WO2022066146A1 - Procédé et composition pharmaceutique pour le traitement ou la prévention de la trichomonase et leurs utilisations - Google Patents

Procédé et composition pharmaceutique pour le traitement ou la prévention de la trichomonase et leurs utilisations Download PDF

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Publication number
WO2022066146A1
WO2022066146A1 PCT/US2020/052032 US2020052032W WO2022066146A1 WO 2022066146 A1 WO2022066146 A1 WO 2022066146A1 US 2020052032 W US2020052032 W US 2020052032W WO 2022066146 A1 WO2022066146 A1 WO 2022066146A1
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Prior art keywords
secnidazole
subject
microgranule
trichomoniasis
microgranule formulation
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PCT/US2020/052032
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English (en)
Inventor
Helen S. PENTIKIS
David Palling
Richard Holl
Gregory Kaufman
Carol J. BRAUN
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Lupin Inc.
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Priority to CA3193245A priority Critical patent/CA3193245A1/fr
Priority to EP20955432.8A priority patent/EP4236918A1/fr
Priority to PCT/US2020/052032 priority patent/WO2022066146A1/fr
Publication of WO2022066146A1 publication Critical patent/WO2022066146A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core

Definitions

  • This invention relates to method and pharmaceutical composition for treating or preventing trichomoniasis or Trichomonas vaginalis (T. vaginalis) infection in a subject and uses thereof.
  • Trichomoniasis is a sexually transmitted disease caused by the parasite, T. vaginalis, and the most common non-viral sexually transmitted infection (“STI”) in the world.
  • STI non-viral sexually transmitted infection
  • the World Health Organization estimates an incidence of trichomoniasis of 276 million new cases each year and prevalence of 187 million of infected individuals. (Menezes, et al., “Trichomoniasis - are we giving the deserved attention to the most common non-viral sexually transmitted disease worldwide?”, Microb.
  • vaginalis infection prevalence was 4.2% among black males, 8.9% among black females, and 0.03% and 0.8%, respectively, among males and females of other races/ethnicities, and infection is more common in women than in men (Patel, et al., “Prevalence and Correlates of Trichomoniasis vaginalis Infection Among Men and Women in the United States,” Clinical Infectious Diseases, 67(2):211-7 (2018)). Also, T.
  • vaginalis infection affects >11% of women aged > 40 years, and older women are more likely than younger women to be infected (Ginocchio, et al., “Prevalence of Trichomonas vaginalis and Coinfection with Chlamydia trachomatis and Neisseria gonorrhoeae in the United States as Determined by the Aptima Trichomonas vaginalis Nucleic Acid Amplification Assay,” J. Clinical Microbiology, 50(8):2601-2608 (2012)).
  • T. vaginalis infection is also commonly detected in sexually transmitted diseases (“STDs”) clinic patients (Meites, et al. "Trichomonas vaginalis in selected U.S.
  • Men infected with trichomoniasis can experience symptoms of urethritis, epididymitis, or prostatitis, and women infected with trichomoniasis can experience discomfort with urination; itching, burning, redness or soreness of the genitals; or a change in their vaginal discharge, which may be diffuse, malodorous, and/or yellow-green with or without vulvar irritation.
  • most people who are infected with trichomoniasis (approximately 70% to 85%) are asymptomatic or have minimal symptoms, and, as a result, are unaware of the infection and do not seek treatment. Untreated infections may last for months or years, and sexual partners may readily pass their infection through sexual intercourse.
  • T. vaginalis Screening procedures and diagnostic testing for T. vaginalis in a subject (such as human - male or female) presently exist, and routine screening of asymptomatic women with HIV infection for T. vaginalis is recommended because of the adverse events associated with asymptomatic trichomoniasis and Human Immunodeficiency Virus (“HIV”) infection.
  • a subject such as human - male or female
  • HIV Human Immunodeficiency Virus
  • diagnostic testing for T. vaginalis should be performed in women seeking care for vaginal discharge, and screening may be considered for persons receiving care in high- prevalence settings (e.g., STD clinics and correctional facilities) and for asymptomatic persons at high risk for infection e.g., persons with multiple sex partners, exchanging for payment, illicit drug use, or a history of STD). See CDC 2015 Guidelines - Trichomoniasis.” Screening for T. vaginalis should be performed in women seeking care for vaginal discharge. See id. Also, because of the high rate of reinfection among women treated for trichomoniasis, retesting for T.
  • vaginalis is recommended for all sexually active women within 3 months following initial treatment, regardless of whether they believe their sex partners were treated. See id. Testing by nucleic acid amplification testing (“NAAT”), which is the preferred diagnostic test for T. vaginalis infection, can be conducted as soon as 2 weeks after treatment. See id. & 2020 ACOG Practice Bulletin, p.e5-e7.
  • NAAT nucleic acid amplification testing
  • FDA-approved commercial tests such as DNA hybridization probe tests (such as BD AffirmTM VPIII Microbial Identification System from Becton Dickinson in Sparks, MD), multiplex PCR panel tests (such as BD MAXTM CT/GC/TV Assay using the BD MAXTM System from Becton Dickinson in Sparks, MD) & antigen-detection testing (such as OSOM® Trichomonas Rapid Test from Sekisui Diagnostics in Framingham, MA)) or vaginal culture. See id.
  • DNA hybridization probe tests such as BD AffirmTM VPIII Microbial Identification System from Becton Dickinson in Sparks, MD
  • multiplex PCR panel tests such as BD MAXTM CT/GC/TV Assay using the BD MAXTM System from Becton Dickinson in Sparks, MD
  • antigen-detection testing such as OSOM® Trichomonas Rapid Test from Sekisui Diagnostics in Framingham, MA
  • Trichomoniasis or T. vaginalis infection is associated with serious health consequences, such as preterm birth, adverse pregnancy outcomes, infertility, HIV acquisition and cancer.
  • vaginalis infection in HIV-infected women also have increased risk for pelvic inflammatory disease (“PID”)
  • PID pelvic inflammatory disease
  • Minkoff, et al. “Risk factors for prematurity and premature rupture of membranes: a prospective study of the vaginal flora in pregnancy,” Am. J. Obstet. Gynecol., 150:965-72 (1984); Cotch, et al., “Trichomonas vaginalis associated with low birth weight and preterm delivery,” Sex. Transm. Dis., 24:353-60 (1997); Moodley, et al., “Trichomonas vaginalis is associated with pelvic inflammatory disease in women infected with human immunodeficiency virus,” Clin. Infect. Dis., 34:519-22 (2002) (“Moodley”)).
  • nitroimidazoles are the only class of antimicrobial medications known to be effective against T. vaginalis infections, and from this class, metronidazole and tinidazole have been cleared by the U.S. Food & Drug Administration (“FDA”) for the oral or parenteral treatment of trichomoniasis.
  • FDA U.S. Food & Drug Administration
  • the CDC 2015 Guidelines - Trichomoniasis recommends the following treatment regimen for trichomoniasis: metronidazole (2 grams orally in a single dose) or tinidazole (2 grams orally in a single dose) or, as an alternative regimen, metronidazole (500 mg orally twice a day for 7 days).
  • the CDC 2015 Guidelines - Trichomoniasis additionally states that tinidazole is generally more expensive, reaches higher levels in serum and the genitourinary tract, has a longer half-life than metronidazole (12.5 hours versus 7.3 hours), and has fewer gastrointestinal side effects. Also, the CDC 2015 Guidelines - Trichomoniasis states in randomized clinical trials, recommended metronidazole regimens have resulted in cure rates of approximately 84%-98%, and the recommended tinidazole regimen has resulted in cure rates of approximately 92%-100%.
  • subjects with trichomoniasis or T. vaginalis infection may have one or more additional diseases or medical complications, such as HIV and/or bacterial vaginosis, and such subjects experience persistent or recurrent trichomoniasis or T. vaginalis infection.
  • additional diseases or medical complications such as HIV and/or bacterial vaginosis
  • T. vaginalis infection may be expired.
  • Typical treatment for these subjects is the CDC’s alternative regimen of metronidazole 500 mg orally, twice a day for 7 days, rather than the CDC’s recommended single dose treatments, which are shown to be less effective with these subjects.
  • the CDC warns that are factors that decrease the effectiveness of the recommended single dose treatments for trichomoniasis in these subjects, including impaired immunity, increased resistance to metronidazole and/or tinidazole, changes in vaginal ecology, use of antiretroviral therapy and increased rates of asymptomatic bacterial vaginosis coinfections. (CDC 2015 Guidelines - Trichomoniasis). For example, there is increasing evidence showing single-dose treatment of metronidazole may be insufficient to treat trichomoniasis.
  • tinidazole When a subject is infected with metronidazole-resistant trichomonas, tinidazole is typically used as a second-line therapy for such subject.
  • tinidazole is about ten times more expensive than metronidazole, and hence presenting a financial barrier for those who are in need of a metronidazole alternative to treat their trichomoniasis or T. vaginalis infection.
  • high-level metronidazole and tinidazole-resistant trichomoniasis is treated with a high dose oral and vaginal tinidazole (e.g., 500 mg taken orally, twice a day + 500 mg taken vaginally twice a day for 14 days; or 1 gram taken orally, three times a day + 500 mg taken vaginally, three times a day for 14 days; or 400 mg taken orally, three times a day for 10 days; or 500 mg taken orally, three times a day for at least 10 days;) or a combination of high-dose oral tinidazole (1 gram, three times a day) and intravaginal paromomycin cream (6.25%, 5 grams vaginally nightly) for 14 days.
  • a high dose oral and vaginal tinidazole e.g., 500 mg taken orally, twice a day + 500 mg taken vaginally twice a day for 14 days; or 1 gram taken orally, three times a day
  • Embodiments described herein are directed to a method of treating or preventing trichomoniasis or T. vaginalis infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of secnidazole or a pharmaceutically acceptable salt thereof in a microgranule formulation.
  • the secnidazole or the pharmaceutically acceptable salt thereof in the microgranule formulation is administered orally.
  • the secnidazole or the pharmaceutically acceptable salt thereof in the microgranule formulation comprises a plurality of microgranules.
  • each microgranule comprises an inactive core (such as a sugar core, microcrystalline cellulose core or any core that does not contain any active pharmaceutical ingredient (“API”)) and a layer outside of the inactive core.
  • the layer outside of the inactive core comprises secnidazole.
  • each microgranule further comprises as a coating layer that is outside of the layer outside of the inactive core.
  • the coating layer comprises a delayed release element (such as ethyl acrylate-methyl methacrylate copolymer) and/or an anti-tacking element (such as glycerol monostearate).
  • the plurality of microgranules has a particle size diameter in the range of about 400 micrometers to about 841 micrometers. In some embodiments, the particle size diameter of the microgranule is measured using laser diffraction. In some embodiments, wherein the therapeutically effective amount of secnidazole is an amount of secnidazole that exhibits a maximum plasma concentration (Cmax) of secnidazole in the subject of about 17.4 pg/ml and about 26.5 pg/ml, or about 34.5 pg/ml to about 58.3 pg/ml, or about 26 pg/ml to about 34 pg/ml, or about 26 pg/ml to about 58 pg/ml.
  • Cmax maximum plasma concentration
  • the therapeutically effective amount of secnidazole is an amount of secnidazole that exhibits a time to maximum plasma concentration (Tmax) of secnidazole in the subject of about 2 hours to about 6 hours, or about 3 hours to about 4 hours, or about 6 hours to about 24 hours, or about 2 hours to about 24 hours. In some embodiments, wherein the therapeutically effective amount of secnidazole is an amount of secnidazole that exhibits a time to drug elimination half-life (ti/2) of about 11 hours to about 20 hours in the subject. In some embodiments, wherein secnidazole is the sole drug in the microgranule formulation.
  • the secnidazole microgranule formulation further comprises one or more of the following ingredients selected from at least one inert core (sugar spheres being preferred); at least one binding agent (povidone being preferred); at least one plasticizer (polyethylene glycol being preferred, and polyethylene glycol 4000 being most preferred); at least one film-forming polymer (poly(meth)acrylates being preferred and ethyl acrylate-methyl methacrylate copolymer being most preferred), at least one anti-tacking agent (talc being preferred); at least one anti-static agent (talc being preferred); and a combination thereof.
  • at least one inert core sucgar spheres being preferred
  • at least one binding agent povidone being preferred
  • plasticizer polyethylene glycol being preferred, and polyethylene glycol 4000 being most preferred
  • at least one film-forming polymer poly(meth)acrylates being preferred and ethyl acrylate-methyl methacrylate copolymer being most preferred
  • talc anti-tack
  • the microgranule formulation further comprises at least one compound selected from the group consisting of sugar spheres, povidone, polyethylene glycol (such as polyethylene glycol 4000), ethyl acrylate-methyl methacrylate copolymer (such as the product ethyl acrylate-methyl methacrylate copolymer sold under the trademark Eudragit® NE30D), talc, colloidal silicon dioxide, and a combination thereof.
  • the secnidazole in a microgranule formulation may be mixed, stirred, or otherwise integrated into a food substance.
  • the food substance includes, but not limited to, a liquid, semisolid, or soft food.
  • the food substance may include, but not limited to, applesauce, yogurt, pudding or the like.
  • integration of the secnidazole microgranule formulation into a food substance has a taste masking function.
  • a method of treating or preventing trichomoniasis or T. vaginalis infection in a subject in need thereof comprising administering to the subject a microgranule formulation comprising a therapeutically effective amount of secnidazole, wherein the microgranule formulation comprises a plurality of microgranules having a volume- weighted particle size distribution within a microgranule population, wherein the volume- weighted particle size distribution as measured by mean diameter from a representative sample of the microgranule population comprises (a) at least 10% of the microgranule population having a volume-weighted particle size equal to or larger than about 470 micrometers, and/or (b) 50% of the microgranule population having a volume-weighted particle size in a range of from about 640 micrometers to about 810 micrometers; and/or (c) 90% of the microgranule population having a volume-weighted particle size smaller than about 1170 micrometers.
  • each microgranule comprises a sugar core or a microcrystalline cellulose core, and a layer outside of the sugar core or the microcrystalline cellulose core, the layer comprising secnidazole.
  • each microgranule further comprises as a coating layer that is outside of the layer outside of the inactive core.
  • the coating layer comprises a delayed release element (such as ethyl acrylate-methyl methacrylate copolymer) and/or an anti-tacking element (such as glycerol monostearate).
  • the therapeutically effective amount of secnidazole is an amount of secnidazole that exhibits a Cmax of secnidazole in the subject of about 17.4 pg/ml and about 26.5 pg/ml, or about 34.5 pg/ml to about 58.3 pg/ml, or about 26 pg/ml to about 34 pg/ml, or about 26 pg/ml to about 58 pg/ml.
  • the therapeutically effective amount of secnidazole is an amount of secnidazole that exhibits a Tmax of secnidazole in the subject of about 2 hours to about 6 hours, or about 3 hours to about 4 hours, or about 6 hours to about 24 hours, or about 2 hours to about 24 hours. In some embodiments, wherein the therapeutically effective amount of secnidazole is an amount of secnidazole that exhibits a ti/2 of about 11 hours to about 20 hours in the subject. In some embodiments, wherein secnidazole is the sole drug in the microgranule formulation.
  • the secnidazole microgranule formulation further comprises one or more of the following ingredients selected from at least one inert core (sugar spheres being preferred); at least one binding agent (povidone being preferred); at least one plasticizer (polyethylene glycol being preferred, and polyethylene glycol 4000 being most preferred); at least one film-forming polymer (poly(meth)acrylates being preferred and ethyl acrylate-methyl methacrylate copolymer being most preferred), at least one anti-tacking agent (talc being preferred); at least one antistatic agent (talc being preferred); and a combination thereof.
  • at least one inert core sucgar spheres being preferred
  • at least one binding agent povidone being preferred
  • plasticizer polyethylene glycol being preferred, and polyethylene glycol 4000 being most preferred
  • at least one film-forming polymer poly(meth)acrylates being preferred and ethyl acrylate-methyl methacrylate copolymer being most preferred
  • talc anti-tacking
  • the microgranule formulation further comprises at least one compound selected from the group consisting of sugar spheres, povidone, polyethylene glycol (such as polyethylene glycol 4000), ethyl acrylate-methyl methacrylate copolymer (such as the product ethyl acrylate-methyl methacrylate copolymer sold under the trademark Eudragit® NE30D), talc, colloidal silicon dioxide, and a combination thereof.
  • the secnidazole in a microgranule formulation may be mixed, stirred, or otherwise integrated into a food substance.
  • the food substance includes, but not limited to, a liquid, semisolid, or soft food.
  • the food substance may include, but not limited to, applesauce, yogurt, pudding or the like.
  • integration of the secnidazole microgranule formulation into a food substance has a taste masking function.
  • Embodiments described herein are directed to a method of treating or preventing trichomoniasis or T. vaginalis infection in a subject in need thereof, the method comprising administering to the subject a microgranule formulation comprising a therapeutically effective amount of nitroimidazole compound or a pharmaceutically acceptable salt thereof, wherein the microgranule formulation comprises a plurality of microgranules, wherein each microgranule comprises a core and a coating, wherein the core comprises the nitroimidazole compound or the pharmaceutically acceptable salt thereof, and wherein the coating surrounds the core.
  • the nitroimidazole compound is secnidazole, metronidazole, tinidazole, nimorazole, dimetridazole, 6-Amino PA824, orinidazole, megazol, azanidazole, benznidazole, pimonidazole or a combination thereof.
  • the nitroimidazole compound is secnidazole.
  • the nitroimidazole compound is in the core.
  • the nitroimidazole compound comprises at least 70% of the core by weight.
  • the coating covers partially or all of the exterior surface of the core.
  • the coating does not contain a nitroimidazole compound.
  • the nitroimidazole compound comprises at least about 70% of the core by weight; at least about 75% of the core by weight; at least about 80% of the core by weight; at least about 85% of the core by weight; at least about 90% of the core by weight; or about at least about 95% of the core by weight.
  • the nitroimidazole compound comprises about 70% of the core by weight; about 75% of the core by weight; about 80% of the core by weight; about 85% of the core by weight; about 90% of the core by weight; or about 95% of the core by weight.
  • the plurality of microgranules comprise about 1 gram to about 4 grams of the nitroimidazole compound. In some embodiments, the plurality of microgranules comprises a therapeutically effective amount of nitroimidazole compound.
  • the core further comprises at least one polymer. In some embodiments, the polymer can be, but not limited to, Avicel®, Methocel®, hydroxyl propyl cellulose, acacia, guar gum, povidone, lactose monohydrate, or a combination thereof. In some embodiments, the core further comprises Avicel®, Methocel® or a combination thereof.
  • the core further comprises cellulose microcrystalline (such as the product cellulose microcrystalline sold under the trademark Avicel® PH-101), methyl cellulose (such as the product methyl cellulose sold under the trademark Methocel® AV15LV) or a combination thereof.
  • the polymer comprises about 30% of the core by weight.
  • the ratio of the nitroimidazole compound to the at least one polymer in the core may be about 70:30, or lesser than about 70:30, or more than greater than 70:30.
  • the secnidazole in a microgranule formulation may be mixed, stirred, or otherwise integrated into a food substance.
  • the food substance includes, but not limited to, a liquid, semisolid, or soft food. In some embodiments, the food substance may include, but not limited to, applesauce, yogurt, pudding or the like. In some embodiments, integration of the secnidazole microgranule formulation into a food substance has a taste masking function.
  • the core comprises an active ingredient and at least one polymer. In some embodiments, the active ingredient is secnidazole or other nitroimidazole compounds described herein.
  • the core further comprises one or more dispersion agent or binding agent.
  • the dispersion agent or binding agent includes, but not limited to, microcrystalline cellulose, methylcellulose, hydroxyl propyl cellulose, acacia, guar gum, povidone, lactose monohydrate, or a combination thereof.
  • the core further comprises one or more microlubricant or anti-tacking agent.
  • the microlubricant or anti-tacking agent includes, but not limited to, sodium stearate, magnesium stearate, stearic acid, talc or a combination thereof.
  • the core further comprises a binder (such as, but not limited to, starch).
  • the coating may be modified to modulate drug absorption of the drug by varying the composition of the coating, the percentage weight of the composition, or any combination thereof.
  • the coating comprises a polymer.
  • the polymer includes, but not limited to, polyvinylpyrrolidone, ethylcellulose, the product 2-Methylprop-2-enoic acid— N-N-dimethylmethanamine (2/1) sold under the trademark Eudragit® RL, the product anionic copolymers of methacrylic acid and methyl methacrylate at a ratio of approximately 1 : 1 sold under the trademark Eudragit® L, the product amino methacrylate copolymer sold under the trademark Eudragit® E, the product anionic copolymers of methacrylic acid and methyl methacrylate at a ratio of approximately 1 :2 sold under the trademark Eudragit® S, cellulose acetate, polyvinyl alcohol, shellac, methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate trimell
  • the polymer can be, but not limited to, Eudagrit®, ethyl cellulose, Methocel®, glyceryl behenate, or a combination thereof.
