety of forms depending on the form of composition desired for administration. For example, 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. . Examples of excipients suitable for use in solid oral dosage forms (eg, powders, tablets, capsules, and caplets) are starches, sugars, microcrystalline cellulose, kaolin, diluents, granulating agents , Lubricants, binders, stabilizers, and disintegrants.

  For ease of administration, tablets, caplets, and capsules (eg, hard gelatin, HPMC, or starch capsules) are the most advantageous solid oral dosage unit forms, in this case solid pharmaceutical products Geometrical excipients are used. If desired, tablets or caplets can be coated by standard aqueous or nonaqueous techniques. These dosage forms can be made by any pharmaceutical method. In general, one or more active ingredients are mixed uniformly and intimately with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, the product is shaped to the desired appearance, thereby producing a pharmaceutical product. Compositions and dosage forms are manufactured.

  For example, a tablet can be produced by compression or molding. Compressed tablets by compressing one or more active ingredients into a free-flowing form such as powder or granules in a suitable machine, optionally mixed with one or more excipients Can be manufactured. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

  Examples of excipients that can be used in the oral dosage forms of the present invention include, but are not limited to, binders, stabilizers, fillers, disintegrants, and lubricants. Suitable binders for use in pharmaceutical compositions and dosage forms are corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as gum arabic, sodium alginate, alginic acid, other alginic acids Salts, powdered tragacanth, guar gum, cellulose and its derivatives (eg, ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropyl methylcellulose (eg, number 2208 2906, 2910), microcrystalline cellulose, and mixtures thereof, but are not limited thereto.

Suitable forms of microcrystalline cellulose are Avicel-PH-101, Avicel-PH-103, Avicel RCC-581, and Avicel-PH-105 (FMC Corporation, American Viscose Division, Materials sold as Avicel Sales Department, Marks Hook, Pennsylvania, USA), as well as 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-103 ^™ Starch 1500LM.

  Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein are calcium carbonate (eg granules or powder), microcrystalline cellulose, powdered cellulose, dexolates, kaolin, mannitol , Silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The binder or filler in the pharmaceutical composition of the present invention is typically present in from about 50 to about 99% by weight of the pharmaceutical composition or dosage form.

  Disintegrants can be used in pharmaceutical compositions and dosage forms to provide tablets or caplets that disintegrate when exposed to an aqueous environment. Tablets or caplets containing too much disintegrant may disintegrate on storage, but too little content may be insufficient for disintegration to occur and as a result one or more from the storage form The rate and extent of active ingredient release can vary. Therefore, a solid oral dosage form of the present invention should be produced using a sufficient amount of disintegrant that is neither too little nor too much to adversely release one or more active ingredients. is there. The amount of disintegrant used will vary based on the type of formulation and mode of administration and can be readily recognized by those skilled in the art. A typical pharmaceutical composition comprises about 0.5 to about 15% by weight of a disintegrant, preferably about 1 to about 5% by weight of a disintegrant.

  Disintegrants that can be used to produce the pharmaceutical compositions and dosage forms of the present invention are agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium glycolate starch , Potato or tapioca starch, other starches, pregelatinized starch, clay, other algins, other celluloses, gums, and mixtures thereof.

  Antioxidants can be used in the pharmaceutical compositions and dosage forms to prevent degradation or radical oxidation of the active ingredient. Examples of suitable antioxidants include phenolic antioxidants including but not limited to ascorbic acid, butylated hydroxyanisole (BHA) and propyl gallate, and citrate, EDTA, and DTPA. Include, but are not limited to, chelating agents.

  Lubricants that can be used to produce the pharmaceutical compositions and dosage forms of the present invention are calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid Sodium lauryl sulfate, hydrogenated vegetable oils (eg, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, and their Including but not limited to mixtures. Another lubricant is, for example, a syloid silica gel (AEROSIL 200 manufactured by WR Grace Co., Baltimore, Maryland), a synthetic silica coagulated. Aerosol (sold by Degussa Co., Plano, Texas), CAB-O-SIL (sold by Cabot Co., Boston, Massachusetts) Exothermic silicon dioxide), as well as mixtures thereof. When used, lubricants are typically used in an amount of less than about 1% by weight of the pharmaceutical composition or dosage form to which they are added.

  Another oral dosage form of the pharmaceutical composition of the present invention is a soft elastic gelatin capsule. Soft elastic gelatin capsule unit dosage forms can be prepared using conventional methods known in the art. For example, Ebert, Pharm. Tech, 1 (5): 44-50 (1977). In general, soft elastic gelatin capsules (also known as “soft gels”) have an elastic or soft, spherical or elliptical gelatin shell, which is typically more than that of hard gelatin capsules. A little thicker, where a plasticizer, such as glycerin, sorbitol, or a similar polyol, is added to the gelatin. Any type of gelatin and the amount of plasticizer and water can be used to change the hardness of the capsule shell. Soft gelatin shells can contain preservatives such as methyl- and propylparabins and sorbic acid to prevent fungal and mold growth. Dissolving or suspending the active ingredient in liquid excipients or carriers, such as vegetable or mineral oils, glycols such as polyethylene glycol and propylene glycol, triglycerides, surfactants such as polysorbates, or combinations thereof Can do.

Delayed Release Dosage Forms Active ingredients of the invention can be administered by modified or delayed release means or by delivery devices known to those skilled in the art. Examples are included in US Pat. Nos. 3,845,770, 3,916,899, 3,536,809, 3,598,123, which are incorporated herein by reference. No. 4,008,719, No. 5675,533, No. 5,095,595, No. 5,591,767, No. 5,120,548 , No. 5,073,543, No. 5,639,476, No. 5,354,556, and No. 5,733,566 However, it is not limited to them. Using such dosage forms, for example, using hydroxymethylcellulose, other polymer matrices, gels, osmotic membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof 1 Delayed or modified-release of species or more active ingredients can be provided to provide the desired release at various rates. Appropriate modified-release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the active ingredients of the present invention. The invention therefore encompasses single unit dosage forms suitable for oral administration such as, but not limited to, tablets, pills, capsules, and caplets adapted for modified-release.

All modified-release pharmaceutical products have a common goal of improving drug therapy compared to those obtained with their unregulated counterparts. Ideally, the use of optimally designed controlled-release formulations in medical treatment is characterized by using minimal drug substance in the shortest time to cure or control the disease or condition. Advantages of modified-release formulations include extended drug activity, reduced dosage frequency, and increased patient compliance. In addition, controlled-release formulations can be used to affect the onset time or other characteristics, such as drug blood levels, and consequently the occurrence of side effects (eg, bad effects). You can also.

  Most modified-release formulations initially release an amount of drug (active ingredient) that immediately produces the desired therapeutic effect and gradually and continuously release another amount of the drug to treat or prevent over a long period of time. Designed to keep this level of effect. In order to maintain this constant level in the body, the drug must be released at a rate that will replace the amount of drug that is metabolized from the dosage form and excreted from the body. Modulation-release of the active ingredient may be stimulated by a variety of conditions including but not limited to pH, temperature, enzymes, water, or other physiological conditions or may be stimulated by compounds. sell.