  • the polymer is the product ethyl acrylate-methyl methacrylate copolymer sold under the trademark Eudagrit® NE30D.
  • the polymer is the product ethyl acrylate-methyl methacrylate copolymer sold under the trademark Eudagrit® NE30D comprises about 5.795% of the composition of weight.
  • the coating further comprises a polyether polymer.
  • the polyether polymer can be, but limited to, polyethylene glycol (“PEG”), acetyl tributyl citrate, triethyl citrate, dibutyl phthalate, dibutyl sebacate, gelatin, propylene glycol, triacetin or a combination thereof.
  • the polyether polymer is PEG.
  • the PEG is PEG 4000.
  • the coating comprises about 10% to about 13% of the composition by weight. In some embodiments, the coating comprises about 13% or less than about 13% of the composition by weight. In some embodiments, the coating comprises about 10% or more than 10% of the composition by weight.
  • the PEG (such as PEG 4000) comprises about 1.75% of the composition by weight. In some embodiments, the PEG (such as PEG 4000) comprises about 1.75% of an individual microgranule by weight.
  • auxiliary coating aids such as a minor amount (about 1 to about 5% by weight based on the active core component and the total weight of the final coating) of a plasticizer such as, but not limited to, acetyltributyl citrate, triacetin, acetylated monoglyceride, grape seed oil, olive oil, sesame oil, acetyltri ethylcitrate, glycerin sorbitol, diethyloxalate, diethylmalate, diethylfumarate, dibutylsuccinate, diethylmalonate, dioctylphthalate, dibutylsebacate, tri ethyl citrate, tributyl citrate, glyceroltributyrate, polyethyleneglycol, propylene glycol or a combination thereof with or without an antisticking agent (such as, but limited to, a silicate such as, but not limited to, tal
  • the pharmaceutical composition further comprises talc.
  • the plurality of microgranules further comprises talc.
  • the talc is a blending agent.
  • the core comprises a spheronized microgranule.
  • the microgranules may be formed by wet granulation followed by extrusion and spheronization.
  • the core further comprises a binder.
  • the binder may be starch.
  • the active ingredients may be contained in such compositions with pharmaceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water-soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives and the like.
  • the therapeutically effective amount of secnidazole in the microgranule formulation is 1 gram or 2 grams. In some embodiments, the therapeutically effective amount of secnidazole in the microgranule formulation is 2 grams, 4 grams or 6 grams. In some embodiments, the therapeutically effective amount of secnidazole is 2 grams.
  • the plurality of microgranules comprising a daily dose amount of a nitroimidazole compound may be configured as a single unit dose or multiple unit doses. In some embodiments, the multiple unit doses can be two, three or four unit doses per day. In some embodiments, the unit dose may be a portion of the daily dose amount of the nitroimidazole compound. In some embodiments, the nitroimidazole compound is secnidazole and the daily dose amount is about 1 gram, about 2 grams, about 3 grams, about 4 grams, about 5 grams or about 6 grams.
  • the daily dose amount can be configured as one, two, three, four or more unit doses per day.
  • the plurality of microgranules comprising about 2 grams of secnidazole may be configured as 2 unit doses, each unit dose comprising about 1 gram of secnidazole, or about 4 grams of secnidazole configured as 2 unit doses, each unit dose comprising about 2 grams of secnidazole, or about 6 grams of secnidazole configured as 3 unit doses, each unit dose comprising about 2 grams of secnidazole.
  • the plurality of microgranules comprising about 2 grams of secnidazole may be configured as 4 unit doses, each until dose comprising about 0.5 grams of secnidazole.
  • the unit doses in a multiple unit dose regime may have unit doses of equal or different amounts of secnidazole.
  • the plurality of microgranules comprising about 2 grams of secnidazole may be configured as 3 unit doses, where one unit dose comprises about 1 gram of secnidazole and the other two unit doses each comprises about 0.5 grams of secnidazole.
  • Administration of such multiple unit doses to the subject can done during different times in the day (for example, every 6 hours, 8 hours, or 12 hours) or at the same time.
  • microgranule formulations described herein may be prepared, packaged, or sold in bulk, as a single unit dose or as multiple unit doses and may be administered in orally.
  • therapeutically effective amounts, daily doses, or single unit doses of the secnidazole (or other nitroimidazole composition) microgranule formulations described herein may be administered once per day or multiple times per day, such as twice per day; 3 times per day; 4 times per day; 5 times per day; or more than 5 times per day.
  • the treatment or use period can be 1 day, 2 days, 3 days, 4 days, 5 days, 6, days, 7 days, 8 days, 9 days, 10 days, 11 days, 12, days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days,
  • the dosing schedule of the invention can be about 1 gram, about 2 grams, about 3 grams, or about 4 grams of secnidazole (or other nitroimidazole composition) per day for 1 day, 2 days, 3 days, 4 days, 5 days, 6, days, 7 days, 8 days, 9 days, 10 days, 11 days, 12, days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days,
  • the dosing can be done with 1 day, 2 days, 3 days, 4 days or more than 4 days apart each dose.
  • the dosing schedule of the invention can be about 2 grams of secnidazole (or other nitroimidazole composition) per day, taken about 3 days or about 4 days apart x 2.
  • the dosing schedule of the invention can be about 2 grams to 4 grams of secnidazole per day for 1 day to 14 days. The invention herein contemplates all of the dosage schedule combinations set forth in this application.
  • Embodiments are also directed to a dosage regimen for administering a therapeutically effective amount of a nitroimidazole compound (such as secnidazole) for the methods and uses described herein.
  • a nitroimidazole compound such as secnidazole
  • the methods and uses described herein can comprises a dosage regimen that includes a plurality of daily doses having an equal amount of the nitroimidazole compound as the initial dose in one or more unit doses.
  • the dosage regimen can include an initial dose of the nitroimidazole compound in one or more unit doses, then one or more subsequent daily doses having a lower amount of the nitroimidazole compound than the initial doses in one or more unit dose.
  • the dosage regimen may administer one or more initial doses followed by one or more maintenance doses.
  • the one or more doses following the administering of the one or more initial doses can be maintenance doses.
  • Such maintenance doses can have a lower or higher amount of the nitroimidazole compound than the one or more initial doses.
  • Some embodiments are directed to a method of manufacturing a plurality of microgranules comprising a nitroimidazole compound, such as secnidazole.
  • the method of manufacturing a plurality of microgranules comprises forming a plurality of microgranule cores.
  • forming a plurality of microgranule cores comprises a wet granulation step.
  • the wet granulation step comprises mixing a nitroimidazole compound with one or more polymers to form a mixture, and hydrating the mixture to form a hydrated mixture.
  • hydrating the mixture comprises the addition of water to the mixture.
  • the wet granulation step is carried out in a planetary mixer or high shear granulator.
  • forming a plurality of microgranules cores further comprises an extrusion step.
  • the hydrated mixture is passed through an extruder to form a plurality of extruded microgranule cores.
  • the hydrated mixture is passed through an extruder (such as a Niro Extruder) fitted with a 0.8mm screen to form a plurality of extruded microgranule cores.
  • forming a plurality of microgranule cores further comprises a spheronization step to form a plurality of spheronized microgranule cores.
  • the extruded microgranule cores are spheronized to form a plurality of spheronized microgranule cores.
  • the spheronization step is carried out using a spheronizer (such as a Niro Spheronizer).
  • forming a plurality of microgranule cores further comprise drying and screening the plurality of spheronized microgranule cores.
  • the plurality of spheronized microgranule cores is dried using a Glatt fluid bed and screened to remove fine and oversize material to form a plurality of microgranule cores.
  • the method of manufacturing a plurality of microgranules comprises coating the plurality of microgranule cores to form a plurality of coated microgranules.
  • coating the plurality of microgranule cores comprises coating the plurality of microgranule cores comprises coating the plurality of microgranule cores with one or more polymers.
  • the one or more polymers can be, but not limited to, PEG (such as PEG 4000), Eudragit® (such as the product ethyl acrylate-methyl methacrylate copolymer sold under the trademark Eudagrit® NE30D), talc or a combination thereof, wherein the one or more polymers is sprayed on the plurality of microgranule cores using a Glatt fluid bed to form a plurality of coated microgranules.
  • PEG such as PEG 4000
  • Eudragit® such as the product ethyl acrylate-methyl methacrylate copolymer sold under the trademark Eudagrit® NE30D
  • talc or a combination thereof
  • the method of manufacturing a plurality of microgranules further comprises drying and screening the plurality of coated microgranules.
  • the plurality of coated microgranules are dried in a Glatt fluid bed and screened to remove fine and oversize material.
  • the method of manufacturing a plurality of microgranules further comprises blending and curing the plurality of coated microgranules.
  • blending and curing the plurality of coated microgranules comprises bending the plurality of coated microgranules with talc in a V-blender and curing in a tray dryer at 40°C for 24 hours.
  • administering a therapeutically effective amount of secnidazole to a subject comprises administering a secnidazole or a pharmaceutically acceptable salt thereof in a controlled release form to the subject.
  • the coating described herein can delay disintegration and absorption in the gastrointestinal tract and thereby providing a controlled and/or sustained action over a longer period than an immediate release composition. Additionally, such coatings can be adapted for release of a secnidazole in a predetermined pattern (e.g., in order to achieve a controlled release composition) or it can be adapted not to release the active compound until after passage of the stomach (enteric coating).
  • Suitable coatings encompassed by such embodiments may include, but are not limited to, sugar coating, film coating (e.g., but not limited to, hydroxypropyl methylcellulose, methylcellulose, methyl hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose, acrylate copolymers, polyethylene glycols, polyvinylpyrrolidone or a combination thereof), or an enteric coating (e.g., but not limited to, methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, shellac, ethyl cellulose or a combination thereof).
  • film coating e.g., but not limited to, hydroxypropyl methylcellulose, methylcellulose, methyl hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose, acrylate copolymers, polyethylene glycol
  • a time delay material such as, but not limited to, glyceryl monostearate or glyceryl distearate can be incorporated into the coatings of some embodiments.
  • the coating can be adapted to protect the composition from unwanted chemical changes, for example, but not limited to, to reduce chemical degradation prior to the release of API.
  • particle size of microgranules can be measured using various commonly available methods such as measurement using light (e.g., light-scattering or laser diffraction methods or turbidimetric methods), sedimentation methods (e.g., pipette analysis using an Andreassen pipette, sedimentation scales, photosedimentometers or sedimentation in a centrifugal force), pulse methods (e.g., Coulter counter), or sorting by means of gravitational or centrifugal force.
  • light e.g., light-scattering or laser diffraction methods or turbidimetric methods
  • sedimentation methods e.g., pipette analysis using an Andreassen pipette, sedimentation scales, photosedimentometers or sedimentation in a centrifugal force
  • pulse methods e.g., Coulter counter
  • PK pharmacokinetics
  • Noncompartmental PK analysis is highly dependent on estimation of total drug exposure. Total drug exposure is most often estimated by area under the curve (“AUC”) methods, with the trapezoidal rule (numerical integration) the most common method.
  • Compartmental PK analysis uses kinetic models to describe and predict the concentration-time curve. Single compartment models wherein linear pharmacokinetics is so- called because the graph of the relationship between the various factors involved (dose, blood plasma concentrations, elimination, etc.) gives a straight line or an approximation to one.
  • the therapeutically effective amount of secnidazole in a microgranule formulation is administered as a single dose.
  • the therapeutically effective amount of secnidazole in a microgranule formulation administered as a single dose is the only dose required to be administered to the subject to achieve a post-treatment clinical outcome, resolution of one or more symptoms of trichomoniasis or T. vaginalis infection, or a combination thereof.
  • microgranule formulation is packaged as a unit dose or a single unit dose.
  • a unit dose also defined as single dose herein, is a dosage in a form that includes therapeutically effective amount of secnidazole in a microgranule formulation.
  • the unit dose could be administered to a subject as a single unit dose, wherein the therapeutically effective amount of secnidazole in a microgranule formulation is included in a single package, such as, one pouch, packet, sachet, or bottle.
  • the microgranule formulation is packaged in such a way as to provide a barrier to oxygen and moisture.
  • the microgranule formulation is packaged in a foil pouch or sachet.
  • the foil pouch or sachet is made of a polyester-faced laminated or polyethylene- metallocene-lined aluminum foil pouching material that provides a barrier to oxygen and moisture.
  • the pouch or sachet is made from a material such as, but not limited to, the product polyester-faced laminated pouching material sold under the trademark FASSON® RAPID-ROLL® White Cosmetic Web 350 HB.
  • the microgranule formulation can include a plurality of microgranules comprising inert cores made from microcrystalline cellulose.
  • the inert cores made from microcrystalline cellulose can replace sugar spheres/sugar cores.
  • glycerol monostearate e.g., the product glycerol monostearate sold under the trademark PLASCRYL® T20 by Evonik
  • PLASCRYL® T20 can be used as an anti-tacking agent.
  • glycerol monostearate can be used in Eudragit coatings in place of talc.
  • the plurality of microgranules may be contained, or encased in a capsule (soft shell or hard shell capsule), a gel capsule or any other suitable encapsulation medium known in the art.
  • the plurality of microgranules may be configured as a powder for reconstitution as a suspension.
  • a plurality of microgranules corresponding to a therapeutically effective amount of the nitroimidazole compound (such as secnidazole) may be encased, or encapsulated in one or more sachets, capsules (soft shell or hard shell capsule), gel caps, or any other suitable encapsulation medium known in the art.
  • the methods and uses described herein further comprises administering paromomycin, tinidazole, metronidazole, boric acid or a combination thereof to a subject who is resistant or allergic to metronidazole and/or tinidazole, or the subject who is infected metronidazole and/or tinidazole-resistant trichomoniasis with or when metronidazole and/or tinidazole is contraindicated.
  • the administration of paromomycin, tinidazole, metronidazole, boric acid or a combination thereof to the subject is on the same day or a different day relative to the administration of secnidazole to the subject.
  • the administration of the compounds of the combination therapy e.g., secnidazole, paromomycin, tinidazole, metronidazole, boric acid or a combination thereof
  • the compounds of the combination therapy e.g., secnidazole, paromomycin, tinidazole, metronidazole, boric acid or a combination thereof
  • the methods and uses described herein further comprises co-administering an additional compound selected from ethinyl estradiol (EE2), norethindrone (NET), or a combination thereof.
  • the additional compound is administered on the same day as the secnidazole microgranule formulation.
  • the additional compound is administered on a different day than the secnidazole microgranule formulation.
  • the secnidazole microgranule formulation does not affect the contraceptive efficacy of the additional compound selected from EE2, NET, or a combination thereof.
  • the subject has a resolution of one or more symptoms of trichomoniasis or T. vaginalis infection within up to about seven days after administration to the subject.
  • the subject has an alleviation of one or more symptoms of trichomoniasis or T. vaginalis infection within up to about three days after administration to the subject.
  • the subject is a male or female; adult or child. In some embodiments, the subject is a healthy male or healthy female. In some embodiments, the subject is a pregnant female. In some embodiments, the subject is a healthy pregnant female. In some embodiments, the subject has confirmed or suspected trichomoniasis or T. vaginalis infection. In some embodiments, the subject is resistant to metronidazole and/or tinidazole. In some embodiments, the subject suffers from recurrent trichomoniasis or T. vaginalis infection, that is, the subject having had 2 or more trichomoniasis episodes or T. vaginalis infections in the past 12 months.
  • the subject is also HIV-positive, such as a HIV-positive male, a HIV-positive female or a HIV-positive pregnant female. In some embodiments, the subject is also infected (or co-infected) with bacterial vaginosis. In some embodiments, the subject is a female or pregnant female is HIV-positive and also infected (or co-infected) with bacterial vaginosis. In some embodiments, the subject is a child who is less than 18 years of age, or an adult who is at least 18 years old.
  • the subject is a female or pregnant female also infected (or co-infected) with bacterial vaginosis, or has confirmed or suspected bacterial vaginosis.
  • the subject is a female having had 3 or fewer bacterial vaginosis infections/episodes in the past 12 months.
  • the subject is a female having had 4 or more bacterial vaginosis infections/episodes in the past 12 months.
  • the subject is a female presenting with thin, homogeneous vaginal discharge, a positive potassium hydroxide (“KOH”) Whiff test, vaginal fluid pH greater than or equal to 4.7, and the presence of “clue cells” greater than 20% of total epithelial cells, or any combination thereof.
  • the female with bacterial vaginosis presents with the four Amsel criteria parameters and a gram stain slide Nugent score equal to, or higher than four on bacterial analysis of vaginal samples.
  • the four Amsel criteria parameters are abnormal vaginal discharge (e.g., thin, homogenous vaginal discharge), a positive KOH Whiff test, vaginal fluid pH greater than or equal to 4.7, and the presence of clue cells greater than 20% of total epithelial cells. (See Amsel et al., “Nonspecific vaginitis. Diagnostic criteria and microbial and epidemiologic associations,” Am. J. Med., 74(1): 14— 22 (1983))(“ Amsel”).
  • abnormal vaginal discharge e.g., thin, homogenous vaginal discharge
  • a positive KOH Whiff test e.g., vaginal fluid pH greater than or equal to 4.7
  • clue cells greater than 20% of total epithelial cells.
  • Some embodiments further comprise determining a post-treatment clinical outcome.
  • a post-treatment clinical outcome is indicative of a clinical outcome responder.
  • Some embodiments further comprise determining a post-treatment clinical outcome.
  • a post-treatment clinical outcome of clinical cure is defined as a clinical outcome responder.
  • a clinical outcome responder is a subject with normal vaginal discharge, a negative T. vaginalis test, a negative KOH Whiff test, and clue cells less than 20% of total epithelial cells, post-treatment.
  • a clinical outcome responder is a subject with a gram stain slide Nugent score of less than four, posttreatment.
  • a clinical outcome responder is a subject with normal vaginal discharge, a negative T. vaginalis test, a negative KOH Whiff test, clue cells less than 20% of total epithelial cells), and a gram stain slide Nugent score of less than four, post-treatment.
  • administering to the subject a therapeutically effective amount of secnidazole in a microgranule formulation results in better than expected effectiveness than U.S. Food & Drug Administration-approved (“FDA-approved”) drugs used in the treatment or prevention of trichomoniasis or T. vaginalis infection.
  • FDA-approved U.S. Food & Drug Administration-approved
  • administering to the subject a therapeutically effective amount of secnidazole in a microgranule formulation results in superior effectiveness than FDA-approved drugs used in the treatment or prevention of trichomoniasis or T. vaginalis infection.
  • administering to the subject a therapeutically effective amount of secnidazole in a microgranule formulation results in a higher rate of clinical cure than FDA-approved drugs used in the treatment or prevention of trichomoniasis or T. vaginalis infection.
  • administering to the subject a therapeutically effective amount of secnidazole in a microgranule formulation results in a better than expected safety profile than FDA-approved drugs used in the treatment or prevention of trichomoniasis or T.
  • administering to the subject a therapeutically effective amount of secnidazole in a microgranule formulation results in a more favorable safety profile than FDA-approved drugs used in the treatment or prevention of trichomoniasis or T. vaginalis infection.
  • the therapeutically effective amount of secnidazole in the microgranule formulation administered as a single dose is the only dose required to be administered to the subject to achieve a post-treatment clinical outcome by resolution of one or more symptoms of trichomoniasis or T. vaginalis infection.
  • the one or more symptoms of trichomoniasis or T. vaginalis infection include, but not limited to:
  • trichomoniasis or T. vaginalis infection include, but not limited to, purulent malodorous discharge (associated with burning, pruritus, dysuria, frequency, lower abdominal pain), or dyspareunia, burning postcoital bleeding, dyspareunia, dysuria, a thin green-yellow frothy discharge, vulvovaginal erythema (erythema of the vulva and vaginal mucosa), punctate hemorrhages, urethritis, cystitis, purulent vaginitis, sequamative inflammatory vaginitis, atrophic vaginitis, erosive lichen planus, elevated vaginal pH (about 5.0 to about 6.0), and any combination thereof.
  • purulent malodorous discharge associated with burning, pruritus, dysuria, frequency, lower abdominal pain
  • dyspareunia burning postcoital bleeding
  • dyspareunia dysuria
  • dysuria dysuria
  • Embodiments herein are also directed to a microgranule formulation for treating or preventing trichomoniasis or T. vaginalis infection in a subject in need thereof comprising secnidazole or a pharmaceutically acceptable salt thereof.
  • the microgranule formulation comprises a therapeutically effective amount of secnidazole or a pharmaceutically acceptable salt thereof.
  • the secnidazole or the pharmaceutically acceptable salt thereof in the microgranule formulation comprises a plurality of microgranules.
  • each microgranule comprises an inactive core (such as a sugar core, microcrystalline cellulose core or any core that does not contain any API and a layer outside of the inactive core.
  • the layer outside of the inactive core comprises secnidazole.
  • each microgranule further comprises as a coating layer that is outside of the layer outside of the inactive core.
  • the coating layer comprises a delayed release element (such as ethyl acrylate-methyl methacrylate copolymer) and/or an anti-tacking element (such as glycerol monostearate).
  • the plurality of microgranules has a particle size diameter in the range of about 400 micrometers to about 841 micrometers. In some embodiments, the particle size diameter of the microgranule is measured using laser diffraction.
  • the therapeutically effective amount of secnidazole is an amount of secnidazole that exhibits a Cmax of secnidazole in the subject of about 17.4 pg/ml and about 26.5 pg/ml, or about 34.5 pg/ml to about 58.3 pg/ml, or about 26 pg/ml to about 34 pg/ml, or about 26 pg/ml to about 58 pg/ml .
  • the therapeutically effective amount of secnidazole is an amount of secnidazole that exhibits a Tmax of secnidazole in the subject of about 2 hours to about 6 hours, or about 3 hours to about 4 hours, or about 6 hours to about 24 hours, or about 2 hours to about 24 hours. In some embodiments, wherein the therapeutically effective amount of secnidazole is an amount of secnidazole that exhibits a ti/2 of about 11 hours to about 20 hours in the subject. In some embodiments, wherein secnidazole is the sole drug in the microgranule formulation.
  • the secnidazole microgranule formulation further comprises one or more of the following ingredients selected from at least one inert core (sugar spheres being preferred); at least one binding agent (povidone being preferred); at least one plasticizer (polyethylene glycol being preferred, and polyethylene glycol 4000 being most preferred); at least one film-forming polymer (poly(meth)acrylates being preferred and ethyl acrylate-methyl methacrylate copolymer being most preferred), at least one anti-tacking agent (talc being preferred); at least one antistatic agent (talc being preferred); and a combination thereof.
  • at least one inert core sucgar spheres being preferred
  • at least one binding agent povidone being preferred
  • plasticizer polyethylene glycol being preferred, and polyethylene glycol 4000 being most preferred
  • at least one film-forming polymer poly(meth)acrylates being preferred and ethyl acrylate-methyl methacrylate copolymer being most preferred
  • talc anti-tacking
  • the microgranule formulation further comprises at least one compound selected from the group consisting of sugar spheres, povidone, polyethylene glycol (such as polyethylene glycol 4000), ethyl acrylate-methyl methacrylate copolymer (such as the product ethyl acrylate-methyl methacrylate copolymer sold under the trademark Eudragit® NE30D), talc, colloidal silicon dioxide, and a combination thereof.
  • the secnidazole in a microgranule formulation may be mixed, stirred, or otherwise integrated into a food substance.
  • the food substance includes, but not limited to, a liquid, semisolid, or soft food.
  • the food substance may include, but not limited to, applesauce, yogurt, pudding or the like.
  • integration of the secnidazole microgranule formulation into a food substance has a taste masking function.
  • a microgranule formulation for treating or preventing trichomoniasis or T. vaginalis infection in a subject in need thereof comprising a microgranule formulation comprising a therapeutically effective amount of secnidazole, wherein the microgranule formulation comprises a plurality of microgranules having a volume-weighted particle size distribution within a microgranule population, wherein the volume-weighted particle size distribution as measured by mean diameter from a representative sample of the microgranule population comprises (a) at least 10% of the microgranule population having a volume-weighted particle size equal to or larger than about 470 micrometers, and/or (b) 50% of the microgranule population having a volume-weighted particle size in a range of from about 640 micrometers to about 810 micrometers; and/or (c) 90% of the microgranule population having a volume- weighted particle size smaller than about 1170 micrometers.
  • each microgranule comprises a sugar core or a microcrystalline cellulose core, and a layer outside of the sugar core or the microcrystalline cellulose core, the layer comprising secnidazole.
  • each microgranule further comprises as a coating layer that is outside of the layer outside of the inactive core.
  • the coating layer comprises a delayed release element (such as ethyl acrylate-methyl methacrylate copolymer) and/or an anti-tacking element (such as glycerol monostearate).
  • the therapeutically effective amount of secnidazole is an amount of secnidazole that exhibits a Cmax of secnidazole in the subject of about 17.4 pg/ml and about 26.5 pg/ml, or about 34.5 pg/ml to about 58.3 pg/ml, or about 26 pg/ml to about 34 pg/ml, or about 26 pg/ml to about 58 pg/ml.
  • the therapeutically effective amount of secnidazole is an amount of secnidazole that exhibits a Tmax of secnidazole in the subject of about 2 hours to about 6 hours, or about 3 hours to about 4 hours, or about 6 hours to about 24 hours, or about 2 hours to about 24 hours. In some embodiments, wherein the therapeutically effective amount of secnidazole is an amount of secnidazole that exhibits a ti/2 of about 11 hours to about 20 hours in the subject. In some embodiments, wherein secnidazole is the sole drug in the microgranule formulation.
  • the secnidazole microgranule formulation further comprises one or more of the following ingredients selected from at least one inert core (sugar spheres being preferred); at least one binding agent (povidone being preferred); at least one plasticizer (polyethylene glycol being preferred, and polyethylene glycol 4000 being most preferred); at least one film-forming polymer (poly(meth)acrylates being preferred and ethyl acrylate-methyl methacrylate copolymer being most preferred), at least one anti-tacking agent (talc being preferred); at least one antistatic agent (talc being preferred); and a combination thereof.
  • at least one inert core sucgar spheres being preferred
  • at least one binding agent povidone being preferred
  • plasticizer polyethylene glycol being preferred, and polyethylene glycol 4000 being most preferred
  • at least one film-forming polymer poly(meth)acrylates being preferred and ethyl acrylate-methyl methacrylate copolymer being most preferred
  • talc anti-tacking
  • the microgranule formulation further comprises at least one compound selected from the group consisting of sugar spheres, povidone, polyethylene glycol (such as polyethylene glycol 4000), ethyl acrylate-methyl methacrylate copolymer (such as the product ethyl acrylate-methyl methacrylate copolymer sold under the trademark Eudragit® NE30D), talc, colloidal silicon dioxide, and a combination thereof.
  • the secnidazole in a microgranule formulation may be mixed, stirred, or otherwise integrated into a food substance.
  • the food substance includes, but not limited to, a liquid, semisolid, or soft food.
  • the food substance may include, but not limited to, applesauce, yogurt, pudding or the like.
  • integration of the secnidazole microgranule formulation into a food substance has a taste masking function.
  • a microgranule formulation for treating or preventing trichomoniasis or T. vaginalis infection in a subject in need thereof comprising a therapeutically effective amount of nitroimidazole compound or a pharmaceutically acceptable salt thereof
  • the microgranule formulation comprises a plurality of microgranules, wherein each microgranule comprises a core and a coating, wherein the core comprises the nitroimidazole compound or the pharmaceutically acceptable salt thereof, and wherein the coating surrounds the core.
  • the nitroimidazole compound is secnidazole, metronidazole, tinidazole, nimorazole, dimetridazole, 6-Amino PA824, orinidazole, megazol, azanidazole, benznidazole, pimonidazole or a combination thereof.
  • the nitroimidazole compound is secnidazole.
  • the nitroimidazole compound is in the core.
  • the nitroimidazole compound comprises at least 70% of the core by weight.
  • the coating covers partially or all of the exterior surface of the core.
  • the coating does not contain a nitroimidazole compound.
  • the nitroimidazole compound comprises at least about 70% of the core by weight; at least about 75% of the core by weight; at least about 80% of the core by weight; at least about 85% of the core by weight; at least about 90% of the core by weight; or about at least about 95% of the core by weight.
  • the nitroimidazole compound comprises about 70% of the core by weight; about 75% of the core by weight; about 80% of the core by weight; about 85% of the core by weight; about 90% of the core by weight; or about 95% of the core by weight.
  • the plurality of microgranules comprise about 1 gram to about 6 grams of the nitroimidazole compound. In some embodiments, the plurality of microgranules comprises a therapeutically effective amount of nitroimidazole compound.
  • the core further comprises at least one polymer. In some embodiments, the polymer can be, but not limited to, Avicel®, Methocel®, hydroxyl propyl cellulose, acacia, guar gum, povidone, lactose monohydrate, or a combination thereof. In some embodiments, the core further comprises Avicel®, Methocel® or a combination thereof.
  • the core further comprises cellulose microcrystalline (such as the product cellulose microcrystalline sold under the trademark Avicel® PH-101), methyl cellulose (such as the product methyl cellulose sold under the trademark Methocel® AV15LV) or a combination thereof.
  • the polymer comprises about 30% of the core by weight.
  • the ratio of the nitroimidazole compound to the at least one polymer in the core may be about 70:30, or lesser than about 70:30, or more than greater than 70:30.
  • the secnidazole in a microgranule formulation may be mixed, stirred, or otherwise integrated into a food substance.
  • the food substance includes, but not limited to, a liquid, semisolid, or soft food. In some embodiments, the food substance may include, but not limited to, applesauce, yogurt, pudding or the like. In some embodiments, integration of the secnidazole microgranule formulation into a food substance has a taste masking function.
  • the core comprises an active ingredient and at least one polymer. In some embodiments, the active ingredient is secnidazole or other nitroimidazole compounds described herein.
  • the microgranule formulation is a delayed release formulation and comprises a plurality of microgranules.
  • the delayed release formulation when administered to a subject provides a secnidazole concentration profile characterized by a change in secnidazole concentration as a function of time that is less than that of an immediate release secnidazole microgranule formulation.
  • the delayed release formulation when administered to a subject provides a secnidazole concentration profile characterized by a Tmax that is greater than that of an immediate release secnidazole microgranule formulation.
  • the delayed release formulation when administered to a subject provides a secnidazole concentration profile characterized by a Cmax that is greater than that of an immediate release secnidazole microgranule formulation. In some embodiments, the delayed release formulation, when administered to a subject provides a secnidazole concentration profile characterized by an Area Under the Receiver Operating Characteristic Curve (“AUC”) that is greater than that of an immediate release secnidazole microgranule formulation. In some embodiments, the microgranule formulation comprises about 1 gram to about 6 grams of secnidazole or a pharmaceutically acceptable salt thereof.
  • each microgranule comprises an inactive core (such as a sugar core, microcrystalline cellulose core or any core that does not contain any API and a layer outside of the inactive core.
  • the layer outside of the inactive core comprises secnidazole.
  • each microgranule further comprises as a coating layer that is outside of the layer outside of the inactive core.
  • the coating layer comprises a delayed release element (such as ethyl acrylate-methyl methacrylate copolymer) and/or an anti-tacking element (such as glycerol monostearate).
  • the plurality of microgranules has a particle size diameter in the range of about 400 micrometers to about 841 micrometers. In some embodiments, the particle size diameter of the microgranule is measured using laser diffraction. In some embodiments, the microgranule formulation comprises about 1 gram, about 2 grams, about 3 grams, about 4 grams, about 5 grams, or about 6 grams of secnidazole or a pharmaceutically acceptable salt thereof. In some embodiments, the microgranule formulation is suitable for oral administration.
  • the secnidazole microgranule formulation further comprises one or more of the following ingredients selected from at least one inert core (sugar spheres being preferred); at least one binding agent (povidone being preferred); at least one plasticizer (polyethylene glycol being preferred, and polyethylene glycol 4000 being most preferred); at least one film-forming polymer (poly(meth)acrylates being preferred and ethyl acrylate-methyl methacrylate copolymer being most preferred), at least one anti-tacking agent (talc being preferred); at least one anti-static agent (talc being preferred); and a combination thereof.
  • at least one inert core sucgar spheres being preferred
  • at least one binding agent povidone being preferred
  • plasticizer polyethylene glycol being preferred, and polyethylene glycol 4000 being most preferred
  • at least one film-forming polymer poly(meth)acrylates being preferred and ethyl acrylate-methyl methacrylate copolymer being most preferred
  • talc anti-tack
  • the microgranule formulation further comprises at least one compound selected from the group consisting of sugar spheres, povidone, polyethylene glycol (such as polyethylene glycol 4000), ethyl acrylate-methyl methacrylate copolymer (such as the product ethyl acrylate-methyl methacrylate copolymer sold under the trademark Eudragit® NE30D), talc, colloidal silicon dioxide, and a combination thereof.
  • the secnidazole in a microgranule formulation may be mixed, stirred, or otherwise integrated into a food substance.
  • the food substance includes, but not limited to, a liquid, semisolid, or soft food.
  • the food substance may include, but not limited to, applesauce, yogurt, pudding or the like.
  • integration of the secnidazole microgranule formulation into a food substance has a taste masking function.
  • Embodiments herein are also directed to a use of secnidazole or a pharmaceutically acceptable salt thereof in a microgranule formulation in the manufacture of a medicament for the treatment or prevention of trichomoniasis or T. vaginalis infection in a subject, wherein the microgranule formulation comprises a therapeutically effective amount of secnidazole or the pharmaceutically acceptable salt thereof in the microgranule formulation.
  • the therapeutically effective amount of secnidazole or the pharmaceutically acceptable salt thereof in the microgranule formulation is an amount of secnidazole or the pharmaceutically acceptable salt thereof, respectively, that exhibits a Cmax of between about 34.5 pg/ml and about 58.3 pg/ml, or about 26 pg/ml to about 34 pg/ml, or about 26 pg/ml to about 58 pg/ml.
  • the therapeutically effective amount of secnidazole or the pharmaceutically acceptable salt thereof in the microgranule formulation is an amount of secnidazole or the pharmaceutically acceptable salt thereof, respectively, that exhibits a Cmax of between about 17.4 pg/ml and about 26.5 pg/ml. In some embodiments, wherein the therapeutically effective amount of secnidazole or the pharmaceutically acceptable salt thereof in the microgranule formulation is an amount of secnidazole or the pharmaceutically acceptable salt thereof, respectively, that exhibit a Tmax of about 3 hours to about 4 hours, or about 6 hours to about 24 hours, or about 2 hours to about 24 hours.
  • the therapeutically effective amount of secnidazole or the pharmaceutically acceptable salt thereof in the microgranule formulation is an amount of secnidazole or the pharmaceutically acceptable salt thereof, respectively, that exhibit a Tmax of 2 hours to 6 hours, or about 6 hours to about 24 hours, or about 2 hours to about 24 hours.
  • a microgranule formulation for the treatment or prevention of trichomoniasis or T. vaginalis infection in a subject, wherein the microgranule formulation comprises a therapeutically effective amount of secnidazole or the pharmaceutically acceptable salt thereof in the microgranule formulation.
  • the therapeutically effective amount of secnidazole or the pharmaceutically acceptable salt thereof in the microgranule formulation is an amount of secnidazole or the pharmaceutically acceptable salt thereof, respectively, that exhibits a Cmax of between about 34.5 pg/ml and about 58.3 pg/ml, or about 26 pg/ml to about 34 pg/ml, or about 26 pg/ml to about 58 pg/ml.
  • the therapeutically effective amount of secnidazole or the pharmaceutically acceptable salt thereof in the microgranule formulation is an amount of secnidazole or the pharmaceutically acceptable salt thereof, respectively, that exhibits a Cmax of between about 17.4 pg/ml and about 26.5 pg/ml. In some embodiments, wherein the therapeutically effective amount of secnidazole or the pharmaceutically acceptable salt thereof in the microgranule formulation is an amount of secnidazole or the pharmaceutically acceptable salt thereof, respectively, that exhibit a Tmax of about 3 hours to about 4 hours, or about 6 hours to about 24 hours, or about 2 hours to about 24 hours.
  • the therapeutically effective amount of secnidazole or the pharmaceutically acceptable salt thereof in the microgranule formulation is an amount of secnidazole or the pharmaceutically acceptable salt thereof, respectively, that exhibit a Tmax of about 2 hours to about 6 hours, or about 6 hours to about 24 hours, or about 2 hours to about 24 hours.
  • a pharmaceutical composition comprising a plurality of microgranules for treating or preventing trichomoniasis or T. vaginalis infection in a subject, wherein the plurality of microgranules comprises a therapeutically effective amount of secnidazole or a pharmaceutically acceptable salt thereof, wherein each microgranule comprises a core and a coating, wherein the core comprises an active ingredient and at least one polymer, wherein the active ingredient is the secnidazole or the pharmaceutically acceptable salt thereof, wherein the secnidazole or the pharmaceutically acceptable salt thereof comprises at least 70% of the core by weight, wherein the coating is on the outside of the core, wherein the therapeutically effective amount of the secnidazole or the pharmaceutically acceptable salt thereof is about 1 gram, about 2 grams, about 3 grams, about 4 grams, about 5 grams or about 6 grams; and wherein the pharmaceutical composition is for oral administration.
  • a pharmaceutical composition in preparation of a medicament comprising a plurality of microgranules for treating or preventing trichomoniasis or T. vaginalis infection in a subject
  • the plurality of microgranules comprises a therapeutically effective amount of secnidazole or a pharmaceutically acceptable salt thereof
  • each microgranule comprises a core and a coating, wherein the core comprises an active ingredient and at least one polymer, wherein the active ingredient is the secnidazole or the pharmaceutically acceptable salt thereof, wherein the secnidazole or the pharmaceutically acceptable salt thereof comprises at least 70% of the core by weight, wherein the coating is on the outside of the core, wherein the therapeutically effective amount of the secnidazole or the pharmaceutically acceptable salt thereof is about 1 gram, about 2 grams, about 3 grams, about 4 grams, about 5 grams, or about 6 grams; and wherein the pharmaceutical composition is for oral administration.
  • Embodiments herein are also directed to a method of making the secnidazole microgranule formulation, the method comprising coating one or more sugar spheres and/or microcrystalline cellulose spheres.
  • the process comprises (a) layering secnidazole on one or more sugar spheres and/or microcrystalline cellulose spheres; (b) layering a seal coating on top of the secnidazole on the one or more sugar spheres and/or microcrystalline cellulose spheres to produce end products of (b), wherein the seal coating comprises polyethylene glycol (such as polyethylene glycol 4000); (c) layering a top coating on top of the end products of (b) to product end products of (c), wherein the top coating comprises with ethyl acrylate-methyl methacrylate copolymer (such as the product ethyl acrylate-methyl methacrylate copolymer sold under the trademark Eudragit® NE30D); and (d) curing the end products
  • the process comprises (a) layering secnidazole on one or more sugar spheres and/or microcrystalline cellulose spheres; (b) layering a seal coating on top of the secnidazole on the one or more sugar spheres and/or microcrystalline cellulose spheres to produce end products of (b), wherein the seal coating comprises ethyl acrylate-methyl methacrylate copolymer (such as the product ethyl acrylate-methyl methacrylate copolymer sold under the trademark Eudragit® NE30D); and (c) curing the end products of (b).
  • the seal coating comprises ethyl acrylate-methyl methacrylate copolymer (such as the product ethyl acrylate-methyl methacrylate copolymer sold under the trademark Eudragit® NE30D); and (c) curing the end products of (b).
  • coating with ethyl acrylate-methyl methacrylate copolymer provides a delayed release formulation.
  • Other grades of the product ethyl acrylate-methyl methacrylate copolymer sold under the trademark Eudragit® can also be used in the formulations, e.g., Eudragit® E (either E 100 or E PO) or the product methyl methacrylate and diethylaminoethyl methacrylate copolymer dispersion sold under the trademark Kollicoat® SmartSeal.
  • a method of making the secnidazole microgranule formulation comprises blending with talc. In some embodiments, blending with talc increases the flowability of the secnidazole microgranule formulation.
  • Figure 1 illustrates the mean standard deviation (“( ⁇ SD)”) SYM-1219 plasma concentration (pg/mL) for the 1 g dose (circle markers) and the 2 g dose (triangle markers) over time.
  • ⁇ SD mean standard deviation
  • Figure 2 illustrates the mean ( ⁇ SD) EE2 plasma concentrations (pg/mL) for Group Bl over time where (1) EE2 was administered alone (circle markers) on Day 1 of Period 1; and (2) EE2 was administered in conjunction with 2 gram microgranule formulation SYM- 1219 on Day 1 of Period 2 (triangle markers).
  • Figure 3 illustrates the mean ( ⁇ SD) EE2 plasma concentrations (pg/mL) for Group B2 over time where (1) EE2 was administered alone (circle markers) on Day 1 of Period 1; and (2) 2 gram microgranule formulation SYM-1219 was administered on Day 1 of Period 2 and EE2 was administered on Day 2 of Period 2 (triangle markers).