  Alternatively, the modified-release pharmaceutical product may contain other active ingredients such as cis-itraconazole, posaconazole or sapaconazole malic acid co-crystals and cis-itraconazole, posaconazole or sapaconazole-HCl, or water thereof. May be designed to initially release one or more other active ingredients (eg, metabolic inhibitors) that may affect the properties of the solvate, solvate, polymorph, or co-crystal) it can. For example, metabolic inhibitors, such as CYP3A4 inhibitors, can be used to inhibit the initial liver metabolism of the active ingredient.

Topical dosage forms The topical dosage forms of the present invention include creams, lotions, ointments, shampoos, sprays, aerosols, solutions, emulsions, and other forms known to those skilled in the art. However, it is not limited to them. For example, ^{Remington's Pharmacuetical Sciences, 18 th ed} . , Mack Publishing, Easton
PA (1990), and Introduction to Pharmaceutical Dosage Forms, 4 ^th ed. , Lea & Febiger, Philadelph (1985). For non-sprayable topical dosage forms, a sticky or semi-comprising carrier or one or more excipients compatible with topical application and preferably having a dynamic viscosity greater than water. A solid or solid form is typically used. Suitable formulations include, but are not limited to, solutions, suspensions, emulsions, creams, ointments, powders, liniments, salves, etc., which may be sterilized if desired or various such as, for example, osmotic pressure Are mixed with auxiliaries (eg preservatives, stabilizers, wetting agents, buffers or salts) to affect the properties of Other suitable topical dosage forms include nebulizable aerosol formulations in which the volatile substance (eg, a gaseous radioactive agent) is preferably pressurized with the active ingredient in combination with a solid or liquid inert carrier. , Eg freon) or in squeeze bottles. If desired, a hydrating or humidifying agent can be added to the pharmaceutical composition and dosage form. Examples of such additional ingredients are known in the art. For ^{example, Remington's Pharmacuetical Sciences, 18 th} ed. , Mack Publishing, Easton PA (1990).

Parenteral dosage forms Parenteral dosage forms are administered to patients in a variety of ways including, but not limited to, subcutaneous, intravenous (including large pill injections), intramuscular, and intraarterial. be able to. Parenteral dosage forms are preferably bactericidal or sterilizable prior to administration to a patient because administration of parenteral dosage forms typically avoids the patient's natural defenses against impurities . Examples of parenteral dosage forms include conditioned injection solutions, dry products that are readily dissolved or suspended in pharmaceutically acceptable vehicles for injection, conditioned suspensions, and emulsions. , But not limited to them.

  Appropriate vehicles that can be used to provide parenteral dosage forms of the invention are known to those skilled in the art. Examples include sterile water, USP injection water, saline solution, glucose solution; aqueous vehicles including but not limited to sodium chloride injection, Ringer's injection, dextrose injection, dextrose and sodium chloride injection, and lactic acid-treated Ringer's injection; Water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and propylene glycol; and, for example, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate Including but not limited to non-aqueous vehicles. The solution is preferably isotonic and has a physiological pH.

  Compounds that increase the solubility of the active ingredient (s) disclosed herein can also be added to the parenteral dosage forms of the invention.

Transdermal and mucosal dosage forms The transdermal and mucosal dosage forms of the present invention are ophthalmic solutions, patches, sprays, aerosols, lotions, suppositories, ointments, gels, solutions, emulsions, suspensions, Or other forms known to those skilled in the art, but not limited thereto. For example, ^{Remington's Pharmacuetical Sciences, 18 th ed} . , Mack Publishing, Easton PA (1990), and Introduction to
Pharmaceutical Dosage Forms, 4 ^th ed. , Lea
& Febiger, Philadelph (1985). Dosage forms suitable for treating mucosal tissue in the oral cavity can be formulated as mouth washes, as mouth gels, or as cheek patches. In addition, transdermal dosage forms include “receiver type” or “matrix type” patches that are applied to the skin and worn over a period of time to allow penetration of the desired amount of the active ingredient. Can do.

  Suitable excipients (eg, carriers and diluents) and other materials that can be used to provide transdermal and mucosal dosage forms encompassed by the present invention are known to those skilled in the pharmaceutical industry, and the pharmaceutical The specific composition or dosage form will depend on the particular tissue or organ to which it will be applied. With this fact in mind, typical excipients for producing dosage forms that are non-toxic and pharmaceutically acceptable are water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1 , 3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof, but are not limited thereto.

  Depending on the specific tissue to be treated, additional components can be used prior to, simultaneously with, or subsequent to treatment with the active ingredients of the present invention. For example, penetration enhancers can be used to assist in delivering the active ingredients to or across the tissue. Suitable penetration enhancers are acetone; various alcohols such as ethanol, oleyl, tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethylacetamide; dimethylformamide; polyethylene glycol; pyrrolidones such as polyvinyl pyrrolidone, Kollidon varieties ( Povidone, Polyvidone); urea; and various water-soluble or insoluble sugar esters, such as TWEEN 80 (polysorbate 80) and Span 60 (sorbitan monostearate). Including but not limited to.

The pH of the pharmaceutical composition or dosage form, or the tissue to which the pharmaceutical composition or dosage form is applied, can be adjusted to improve delivery of one or more active ingredients. Similarly, the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery. Compounds such as stearates can be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients to improve delivery. In this regard, stearates can be used as lipid vehicles for formulations, as emulsifiers or surfactants, and as delivery-enhancing or penetration-enhancing agents. Various hydrates, solvates, polymorphs, or co-crystals of the active ingredient can be used to further adjust the properties of the resulting composition.

Methods of treatment and prevention Cis-Itraconazole, posaconazole or sapaconazole pharmaceutically acceptable salts and co-crystals, and their pharmaceutical compositions and dosage forms are local and systemic fungi, Yeast and have effective activity against dermatophyte infections and are useful for treating or preventing them. For example, using pharmaceutically acceptable salts and co-crystals of cis-itraconazole, posaconazole or saperconazole, and their pharmaceutical compositions and dosage forms, Blast myces, Aspergillus, Histoplasma, Nail fungus, coccidioides, paracoccidioides, cloptococcus, dermatophytes, and candida infections can be treated or prevented.

The degree of prophylactic or therapeutic dose of each active ingredient in the acute or chronic treatment of the disease or condition will vary depending on the disease or condition itself, the specific active ingredient, and the mode of administration. Dose, frequency, or both can also vary depending on the patient's age, weight, response, medical history, and whether the patient is taking other drugs or medications simultaneously or intermittently. Suitable dosage formulations have been reported, for example, in the literature and recommended by Physician's Desk Reference ^(R) (56 ^th ed., 2002) for itraconazole or saperconazole and are also in scope for posaconazole dose determination By following the dosage and prescribing prescriptions that can be expanded, it can be easily selected by the expert using the due consideration of such factors. Unless stated otherwise, the degree of prophylactic or therapeutic dosage of active ingredients used in embodiments of the present invention will be safe and effective (eg, approved by regulations).