  • Figure 4 illustrates the mean ( ⁇ SD) NET plasma levels (ng/mL) for Group Bl over time where (1) NET alone was administered on Day 1 of Period 1 (circle markers), and (2) NET followed by 2 gram microgranule formulation of SYM-1219 was administered on Day 1 of Period 2 (triangle markers).
  • Figure 5 illustrates the mean ( ⁇ SD) NET plasma levels (ng/mL) for Group B2 over time where (1) NET alone was administered on Day 1 of Period 1 (circle markers), and (2) 2 gram microgranule formulation of SYM-1219 was administered on Day 1 of Period 2 and NET was administered on Day 2 of Period 2 (triangle markers).
  • FIG. 6 illustrates a distribution of secnidazole and metronidazole minimum lethal concentrations (“MLCs”) for 100 clinical isolates.
  • MLCs minimum lethal concentrations
  • Susceptibility to metronidazole and secnidazole was defined as MLCs of ⁇ 25 pg/ml, low-level resistance as MLCs of 50 pg/ml to 100 pg/ml, moderate-level resistance as MLCs of 200 pg/ml, and high-level resistance as MLCs of > 400 pg/ml.
  • Figure 7 illustrates a comparison of metronidazole and secnidazole activities in 100 T. vaginalis isolates.
  • the MLCs for each drug were determined as described in this Figure in in Example 3 - Microbiology - Susceptibility Testing below.
  • the MLCs for metronidazole were consistently higher than for those for secnidazole (P ⁇ 0.0001, Wilcoxon signed-rank test)
  • Figure 8 illustrates a regression analyses of MLCs for metronidazole and secnidazole.
  • the diagonal line represents the line of identity, indicating equal concentrations of the two drugs.
  • the term “about” is intended to qualify the numerical values that it modifies, denoting such a value as variable within a margin of error. When no particular margin of error (such as, for example, standard deviation to a mean value) is recited, the term “about” means plus or minus 10% of the numerical value of the number with which it is being used. For example, “about 50%” means in the range of 45% to 55%. Ranges may be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value.
  • bioequivalent or “bioequivalence” is a term of art and is intended to be defined in accordance with Approved Drug Products with Therapeutic Equivalence Evaluations, 34th Edition, which is published by the U.S. Department of Health and Human Services, and is commonly known as the "Orange Book”. Bioequivalence of different formulation of the same drug substance involves equivalence with respect to the rate and extent of drug absorption. The extent and rate of absorption of the test formulation is compared to a reference formulation in order to determine whether the two formulations are bioequivalent.
  • the standard bioequivalence study is conducted in crossover fashion by extensive testing which includes administering single doses of the test and reference drugs to a number of volunteers, usually 12 to 24 healthy normal adults, and then measuring the blood or plasma levels of the drug over time.
  • Detailed guidelines for establishing the bioequivalence of a formulation with a reference formulation have been published by the FDA Office of Generic Drugs, Division of Bioequivalence.
  • the term “daily dose amount” refers to the amount of API (such as secnidazole) per day that is administered or prescribed to a subject. This amount can be administered to the subject in multiple unit doses or a single unit dose, in a single time during the day or at multiple times during the day.
  • the term “pharmaceutically acceptable” is that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for human pharmaceutical use and/or veterinary use.
  • the term “pharmaceutically acceptable salt” refers to a salt of secnidazole that is pharmaceutically acceptable, as defined above, and possesses the desired pharmaceutical activity.
  • Such salt includes an acid addition salt formed with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4- hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methylsulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxy-
  • a pharmaceutically acceptable salt also includes a base addition salt that may be formed when one or more acidic protons present are capable of reacting with an inorganic or organic base.
  • Acceptable inorganic bases include, but not limited to, sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide, calcium hydroxide, and the like.
  • Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methyl-lucamine, and the like.
  • the terms “subject” or “patient” are interchangeable and may be taken to mean any living organism that may be treated with the methods/uses/compounds/compositions of the invention.
  • the term “subject” or “patient” may include, but is not limited to, mammal (non-human and human), primate, and other animals, such as domesticated animals (e.g., household pets, including cats and dogs) and nondomesticated animals (e.g., wildlife).
  • the term “subject” or “patient” is mammal, such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, or humans.
  • the term “subject” or “patient” is a human. In some embodiments, the “subject” or “patient” is male or female; adult or child. In some embodiments, the subject is a human male or human female. In some embodiments, the subject is a healthy male or healthy female. In some embodiments, the subject is a pregnant female. In some embodiments, the subject is a healthy pregnant female. In some embodiments, the subject has trichomoniasis or T. vaginalis infection. In some embodiments, the subject is resistant to metronidazole and/or tinidazole. In some embodiments, the subject suffers from recurrent trichomoniasis or T.
  • vaginalis infection that is, the subject having had 2 or more trichomoniasis episodes or T. vaginalis infections in the past 12 months.
  • the subject is also HIV-positive, such as a HIV-positive male, a HIV-positive female or a HIV-positive pregnant female.
  • the subject is also infected (or co-infected) with bacterial vaginosis.
  • the subject is a female or pregnant female is HIVpositive and also infected (or co-infected) with bacterial vaginosis.
  • the subject is a child who is less than 18 years of age, or an adult who is at least 18 years old.
  • the human female is of an age ranging from a post-menarchal adolescent to a premenopausal woman.
  • the subject is a pregnant human female.
  • the subject is a female presenting with purulent malodorous discharge (associated with burning, pruritus, dysuria, frequency, lower abdominal pain), dyspareunia, burning postcoital bleeding, dyspareunia, dysuria, a thin green-yellow frothy discharge, vulvovaginal erythema (erythema of the vulva and vaginal mucosa), punctate hemorrhages, urethritis, cystitis, purulent vaginitis, sequamative inflammatory vaginitis, atrophic vaginitis, erosive lichen planus, an elevated vaginal pH (about 5.0 to about 6.0), or any combination thereof.
  • the subject is asymptomatic.
  • the subject is a female with confirmed trichomoniasis, wherein the diagnosis of T. vaginalis is confirmed by laboratory testing, including, but not limited to, motile trichomonads on wet mount, positive culture, increase in polymorphonuclear leukocytes, positive nucleic acid amplification test, or positive rapid antigen, nucleic acid probe test cervical cytology, or any combination thereof; microscopy, including, but not limited to, culture subjects vaginal discharge on Diamond's medium (which is a key step in the evaluation of vaginal discharge, and is often the first step in the diagnostic evaluation for trichomoniasis) Microscopy is convenient and low cost.
  • nucleic acid amplification tests can then be done for subjects with nondiagnostic (or negative) wet mounts. In some embodiments, if NAAT is not available, rapid diagnostic kits or culture are then performed. Additional laboratory tests include, but not limited to, the APTIMA® T. vaginalis assay, the APTIMA® TV assay, the Amplicor® assay (a PCR assay for detection of Neisseria gonorrhoeae and Chlamydia trachomatis that has been modified to detect T. vaginalis in vaginal/endocervical swabs or urine); NuSwab® Vaginitis Plus (VG+), or any combination thereof.
  • APTIMA® T. vaginalis assay the APTIMA® TV assay
  • Amplicor® assay a PCR assay for detection of Neisseria gonorrhoeae and Chlamydia trachomatis that has been modified to detect T. vaginalis in vaginal
  • Positive rapid antigen, nucleic acid probe tests also include, but not limited to, the Affirm® VP III Microbial Identification System, and the OSOM® Trichomonas Rapid Test.
  • the subject is a female with suspected trichomoniasis.
  • suspected trichomoniasis is indicated by the presence of purulent malodorous discharge (associated with burning, pruritus, dysuria, frequency, lower abdominal pain), or dyspareunia, burning postcoital bleeding, dyspareunia, dysuria, a thin green-yellow frothy discharge, vulvovaginal erythema (erythema of the vulva and vaginal mucosa), punctate hemorrhages, urethritis, cystitis, purulent vaginitis, sequamative inflammatory vaginitis, atrophic vaginitis, erosive lichen planus, elevated vaginal pH (about 5.0 to about 6.0), or any combination thereof.
  • purulent malodorous discharge associated with burning, pruritus, dysuria, frequency, lower abdominal pain
  • dyspareunia burning postcoital bleeding
  • dyspareunia dysuria
  • dysuria dysuria
  • dysuria a thin green-yello
  • the subject is a female or pregnant female also infected (or coinfected) with bacterial vaginosis, or has confirmed or suspected bacterial vaginosis.
  • the disclosed methods/uses/compounds/compositions of the invention can be utilized to treat and/or prevent trichomoniasis or T. vaginalis infection in a subject in need thereof.
  • the term “subject in need thereof,” includes, but not limited to, a subject having or at risk for developing trichomoniasis or a T. vaginalis infection.
  • the terms “treat,” “treating” or “treatment” of a disease, condition or disorder includes: (a) preventing or delaying the appearance of clinical symptoms of the disease, condition or disorder developing in a subject that may be afflicted with or predisposed to the disease, condition or disorder but does not yet experience or display clinical or subclinical symptoms of the disease, condition or disorder; (b) inhibiting the disease, condition or disorder, i.e., arresting or reducing the development of the disease, condition or disorder or at least one clinical or subclinical symptom thereof; (c) ameliorating or lessening the severity of the disease, condition or disorder or at least one of its clinical or subclinical symptoms; or (d) relieving the disease, condition or disorder, i.e., causing regression of the disease, condition or disorder or at least one of its clinical or subclinical symptoms.
  • terapéutica means an agent utilized to treat, combat, ameliorate or prevent an unwanted disease, condition or disorder in a subject.
  • pharmaceutically effective amount or “therapeutically effective amount” or “therapeutic dose” as used herein are used interchangeably and refer to the amount of an active agent or pharmaceutical compound or composition that elicits a clinical, biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor, or other clinical professional.
  • a clinical, biological or medical response may include, for example, one or more of the following: (1) preventing or delaying a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display pathology or symptoms of the disease, condition or disorder, (2) inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptoms of the disease, condition or disorder or arresting further development of the pathology and/or symptoms of the disease, condition or disorder, (3) ameliorating or lessening the severity of a disease, condition or disorder in an individual that is experiencing or exhibiting the pathology or symptoms of the disease, condition or disorder or reversing the pathology and/or symptoms experienced or exhibited by the individual, or (4) relieving the disease, condition or disorder, i.e., causing regression of the disease, condition or disorder or at least one of its clinical or subclinical symptoms, in the individual.
  • the "therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness
  • volume-weighted particle size distribution refers to a distribution where the contribution of each particle in the distribution relates to the volume of the particle (equivalent to the mass if the density is uniform), i.e., the particles contribution will be proportional to its size (see, e.g., Powder Sampling and Particle Size Determination by T. Allen, 1st Edition, Elsevier Science, 2003 and Particle Size Measurement by T. Allen, Chapman & Hall, 4th Edition, 1992). Static light scattering techniques such as laser diffraction and other techniques known in the art can be used to determine volume-weighted particle size distribution.
  • Cmax refers to the maximum concentration that a compound or drug achieves in a tested area in a subject after the drug has been administered and prior to the administration of the next dose.
  • the tested area can be, for example, plasma.
  • Tmax refers to a period of time between the administration of a given dose of a compound or drug to a subject and the point in time when Cmax is reached.
  • Secnidazole [l-(2-hydroxypropyl)-2-methyl-5-nitromidazole] is a 5- nitroimidazole derivative compound, having a molecular weight of 185.183 g/mol and a molecular formula of C7H11N3O3. The structure of secnidazole is shown below:
  • Embodiments described in this application are directed to secnidazole (and pharmaceutically acceptable salts thereof) formulations (such as SYM-1219) and the use of a secnidazole formulation for treating or preventing trichomoniasis or T. vaginalis infection in a subject in need thereof.
  • One of the surprising effects of this invention is that it is a more effective therapy for trichomoniasis or T. vaginalis infection in a subject in need thereof with decreased side effects.
  • Embodiments described herein are directed to a method of treating or preventing trichomoniasis or T. vaginalis infection in a subject in need thereof comprising administering to the subject a therapeutically effective amount of secnidazole or a pharmaceutically acceptable salt thereof in a microgranule formulation.
  • the secnidazole or the pharmaceutically acceptable salt thereof in the microgranule formulation is administered orally.
  • the secnidazole or the pharmaceutically acceptable salt thereof in the microgranule formulation comprises a plurality of microgranules.
  • each microgranule comprises an inactive core (such as a sugar core, microcrystalline cellulose core or any core that does not contain any API) and a layer outside of the inactive core.
  • the layer outside of the inactive core comprises secnidazole.
  • each microgranule further comprises as a coating layer that is outside of the layer outside of the inactive core.
  • the coating layer comprises a delayed release element (such as ethyl acrylate-methyl methacrylate copolymer) and/or an anti-tacking element (such as glycerol monostearate).
  • the plurality of microgranules has a particle size diameter in the range of about 400 micrometers to about 841 micrometers. In some embodiments, the particle size diameter of the microgranule is measured using laser diffraction. In some embodiments, wherein the therapeutically effective amount of secnidazole is an amount of secnidazole that exhibits a Cmax of secnidazole in the subject of about 17.4 pg/ml and about 26.5 pg/ml, or about 34.5 pg/ml to about 58.3 pg/ml, or about 26 pg/ml to about 34 pg/ml, or about 26 pg/ml to about 58 pg/ml.
  • the therapeutically effective amount of secnidazole is an amount of secnidazole that exhibits a Tmax of secnidazole in the subject of about 2 hours to about 6 hours, or about 3 hours to about 4 hours, or about 6 hours to about 24 hours, or about 2 hours to about 24 hours. In some embodiments, wherein the therapeutically effective amount of secnidazole is an amount of secnidazole that exhibits a ti/2 of about 11 hours to about 20 hours in the subject. In some embodiments, wherein secnidazole is the sole drug in the microgranule formulation.
  • the secnidazole microgranule formulation further comprises one or more of the following ingredients selected from at least one inert core (sugar spheres being preferred); at least one binding agent (povidone being preferred); at least one plasticizer (polyethylene glycol being preferred, and polyethylene glycol 4000 being most preferred); at least one film-forming polymer (poly(meth)acrylates being preferred and ethyl acrylate-methyl methacrylate copolymer being most preferred), at least one anti-tacking agent (talc being preferred); at least one antistatic agent (talc being preferred); and a combination thereof.
  • at least one inert core sucgar spheres being preferred
  • at least one binding agent povidone being preferred
  • plasticizer polyethylene glycol being preferred, and polyethylene glycol 4000 being most preferred
  • at least one film-forming polymer poly(meth)acrylates being preferred and ethyl acrylate-methyl methacrylate copolymer being most preferred
  • talc anti-tacking
  • the microgranule formulation further comprises at least one compound selected from the group consisting of sugar spheres, povidone, polyethylene glycol (such as polyethylene glycol 4000), ethyl acrylate-methyl methacrylate copolymer (such as the product ethyl acrylate-methyl methacrylate copolymer sold under the trademark Eudragit® NE30D), talc, colloidal silicon dioxide, and a combination thereof.
  • the secnidazole in a microgranule formulation may be mixed, stirred, or otherwise integrated into a food substance.
  • the food substance includes, but not limited to, a liquid, semisolid, or soft food.
  • the food substance may include, but not limited to, applesauce, yogurt, pudding or the like.
  • integration of the secnidazole microgranule formulation into a food substance has a taste masking function.
  • the method comprising administering to the subject a microgranule formulation comprising a therapeutically effective amount of secnidazole, wherein the microgranule formulation comprises a plurality of microgranules having a volume- weighted particle size distribution within a microgranule population, wherein the volume- weighted particle size distribution as measured by mean diameter from a representative sample of the microgranule population comprises (a) at least 10% of the microgranule population having a volume-weighted particle size equal to or larger than about 470 micrometers, and/or (b) 50% of the microgranule population having a volume-weighted particle size in a range of from about 640 micrometers to about 810 micrometers; and/or (c) 90% of the microgranule population having a volume-weighted particle size smaller than about 1170 micrometers.
  • each microgranule comprises a sugar core or a microcrystalline cellulose core, and a layer outside of the sugar core or the microcrystalline cellulose core, the layer comprising secnidazole.
  • each microgranule further comprises as a coating layer that is outside of the layer outside of the inactive core.
  • the coating layer comprises a delayed release element (such as ethyl acrylate-methyl methacrylate copolymer) and/or an anti-tacking element (such as glycerol monostearate).
  • the therapeutically effective amount of secnidazole is an amount of secnidazole that exhibits a Cmax of secnidazole in the subject of about 17.4 pg/ml and about 26.5 pg/ml, or about 34.5 pg/ml to about 58.3 pg/ml, or about 26 pg/ml to about 34 pg/ml, or about 26 pg/ml to about 58 pg/ml..
  • the therapeutically effective amount of secnidazole is an amount of secnidazole that exhibits a Tmax of secnidazole in the subject of about 2 hours to about 6 hours, or about 3 hours to about 4 hours, or about 6 hours to about 24 hours, or about 2 hours to about 24 hours. In some embodiments, wherein the therapeutically effective amount of secnidazole is an amount of secnidazole that exhibits a ti/2 of about 11 hours to about 20 hours in the subject. In some embodiments, wherein secnidazole is the sole drug in the microgranule formulation.
  • the secnidazole microgranule formulation further comprises one or more of the following ingredients selected from at least one inert core (sugar spheres being preferred); at least one binding agent (povidone being preferred); at least one plasticizer (polyethylene glycol being preferred, and polyethylene glycol 4000 being most preferred); at least one film-forming polymer (poly(meth)acrylates being preferred and ethyl acrylate-methyl methacrylate copolymer being most preferred), at least one anti-tacking agent (talc being preferred); at least one antistatic agent (talc being preferred); and a combination thereof.
  • at least one inert core sucgar spheres being preferred
  • at least one binding agent povidone being preferred
  • plasticizer polyethylene glycol being preferred, and polyethylene glycol 4000 being most preferred
  • at least one film-forming polymer poly(meth)acrylates being preferred and ethyl acrylate-methyl methacrylate copolymer being most preferred
  • talc anti-tacking
  • the microgranule formulation further comprises at least one compound selected from the group consisting of sugar spheres, povidone, polyethylene glycol (such as polyethylene glycol 4000), ethyl acrylate-methyl methacrylate copolymer (such as the product ethyl acrylate-methyl methacrylate copolymer sold under the trademark Eudragit® NE30D), talc, colloidal silicon dioxide, and a combination thereof.
  • the secnidazole in a microgranule formulation may be mixed, stirred, or otherwise integrated into a food substance.
  • the food substance includes, but not limited to, a liquid, semisolid, or soft food.
  • the food substance may include, but not limited to, applesauce, yogurt, pudding or the like.
  • integration of the secnidazole microgranule formulation into a food substance has a taste masking function.
  • a method of treating or preventing trichomoniasis or T. vaginalis infection in a subject in need thereof comprising administering to the subject a microgranule formulation comprising a therapeutically effective amount of nitroimidazole compound or a pharmaceutically acceptable salt thereof, wherein the microgranule formulation comprises a plurality of microgranules, wherein each microgranule comprises a core and a coating, wherein the core comprises the nitroimidazole compound or the pharmaceutically acceptable salt thereof, and wherein the coating surrounds the core.
  • the nitroimidazole compound is secnidazole, metronidazole, tinidazole, nimorazole, dimetridazole, 6-Amino PA824, orinidazole, megazol, azanidazole, benznidazole, pimonidazole or a combination thereof.
  • the nitroimidazole compound is secnidazole.
  • the nitroimidazole compound is in the core.
  • the nitroimidazole compound comprises at least 70% of the core by weight.
  • the coating covers partially or all of the exterior surface of the core.
  • the coating does not contain a nitroimidazole compound.
  • the nitroimidazole compound comprises at least about 70% of the core by weight; at least about 75% of the core by weight; at least about 80% of the core by weight; at least about 85% of the core by weight; at least about 90% of the core by weight; or about at least about 95% of the core by weight.
  • the nitroimidazole compound comprises about 70% of the core by weight; about 75% of the core by weight; about 80% of the core by weight; about 85% of the core by weight; about 90% of the core by weight; or about 95% of the core by weight.
  • the plurality of microgranules comprise about 1 gram to about 6 grams of the nitroimidazole compound. In some embodiments, the plurality of microgranules comprises a therapeutically effective amount of nitroimidazole compound.
  • the core further comprises at least one polymer. In some embodiments, the polymer can be, but not limited to, Avicel®, Methocel®, hydroxyl propyl cellulose, acacia, guar gum, povidone, lactose monohydrate, or a combination thereof. In some embodiments, the core further comprises Avicel®, Methocel® or a combination thereof.
  • the core further comprises cellulose microcrystalline (such as the product cellulose microcrystalline sold under the trademark Avicel® PH-101), methyl cellulose (such as the product methyl cellulose sold under the trademark Methocel® AV15LV) or a combination thereof.