  In one aspect of the invention, the active ingredient (eg, cis-itraconazole, posaconazole or sapaconazole di-mesylate, cis-itraconazole, posaconazole or sapaconazole tartrate, cis-itraconazole, posaconazole or sapaconazole fumarate) -Crystals, cis-itraconazole, posaconazole or sapaconazole malonic acid co-crystal, cis-itraconazole, posaconazole or sapaconazolemaleic acid co-crystal, cis-itraconazole, posaconazole or sapaconazole adipic acid co-crystal, cis- Itraconazole, posaconazole or saperconazole malic acid co-crystal, cis-itraconazole, posaconazole or saperconazole succinic acid co-crystal Crystals, cis-itraconazole, posaconazole or sapaconazole-HCl, cis-itraconazole, posaconazole or sapaconazole phosphate, cis-itraconazole, posaconazole or sapaconazole sulfate, or cis-itraconazole, posaconazole or sapaconazole benzene sulfone Acid salts, or multicomponent crystal systems, hydrates, solvates, polymorphs, or co-crystals thereof) in an amount of about 10 mg to about 1000 mg, preferably in an amount of about 25 mg to about 500 mg. More preferably in an amount of about 40 mg to about 400 mg, and most preferably in an amount of about 50 mg to about 200 mg. The dose can be administered in a single or divided dose. The doses and frequencies indicated above are encompassed by the terms “therapeutically effective”, “prophylactically effective”, and “therapeutically or prophylactically effective” as used herein.

The suitability of a particular mode of administration used for a particular active ingredient depends on the active ingredient itself (eg, whether it can be administered orally without breaking down before entering the blood stream) and the disease or condition being treated or prevented Will depend on symptoms. For example, topical administration is typically preferred for the treatment or prevention of local skin diseases or conditions, while oral or parenteral administration is typically systemic diseases or symptoms or in the body of a patient. Preferred for disease or symptom. Similarly, oral or parenteral administration is preferred for the treatment or prevention of acute illnesses or symptoms, whereas transdermal or subcutaneous modes of administration can be used for the treatment or prevention of chronic illnesses or symptoms.

Preparation of a soluble crystalline form of cis-itraconazole, posaconazole or saperconazole The soluble crystalline form of cis-itraconazole, posaconazole or saperconazole can be prepared using various methods known to those skilled in the art. For example, methods for chemical synthesis of (±) cis-itraconazole are described in US Pat. No. 4,267,179 and Heeres, L. et al. , J .; Med. Chem. , 2 7: 894-900) 1984. The four individual stereoisomeric forms of the compound of formula (I), or diastereomeric pairs or mixtures thereof, are for example US Pat. No. 5,998,413, which is incorporated herein by reference. It can be prepared and purified using various methods known to those skilled in the art, such as those described in the specification and US Pat. No. 5,474,997.

  Cis-itraconazole, posaconazole or sapaconazole salts and co-crystals can be obtained by converting cis-itraconazole, posaconazole or sapaconazole free base to suitable acids such as malic acid, hydrochloric acid, sulfuric acid, fumaric acid, phosphoric acid, tartaric acid, maleic acid Pharmaceutically acceptable salts prepared by treatment with organic or inorganic acids, including but not limited to, malonic acid, adipic acid, benzenesulfonic acid, and the like. For example, the salt or co-crystal production process is performed in a solvent system in which both reactants (ie, conazole, eg cis-itraconazole, posaconazole or sapaconazole free base and the respective acids) are sufficiently soluble. be able to. In one method, a solvent or solvent system is used to crystallize or precipitate, where the resulting salts and co-crystals are slightly soluble or not soluble at all. Alternatively, a solvent in which the desired salt and co-crystal are highly soluble can be used, and then an antisolvent (ie, a solvent in which the resulting salt is slightly soluble) is added to the solution. Other variations for salt formation or crystallization include concentration of the salt and co-crystal solution (eg, by heating under reduced pressure if necessary or by slowly evaporating the solvent, eg, at room temperature) or seeding. This includes seeding with the addition of crystals or setting the activity of water required for hydrate formation. In a preferred embodiment, cis-itraconazole, posaconazole or saperconazole and a dicarboxylic acid (eg, a dicarboxylic acid of formula (IV)) are dissolved in THF at 60 ° C. or higher, cooled to room temperature and cis-itraconazole, posaconazole, or supper. Seed with Conazole-L-tartrate. Specific examples of the preparation of cis-itraconazole salts and co-crystals are given below.

  The invention is further defined with reference to the following examples. It will be apparent to those skilled in the art that many modifications, both materials and methods, can be made without departing from the scope of the invention.

  Samples were measured by powder x-ray diffraction (PXRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and / or sample hygroscopicity was measured as indicated below.

Analytical equipment and process

Gravimetric analysis Thermogravimetric analysis of each sample was performed using QW-series, version 1.0.0.78, Thermal Advantage Release 2.0 ( ^(c) 2001TA Instruments) as control software. -Water LLC), the following parts: QDdv. exe version 1.0.0.78 build 78.2; RHBASE. DLL version 1.0.0.78 structure 78.2; RHCOMM. DLL version 1.0.0.78 structure 78.0; RHDLL. DLL version 1.0.0.78 structure 78.1; and TGA. It was performed using a Q500 thermogravimetric analyzer (TA / Instrument, Newcastle, Del., USA) having DLL version 1.0.0.78 structure 78.1. Furthermore, the analysis software used is Windows 95/95/2000 / NT, version 3.1E; Common Analysis 2000 ( ^(c) 19991-2001 TA Instruments-Water LLC) for structure 3.1.1.40. there were.

  For all of the experiments, the basic process for performing thermogravimetric analysis is to place an aliquot of the sample in a platinum sample pan (Pan Part # 952019.906; TA / Instrument, Newcastle, Delaware, USA). Comprising transferring to. The pan was placed on a filling platform and then automatically filled into the Q500 thermogravimetric analyzer using control software. Samples were fluidized dry nitrogen (compressed nitrogen, grade 4.8 (BOC Gases, Murray Hill) over a temperature range (generally 25 ° C. to 300 ° C.) at 10 ° C./min. Thermograms were obtained by heating individually using a sample purge flow rate of 60 mL / min and a balanced purge flow rate of 4 mL / min. Thermal transitions (eg, weight changes) were observed and analyzed using analysis software equipped with the instrument.

Differential Scanning Calorimetry DSC analysis of each sample was performed as control software, Advantage for QW-series, version 1.0.0.78, Thermal Advantage Release 2.0 ( ^(c) 2001TA Instruments-Water LLC ) And the following parts: QDdv. exe version 1.0.0.78 structure 78.2; RHBASE. DLL version 1.0.0.78 structure 78.2; RHCOMM. DLL version 1.0.0.78 structure 78.0; RHDLL. DLL version 1.0.0.78 structure 78.1; and TGA. This was performed using a Q1000 differential scanning calorimeter (TA / Instrument, Newcastle, Del., USA) having DLL version 1.0.0.78 structure 78.1. In addition, the analysis software used was Windows 95/95/2000 / NT, version 3.1E; Common Analysis 2000 ( ^(c) 2001TA Instruments-Water LLC) for structure 3.1.0.40. .

For all of the experiments, aliquots of the samples were weighed into aluminum sample pans (Pan part # 900786.091; Lid part # 900779.901 (TA Instruments, Newcastle, Delaware, USA). The sample pan was closed by sandwiching it for dry samples or by pressure fitting for wet samples (eg hydrated or solvated samples) Is not hermetically sealed for most samples.) Fill the sample pan into a Q1000 differential scanning calorimeter equipped with an automatic sampler and use it to control at 10 ° C / min From T _min (typically 30 ° C.) to T _max (typically 300 ° C.) as a control Thermograms were obtained by individually heating with an aluminum pan of 1. Sample purge of dry nitrogen (compressed nitrogen, grade 4.8 (BOC Gasses, Murray Hill, NJ, USA)) Used as gas and set to a flow rate of 50 mL / min Thermal transitions were observed and analyzed using analysis software equipped with the instrument.

Powder X- ray diffraction All X- ray powder diffraction pattern of copper raw material _(Cu / K α 1.5406Å), manual x-y stage, and 0.3mm collimator instrumented D / Max Rapid (Max Obtained using a Rapid X-ray diffractometer (Rigaku / MSC, The Woodlands, Texas, USA). Samples are cut into 0.3 mm quartz capillaries (Charles Super Company, Natick, Massachusetts, USA) with the closed end of the tube cut and the small open end of the capillary powdered The sample was packed by placing it in a bed of sampled or slurried sample sediment. The precipitate can be amorphous or crystalline. The filled capillary tube was placed in a holder that was placed in an xy stage and fitted. Control software (Lint Rapid Control Software) while oscillating around the omega axis from 0-5 degrees to 1 degree / second and rotating around the phi axis over 360 degrees at 2 degrees / second (RINT Rapid Control Software), Rigaku Rapid / XRD, version 1.0.0 ( ^(c) 1999 Rigaku Co.) with ambient power setting at 46kV A diffractogram was obtained when used in shift mode at 40 mA. Unless otherwise noted, the exposure time was 15 minutes.

  The resulting diffractogram is provided by Rigaku along with the instrument using a cyllnt facility with a step size of 0.02 degrees with 2-theta from 2-60 degrees and chai from 0-36 degrees (1 section) Integrated in RINT Rapid display Software, version 1.18 (Rigaku / MSC). The dark count was set to 8 per system scale by Rigaku. No normalization or omega, key or fee offset was used for integration.

  The relative intensity of the peaks in the diffractogram was determined by visual comparison of the peaks in the diffractogram. Since the peak intensity can vary from sample to sample due to crystalline impurities, the relative intensity of the peaks is not always the limit of the PXRD pattern. Furthermore, the angle of each peak can vary by about +/− 0.1 ° C. Depending on the calibration, settings, and other variations from device to device and from operator to operator, the entire pattern or most of the pattern peaks can also vary by about +/− 0.1 ° C. The relative intensity is displayed as strong (S), medium (M), and weak (W).

The hygroscopic characteristics for the samples from each of the hygroscopic bottles 1-5 as well as the cis-itraconazole free base are the relative humidity (ie 0%, 30%, 57%, And 75%) and was measured by incubating the sample in that environment for about 8 hours at room temperature (20-25 ° C.). The humidity chamber is a theta consisting of a desiccant / salt bath at the bottom with an open bottle containing the sample suspended at the top. Use solid phosphorus pentoxide to obtain ~ 0% relative humidity, use saturated aqueous magnesium bromide to give ~ 30% relative humidity, and saturated aqueous sodium bromide to give ~ 57% relative humidity And a saturated aqueous sodium chloride solution was used to give ~ 75% relative humidity.

The relative hygroscopicity of each sample is the content of the present invention, which is incorporated herein by reference.
ion to Commercial Dosage Form, "Ed. Mark Gibson, published by IHS Health Group Co ,; 49 (2001). Samples showing a loss greater than 0.2 wt.% And less than 2 wt.% After 8 hours incubation at 25 ° C. in 75% relative humidity are classified as slightly hygroscopic. Samples showing a loss of greater than 2 wt.% And less than 15 wt.% After 8 hours of incubation at 25 ° C. are classified as hygroscopic, and incubation at 25 ° C. for 8 hours within 75% relative humidity May later be greater than 15% by weight A sample showing a loss equal to that is classified as very hygroscopic.

Example 1
Cis-itraconazole HCL: DL-tartaric acid co-crystal DL-tartaric acid co-crystal of itraconazole hydrochloride was prepared. To a suspension of itraconazole free base (20.1 g, 0.0285 mol) in absolute ethanol (100 mL) was added hydrochloric acid (HCl) (1.56 g, 0.0428 mol) and DL-tartaric acid (2.99 g, 0.0171). Mol) in absolute ethanol (100 mL) was added. A clear solution formed upon stirring and heating to reflux. The hot solution was gravity filtered and allowed to cool to room temperature (25 ° C.). Cooling produced white crystals. 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 material was found to be itraconazole hydrochloride DL-tartaric acid co-crystal. The solid was identified by PXRD and DSC as shown in FIGS. 5 (a) and 5 (b), respectively.

  Cis-Itraconazole HCl: DL-tartaric acid co-crystals are 3.72, 10.94, 13.90, 14.19, 16.61, 17.71, 19.01, 19.76, 21.29, 21. Any one, any two of the peaks in FIG. 5 (a) including, but not limited to, .91, 24.10, and 24.89 degrees 2-theta (as rigaku, collected data) , Any three, any four, any five, or any six or more.

  The DSC thermogram of cis-itraconazole HCl: DL-tartaric acid co-crystal showed an endothermic transition at about 161 ° C., as shown in FIG. 5 (b).

Example 2
Cis-itraconazole HCL: D-tartaric acid co-crystal D-tartaric acid co-crystal of itraconazole hydrochloride was prepared. A suspension of itraconazole free base (20.1 g, 0.0285 mol) in absolute ethanol (100 mL) was added hydrochloric acid (HCl) (1.56 g, 0.0428 mol) and D-tartaric acid (2.99 g, 0.0171). Mol) in absolute ethanol (100 mL) was added. A clear solution formed upon stirring and heating to reflux. The hot solution was gravity filtered and allowed to cool to room temperature (25 ° C.). Cooling produced white crystals. 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 material was found to be D-tartaric acid co-crystal of itraconazole hydrochloride. The solid was identified by PXRD and DSC as shown in FIGS. 6 (a) and 6 (b), respectively.

Cis-Itraconazole HCl: D-tartaric acid co-crystals are 3.72, 10.92, 13.89, 14.17, 16.61, 17.67, 19.00, 19.75, 21.29, 21. Any one, any two of the peaks in FIG. 5 (a) including, but not limited to, .95, 24.05, and 24.87 degrees 2-theta (as Rigaku, as collected data) Any three, any four, any five, or any six or more.

  The DSC thermogram of cis-Itraconazole HCl: DL-tartaric acid co-crystal showed an endothermic transition at about 161 ° C. as shown in FIG. 6 (b).