  • the polymer comprises about 30% of the core by weight.
  • the ratio of the nitroimidazole compound to the at least one polymer in the core may be about 70:30, or lesser than about 70:30, or more than greater than 70:30.
  • the secnidazole in a microgranule formulation may be mixed, stirred, or otherwise integrated into a food substance.
  • the food substance includes, but not limited to, a liquid, semisolid, or soft food. In some embodiments, the food substance may include, but not limited to, applesauce, yogurt, pudding or the like. In some embodiments, integration of the secnidazole microgranule formulation into a food substance has a taste masking function.
  • the core comprises an active ingredient and at least one polymer. In some embodiments, the active ingredient is secnidazole or other nitroimidazole compounds described herein.
  • the core further comprises one or more dispersion agent or binding agent.
  • the dispersion agent or binding agent includes, but not limited to, microcrystalline cellulose, methylcellulose, hydroxyl propyl cellulose, acacia, guar gum, povidone, lactose monohydrate, or a combination thereof.
  • the core further comprises one or more microlubricant or anti-tacking agent.
  • the microlubricant or anti-tacking agent includes, but not limited to, sodium stearate, magnesium stearate, stearic acid, talc or a combination thereof.
  • the core further comprises a binder (such as, but not limited to, starch).
  • the coating may be modified to modulate drug absorption of the drug by varying the composition of the coating, the percentage weight of the composition, or any combination thereof.
  • the coating comprises a polymer.
  • the polymer includes, but not limited to, polyvinylpyrrolidone, ethylcellulose, the product 2-Methylprop-2-enoic acid— N-N-dimethylmethanamine (2/1) sold under the trademark Eudragit® RL, the product anionic copolymers of methacrylic acid and methyl methacrylate at a ratio of approximately 1 : 1 sold under the trademark Eudragit® L, the product amino methacrylate copolymer sold under the trademark Eudragit® E, the product anionic copolymers of methacrylic acid and methyl methacrylate at a ratio of approximately 1 :2 sold under the trademark Eudragit® S, cellulose acetate, polyvinyl alcohol, shellac, methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate trimell
  • the polymer can be, but not limited to, Eudagrit®, ethyl cellulose, Methocel®, glyceryl behenate, or a combination thereof.
  • the polymer is the product ethyl acrylate-methyl methacrylate copolymer sold under the trademark Eudagrit® NE30D.
  • the polymer is the product ethyl acrylate-methyl methacrylate copolymer sold under the trademark Eudagrit® NE30D comprises about 5.795% of the composition of weight.
  • the coating further comprises a polyether polymer.
  • the polyether polymer can be, but limited to, polyethylene glycol (“PEG”), acetyl tributyl citrate, triethyl citrate, dibutyl phthalate, dibutyl sebacate, gelatin, propylene glycol, triacetin or a combination thereof.
  • the polyether polymer is PEG.
  • the PEG is PEG 4000.
  • the coating comprises about 10% to about 13% of the composition by weight. In some embodiments, the coating comprises about 13% or less than about 13% of the composition by weight. In some embodiments, the coating comprises about 10% or more than 10% of the composition by weight.
  • the PEG (such as PEG 4000) comprises about 1.75% of the composition by weight. In some embodiments, the PEG (such as PEG 4000) comprises about 1.75% of an individual microgranule by weight.
  • auxiliary coating aids such as a minor amount (about 1 to about 5% by weight based on the active core component and the total weight of the final coating) of a plasticizer such as, but not limited to, acetyltributyl citrate, triacetin, acetylated monoglyceride, grape seed oil, olive oil, sesame oil, acetyltri ethylcitrate, glycerin sorbitol, diethyloxalate, diethylmalate, diethylfumarate, dibutylsuccinate, diethylmalonate, dioctylphthalate, dibutylsebacate, tri ethyl citrate, tributyl citrate, glyceroltributyrate, polyethyleneglycol, propylene glycol or a combination thereof with or without an antisticking agent (such as, but limited to, a silicate such as, but not limited to, tal
  • the pharmaceutical composition further comprises talc.
  • the plurality of microgranules further comprises talc.
  • the talc is a blending agent.
  • the core comprises a spheronized microgranule.
  • the microgranules may be formed by wet granulation followed by extrusion and spheronization.
  • the core further comprises a binder.
  • the binder may be starch.
  • the active ingredients may be contained in such compositions with pharmaceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water-soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives and the like.
  • pharmaceutically acceptable diluents fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water-soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives and the like.
  • the means and methods for administration are known in the art and an artisan can refer to various pharmacologic references for guidance. For example, Modem Pharmaceutics, G.S. Banker & C.T. Rhodes, 4 th Edition, CRC Press (2002); Goodman & Gilman's The Pharmaceutical Basis of Therapeutics, L.L. Brunton, R.
  • the therapeutically effective amount of secnidazole in the microgranule formulation is about 1 gram to about 4 grams, or about 1 gram to about 6 grams.
  • the therapeutically effective amount of secnidazole in the microgranule formulation is 1 gram, 2 grams, 3 grams, 4 grams, 5 grams, or 6 grams. In some embodiments, the therapeutically effective amount of secnidazole in the microgranule formulation is 2 grams, 4 grams, or 6 grams.
  • the plurality of microgranules comprising a daily dose amount of a nitroimidazole compound may be configured as a single unit dose or multiple unit doses. In some embodiments, the multiple unit doses can be two, three or four unit doses per day. In some embodiments, the unit dose may be a portion of the daily dose amount of the nitroimidazole compound. In some embodiments, the nitroimidazole compound is secnidazole and the daily dose amount is about 1 gram, about 2 grams, about 3 grams about 4 grams, about 5 grams, or about 6 grams.
  • the daily dose amount can be configured as one, two, three, four or more unit doses per day.
  • the plurality of microgranules comprising about 2 grams of secnidazole may be configured as 2 unit doses, each unit dose comprising about 1 gram of secnidazole.
  • the plurality of microgranules comprising about 2 grams of secnidazole may be configured as 4 unit doses, each until dose comprising about 0.5 grams of secnidazole.
  • the unit doses in a multiple unit dose regime may have unit doses of equal or different amounts of secnidazole.
  • the plurality of microgranules comprising about 2 grams of secnidazole may be configured as 3 unit doses, where one unit dose comprises about 1 gram of secnidazole and the other two unit doses each comprises about 0.5 grams of secnidazole.
  • microgranule formulations described herein may be prepared, packaged, or sold in bulk, as a single unit dose or as multiple unit doses and may be administered in orally.
  • microgranule formulation is packaged as a unit dose or a single unit dose.
  • a unit dose also defined as single dose herein, is a dosage in a form that includes therapeutically effective amount of secnidazole in a microgranule formulation.
  • the unit dose could be administered to a subject as a single unit dose, wherein the therapeutically effective amount of secnidazole in a microgranule formulation is included in a single package, such as, one pouch, packet, sachet, or bottle.
  • the microgranule formulation is packaged in such a way as to provide a barrier to oxygen and moisture.
  • the microgranule formulation is packaged in a foil pouch or sachet.
  • the foil pouch or sachet is made of a polyester-faced laminated or polyethylene- metallocene-lined aluminum foil pouching material that provides a barrier to oxygen and moisture.
  • the pouch or sachet is made from a material such as, but not limited to, the product polyester-faced laminated pouching material sold under the trademark FASSON® RAPID-ROLL® White Cosmetic Web 350 HB.
  • the microgranule formulation can include a plurality of microgranules comprising inert cores made from microcrystalline cellulose.
  • the inert cores made from microcrystalline cellulose can replace sugar spheres/sugar cores.
  • glycerol monostearate e.g., the product glycerol monostearate sold under the trademark PLASCRYL® T20 by Evonik
  • PLASCRYL® T20 can be used as an anti-tacking agent.
  • glycerol monostearate can be used in Eudragit coatings in place of talc.
  • therapeutically effective amounts, daily doses, or single unit doses of the secnidazole (or other nitroimidazole composition) microgranule formulations described herein may be administered once per day or multiple times per day, such as twice per day; 3 times per day; 4 times per day; 5 times per day; or more than 5 times per day.
  • the treatment or use period can be 1 day, 2 days, 3 days, 4 days, 5 days, 6, days, 7 days, 8 days, 9 days, 10 days, 11 days, 12, days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days or 31 days.
  • the dosing schedule of the invention can be about 1 gram, about 2 grams, about 3 grams, about 5 grams, or about 6 grams of secnidazole (or other nitroimidazole composition) per day for 1 day, 2 days, 3 days, 4 days, 5 days, 6, days, 7 days, 8 days, 9 days, 10 days, 11 days, 12, days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days or 31 days.
  • the dosing can be done with 1 day, 2 days, 3 days, 4 days or more than 4 days apart each dose.
  • the dosing schedule of the invention can be about 2 grams of secnidazole (or other nitroimidazole composition) per day, taken about 3 days or about 4 days apart x 2.
  • the invention herein contemplates all of the dosage schedule combinations set forth in this application.
  • Embodiments are also directed to a dosage regimen for administering a therapeutically effective amount of a nitroimidazole compound (such as secnidazole) for the methods and uses described herein.
  • a nitroimidazole compound such as secnidazole
  • the methods and uses described herein can comprises a dosage regimen that includes a plurality of daily doses having an equal amount of the nitroimidazole compound as the initial dose in one or more unit doses.
  • the dosage regimen can include an initial dose of the nitroimidazole compound in one or more unit doses, then one or more subsequent daily doses having a lower amount of the nitroimidazole compound than the initial doses in one or more unit dose.
  • the dosage regimen may administer one or more initial doses followed by one or more maintenance doses.
  • the one or more doses following the administering of the one or more initial doses can be maintenance doses.
  • Such maintenance doses can have a lower or higher amount of the nitroimidazole compound than the one or more initial doses.
  • the therapeutically effective amount of secnidazole in a microgranule formulation is administered as a single dose.
  • the therapeutically effective amount of secnidazole in a microgranule formulation administered as a single dose is the only dose required to be administered to the subject to achieve a post-treatment clinical outcome, resolution of one or more symptoms of trichomoniasis or T. vaginalis infection, or a combination thereof.
  • the methods and uses described herein further comprises administering paromomycin, tinidazole, metronidazole, boric acid or a combination thereof to a subject who is resistant or allergic to metronidazole and/or tinidazole, or the subject who is infected metronidazole and/or tinidazole-resistant trichomoniasis with or when metronidazole and/or tinidazole is contraindicated.
  • the administration of paromomycin, tinidazole, metronidazole, boric acid or a combination thereof to the subject is on the same day or a different day relative to the administration of secnidazole to the subject.
  • the administration of the compounds of the combination therapy e.g., secnidazole, paromomycin, tinidazole, metronidazole, boric acid or a combination thereof
  • the methods and uses described herein further comprises co-administering an additional compound selected from EE2, NET, or a combination thereof.
  • the additional compound is administered on the same day as the secnidazole microgranule formulation.
  • the additional compound is administered on a different day than the secnidazole microgranule formulation.
  • the secnidazole microgranule formulation does not affect the contraceptive efficacy of the additional compound selected from EE2, NET, or a combination thereof.
  • the subject has a resolution of one or more symptoms of trichomoniasis or T. vaginalis infection within up to about seven days after administration to the subject.
  • the subject has an alleviation of one or more symptoms of trichomoniasis or T. vaginalis infection within up to about three days after administration to the subject.
  • the subject is a male or female; adult or child. In some embodiments, the subject is a healthy male or healthy female. In some embodiments, the subject is a pregnant female. In some embodiments, the subject is a healthy pregnant female. In some embodiments, the subject has confirmed or suspected trichomoniasis or T. vaginalis infection. In some embodiments, the subject is resistant to metronidazole and/or tinidazole. In some embodiments, the subject suffers from recurrent trichomoniasis or T. vaginalis infection, that is, the subject having had 2 or more trichomoniasis episodes or T. vaginalis infections in the past 12 months.
  • the subject is also HIV-positive, such as a HIV-positive male, a HIV-positive female or a HIV-positive pregnant female. In some embodiments, the subject is also infected (or co-infected) with bacterial vaginosis. In some embodiments, the subject is a female or pregnant female is HIV-positive and also infected (or co-infected) with bacterial vaginosis. In some embodiments, the subject is a child who is less than 18 years of age, or an adult who is at least 18 years old.
  • the subject is a female or pregnant female also infected (or co-infected) with bacterial vaginosis, or has confirmed or suspected bacterial vaginosis.
  • the subject is a female having had 3 or fewer bacterial vaginosis infections/episodes in the past 12 months.
  • the subject is a female having had 4 or more bacterial vaginosis infections/episodes in the past 12 months.
  • the subject is a female presenting with thin, homogeneous vaginal discharge, a positive KOH Whiff test, vaginal fluid pH greater than or equal to 4.7, and the presence of “clue cells” greater than 20% of total epithelial cells, or any combination thereof.
  • the female with bacterial vaginosis presents with the four Amsel criteria parameters and a gram stain slide Nugent score equal to, or higher than four on bacterial analysis of vaginal samples.
  • the four Amsel criteria parameters are abnormal vaginal discharge (e.g., thin, homogenous vaginal discharge), a positive KOH Whiff test, vaginal fluid pH greater than or equal to 4.7, and the presence of clue cells greater than 20% of total epithelial cells. (See Amsel).
  • Some embodiments further comprise determining a post-treatment clinical outcome.
  • a post-treatment clinical outcome is indicative of a clinical outcome responder.
  • Some embodiments further comprise determining a post-treatment clinical outcome.
  • a post-treatment clinical outcome of clinical cure is defined as a clinical outcome responder.
  • a clinical outcome responder is a subject with normal vaginal discharge, a negative T. vaginalis test, a negative KOH Whiff test, and clue cells less than 20% of total epithelial cells, post-treatment.
  • a clinical outcome responder is a subject with a gram stain slide Nugent score of less than four, posttreatment.
  • a clinical outcome responder is a subject with normal vaginal discharge, a negative T. vaginalis test, a negative KOH Whiff test, clue cells less than 20% of total epithelial cells), and a gram stain slide Nugent score of less than four, post-treatment.
  • administering to the subject a therapeutically effective amount of secnidazole in a microgranule formulation results in better than expected effectiveness than U.S. FDA-approved drugs used in the treatment or prevention of trichomoniasis or T. vaginalis infection.
  • administering to the subject a therapeutically effective amount of secnidazole in a microgranule formulation results in superior effectiveness than FDA- approved drugs used in the treatment or prevention of trichomoniasis or T. vaginalis infection.
  • administering to the subject a therapeutically effective amount of secnidazole in a microgranule formulation results in a higher rate of clinical cure than FDA- approved drugs used in the treatment or prevention of trichomoniasis or T. vaginalis infection.
  • administering to the subject a therapeutically effective amount of secnidazole in a microgranule formulation results in a better than expected safety profile than FDA-approved drugs used in the treatment or prevention of trichomoniasis or T.
  • administering to the subject a therapeutically effective amount of secnidazole in a microgranule formulation results in a more favorable safety profile than FDA-approved drugs used in the treatment or prevention of trichomoniasis or T. vaginalis infection.
  • the therapeutically effective amount of secnidazole in the microgranule formulation administered as a single dose is the only dose required to be administered to the subject to achieve a post-treatment clinical outcome by resolution of one or more symptoms of trichomoniasis or T. vaginalis infection.
  • the one or more symptoms of trichomoniasis or T. vaginalis infection include, but not limited to:
  • trichomoniasis or T. vaginalis infection include, but not limited to, purulent malodorous discharge (associated with burning, pruritus, dysuria, frequency, lower abdominal pain), or dyspareunia, burning postcoital bleeding, dyspareunia, dysuria, a thin green-yellow frothy discharge, vulvovaginal erythema (erythema of the vulva and vaginal mucosa), punctate hemorrhages, urethritis, cystitis, purulent vaginitis, sequamative inflammatory vaginitis, atrophic vaginitis, erosive lichen planus, elevated vaginal pH (about 5.0 to about 6.0), and any combination thereof.
  • purulent malodorous discharge associated with burning, pruritus, dysuria, frequency, lower abdominal pain
  • dyspareunia burning postcoital bleeding
  • dyspareunia dysuria
  • dysuria dysuria
  • Embodiments herein are also directed to a microgranule formulation for treating or preventing trichomoniasis or T. vaginalis infection in a subject in need thereof comprising secnidazole or a pharmaceutically acceptable salt thereof.
  • the microgranule formulation comprises a therapeutically effective amount of secnidazole or a pharmaceutically acceptable salt thereof.
  • the secnidazole or the pharmaceutically acceptable salt thereof in the microgranule formulation comprises a plurality of microgranules.
  • each microgranule comprises an inactive core (such as a sugar core, microcrystalline cellulose core or any core that does not contain any API and a layer outside of the inactive core.
  • the layer outside of the inactive core comprises secnidazole.
  • each microgranule further comprises as a coating layer that is outside of the layer outside of the inactive core.
  • the coating layer comprises a delayed release element (such as ethyl acrylate-methyl methacrylate copolymer) and/or an anti-tacking element (such as glycerol monostearate).
  • the plurality of microgranules has a particle size diameter in the range of about 400 micrometers to about 841 micrometers. In some embodiments, the particle size diameter of the microgranule is measured using laser diffraction.
  • the therapeutically effective amount of secnidazole is an amount of secnidazole that exhibits a Cmax of secnidazole in the subject of about 17.4 pg/ml and about 26.5 pg/ml, or about 34.5 pg/ml to about 58.3 pg/ml, or about 26 pg/ml to about 34 pg/ml, or about 26 pg/ml to about 58 pg/ml.
  • the therapeutically effective amount of secnidazole is an amount of secnidazole that exhibits a Tmax of secnidazole in the subject of about 2 hours to about 6 hours, or about 3 hours to about 4 hours, or about 6 hours to about 24 hours, or about 2 hours to about 24 hours. In some embodiments, wherein the therapeutically effective amount of secnidazole is an amount of secnidazole that exhibits a ti/2 of about 11 hours to about 20 hours in the subject. In some embodiments, wherein secnidazole is the sole drug in the microgranule formulation.
  • the secnidazole microgranule formulation further comprises one or more of the following ingredients selected from at least one inert core (sugar spheres being preferred); at least one binding agent (povidone being preferred); at least one plasticizer (polyethylene glycol being preferred, and polyethylene glycol 4000 being most preferred); at least one film-forming polymer (poly(meth)acrylates being preferred and ethyl acrylate-methyl methacrylate copolymer being most preferred), at least one anti-tacking agent (talc being preferred); at least one anti- static agent (talc being preferred); and a combination thereof.
  • at least one inert core sucgar spheres being preferred
  • at least one binding agent povidone being preferred
  • plasticizer polyethylene glycol being preferred, and polyethylene glycol 4000 being most preferred
  • at least one film-forming polymer poly(meth)acrylates being preferred and ethyl acrylate-methyl methacrylate copolymer being most preferred
  • talc anti-tack
  • the microgranule formulation further comprises at least one compound selected from the group consisting of sugar spheres, povidone, polyethylene glycol (such as polyethylene glycol 4000), ethyl acrylate-methyl methacrylate copolymer (such as the product ethyl acrylate-methyl methacrylate copolymer sold under the trademark Eudragit® NE30D), talc, colloidal silicon dioxide, and a combination thereof.
  • the secnidazole in a microgranule formulation may be mixed, stirred, or otherwise integrated into a food substance.
  • the food substance includes, but not limited to, a liquid, semisolid, or soft food.
  • the food substance may include, but not limited to, applesauce, yogurt, pudding or the like.
  • integration of the secnidazole microgranule formulation into a food substance has a taste masking function.
  • a microgranule formulation for treating or preventing trichomoniasis or T. vaginalis infection in a subject in need thereof comprising a microgranule formulation comprising a therapeutically effective amount of secnidazole, wherein the microgranule formulation comprises a plurality of microgranules having a volume-weighted particle size distribution within a microgranule population, wherein the volume-weighted particle size distribution as measured by mean diameter from a representative sample of the microgranule population comprises (a) at least 10% of the microgranule population having a volume-weighted particle size equal to or larger than about 470 micrometers, and/or (b) 50% of the microgranule population having a volume-weighted particle size in a range of from about 640 micrometers to about 810 micrometers; and/or (c) 90% of the microgranule population having a volume- weighted particle size smaller than about 1170 micrometers.
  • each microgranule comprises a sugar core or a microcrystalline cellulose core, and a layer outside of the sugar core or the microcrystalline cellulose core, the layer comprising secnidazole.
  • each microgranule further comprises as a coating layer that is outside of the layer outside of the inactive core.
  • the coating layer comprises a delayed release element (such as ethyl acrylate-methyl methacrylate copolymer) and/or an anti-tacking element (such as glycerol monostearate).