Example 3
Cis-itraconazole HCL: L-tartaric acid co-crystal L-tartaric acid co-crystal of itraconazole hydrochloride was prepared. To a suspension of itraconazole free base (20.1 g, 0.0285 mol) in absolute ethanol (100 mL) was added hydrochloric acid (HCl) (1.56 g, 0.0428 mol) and L-tartaric acid (2.99 g, 0.0171). Mol) in absolute ethanol (100 mL) was added. A clear solution formed upon stirring and heating to reflux. The hot solution was gravity filtered and allowed to cool to room temperature (25 ° C.). Cooling produced white crystals. 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 material was found to be L-tartaric acid co-crystal of itraconazole hydrochloride. The solid was identified by PXRD and DSC as shown in FIGS. 7 (a) and 7 (b), respectively.

  Cis-Itraconazole HCl: L-tartaric acid co-crystals are 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, as collected data) including any one of the peaks in FIG. 7 (a), any two, any three One, any four, any five, or any six or more.

  The DSC thermogram of cis-itraconazole HCl: DL-tartaric acid co-crystal showed an endothermic transition at about 162 ° C. as shown in FIG. 7 (b).

  The co-crystal of the cis-itraconazole salt showed a hygroscopicity that was reduced from that of the cis-itraconazole salt. In the case of cis-itraconazole HCl: DL-tartaric acid, cis-itraconazole HCl: D-tartaric acid, and cis-itraconazole HCl: L-tartaric acid co-crystal, the DL-tartaric acid co-crystal is among the three co-crystals. And has the lowest hygroscopicity. This may be due to the presence of di-HCl cis-itraconazole in the D- and L-tartaric acid co-crystal samples.

  Furthermore, the stability of the cis-itraconazole HCl: DL-tartaric acid co-crystal is higher under certain solvent conditions than that in the co-crystal with the free base, such as cis-itraconazole: succinic acid. Cis-Itraconazole HCl: DL-tartaric acid co-crystals are stable over time in solvents, but cis-Itraconazole: succinic acid co-crystals can decompose into free base and succinic acid. This indicates that cis-itraconazole HCl: DL-tartaric acid co-crystals are better candidates for pharmaceutical composition or drug development compared to cis-itraconazole: succinic acid co-crystals.

  Finally, the tartaric acid co-crystal of cis-itraconazole HCl salt is moistened with water, while the co-crystal comprising the cis-itraconazole free base is water repellent. As indicated above, this also indicates that cis-itraconazole HCl: DL-tartaric acid co-crystals are better candidates for the development of pharmaceutical compositions or drugs compared to cis-itraconazole: succinic acid co-crystals .

Example 4
In vivo study of oral bioavailability in dogs
Formulation M1 Production-Itraconazole HCl: DL-tartaric acid co-crystal 367.0 mg of hydroxypropylcellulose 100,000 (HPC) was weighed into a glass mortar. 366.3 mg of itraconazole HCl: DL-tartaric acid co-crystal was added to the mortar. The composition was ground using a pestle and mixed with a spatula until the powder was well mixed and the appearance looked uniform.

  736.9 mg of d-alpha tocopheryl polyethylene glycol 1000 (TPGS) succinate was added to the bottle and heated to 60 ° C. to melt.

  The co-crystal and HPC blended powder was added to the molten TPGS and mixed by both rotation and stirring with a spatula until uniform. The formulation was allowed to cool to room temperature to yield a waxy white solid. The resulting formulation was called M1.

Effect of gastric pH on the pharmacokinetic performance of itraconazole and its main metabolite hydroxy-itraconazole after oral administration of Sporanox® and Formulation M1 (see M1 manufacture above ⁾ in male Beagle dogs The test was completed. A dose of 2.5 mg / kg was used. This dose is comparable roughly to those used by the human (100 mg / 70 kg human is approximately 1.4 mg / kg, package insert agent per about Supora Knox ^(R) capsules, optionally used dose of 200mg ) In the first series of dog experiments, the gastric pH was lowered to about pH 2 by subcutaneous injection of pentagastrin. Approximately 40-50 minutes prior to dose administration, a solution of pentagastrin was administered subcutaneously to each dog at a dose of 0.1 mL / kg in an attempt to stimulate gastric secretion. Pentagastrin was prepared as a solution in dimethyl sulfoxide (DMSO) and hydroxypropyl beta-cyclodextrin (HPCD in water) at a concentration of 1.5 mg / mL on the day of dosing. When the stomach pH reached a value of about 2.0 (actual range: 1.9 to 2.4), dogs received their formulations. Animals Supora Knox ^(R) was administered beads (itraconazole / kg of 2.5 mg) and 1 week (i.e., washout period) after, M1 formulation after the same formulation of pentagastrin pretreatment (2.5 mg itraconazole / kg ) Was administered. In a second set of experiments, Pepcid ^(Pepcid) (R) AC increased gastric pH by oral administration of the commercial formulation (total dose / dog 10 mg) (i.e., about pH7 or 8). Thereafter, the two dogs of the four animals that Supora Knox the ^(R) was received in dose of itraconazole / kg orally 2.5 mg, orally dose of M1 in the remaining two animals Was taken. After each dose administration, blood samples were collected sequentially and plasma samples were analyzed for parent drug and its hydroxy metabolite. PhAST ^(R) software program (version 2.3-004, by using the Phoenix International Life Saiensesu, Inc. (Phoenix International Life Sciences Inc.), itraconazole and hydroxy in plasma - itraconazole of pharmacokinetic analysis The highest experimental concentration was considered to be the peak concentration (C _max ), the time to C _max was indicated by T _max (observed value), the observed terminal phase rate constant (K _el ). Is calculated from 2 or more terminal points (non 0 and non C _max ) of log-linear regression wherever possible (the number of points included in the calculation optimizes the r ² value of the regression analysis) was such as to reduction). end half-life (t _1/2) 0. 93 was calculated by the measured. Area under the plasma concentration versus time curve from hour 0 to the last quantifiable concentration (AUC _0-t) linear trapezoidal method by dividing by K _el. H 0 AUC _0-∞ , the area under the plasma concentration for the time curve from _{0 to infinity,} was calculated as the sum of the ratios of the last plasma concentrations up to AUC _0-t and K _el Apparent systemic clearance (CL / F) was measured by dividing the dose by the area under the curve from time 0 to infinity, and values below the limit of quantification were designated as 0 for pharmacokinetic analysis.

Table 1 shows the Supora Knox ^(R) or once in vivo testing of itraconazole pharmacokinetic parameters in plasma after oral administration of the results of the formulation M1 for male beagle dogs.

Comparison with pentagastrin pretreatment data (acidic stomach) and Pepcid ^(R) AC pretreatment data (basic stomach) is approximately in the AUC of about 4-fold reduction and formulations M1 in AUC of Supora Knox ^(R) 2 A fold decrease is shown. Surprisingly, these data show significantly reduced food effect of M1 formulation when compared to Supora Knox ^(R). M1 formulation in Table 1, to have a reduced sensitivity to pH increases in the stomach when compared with Supora Knox ^(R) is shown.

Table 2 male beagles above single oral administration of Supora Knox for (pentagastrin administration) ^(R) (2.5 mg itraconazole / kg) hydroxy in plasma after - the concentration of itraconazole metabolite (ng / ML).

  Table 3 shows the concentration of hydroxy-itraconazole metabolite in plasma (ng / mL) after the above single oral administration (2.5 mg of itraconazole / kg) of formulation M1 to male beagle dogs (administered with pentagastrin) ).

Formulation J12A Preparation-Itraconazole HCl: DL-tartaric acid co-crystal 250.3 mg Itraconazole HCl: DL-tartaric acid co-crystal, 600.1 mg 5 cps hydroxypropyl methylcellulose (HPMC) and 50.3 mg alpha-lactose monohydrate The product was dispersed in a glass mortar. The composition was ground using a pestle and mixed with a spatula until the powder was well mixed and the appearance looked uniform.

  50 microliters of isopropanol was added to the mortar as a granulating liquid. The mixture was ground and mixed until a uniform consistency was observed.

  The formulation was pressed into pellets using a Stokes Tablet Press (DT Industries model 511). The pellets were pressed to an average applied pressure of 14000 psi to a diameter of 2.38 mm and a height of 1.30 mm. The average pellet mass was 5.8 mg. The resulting formulation was called J12A.

  A study of the pharmacokinetic performance of itraconazole after oral administration of a small tablet formulation in male beagle dogs was completed. Prior to dose administration and after an overnight fast, two beagle dogs were weighed and their stomach pH was adjusted to about pH 2 by administration of a solution of pentagastrin. Dog stomach pH was measured by telemetric engineering and recorded for all animals prior to dosing. Approximately 40-50 minutes prior to dose administration, a solution of pentagastrin was administered subcutaneously to each dog at a dose of 0.1 mL / kg in an attempt to stimulate gastric secretion. Pentagastrin was prepared as a solution in dimethyl sulfoxide (DMSO) and hydroxypropyl beta-cyclodextrin (HPCD in water) at a concentration of 1.5 mg / mL on the day of dosing. When the stomach pH reaches a value of about 2.0 (actual range: 1.9 to 2.4), dogs take 1 capsule of J12A orally at a target dose of 2.5 mg / kg itraconazole Accepted by quantity. After dose administration, blood samples were collected from each animal at the time selected by cervical venipuncture.

  Table 4 shows plasma concentrations of itraconazole and hydroxy-itraconazole (ng / mL) after a single oral dose of J12A (2.5 mg / kg) to male beagle dogs.

  Table 5 shows the mean pharmacokinetic parameters of itraconazole in plasma after a single oral dose of J12A (2.5 mg itraconazole / kg) to male beagle dogs.

  Table 6 shows the mean pharmacokinetic parameters of hydroxy-itraconazole in plasma after a single oral dose of J12A (2.5 mg itraconazole / kg) to male beagle dogs.

Example 5
The cis-itraconazole polymorph cis-itraconazole can be prepared as described in the prior art (see US Pat. No. 4,267,179). Several polymorphic forms of cis-itraconazole were unexpectedly discovered. FIG. 8 shows a PXRD diffractogram of the form previously disclosed (designated here as form A). Form A is 4.57, 8.67, 10.72, 14.41, 16.55, 17.48, 17.96, 19.32, 20.33, 22.41, 23.43, 25. Any one, any two, any three, any four, any of the peaks in the PXRD diffractogram in FIG. 8 including, but not limited to, 29, and 27.06 degrees 2-theta Or five, or any six or more.

  Forms B, C, and D were identified by PXRD. Identification data and manufacturing methods are described below for each of these forms.

Cis-Itraconazole Form B
Form B was obtained from crystallized cis-itraconazole recovered from the dissolution test of a cis-itraconazole HCl: DL-tartaric acid co-crystal formulation. The formulation contains 25% cis-itraconazole: DL-tartaric acid co-crystals, 25% poloxamer 407, 25% PEG6000, 20% Avicel, and 5% HPMC 5 cps. The formulation was dry blended in a mortar and pestle. About 100 mg of the formulation was filled into gelatin capsules and the capsules were dropped into about 10 mL of simulated gastric fluid (SGF) at pH 2.0 and 37 ° C. After about 30 minutes, 700 microliters of SGF was removed and spun down on a centrifugal filter. The recovered solid was air dried for 30 minutes and analyzed by PXRD. PXRD showed that the co-crystal no longer exists and that cis-itraconazole crystallized as Form B. Form B is 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 any one of the peaks in the PXRD diffractogram in FIG. 9 including, but not limited to, 2-theta, It can be identified by any two, any three, any four, any five, or any six or more.

Cis-Itraconazole Form C
Form C was obtained from crystallized cis-itraconazole recovered from a dissolution test of a cis-itraconazole HCl: DL-tartaric acid co-crystal formulation. The formulation contains 25% cis-itraconazole: DL-tartaric acid co-crystal, 25% vitamin-E TPGS, 25% PEG 20000, 20% 25% HPMC 5 cps, theta. The formulation was dry blended in a mortar and pestle. About 100 mg of the formulation was filled into gelatin capsules and the capsules were dropped into about 10 mL of simulated gastric fluid (SGF) at pH 2.0 and 37 ° C. After about 30 minutes, 700 microliters of SGF was removed and spun down on a centrifugal filter. The recovered solid was air dried for 30 minutes and analyzed by PXRD. PXRD showed that the co-crystal no longer exists and that cis-itraconazole crystallized as Form C. Form C has 7.22, 8.68, 11.08, 14.10, 15.75, 16.42, 17.58, 18.47, 18.88, 19.77, 21.71, and 22 Any one, any two, any three, any four, any five of the peaks in the PXRD diffractogram in Figure 10 including, but not limited to, 94 degree 2-theta Alternatively, any 6 or more can be identified.

Cis-Itraconazole Form D
Form D was obtained from crystallized cis-itraconazole recovered from the dissolution test of a cis-itraconazole HCl: DL-tartaric acid co-crystal formulation. The formulation contains 25% cis-itraconazole: DL-tartaric acid co-crystal, 25% vitamin-E TPGS, 25% PEG 20000, 25% HPMC 5 cps, theta. The formulation was dry blended in a mortar and pestle. About 100 mg of the formulation was filled into gelatin capsules and the capsules were dropped into about 10 mL of simulated gastric fluid (SGF) at pH 2.0 and 37 ° C. After about 10 minutes, 700 microliters of SGF was removed and spun down on a centrifugal filter. The recovered solid was air dried for 30 minutes and analyzed by PXRD. PXRD showed that the co-crystal no longer exists and that cis-itraconazole crystallized as Form D. Form D is 5.97, 7.22, 8.74, 11.09, 14.09, 15.77, 16.46, 17.60, 18.50, 18.93, 19.77, 21. Any one, any two, any three of the peaks in the PXRD diffractogram in FIG. 11, including but not limited to 71, 22.97, 23.90, and 26.97 degrees 2-theta One, any four, any five, or any six or more. FIG. 12 shows a comparison of four PXRD diffractograms of cis-itraconazole forms A, B, C, and D.