  • the therapeutically effective amount of secnidazole is an amount of secnidazole that exhibits a Cmax of secnidazole in the subject of about 17.4 pg/ml and about 26.5 pg/ml, or about 34.5 pg/ml to about 58.3 pg/ml, or about 26 pg/ml to about 34 pg/ml, or about 26 pg/ml to about 58 pg/ml.
  • the therapeutically effective amount of secnidazole is an amount of secnidazole that exhibits a Tmax of secnidazole in the subject of about 2 hours to about 6 hours, or about 3 hours to about 4 hours, or about 6 hours to about 24 hours, or about 2 hours to about 24 hours. In some embodiments, wherein the therapeutically effective amount of secnidazole is an amount of secnidazole that exhibits a ti/2 of about 11 hours to about 20 hours in the subject. In some embodiments, wherein secnidazole is the sole drug in the microgranule formulation.
  • the secnidazole microgranule formulation further comprises one or more of the following ingredients selected from at least one inert core (sugar spheres being preferred); at least one binding agent (povidone being preferred); at least one plasticizer (polyethylene glycol being preferred, and polyethylene glycol 4000 being most preferred); at least one film-forming polymer (poly(meth)acrylates being preferred and ethyl acrylate-methyl methacrylate copolymer being most preferred), at least one anti-tacking agent (talc being preferred); at least one antistatic agent (talc being preferred); and a combination thereof.
  • at least one inert core sucgar spheres being preferred
  • at least one binding agent povidone being preferred
  • plasticizer polyethylene glycol being preferred, and polyethylene glycol 4000 being most preferred
  • at least one film-forming polymer poly(meth)acrylates being preferred and ethyl acrylate-methyl methacrylate copolymer being most preferred
  • talc anti-tacking
  • the microgranule formulation further comprises at least one compound selected from the group consisting of sugar spheres, povidone, polyethylene glycol (such as polyethylene glycol 4000), ethyl acrylate-methyl methacrylate copolymer (such as the product ethyl acrylate-methyl methacrylate copolymer sold under the trademark Eudragit® NE30D), talc, colloidal silicon dioxide, and a combination thereof.
  • the secnidazole in a microgranule formulation may be mixed, stirred, or otherwise integrated into a food substance.
  • the food substance includes, but not limited to, a liquid, semisolid, or soft food.
  • the food substance may include, but not limited to, applesauce, yogurt, pudding or the like.
  • integration of the secnidazole microgranule formulation into a food substance has a taste masking function.
  • a microgranule formulation for treating or preventing trichomoniasis or T. vaginalis infection in a subject in need thereof comprises a plurality of microgranules, wherein the plurality of microgranules comprises a therapeutically effective amount of nitroimidazole compound or a pharmaceutically acceptable salt thereof, wherein each microgranule comprises a core and a coating, wherein the core comprises the nitroimidazole compound or the pharmaceutically acceptable salt thereof, and wherein the coating surrounds the core.
  • the nitroimidazole compound is secnidazole, metronidazole, tinidazole, nimorazole, dimetridazole, 6-Amino PA824, orinidazole, megazol, azanidazole, benznidazole, pimonidazole or a combination thereof.
  • the nitroimidazole compound is secnidazole.
  • the nitroimidazole compound is in the core.
  • the nitroimidazole compound comprises at least 70% of the core by weight.
  • the coating covers partially or all of the exterior surface of the core.
  • the coating does not contain a nitroimidazole compound.
  • the nitroimidazole compound comprises at least about 70% of the core by weight; at least about 75% of the core by weight; at least about 80% of the core by weight; at least about 85% of the core by weight; at least about 90% of the core by weight; or about at least about 95% of the core by weight.
  • the nitroimidazole compound comprises about 70% of the core by weight; about 75% of the core by weight; about 80% of the core by weight; about 85% of the core by weight; about 90% of the core by weight; or about 95% of the core by weight.
  • the plurality of microgranules comprise about 1 gram to about 6 grams of the nitroimidazole compound. In some embodiments, the plurality of microgranules comprises a therapeutically effective amount of nitroimidazole compound.
  • the core further comprises at least one polymer. In some embodiments, the polymer can be, but not limited to, Avicel®, Methocel®, hydroxyl propyl cellulose, acacia, guar gum, povidone, lactose monohydrate, or a combination thereof. In some embodiments, the core further comprises Avicel®, Methocel® or a combination thereof.
  • the core further comprises cellulose microcrystalline (such as the product cellulose microcrystalline sold under the trademark Avicel® PH-101), methyl cellulose (such as the product methyl cellulose sold under the trademark Methocel® AV15LV) or a combination thereof.
  • the polymer comprises about 30% of the core by weight.
  • the ratio of the nitroimidazole compound to the at least one polymer in the core may be about 70:30, or lesser than about 70:30, or more than greater than 70:30.
  • the secnidazole in a microgranule formulation may be mixed, stirred, or otherwise integrated into a food substance.
  • the food substance includes, but not limited to, a liquid, semisolid, or soft food. In some embodiments, the food substance may include, but not limited to, applesauce, yogurt, pudding or the like. In some embodiments, integration of the secnidazole microgranule formulation into a food substance has a taste masking function.
  • the core comprises an active ingredient and at least one polymer. In some embodiments, the active ingredient is secnidazole or other nitroimidazole compounds described herein.
  • the microgranule formulation is a delayed release formulation and comprises a plurality of microgranules.
  • the delayed release formulation when administered to a subject provides a secnidazole concentration profile characterized by a change in secnidazole concentration as a function of time that is less than that of an immediate release secnidazole microgranule formulation.
  • the delayed release formulation when administered to a subject provides a secnidazole concentration profile characterized by a Tmax that is greater than that of an immediate release secnidazole microgranule formulation.
  • the delayed release formulation when administered to a subject provides a secnidazole concentration profile characterized by a Cmax that is greater than that of an immediate release secnidazole microgranule formulation. In some embodiments, the delayed release formulation, when administered to a subject provides a secnidazole concentration profile characterized by an AUC that is greater than that of an immediate release secnidazole microgranule formulation. In some embodiments, the microgranule formulation comprises about 1 gram to about 6 grams of secnidazole or a pharmaceutically acceptable salt thereof.
  • each microgranule comprises an inactive core (such as a sugar core, microcrystalline cellulose core or any core that does not contain any API and a layer outside of the inactive core.
  • the layer outside of the inactive core comprises secnidazole.
  • each microgranule further comprises as a coating layer that is outside of the layer outside of the inactive core.
  • the coating layer comprises a delayed release element (such as ethyl acrylatemethyl methacrylate copolymer) and/or an anti-tacking element (such as glycerol monostearate).
  • the plurality of microgranules has a particle size diameter in the range of about 400 micrometers to about 841 micrometers. In some embodiments, the particle size diameter of the microgranule is measured using laser diffraction. In some embodiments, the microgranule formulation comprises about 1 gram, about 2 grams, about 3 grams, about 4 grams, about 5 grams, or about 6 grams of secnidazole or a pharmaceutically acceptable salt thereof. In some embodiments, the microgranule formulation is suitable for oral administration.
  • the secnidazole microgranule formulation further comprises one or more of the following ingredients selected from at least one inert core (sugar spheres being preferred); at least one binding agent (povidone being preferred); at least one plasticizer (polyethylene glycol being preferred, and polyethylene glycol 4000 being most preferred); at least one film-forming polymer (poly(meth)acrylates being preferred and ethyl acrylate-methyl methacrylate copolymer being most preferred), at least one anti-tacking agent (talc being preferred); at least one antistatic agent (talc being preferred); and a combination thereof.
  • at least one inert core sucgar spheres being preferred
  • at least one binding agent povidone being preferred
  • plasticizer polyethylene glycol being preferred, and polyethylene glycol 4000 being most preferred
  • at least one film-forming polymer poly(meth)acrylates being preferred and ethyl acrylate-methyl methacrylate copolymer being most preferred
  • talc anti-tacking
  • the microgranule formulation further comprises at least one compound selected from the group consisting of sugar spheres, povidone, polyethylene glycol (such as polyethylene glycol 4000), ethyl acrylate-methyl methacrylate copolymer (such as the product ethyl acrylate-methyl methacrylate copolymer sold under the trademark Eudragit® NE30D), talc, colloidal silicon dioxide, and a combination thereof.
  • the secnidazole in a microgranule formulation may be mixed, stirred, or otherwise integrated into a food substance.
  • the food substance includes, but not limited to, a liquid, semisolid, or soft food.
  • the food substance may include, but not limited to, applesauce, yogurt, pudding or the like.
  • integration of the secnidazole microgranule formulation into a food substance has a taste masking function.
  • Embodiments herein are also directed to a use of secnidazole or a pharmaceutically acceptable salt thereof in a microgranule formulation in the manufacture of a medicament for the treatment or prevention of trichomoniasis or T. vaginalis infection in a subject, wherein the microgranule formulation comprises a therapeutically effective amount of secnidazole or the pharmaceutically acceptable salt thereof in the microgranule formulation.
  • the therapeutically effective amount of secnidazole or the pharmaceutically acceptable salt thereof in the microgranule formulation is an amount of secnidazole or the pharmaceutically acceptable salt thereof, respectively, that exhibits a Cmax of between about 34.5 pg/ml and about 58.3 pg/ml, or about 26 pg/ml to about 34 pg/ml, or about 26 pg/ml to about 58 pg/ml.
  • the therapeutically effective amount of secnidazole or the pharmaceutically acceptable salt thereof in the microgranule formulation is an amount of secnidazole or the pharmaceutically acceptable salt thereof, respectively, that exhibits a Cmax of between about 17.4 pg/ml and about 26.5 pg/ml. In some embodiments, wherein the therapeutically effective amount of secnidazole or the pharmaceutically acceptable salt thereof in the microgranule formulation is an amount of secnidazole or the pharmaceutically acceptable salt thereof, respectively, that exhibit a Tmax of about 3 hours to about 4 hours, or about 6 hours to about 24 hours, or about 2 hours to about 24 hours.
  • the therapeutically effective amount of secnidazole or the pharmaceutically acceptable salt thereof in the microgranule formulation is an amount of secnidazole or the pharmaceutically acceptable salt thereof, respectively, that exhibit a Tmax of 2 hours to 6 hours, or about 6 hours to about 24 hours, or about 2 hours to about 24 hours.
  • the plurality of microgranules each having a particle size range of about 400 micrometers to about 841 micrometers.
  • a microgranule formulation for the treatment or prevention of trichomoniasis or T. vaginalis infection in a subject, wherein the microgranule formulation comprises a therapeutically effective amount of secnidazole or the pharmaceutically acceptable salt thereof in the microgranule formulation.
  • the therapeutically effective amount of secnidazole or the pharmaceutically acceptable salt thereof in the microgranule formulation is an amount of secnidazole or the pharmaceutically acceptable salt thereof, respectively, that exhibits a Cmax of between about 34.5 pg/ml and about 58.3 pg/ml, or about 26 pg/ml to about 34 pg/ml, or about 26 pg/ml to about 58 pg/ml.
  • the therapeutically effective amount of secnidazole or the pharmaceutically acceptable salt thereof in the microgranule formulation is an amount of secnidazole or the pharmaceutically acceptable salt thereof, respectively, that exhibits a Cmax of between about 17.4 pg/ml and about 26.5 pg/ml. In some embodiments, wherein the therapeutically effective amount of secnidazole or the pharmaceutically acceptable salt thereof in the microgranule formulation is an amount of secnidazole or the pharmaceutically acceptable salt thereof, respectively, that exhibit a Tmax of about 3 hours to about 4 hours, or about 6 hours to about 24 hours, or about 2 hours to about 24 hours.
  • the therapeutically effective amount of secnidazole or the pharmaceutically acceptable salt thereof in the microgranule formulation is an amount of secnidazole or the pharmaceutically acceptable salt thereof, respectively, that exhibit a Tmax of about 2 hours to about 6 hours.
  • the plurality of microgranules each having a particle size range of about 400 micrometers to about 841 micrometers.
  • a pharmaceutical composition comprising a plurality of microgranules for treating or preventing trichomoniasis or T. vaginalis infection in a subject, wherein the plurality of microgranules comprises a therapeutically effective amount of secnidazole or a pharmaceutically acceptable salt thereof, wherein the plurality of microgranules having a volume-weighted particle size distribution within a microgranule population, wherein the volume-weighted particle size distribution as measured by mean diameter using laser diffraction from a representative sample of the microgranule population comprises at least about 10% of the microgranule population having a volume-weighted particle size about equal to or larger no less than 470 micrometers, and/or about 50% of the microgranule population having a volume-weighted particle size between about no less than 640 micrometers and about no more than 810 micrometers, and/or about 90% of the microgranule population having a volume- weighted particle size about no more than 1170
  • a pharmaceutical composition comprising a plurality of microgranules for treating or preventing trichomoniasis or T. vaginalis infection in a subject, wherein the plurality of microgranules comprises a therapeutically effective amount of secnidazole or a pharmaceutically acceptable salt thereof, wherein each microgranule comprises a core and a coating, wherein the core comprises an active ingredient and at least one polymer, wherein the active ingredient is the secnidazole or the pharmaceutically acceptable salt thereof, wherein the secnidazole or the pharmaceutically acceptable salt thereof comprises at least 70% of the core by weight, wherein the coating is on the outside of the core, wherein the therapeutically effective amount of the secnidazole or the pharmaceutically acceptable salt thereof is about 1 gram, about 2 grams, about 3 grams, about 4 grams, about 5 grams, or about 6 grams; and wherein the pharmaceutical composition is for oral administration.
  • a pharmaceutical composition in preparation of a medicament comprising a plurality of microgranules for treating or preventing trichomoniasis or T. vaginalis infection in a subject
  • the plurality of microgranules comprises a therapeutically effective amount of secnidazole or a pharmaceutically acceptable salt thereof
  • each microgranule comprises a core and a coating, wherein the core comprises an active ingredient and at least one polymer, wherein the active ingredient is the secnidazole or the pharmaceutically acceptable salt thereof, wherein the secnidazole or the pharmaceutically acceptable salt thereof comprises at least 70% of the core by weight, wherein the coating is on the outside of the core, wherein the therapeutically effective amount of the secnidazole or the pharmaceutically acceptable salt thereof is about 1 gram, about 2 grams, about 3 grams, about 4 grams, about 5 grams, or about 6 grams; and wherein the pharmaceutical composition is for oral administration.
  • Embodiments herein are also directed to a method of making the secnidazole microgranule formulation, the method comprising coating one or more sugar spheres and/or microcrystalline cellulose spheres.
  • the process comprises (a) layering secnidazole on one or more sugar spheres and/or microcrystalline cellulose spheres; (b) layering a seal coating on top of the secnidazole on the one or more sugar spheres and/or microcrystalline cellulose spheres to produce end products of (b), wherein the seal coating comprises polyethylene glycol (such as polyethylene glycol 4000); (c) layering a top coating on top of the end products of (b) to product end products of (c), wherein the top coating comprises with ethyl acrylate-methyl methacrylate copolymer (such as the product ethyl acrylate-methyl methacrylate copolymer sold under the trademark Eudragit® NE30D); and (d) curing the end products
  • the process comprises (a) layering secnidazole on one or more sugar spheres and/or microcrystalline cellulose spheres; (b) layering a seal coating on top of the secnidazole on the one or more sugar spheres and/or microcrystalline cellulose spheres to produce end products of (b), wherein the seal coating comprises ethyl acrylate-methyl methacrylate copolymer (such as the product ethyl acrylate-methyl methacrylate copolymer sold under the trademark Eudragit® NE30D); and (c) curing the end products of (b).
  • the seal coating comprises ethyl acrylate-methyl methacrylate copolymer (such as the product ethyl acrylate-methyl methacrylate copolymer sold under the trademark Eudragit® NE30D); and (c) curing the end products of (b).
  • coating with ethyl acrylate-methyl methacrylate copolymer provides a delayed release formulation.
  • Other grades of the product ethyl acrylate-methyl methacrylate copolymer sold under the trademark Eudragit® can also be used in the formulations, e.g., Eudragit® E (either E 100 or E PO) or the product methyl methacrylate and diethylaminoethyl methacrylate copolymer dispersion sold under the trademark Kollicoat® SmartSeal.
  • a method of making the secnidazole microgranule formulation comprises blending with talc. In some embodiments, blending with talc increases the flowability of the secnidazole microgranule formulation.
  • Some embodiments are directed to a method of manufacturing a plurality of microgranules comprising a nitroimidazole compound, such as secnidazole.
  • the method of manufacturing a plurality of microgranules comprises forming a plurality of microgranule cores.
  • forming a plurality of microgranule cores comprises a wet granulation step.
  • the wet granulation step comprises mixing a nitroimidazole compound with one or more polymers to form a mixture, and hydrating the mixture to form a hydrated mixture.
  • hydrating the mixture comprises the addition of water to the mixture.
  • the wet granulation step is carried out in a planetary mixer or high shear granulator.
  • forming a plurality of microgranules cores further comprises an extrusion step.
  • the hydrated mixture is passed through an extruder to form a plurality of extruded microgranule cores.
  • the hydrated mixture is passed through an extruder (such as a Niro Extruder) fitted with a 0.8mm screen to form a plurality of extruded microgranule cores.
  • forming a plurality of microgranule cores further comprises a spheronization step to form a plurality of spheronized microgranule cores.
  • the extruded microgranule cores are spheronized to form a plurality of spheronized microgranule cores.
  • the spheronization step is carried out using a spheronizer (such as a Niro Spheronizer).
  • forming a plurality of microgranule cores further comprise drying and screening the plurality of spheronized microgranule cores.
  • the plurality of spheronized microgranule cores is dried using a Glatt fluid bed and screened to remove fine and oversize material to form a plurality of microgranule cores.
  • the method of manufacturing a plurality of microgranules comprises coating the plurality of microgranule cores to form a plurality of coated microgranules.
  • coating the plurality of microgranule cores comprises coating the plurality of microgranule cores comprises coating the plurality of microgranule cores with one or more polymers.
  • the one or more polymers can be, but not limited to, PEG (such as PEG 4000), Eudragit® (such as the product ethyl acrylate-methyl methacrylate copolymer sold under the trademark Eudagrit® NE30D), talc or a combination thereof, wherein the one or more polymers is sprayed on the plurality of microgranule cores using a Glatt fluid bed to form a plurality of coated microgranules.
  • PEG such as PEG 4000
  • Eudragit® such as the product ethyl acrylate-methyl methacrylate copolymer sold under the trademark Eudagrit® NE30D
  • talc or a combination thereof
  • the method of manufacturing a plurality of microgranules further comprises drying and screening the plurality of coated microgranules.
  • the plurality of coated microgranules are dried in a Glatt fluid bed and screened to remove fine and oversize material.
  • the method of manufacturing a plurality of microgranules further comprises blending and curing the plurality of coated microgranules.
  • blending and curing the plurality of coated microgranules comprises bending the plurality of coated microgranules with talc in a V-blender and curing in a tray dryer at 40°C for 24 hours.
  • administering a therapeutically effective amount of secnidazole to a subject comprises administering a secnidazole or a pharmaceutically acceptable salt thereof in a controlled release form to the subject.
  • the coating described herein can delay disintegration and absorption in the gastrointestinal tract and thereby providing a controlled and/or sustained action over a longer period than an immediate release composition. Additionally, such coatings can be adapted for release of a secnidazole in a predetermined pattern (e.g., in order to achieve a controlled release composition) or it can be adapted not to release the active compound until after passage of the stomach (enteric coating).
  • Suitable coatings encompassed by such embodiments may include, but are not limited to, sugar coating, film coating (e.g., but not limited to, hydroxypropyl methylcellulose, methylcellulose, methyl hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose, acrylate copolymers, polyethylene glycols, polyvinylpyrrolidone or a combination thereof), or an enteric coating (e.g., but not limited to, methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, shellac, ethyl cellulose or a combination thereof).
  • film coating e.g., but not limited to, hydroxypropyl methylcellulose, methylcellulose, methyl hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose, acrylate copolymers, polyethylene glycol
  • a time delay material such as, but not limited to, glyceryl monostearate or glyceryl distearate can be incorporated into the coatings of some embodiments.
  • the coating can be adapted to protect the composition from unwanted chemical changes, for example, but not limited to, to reduce chemical degradation prior to the release of API.
  • multiple doses may be given at pre-determined intervals such as but not limited to once a week, bi-weekly, monthly, bimonthly for the duration of treatment.
  • the duration of treatment may be at least one week.
  • the duration of treatment may be at least one month.
  • the duration of treatment is about six months.
  • Some embodiments are directed to a method of reducing the incidence and/or risk of a preterm birth. Trichomoniasis or T. vaginalis infection may increase the risk of a preterm birth in a subject.
  • a method of reducing the incidence and/or risk of a preterm birth in a subject comprises administering to the subject a therapeutically effective amount of secnidazole or a pharmaceutically acceptable salt thereof.