  While the invention has been described in terms of particular embodiments, it will be apparent to those skilled in the art that various modifications can be made without departing from the spirit and scope of the invention as defined in the claims. Such modifications are also intended to fall within the scope of the appended claims.

FIG. 1 shows a diagram of a conazole co-crystal comprising a trimer consisting of a co-crystal former sandwiched between two antiparallel conazole molecules. FIG. 2 shows a sphere and rod model of a single trimer homologue consisting of two cis-itraconazole molecules and an oxalic acid molecule. FIG. 3 shows a sphere and rod model of a single trimer homologue consisting of two posaconazole and oxalic acid molecules. FIG. 4 shows a sphere and rod model of a single trimer homologue consisting of two sappaconazole molecules and an oxalic acid molecule. FIG. 5 (a) shows a PXRD diffractogram of cis-Itraconazole HCl: DL-tartaric acid co-crystal, and FIG. 5 (b) shows a DSC thermogram of cis-Itraconazole HCl: DL-tartaric acid co-crystal. FIG. 6 (a) shows the PXRD diffractogram of cis-Itraconazole HCl: D-tartaric acid co-crystal, and FIG. 6 (b) shows the DSC thermogram of cis-Itraconazole HCl: D-tartaric acid co-crystal. FIG. 7 (a) shows a PXRD diffractogram of cis-Itraconazole HCl: L-tartaric acid co-crystal, and FIG. 7 (b) shows a DSC thermogram of cis-Itraconazole HCl: L-tartaric acid co-crystal. FIG. 8 is a PXRD diffractogram of cis-itraconazole (Form A). FIG. 9 is a PXRD diffractogram of cis-Itraconazole (Form B). FIG. 10 is a PXRD diffractogram of cis-itraconazole (Form C).

FIG. 11 is a PXRD diffractogram of cis-Itraconazole (Form D).
FIG. 12 is a comparison of PXRD diffractograms of cis-itraconazole forms A, B, C, and D.

Claims (30)