  • a method of reducing the incidence and/or risk of a preterm birth in a subject in need thereof the method comprising administering to the subject a therapeutically effective amount of secnidazole or a pharmaceutically acceptable salt thereof in a microgranule formulation.
  • the secnidazole or the pharmaceutically acceptable salt thereof in the microgranule formulation is administered orally.
  • the secnidazole or the pharmaceutically acceptable salt thereof in the microgranule formulation comprises a plurality of microgranules.
  • each microgranule comprises an inactive core (such as a sugar core, microcrystalline cellulose core or any core that does not contain any API) and a layer outside of the inactive core.
  • the layer outside of the inactive core comprises secnidazole.
  • each microgranule further comprises as a coating layer that is outside of the layer outside of the inactive core.
  • the coating layer comprises a delayed release element (such as ethyl acrylate-methyl methacrylate copolymer) and/or an anti-tacking element (such as glycerol monostearate).
  • a delayed release element such as ethyl acrylate-methyl methacrylate copolymer
  • an anti-tacking element such as glycerol monostearate
  • the plurality of microgranules has a particle size diameter in the range of about 400 micrometers to about 841 micrometers. In some embodiments, the particle size diameter of the microgranule is measured using laser diffraction.
  • the therapeutically effective amount of secnidazole is an amount of secnidazole that exhibits a Cmax of secnidazole in the subject of about 17.4 pg/ml and about 26.5 pg/ml, or about 34.5 pg/ml to about 58.3 pg/ml, or about 26 pg/ml to about 34 pg/ml, or about 26 pg/ml to about 58 pg/ml.
  • the therapeutically effective amount of secnidazole is an amount of secnidazole that exhibits a Tmax of secnidazole in the subject of about 2 hours to about 6 hours, or about 3 hours to about 4 hours, or about 6 hours to about 24 hours, or about 2 hours to about 24 hours. In some embodiments, wherein the therapeutically effective amount of secnidazole is an amount of secnidazole that exhibits a ti/2 of about 11 hours to about 20 hours in the subject. In some embodiments, wherein secnidazole is the sole drug in the microgranule formulation.
  • the secnidazole microgranule formulation further comprises one or more of the following ingredients selected from at least one inert core (sugar spheres being preferred); at least one binding agent (povidone being preferred); at least one plasticizer (polyethylene glycol being preferred, and polyethylene glycol 4000 being most preferred); at least one film-forming polymer (poly(meth)acrylates being preferred and ethyl acrylate-methyl methacrylate copolymer being most preferred), at least one anti-tacking agent (talc being preferred); at least one antistatic agent (talc being preferred); and a combination thereof.
  • at least one inert core sucgar spheres being preferred
  • at least one binding agent povidone being preferred
  • plasticizer polyethylene glycol being preferred, and polyethylene glycol 4000 being most preferred
  • at least one film-forming polymer poly(meth)acrylates being preferred and ethyl acrylate-methyl methacrylate copolymer being most preferred
  • talc anti-tacking
  • the microgranule formulation further comprises at least one compound selected from the group consisting of sugar spheres, povidone, polyethylene glycol (such as polyethylene glycol 4000), ethyl acrylate-methyl methacrylate copolymer (such as the product ethyl acrylate-methyl methacrylate copolymer sold under the trademark Eudragit® NE30D), talc, colloidal silicon dioxide, and a combination thereof.
  • the secnidazole in a microgranule formulation may be mixed, stirred, or otherwise integrated into a food substance.
  • the food substance includes, but not limited to, a liquid, semisolid, or soft food.
  • the food substance may include, but not limited to, applesauce, yogurt, pudding or the like.
  • integration of the secnidazole microgranule formulation into a food substance has a taste masking function.
  • the method of reducing the incidence and/or risk of a preterm birth in a subject in need thereof comprising administering to the subject a microgranule formulation comprising a therapeutically effective amount of nitroimidazole compound (such as secnidazole) or a pharmaceutically acceptable salt thereof, wherein the microgranule formulation comprises a plurality of microgranules, wherein each microgranule comprises a core and a coating, wherein the core comprises the nitroimidazole compound or the pharmaceutically acceptable salt thereof, and wherein the coating surrounds the core.
  • the nitroimidazole compound is secnidazole, wherein secnidazole comprises at least 70% of the core by weight.
  • the secnidazole comprises about 1 gram to about 6 grams of the microgranule formulation.
  • the secnidazole microgranule formulation is co-administered with an additional compound selected from EE2, NET, or a combination thereof.
  • the additional compound is administered on the same day as the secnidazole microgranule formulation.
  • the additional compound is administered on a different day than the secnidazole microgranule formulation.
  • the secnidazole microgranule formulation does not affect the contraceptive efficacy of the additional compound.
  • the amount of the food substance is about 4-6 ounces.
  • a method of reducing the incidence and/or risk of a preterm birth in a subject further comprises a term birth. In some embodiments, a method of reducing the incidence and/or risk of a preterm birth in a subject further comprises determining a post-treatment clinical outcome. In some embodiments, a post-treatment clinical outcome is indicative of a clinical outcome responder. Some embodiments further comprise determining a post-treatment clinical outcome. In some embodiments, a post-treatment clinical outcome of clinical cure is defined as a clinical outcome responder. In some embodiments, a clinical outcome responder is a subject with normal vaginal discharge, a negative T.
  • vaginalis test a negative KOH Whiff test
  • clue cells less than or equal to 20% of the total epithelial cells on microscopic examination of a vaginal saline wet mount after treatment with a microgranule formulation comprising about 1 gram to about 6 grams of secnidazole.
  • a clinical outcome responder has a gram stain slide Nugent score of less than four (4) after treatment with a single dose of secnidazole.
  • a clinical outcome responder is a subject with normal vaginal discharge, a negative KOH Whiff test, clue cells less than 20% of total epithelial cells, and a gram stain slide Nugent score of less than four (4) after treatment with a single dose of secnidazole. In some embodiments, a clinical outcome responder has a gram stain slide Nugent score of less than four (4) after treatment with a 2-gram single dose of secnidazole.
  • a clinical outcome responder is a subject with normal vaginal discharge, a negative KOH Whiff test, clue cells less than 20% of total epithelial cells, and a gram stain slide Nugent score of less than four (4) after treatment with a 2-gram single dose of secnidazole.
  • a post-treatment clinical outcome is observable after about 24 hours, about 48 hours, about 72 hours, about 96 hours, about 120 hours, about 168 hours after administration to the subject.
  • a post-treatment clinical outcome is observable after about 7 days to about 10 days, about 11 days to about 20 days or about 21 days to about 30 days after administration to the subject.
  • a method of reducing the incidence and/or risk of a preterm birth in a subject further comprises an alleviation of one or more symptoms of trichomoniasis or T. vaginalis infection within up to about three days after administration to the subject.
  • a method of treating trichomoniasis or T. vaginalis infection further comprises an alleviation of one or more symptoms of trichomoniasis or T. vaginalis infection within up to about three days after administration to the subject.
  • the one or more symptoms include, but are not limited to, purulent malodorous discharge (associated with burning, pruritus, dysuria, frequency, lower abdominal pain), or dyspareunia, burning postcoital bleeding, dyspareunia, dysuria, a thin green-yellow frothy discharge, vulvovaginal erythema (erythema of the vulva and vaginal mucosa), punctate hemorrhages, urethritis, cystitis, purulent vaginitis, sequamative inflammatory vaginitis, atrophic vaginitis, erosive lichen planus, elevated vaginal pH (about 5.0 to about 6.0), and any combination thereof.
  • purulent malodorous discharge associated with burning, pruritus, dysuria, frequency, lower abdominal pain
  • dyspareunia burning postcoital bleeding
  • dyspareunia dysuria
  • dysuria dysuria
  • alleviation refers to a lessening of the severity of one or more symptoms. In some embodiments, alleviation of one or more symptoms of trichomoniasis or T. vaginalis infection occurs within about 24 hours, about 48 hours, about 72 hours, about 96 hours, about 120 hours, about 144 hours or about 168 hours after administration to the subject. In some embodiments, alleviation of one or more symptoms of trichomoniasis or T. vaginalis infection occurs within about 7 days to about 10 days, about 11 days to about 20 days or about 21 days to about 30 days after administration to the subject.
  • a method of reducing the incidence and/or risk of a preterm birth in a subject further comprises a resolution of one or more symptoms of trichomoniasis or T. vaginalis infection within up to about seven days after administration to the subject.
  • a method of treating trichomoniasis or T. vaginalis infection further comprises a resolution of one or more symptoms of trichomoniasis or T. vaginalis infection within up to about seven days after administration to the subject.
  • the one or more symptoms include, but are not limited to, purulent malodorous discharge (associated with burning, pruritus, dysuria, frequency, lower abdominal pain), or dyspareunia, burning postcoital bleeding, dyspareunia, dysuria, a thin green-yellow frothy discharge, vulvovaginal erythema (erythema of the vulva and vaginal mucosa), punctate hemorrhages, urethritis, cystitis, purulent vaginitis, sequamative inflammatory vaginitis, atrophic vaginitis, erosive lichen planus, elevated vaginal pH (about 5.0 to about 6.0), and any combination thereof.
  • purulent malodorous discharge associated with burning, pruritus, dysuria, frequency, lower abdominal pain
  • dyspareunia burning postcoital bleeding
  • dyspareunia dysuria
  • dysuria dysuria
  • resolution of one or more symptoms of trichomoniasis or T. vaginalis infection occurs within about 24 hours, about 48 hours, about 72 hours, about 96 hours, about 120 hours, or 144 hours or about 168 hours after administration to the subject. In some embodiments, resolution of one or more symptoms of trichomoniasis or T. vaginalis infection occurs within about 7 days to about 10 days, about 11 days to about 20 days or about 21 days to about 30 days after administration to the subject.
  • Some embodiments are directed to a method of reducing the incidence and/or risk of a subject transmitting HIV to or acquiring HIV from a sexual partner.
  • T. vaginalis infection may increase the risk of a HIV transmission to or acquiring HIV from sexual partner.
  • a method of reducing the incidence and/or risk of the subject transmitting HIV to or acquiring HIV from a sexual partner comprises administering to the subject or sexual partner a therapeutically effective amount of secnidazole or a pharmaceutically acceptable salt thereof.
  • a method of reducing the incidence and/or risk of the subject transmitting HIV to or acquiring HIV from a sexual partner comprising administering to the subject or sexual partner a therapeutically effective amount of secnidazole or a pharmaceutically acceptable salt thereof in a microgranule formulation.
  • the secnidazole or the pharmaceutically acceptable salt thereof in the microgranule formulation is administered orally.
  • the secnidazole or the pharmaceutically acceptable salt thereof in the microgranule formulation comprises a plurality of microgranules.
  • each microgranule comprises an inactive core (such as a sugar core, microcrystalline cellulose core or any core that does not contain any API) and a layer outside of the inactive core.
  • the layer outside of the inactive core comprises secnidazole.
  • each microgranule further comprises as a coating layer that is outside of the layer outside of the inactive core.
  • the coating layer comprises a delayed release element (such as ethyl acrylate-methyl methacrylate copolymer) and/or an anti-tacking element (such as glycerol monostearate).
  • the plurality of microgranules has a particle size diameter in the range of about 400 micrometers to about 841 micrometers. In some embodiments, the particle size diameter of the microgranule is measured using laser diffraction. In some embodiments, wherein the therapeutically effective amount of secnidazole is an amount of secnidazole that exhibits a Cmax of secnidazole in the subject or sexual partner of about 17.4 pg/ml and about 26.5 pg/ml, or about 34.5 pg/ml to about 58.3 pg/ml, or about 26 pg/ml to about 34 pg/ml, or about 26 pg/ml to about 58 pg/ml.
  • the therapeutically effective amount of secnidazole is an amount of secnidazole that exhibits a Tmax of secnidazole in the subject or sexual partner of about 2 hours to about 6 hours, or about 3 hours to about 4 hours, or about 6 hours to about 24 hours, or about 2 hours to about 24 hours. In some embodiments, wherein the therapeutically effective amount of secnidazole is an amount of secnidazole that exhibits a ti/2 of about 11 hours to about 20 hours in the subject or sexual partner. In some embodiments, wherein secnidazole is the sole drug in the microgranule formulation.
  • the secnidazole microgranule formulation further comprises one or more of the following ingredients selected from at least one inert core (sugar spheres being preferred); at least one binding agent (povidone being preferred); at least one plasticizer (polyethylene glycol being preferred, and polyethylene glycol 4000 being most preferred); at least one film-forming polymer (poly(meth)acrylates being preferred and ethyl acrylate-methyl methacrylate copolymer being most preferred), at least one anti-tacking agent (talc being preferred); at least one anti-static agent (talc being preferred); and a combination thereof.
  • at least one inert core sucgar spheres being preferred
  • at least one binding agent povidone being preferred
  • plasticizer polyethylene glycol being preferred, and polyethylene glycol 4000 being most preferred
  • at least one film-forming polymer poly(meth)acrylates being preferred and ethyl acrylate-methyl methacrylate copolymer being most preferred
  • talc anti-tack
  • the microgranule formulation further comprises at least one compound selected from the group consisting of sugar spheres, povidone, polyethylene glycol (such as polyethylene glycol 4000), ethyl acrylate-methyl methacrylate copolymer (such as the product ethyl acrylate-methyl methacrylate copolymer sold under the trademark Eudragit® NE30D), talc, colloidal silicon dioxide, and a combination thereof.
  • the method of reducing the incidence and/or risk of a subject transmitting HIV to or acquiring HIV from a sexual partner comprising administering to the subject a microgranule formulation comprising a therapeutically effective amount of nitroimidazole compound (such as secnidazole) or a pharmaceutically acceptable salt thereof, wherein the microgranule formulation comprises a plurality of microgranules, wherein each microgranule comprises a core and a coating, wherein the core comprises the nitroimidazole compound or the pharmaceutically acceptable salt thereof, and wherein the coating surrounds the core.
  • the nitroimidazole compound is secnidazole, wherein secnidazole comprises at least 70% of the core by weight.
  • the secnidazole in a microgranule formulation may be mixed, stirred, or otherwise integrated into a food substance.
  • the food substance includes, but not limited to, a liquid, semisolid, or soft food.
  • the food substance may include, but not limited to, applesauce, yogurt, pudding or the like.
  • integration of the secnidazole microgranule formulation into a food substance has a taste masking function.
  • a method of reducing the incidence and/or risk of a subject transmitting HIV to or acquiring HIV from a sexual partner comprises administering to the subject a single dose of a therapeutically effective amount of secnidazole in a microgranule formulation, wherein the secnidazole comprises about 1 gram to about 6 grams of the microgranule formulation.
  • the secnidazole microgranule formulation is co-administered with an additional compound selected from EE2, NET, or a combination thereof.
  • the additional compound is administered on the same day as the secnidazole microgranule formulation.
  • the additional compound is administered on a different day than the secnidazole microgranule formulation.
  • the secnidazole microgranule formulation does not affect the contraceptive efficacy of the additional compound.
  • the secnidazole microgranule formulation is mixed into a semisolid or soft food substance, such as but not limited to applesauce yogurt and pudding. In some embodiments, the amount of the food substance is about 4-6 ounces.
  • a method of reducing the incidence and/or risk of a subject transmitting HIV to or acquiring HIV from a sexual partner further comprises the absence of HIV transmission. In some embodiments, a method of reducing the incidence and/or risk of a subject transmitting HIV to or acquiring HIV from a sexual partner further comprises determining a post-treatment clinical outcome. In some embodiments, a post-treatment clinical outcome is indicative of a clinical outcome responder. Some embodiments further comprise determining a post-treatment clinical outcome. In some embodiments, a post-treatment clinical outcome of clinical cure is defined as a clinical outcome responder.
  • a clinical outcome responder is a subject or sexual partner with normal vaginal discharge, a negative KOH Whiff test, and clue cells less than or equal to 20% of the total epithelial cells on microscopic examination of a vaginal saline wet mount after treatment with a microgranule formulation comprising about 1 gram to about 6 grams of secnidazole.
  • a clinical outcome responder has a gram stain slide Nugent score of less than four (4) after treatment with a single dose of secnidazole.
  • a clinical outcome responder is a subject with normal vaginal discharge, a negative KOH Whiff test, clue cells less than 20% of total epithelial cells, and a gram stain slide Nugent score of less than four (4) after treatment with a single dose of secnidazole. In some embodiments, a clinical outcome responder has a gram stain slide Nugent score of less than four (4) after treatment with a 2-gram single dose of secnidazole.
  • a clinical outcome responder is a subject with normal vaginal discharge, a negative KOH Whiff test, clue cells less than 20% of total epithelial cells, and a gram stain slide Nugent score of less than four (4) after treatment with a 2-gram single dose of secnidazole.
  • a post-treatment clinical outcome is observable after about 24 hours, about 28 hours, about 72 hours, about 96 hours, about 120 hours, about 144 hours or about 168 hours after administration to the subject of sexual partner.
  • a post-treatment clinical outcome is observable after about 7 days to about 10 days, about 11 days to about 20 days or about 21 days to about 30 after administration to the subject or sexual partner.
  • a method of reducing the incidence and/or risk of a subject transmitting HIV to or acquiring HIV from a sexual partner further comprises an alleviation of one or more symptoms of trichomoniasis or T. vaginalis infection within up to about three days after administration to the subject or sexual partner.
  • a method of treating trichomoniasis or T. vaginalis infection further comprises an alleviation of one or more symptoms of trichomoniasis or T. vaginalis infection within up to about three days after administration to the subject or sexual partner.
  • the one or more symptoms include, but are not limited to, purulent malodorous discharge (associated with burning, pruritus, dysuria, frequency, lower abdominal pain), or dyspareunia, burning postcoital bleeding, dyspareunia, dysuria, a thin green-yellow frothy discharge, vulvovaginal erythema (erythema of the vulva and vaginal mucosa), punctate hemorrhages, urethritis, cystitis, purulent vaginitis, sequamative inflammatory vaginitis, atrophic vaginitis, erosive lichen planus, elevated vaginal pH (about 5.0 to about 6.0), and any combination thereof.
  • purulent malodorous discharge associated with burning, pruritus, dysuria, frequency, lower abdominal pain
  • dyspareunia burning postcoital bleeding
  • dyspareunia dysuria
  • dysuria dysuria
  • alleviation refers to a lessening of the severity of one or more symptoms.
  • alleviation of one or more symptoms of trichomoniasis or T. vaginalis infection occurs within about 24 hours, about 48 hours, about 72 hours, about 96 hours, about 120 hours, about 144 hours or about 168 hours after administration to the subject or sexual partner.
  • alleviation of one or more symptoms of trichomoniasis or T. vaginalis infection occurs within about 7 days to about 10 days, about 11 days to about 20 days or about 21 days to about 30 days after administration to the subject or sexual partner.
  • a method of reducing the incidence and/or risk of a subject transmitting HIV to or acquiring HIV from a sexual partner further comprises a resolution of one or more symptoms of trichomoniasis or T. vaginalis infection within up to about seven days after administration to the subject or sexual partner.
  • a method of treating trichomoniasis or T. vaginalis infection further comprises a resolution of one or more symptoms of trichomoniasis or T. vaginalis infection within up to about seven days after administration to the subject or sexual partner.
  • the one or more symptoms include, but are not limited to, purulent malodorous discharge (associated with burning, pruritus, dysuria, frequency, lower abdominal pain), or dyspareunia, burning postcoital bleeding, dyspareunia, dysuria, a thin green-yellow frothy discharge, vulvovaginal erythema (erythema of the vulva and vaginal mucosa), punctate hemorrhages, urethritis, cystitis, purulent vaginitis, sequamative inflammatory vaginitis, atrophic vaginitis, erosive lichen planus, elevated vaginal pH (about 5.0 to about 6.0), and any combination thereof.
  • purulent malodorous discharge associated with burning, pruritus, dysuria, frequency, lower abdominal pain
  • dyspareunia burning postcoital bleeding
  • dyspareunia dysuria
  • dysuria dysuria
  • resolution of one or more symptoms of trichomoniasis or T. vaginalis infection occurs within about 24 hours, about 48 hours, about 72 hours, about 96 hours, about 120 hours, about 144 hours or about 168 hours after administration to the subject or sexual partner. In some embodiments, resolution of one or more symptoms of trichomoniasis or T. vaginalis infection occurs within about 7 days to about 10 days, about 11 days to about 20 days or about 21 days to about 30 days after administration to the subject or sexual partner.
  • Some embodiments are directed to a method of reducing the incidence and/or risk of a subject acquiring a STI from or transmitting a STI to a sexual partner.
  • Trichomoniasis or T. vaginalis infection may increase the risk of acquiring a STI from or transmitting a STI to a sexual partner.