  A composition comprising a co-crystal of cis-itraconazole.   The composition of claim 1 wherein said co-crystal is a cis-itraconazole salt co-crystal.   The composition of claim 1 wherein the co-crystal is a tartaric acid co-crystal of cis-itraconazole.   The composition of claim 1, wherein the co-crystal is a tartaric acid co-crystal of a cis-itraconazole salt.   The composition of claim 2 wherein the salt is an HCl salt.   The composition of claim 4 wherein said co-crystal has an endothermic transition point at about 161 ° C as measured by DSC. The co-crystal is cis-itraconazole HCl salt tartaric acid co-crystal and (a) the X-ray diffraction pattern comprises peaks at 3.73, 10.95, and 17.75 degrees 2-theta;
(B) the X-ray diffraction pattern comprises peaks at 10.95, 13.83, and 17.75 degrees 2-theta,
(C) the X-ray diffraction pattern comprises peaks at 3.73, 16.53, and 19.65 degrees 2-theta,
(D) the X-ray diffraction pattern comprises peaks at 10.95, 14.19, and 23.95 degrees 2-theta,
(E) the X-ray diffraction pattern comprises peaks at 3.73 and 10.95 degrees 2-theta,
(F) the X-ray diffraction pattern comprises peaks at 3.73 and 13.83 degrees 2-theta,
(G) the X-ray diffraction pattern comprises peaks at 3.73 and 17.75 degrees 2-theta,
(H) the X-ray diffraction pattern comprises peaks at 10.95 and 17.75 degrees 2-theta,
(I) the X-ray diffraction pattern comprises a peak at 3.73 degrees 2-theta,
(J) the X-ray diffraction pattern comprises a peak at 10.95 degrees 2-theta,
(K) the X-ray diffraction pattern comprises a peak at 13.83 degrees 2-theta,
(L) the X-ray diffraction pattern comprises a peak at 16.53 degrees 2-theta,
(M) the X-ray diffraction pattern comprises a peak at 17.75 degrees 2-theta,
(N) the X-ray diffraction pattern comprises a peak at 19.65 degrees 2-theta,
(O) the X-ray diffraction pattern comprises peaks at 3.73, 10.95, 13.83, 16.53, and 17.75 degrees 2-theta;
(P) the X-ray diffraction pattern comprises peaks at 3.73, 14.19, 19.65, 21.11, and 23.95 degrees 2-theta, or (q) the X-ray diffraction pattern is 3.73, 10.95, 13.83, 14.19, 16.53, 17.75, 19.65, 21.11, and 23.95 degrees comprising peaks at 2-theta,
The composition of claim 1 characterized by an X-ray diffraction pattern.   The composition of claim 1 wherein the composition is a pharmaceutical composition.   A composition comprising a co-crystal of cis-itraconazole.   The composition of claim 9 wherein the co-crystal is a cis-itraconazole salt co-crystal.   The composition of claim 9 wherein the co-crystal is a tartaric acid co-crystal of cis-itraconazole.   The composition of claim 9 wherein the co-crystal is a tartaric acid co-crystal of a cis-itraconazole salt.   11. The composition of claim 10, wherein the salt is an HCl salt.   The composition of claim 12, wherein said co-crystal has an endothermic transition point at about 161 ° C as measured by DSC. The co-crystal is cis-itraconazole HCl salt tartaric acid co-crystal and (a) the X-ray diffraction pattern comprises peaks at 3.73, 10.95, and 17.75 degrees 2-theta;
(B) the X-ray diffraction pattern comprises peaks at 10.95, 13.83, and 17.75 degrees 2-theta,
(C) the X-ray diffraction pattern comprises peaks at 3.73, 16.53, and 19.65 degrees 2-theta,
(D) the X-ray diffraction pattern comprises peaks at 10.95, 14.19, and 23.95 degrees 2-theta,
(E) the X-ray diffraction pattern comprises peaks at 3.73 and 10.95 degrees 2-theta,
(F) the X-ray diffraction pattern comprises peaks at 3.73 and 13.83 degrees 2-theta,
(G) the X-ray diffraction pattern comprises peaks at 3.73 and 17.75 degrees 2-theta,
(H) the X-ray diffraction pattern comprises peaks at 10.95 and 17.75 degrees 2-theta,
(I) the X-ray diffraction pattern comprises a peak at 3.73 degrees 2-theta,
(J) the X-ray diffraction pattern comprises a peak at 10.95 degrees 2-theta,
(K) the X-ray diffraction pattern comprises a peak at 13.83 degrees 2-theta,
(L) the X-ray diffraction pattern comprises a peak at 16.53 degrees 2-theta,
(M) the X-ray diffraction pattern comprises a peak at 17.75 degrees 2-theta,
(N) the X-ray diffraction pattern comprises a peak at 19.65 degrees 2-theta,
(O) the X-ray diffraction pattern comprises peaks at 3.73, 10.95, 13.83, 16.53, and 17.75 degrees 2-theta;
(P) the X-ray diffraction pattern comprises peaks at 3.73, 14.19, 19.65, 21.11, and 23.95 degrees 2-theta, or (q) the X-ray diffraction pattern is 3.73, 10.95, 13.83, 14.19, 16.53, 17.75, 19.65, 21.11, and 23.95 degrees comprising peaks at 2-theta,
The composition of claim 9 characterized by an X-ray diffraction pattern. (A) reacting cis-itraconazole free base in a reaction medium comprising a solvent and a co-crystal former to form a crystalline precipitate of the co-crystal of cis-itraconazole, and (b) the crystalline A process for producing a cis-itraconazole co-crystal comprising recovering a precipitate.   The method of claim 16, wherein the reaction medium further comprises a first acid and a second acid. (A) the first acid is tartaric acid;
(B) the first acid is HCl; or (c) the first acid is tartaric acid and the second acid is HCl.
The method of claim 17.   The method of claim 17, wherein the co-crystal is a tartaric acid co-crystal of a cis-itraconazole salt.   20. The method of claim 19, wherein the salt is an HCl salt.   The method of claim 19, wherein the co-crystal has an endothermic transition point at about 161 ° C as measured by DSC. The co-crystal is cis-itraconazole HCl salt tartaric acid co-crystal and (a) the X-ray diffraction pattern comprises peaks at 3.73, 10.95, and 17.75 degrees 2-theta;
(B) the X-ray diffraction pattern comprises peaks at 10.95, 13.83, and 17.75 degrees 2-theta,
(C) the X-ray diffraction pattern comprises peaks at 3.73, 16.53, and 19.65 degrees 2-theta,
(D) the X-ray diffraction pattern comprises peaks at 10.95, 14.19, and 23.95 degrees 2-theta,
(E) the X-ray diffraction pattern comprises peaks at 3.73 and 10.95 degrees 2-theta,
(F) the X-ray diffraction pattern comprises peaks at 3.73 and 13.83 degrees 2-theta,
(G) the X-ray diffraction pattern comprises peaks at 3.73 and 17.75 degrees 2-theta,
(H) the X-ray diffraction pattern comprises peaks at 10.95 and 17.75 degrees 2-theta,
(I) the X-ray diffraction pattern comprises a peak at 3.73 degrees 2-theta,
(J) the X-ray diffraction pattern comprises a peak at 10.95 degrees 2-theta,
(K) the X-ray diffraction pattern comprises a peak at 13.83 degrees 2-theta,
(L) the X-ray diffraction pattern comprises a peak at 16.53 degrees 2-theta,
(M) the X-ray diffraction pattern comprises a peak at 17.75 degrees 2-theta,
(N) the X-ray diffraction pattern comprises a peak at 19.65 degrees 2-theta,
(O) the X-ray diffraction pattern comprises peaks at 3.73, 10.95, 13.83, 16.53, and 17.75 degrees 2-theta;
(P) the X-ray diffraction pattern comprises peaks at 3.73, 14.19, 19.65, 21.11, and 23.95 degrees 2-theta, or (q) the X-ray diffraction pattern is 3.73, 10.95, 13.83, 14.19, 16.53, 17.75, 19.65, 21.11, and 23.95 degrees comprising peaks at 2-theta,
The method of claim 16 characterized by an X-ray diffraction pattern.   A unit dosage form comprising the composition of claim 8.   The composition of claim 1 further comprising an excipient, diluent, or carrier.   A method for preventing or treating systemic or local mold, fungus, yeast, or dermatophyte infection, comprising administering an effective amount of the composition of claim 8 to a mammal.   26. The method of claim 25, wherein the mammal is a human.   A substantially pure polymorph of cis-itraconazole, wherein the polymorph is Form B, Form C, or Form D. The polymorph is ( a ) the form is Form B and the X-ray diffraction pattern comprises peaks at 7.23, 8.60, and 14.41;
( B ) the form is Form B and the X-ray diffraction pattern comprises peaks at 11.02, 17.55, and 20.36,
( C ) the form is Form B and the X-ray diffraction pattern comprises peaks at 16.51, 19.06, and 23.34,
( D ) the form is Form B and the X-ray diffraction pattern comprises peaks at 7.23 and 8.60,
( E ) the form is Form B and the X-ray diffraction pattern comprises peaks at 10.61 and 14.41;
( F ) the form is Form B and the X-ray diffraction pattern comprises peaks at 17.55 and 20.36,
( G ) the form is Form B and the X-ray diffraction pattern comprises a peak at 7.23;
( H ) the form is Form B and the X-ray diffraction pattern comprises a peak at 14.41;
( I ) the form is Form B and the X-ray diffraction pattern comprises a peak at 17.55,
( J ) the form is Form C and the X-ray diffraction pattern comprises peaks at 7.22, 11.08, and 18.47;
( K ) the form is Form C and the X-ray diffraction pattern comprises peaks at 14.10, 17.58, and 19.77;
( L ) the form is Form C and the X-ray diffraction pattern comprises peaks at 15.75, 16.42, and 18.88,
( M ) the form is Form C and the X-ray diffraction pattern comprises peaks at 7.22 and 15.75,
( N ) the form is Form C and the X-ray diffraction pattern comprises peaks at 8.68 and 18.88;
( O ) the form is Form C and the X-ray diffraction pattern comprises peaks at 17.58 and 21.71,
( P ) the form is Form C and the X-ray diffraction pattern comprises a peak at 8.68;
( Q ) the form is Form C and the X-ray diffraction pattern comprises a peak at 15.75;
( R ) the form is Form C and the X-ray diffraction pattern comprises a peak at 18.88;
( S ) the form is Form D and the X-ray diffraction pattern comprises peaks at 5.97, 7.22, and 17.60,
( T ) the form is Form D and the X-ray diffraction pattern comprises peaks at 11.09, 16.46, and 21.71,
( U ) the form is Form D and the X-ray diffraction pattern comprises peaks at 5.97, 17.60, and 18.93;
( V ) the form is Form D and the X-ray diffraction pattern comprises peaks at 5.97 and 14.09,
( W ) the form is Form D and the X-ray diffraction pattern comprises peaks at 5.97 and 17.60,
( X ) the form is Form D and the X-ray diffraction pattern comprises peaks at 5.97 and 7.22.
( Y ) the form is Form D and the X-ray diffraction pattern comprises a peak at 5.97;
( Z ) the form is Form D and the X-ray diffraction pattern comprises a peak at 7.22, or ( aa ) the form is Form D and the X-ray diffraction pattern is 17.60. Comprising a peak at
28. The substantially pure polymorph of cis-itraconazole of claim 27, characterized by a powder X-ray diffraction pattern comprising a peak represented by a 2-theta angle.   A method of reducing the food effect of conazole, comprising administering to a mammal the soluble crystalline form of claim 1 or a preparation of the soluble crystalline form. The soluble crystal form is (a) a co-crystal;
(B) a co-crystal comprising itraconazole,
(C) a co-crystal comprising itraconazole and tartaric acid,
(D) a co-crystal comprising itraconazole HCl salt,
30. The method of claim 29 comprising (e) itraconazole HCl: tartaric acid co-crystal, or (f) itraconazole HCl: DL-tartaric acid co-crystal.

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