  • STIs include, but not limited to, chlamydia, gonorrhea, bacterial vaginosis, herpes simplex virus 2 (“HSV-2”) and human papillomavirus (“HPV”).
  • a method of reducing the incidence and/or risk of the subject acquiring a STI from or transmitting a STI to a sexual partner comprises administering to the subject a therapeutically effective amount of secnidazole or a pharmaceutically acceptable salt thereof.
  • a method of reducing the incidence and/or risk of subject acquiring a STI from or transmitting a STI to a sexual partner the method comprising administering to the subject a therapeutically effective amount of secnidazole or a pharmaceutically acceptable salt thereof in a microgranule formulation.
  • the secnidazole or the pharmaceutically acceptable salt thereof in the microgranule formulation is administered orally.
  • the secnidazole or the pharmaceutically acceptable salt thereof in the microgranule formulation comprises a plurality of microgranules.
  • each microgranule comprises an inactive core (such as a sugar core, microcrystalline cellulose core or any core that does not contain any API) and a layer outside of the inactive core.
  • the layer outside of the inactive core comprises secnidazole.
  • each microgranule further comprises as a coating layer that is outside of the layer outside of the inactive core.
  • the coating layer comprises a delayed release element (such as ethyl acrylate-methyl methacrylate copolymer) and/or an anti-tacking element (such as glycerol monostearate).
  • a delayed release element such as ethyl acrylate-methyl methacrylate copolymer
  • an anti-tacking element such as glycerol monostearate
  • the plurality of microgranules has a particle size diameter in the range of about 400 micrometers to about 841 micrometers. In some embodiments, the particle size diameter of the microgranule is measured using laser diffraction.
  • the therapeutically effective amount of secnidazole is an amount of secnidazole that exhibits a Cmax of secnidazole in the subject of about 17.4 pg/ml and about 26.5 pg/ml, about 34.5 pg/ml to about 58.3 pg/ml, or about 26 pg/ml to about 34 pg/ml, or about 26 pg/ml to about 58 pg/ml.
  • the therapeutically effective amount of secnidazole is an amount of secnidazole that exhibits a Tmax of secnidazole in the subject of about 2 hours to about 6 hours, or about 3 hours to about 4 hours, or about 6 hours to about 24 hours, or about 2 hours to about 24 hours. In some embodiments, wherein the therapeutically effective amount of secnidazole is an amount of secnidazole that exhibits a ti/2 of about 11 hours to about 20 hours in the subject. In some embodiments, wherein secnidazole is the sole drug in the microgranule formulation.
  • the secnidazole microgranule formulation further comprises one or more of the following ingredients selected from at least one inert core (sugar spheres being preferred); at least one binding agent (povidone being preferred); at least one plasticizer (polyethylene glycol being preferred, and polyethylene glycol 4000 being most preferred); at least one film-forming polymer (poly(meth)acrylates being preferred and ethyl acrylate-methyl methacrylate copolymer being most preferred), at least one anti-tacking agent (talc being preferred); at least one anti-static agent (talc being preferred); and a combination thereof.
  • at least one inert core sucgar spheres being preferred
  • at least one binding agent povidone being preferred
  • plasticizer polyethylene glycol being preferred, and polyethylene glycol 4000 being most preferred
  • at least one film-forming polymer poly(meth)acrylates being preferred and ethyl acrylate-methyl methacrylate copolymer being most preferred
  • talc anti-tack
  • the microgranule formulation further comprises at least one compound selected from the group consisting of sugar spheres, povidone, polyethylene glycol (such as polyethylene glycol 4000), ethyl acrylate-methyl methacrylate copolymer (such as the product ethyl acrylate-methyl methacrylate copolymer sold under the trademark Eudragit® NE30D), talc, colloidal silicon dioxide, and a combination thereof.
  • the method of reducing the incidence and/or risk of the subject acquiring a STI from or transmitting a STI to a sexual partner comprises administering to the subject a microgranule formulation comprising a therapeutically effective amount of nitroimidazole compound (such as secnidazole) or a pharmaceutically acceptable salt thereof, wherein the microgranule formulation comprises a plurality of microgranules, wherein each microgranule comprises a core and a coating, wherein the core comprises the nitroimidazole compound or the pharmaceutically acceptable salt thereof, and wherein the coating surrounds the core.
  • the nitroimidazole compound is secnidazole, wherein secnidazole comprises at least 70% of the core by weight.
  • the secnidazole in a microgranule formulation may be mixed, stirred, or otherwise integrated into a food substance.
  • the food substance includes, but not limited to, a liquid, semisolid, or soft food.
  • the food substance may include, but not limited to, applesauce, yogurt, pudding or the like.
  • integration of the secnidazole microgranule formulation into a food substance has a taste masking function.
  • a method of reducing the incidence and/or risk of a subject acquiring a STI from or transmitting a STI to a sexual partner comprises administering to the subject a single dose of a therapeutically effective amount of secnidazole in a microgranule formulation, wherein the secnidazole comprises about 1 gram to about 6 grams of the microgranule formulation.
  • the secnidazole microgranule formulation is co-administered with an additional compound selected from EE2, NET, or a combination thereof.
  • the additional compound is administered on the same day as the secnidazole microgranule formulation.
  • the additional compound is administered on a different day than the secnidazole microgranule formulation.
  • the secnidazole microgranule formulation does not affect the contraceptive efficacy of the additional compound.
  • the secnidazole microgranule formulation is mixed into a semisolid or soft food substance, such as but not limited to applesauce yogurt and pudding. In some embodiments, the amount of the food substance is about 4-6 ounces.
  • a method of reducing the incidence and/or risk of a subject acquiring a STI from or transmitting a STI to a sexual partner further comprises the absence of an STI transmission or acquisition of an STI by the subject.
  • a method of reducing the incidence and/or risk of a subject acquiring an STI from a sexual partner further comprises determining a post-treatment clinical outcome.
  • a posttreatment clinical outcome is indicative of a clinical outcome responder.
  • Some embodiments further comprise determining a post-treatment clinical outcome.
  • a posttreatment clinical outcome of clinical cure is defined as a clinical outcome responder.
  • a clinical outcome responder is a subject with normal vaginal discharge, a negative KOH Whiff test, and clue cells less than or equal to 20% of the total epithelial cells on microscopic examination of a vaginal saline wet mount after treatment with a microgranule formulation comprising about 1 gram to about 6 grams of secnidazole.
  • a clinical outcome responder has a gram stain slide Nugent score of less than four (4) after treatment with a single dose of secnidazole.
  • a clinical outcome responder is a subject with normal vaginal discharge, a negative KOH Whiff test, clue cells less than 20% of total epithelial cells, and a gram stain slide Nugent score of less than four (4) after treatment with a single dose of secnidazole. In some embodiments, a clinical outcome responder has a gram stain slide Nugent score of less than four (4) after treatment with a 2-gram single dose of secnidazole.
  • a clinical outcome responder is a subject with normal vaginal discharge, a negative KOH Whiff test, clue cells less than 20% of total epithelial cells, and a gram stain slide Nugent score of less than four (4) after treatment with a 2-gram single dose of secnidazole.
  • a post-treatment clinical outcome is observable after about 24 hours, about 48 hours, about 72 hours, about 96 hours, about 120 hours, about 144 hours or about 168 hours after administration to the subject.
  • a posttreatment clinical outcome is observable after about 7 to about 10 days, about 11 to about 20 days or about 21 to about 30 days after administration to the subject.
  • a method of reducing the incidence and/or risk of a subject acquiring a STI from or transmitting a STI to a sexual partner further comprises an alleviation of one or more symptoms of trichomoniasis or T. vaginalis infection within up to about three days after administration to the subject.
  • a method of treating trichomoniasis or T. vaginalis infection further comprises an alleviation of one or more symptoms of trichomoniasis or T. vaginalis infection within up to about three days after administration to the subject.
  • the one or more symptoms include, but are not limited to, purulent malodorous discharge (associated with burning, pruritus, dysuria, frequency, lower abdominal pain), or dyspareunia, burning postcoital bleeding, dyspareunia, dysuria, a thin green-yellow frothy discharge, vulvovaginal erythema (erythema of the vulva and vaginal mucosa), punctate hemorrhages, urethritis, cystitis, purulent vaginitis, sequamative inflammatory vaginitis, atrophic vaginitis, erosive lichen planus, elevated vaginal pH (about 5.0 to about 6.0), and any combination thereof.
  • purulent malodorous discharge associated with burning, pruritus, dysuria, frequency, lower abdominal pain
  • dyspareunia burning postcoital bleeding
  • dyspareunia dysuria
  • dysuria dysuria
  • alleviation refers to a lessening of the severity of one or more symptoms. In some embodiments, alleviation of one or more symptoms of trichomoniasis or T. vaginalis infection occurs within about 24 hours, about 48 hours, about 72 hours, about 96 hours, about 120 hours, about 144 hours or about 168 hours after administration to the subject. In some embodiments, alleviation of one or more symptoms of trichomoniasis or T. vaginalis infection occurs within about 7 days to about 10 days, about 11 days to about 20 days or about 21 days to about 30 days after administration to the subject.
  • a method of reducing the incidence and/or risk of a subject acquiring a STI from or transmitting a STI to a sexual partner further comprises a resolution of one or more symptoms of trichomoniasis or T. vaginalis infection within up to about seven days after administration to the subject.
  • a method of treating trichomoniasis or T. vaginalis infection further comprises a resolution of one or more symptoms of trichomoniasis or T. vaginalis infection within up to about seven days after administration to the subject.
  • the one or more symptoms include, but are not limited to, purulent malodorous discharge (associated with burning, pruritus, dysuria, frequency, lower abdominal pain), or dyspareunia, burning postcoital bleeding, dyspareunia, dysuria, a thin greenyellow frothy discharge, vulvovaginal erythema (erythema of the vulva and vaginal mucosa), punctate hemorrhages, urethritis, cystitis, purulent vaginitis, sequamative inflammatory vaginitis, atrophic vaginitis, erosive lichen planus, elevated vaginal pH (about 5.0 to about 6.0), and any combination thereof.
  • purulent malodorous discharge associated with burning, pruritus, dysuria, frequency, lower abdominal pain
  • dyspareunia burning postcoital bleeding
  • dyspareunia dysuria
  • dysuria dysuria
  • resolution of one or more symptoms of trichomoniasis or T. vaginalis infection occurs within about 24 hours, about 48 hours, about 72 hours, about 96 hours, about 120 hours, about 144 hours or about 168 hours after administration to the subject or sexual partner. In some embodiments, resolution of one or more symptoms of trichomoniasis or T. vaginalis infection occurs within about 7 days to about 10 days, about 11 days to about 20 days or about 21 days to about 30 days after administration to the subject or sexual partner.
  • a method of reducing the incidence and/or risk of a subject acquiring a STI from or transmitting a STI to a sexual partner comprises administering to the subject a single dose of a therapeutically effective amount of secnidazole in a microgranule formulation, wherein the secnidazole comprises about 1 gram to about 6 grams of the microgranule formulation.
  • the secnidazole microgranule formulation is co-administered with an additional compound selected from EE2, NET, or a combination thereof.
  • the additional compound is administered on the same day as the secnidazole microgranule formulation.
  • the additional compound is administered on a different day than the secnidazole microgranule formulation.
  • the secnidazole microgranule formulation does not affect the contraceptive efficacy of the additional compound.
  • the secnidazole microgranule formulation is mixed into a semisolid or soft food substance, such as but not limited to applesauce, yogurt, and pudding.
  • the amount of the food substance is about 4-6 ounces.
  • a method of treating trichomoniasis or T. vaginalis infection in a subject further comprises determining a post-treatment clinical outcome.
  • a post-treatment clinical outcome is indicative of a clinical outcome responder.
  • a clinical outcome responder is a subject that is asymptomatic.
  • a post-treatment clinical outcome is observable after about 24 hours, about 48 hours, about 72 hours, about 96 hours, about 120 hours, about 144 hours or about 168 hours after administration to the subject.
  • a post-treatment clinical outcome is observable after about 7 days to about 10 days, about 11 to about 20 days or about 21 to about 30 days after administration to the subject.
  • a method of treating trichomoniasis or T. vaginalis infection further comprises an alleviation of one or more symptoms of trichomoniasis within up to about three days after administration to the subject. In some embodiments, a method of treating trichomoniasis or T. vaginalis infection further comprises an alleviation of one or more symptoms of trichomoniasis or T. vaginalis infection within up to about three days after administration to the subject.
  • the one or more symptoms include, but are not limited to, purulent malodorous discharge (associated with burning, pruritus, dysuria, frequency, lower abdominal pain), or dyspareunia, burning postcoital bleeding, dyspareunia, dysuria, a thin green-yellow frothy discharge, vulvovaginal erythema (erythema of the vulva and vaginal mucosa), punctate hemorrhages, urethritis, cystitis, purulent vaginitis, sequamative inflammatory vaginitis, atrophic vaginitis, erosive lichen planus, elevated vaginal pH (about 5.0 to about 6.0), and any combination thereof.
  • purulent malodorous discharge associated with burning, pruritus, dysuria, frequency, lower abdominal pain
  • dyspareunia burning postcoital bleeding
  • dyspareunia dysuria
  • dysuria dysuria
  • alleviation refers to a lessening of the severity of one or more symptoms. In some embodiments, alleviation of one or more symptoms of trichomoniasis or T. vaginalis infection occurs within about 24 hours, about 48 hours, about 72 hours, about 96 hours, about 120 hours, about 168 hours after administration to the subject. In some embodiments, alleviation of one or more symptoms of trichomoniasis or T. vaginalis infection occurs within about 7 to about 10 days, about 11 to about 20 days or about 21 to about 30 days after administration to the subject.
  • a method of treating trichomoniasis or T. vaginalis infection further comprises a resolution of one or more symptoms of trichomoniasis or T. vaginalis infection within up to about seven days after administration to the subject. In some embodiments, a method of treating trichomoniasis or T. vaginalis infection further comprises a resolution of one or more symptoms of trichomoniasis or T. vaginalis infection within up to about seven days after administration to the subject.
  • the one or more symptoms include, but are not limited to, purulent malodorous discharge (associated with burning, pruritus, dysuria, frequency, lower abdominal pain), or dyspareunia, burning postcoital bleeding, dyspareunia, dysuria, a thin green-yellow frothy discharge, vulvovaginal erythema (erythema of the vulva and vaginal mucosa), punctate hemorrhages, urethritis, cystitis, purulent vaginitis, sequamative inflammatory vaginitis, atrophic vaginitis, erosive lichen planus, elevated vaginal pH (about 5.0 to about 6.0), and any combination thereof.
  • purulent malodorous discharge associated with burning, pruritus, dysuria, frequency, lower abdominal pain
  • dyspareunia burning postcoital bleeding
  • dyspareunia dysuria
  • dysuria dysuria
  • resolution of one or more symptoms of trichomoniasis occurs within about 24 hours, about 48 hours, about 72 hours, about 96 hours, about 120 hours, about 144 hours or about 168 hours after administration to the subject. In some embodiments, resolution of one or more symptoms of trichomoniasis occurs within about 48 hours after administration. In some embodiments, resolution of one or more symptoms of trichomoniasis or T. vaginalis infection occurs within about 7 to about 10 days, about 11 to about 20 days or about 21 to about 30 days after administration to the subject.
  • treatment of trichomoniasis or T. vaginalis infection with a single, 2-gram dose of secnidazole in a microgranule formulation results in better than expected efficacy compared with FDA-approved drugs used in the treatment of trichomoniasis or T. vaginalis infection.
  • a single dose of 2 grams of secnidazole results in a better than expected efficacy compared with FDA-approved drugs currently used in the treatment of trichomoniasis or T. vaginalis infection.
  • treatment of trichomoniasis or T is
  • vaginalis infection with a single, 2-gram dose of secnidazole results in superior efficacy compared with FDA-approved drugs used in the treatment of trichomoniasis or T. vaginalis infection.
  • a single dose of 2 grams of secnidazole results in superior efficacy compared with FDA drugs used in the treatment of trichomoniasis or T. vaginalis infection requiring a single dose during treatment.
  • treatment of trichomoniasis or T. vaginalis infection with a single, 2-gram dose of secnidazole results in a better than expected safety profile compared with FDA-approved drugs used in the treatment of trichomoniasis or T. vaginalis infection.
  • a single dose of 2 grams of secnidazole results in a better than expected safety profile compared with FDA-approved drugs used in the treatment of trichomoniasis or T. vaginalis infection requiring multiple doses during treatment.
  • treatment of trichomoniasis or T is a single dose of 2 grams of secnidazole results in a better than expected safety profile compared with FDA-approved drugs used in the treatment of trichomoniasis or T. vaginalis infection requiring multiple doses during treatment.
  • vaginalis infection with a single, 2-gram dose of secnidazole results in a superior safety profile compared with FDA-approved drugs used in the treatment of trichomoniasis or T. vaginalis infection.
  • a single dose of 2 grams of secnidazole results in a superior safety profile compared with FDA-approved drugs used in the treatment of trichomoniasis r or T. vaginalis infection requiring a single dose during treatment.
  • a method of treating trichomoniasis in a subject in need thereof comprising the steps of:
  • step (c) within 6 days to 12 days after step (b), evaluating the subject for a primary endpoint of microbiological cure.
  • the trichomoniasis diagnostic test includes, but not limited to, a nucleic acid amplification test; a DNA hybridization probe test (such as the BD AffirmTM VPIII Microbial Identification System from Becton Dickinson in Sparks, MD, USA); a multiplex PCR panel test (such as BD MAXTM CT/GC/TV Assay using the BD MAXTM System from Becton Dickinson in Sparks, MD, USA); an antigen-detection test (such as OSOM® Trichomonas Rapid Test from Sekisui Diagnostics in Framingham, MA, USA); a T.
  • a DNA hybridization probe test such as the BD AffirmTM VPIII Microbial Identification System from Becton Dickinson in Sparks, MD, USA
  • a multiplex PCR panel test such as BD MAXTM CT/GC/TV Assay using the BD MAXTM System from Becton Dickinson in Sparks, MD, USA
  • vaginalis culture a wet mount test; a trichomoniasis diagnostic test using broth culture technique (such as the InPouch® TV test from BioMed Diagnostics, Inc. in White City, OR, USA); or a combination thereof.
  • the trichomoniasis diagnostic test requires a vaginal sample, an endocervical sample, a urine sample, a vaginal swab, a urethral swab, a penile-meatal swab, or a combination thereof from the subject.
  • the primary endpoint of microbiological cure is a negative T.
  • the subject also has bacterial vaginosis, is HIV-positive, or a combination thereof.
  • the rate of the primary endpoint of microbiological cure is at least 0.5%, at least 2%, at least 10%, at least 50%, at least 90%, at least 92%, at least 95%, or 100%.
  • a method of treating trichomoniasis in a subject in need thereof comprising the steps of:
  • step (d) within 6 days to 12 days after step (c), evaluating the subject for a primary endpoint of microbiological cure
  • step (e) administering the opposite treatment of step (c) to the subject;
  • the method further comprises the step of, within 7 days to 12 days after step (e), assessing the subject with positive T. vaginalis culture obtained in step (d) for the primary endpoint of microbiological cure.
  • the primary endpoint of microbiological cure is a negative T. vaginalis culture.
  • the rate of primary endpoint of microbiological cure is higher in the single oral dose of SYM-1219 group than the placebo group.
  • the subject also has bacterial vaginosis, is HlV-positive, or a combination thereof.
  • the rate of the primary endpoint of microbiological cure is at least 0.5%, at least 2%, at least 10%, at least 50%, at least 90%, at least 92%, at least 95%, or 100%.
  • the method includes wherein the positive or negative T. vaginalis culture is determined by a trichomoniasis diagnostic test using broth culture technique (such as the InPouch® TV test).
  • a method of treating trichomoniasis in subjects in need thereof comprising the steps of:
  • step (c) evaluating each subject 6 days to 12 days after step (b) (which is Visit 2) for a primary endpoint of microbiological cure (which is a Test of Cure (“TOC”) at Visit 2);
  • TOC Test of Cure
  • step (e) discharging the subjects from treatment who have a negative T. vaginalis culture result obtained in step (c);
  • step (f) assessing the remaining subjects 7 days to 12 days after step (d) (which is Visit 3) for the primary endpoint of microbiological cure, wherein the remaining subjects had a positive T. vaginalis culture result obtained in step (c).
  • the primary endpoint of microbiological cure is a negative T. vaginalis culture. In some embodiments, the rate of primary endpoint of microbiological cure is higher in the single oral dose of SYM-1219 group than the placebo group. In some embodiments, the rate of primary endpoint of microbiological cure at step (c) is higher in the single oral dose of SYM-1219 group than the placebo group. In some embodiments, the subjects comprise subjects also having bacterial vaginosis, are HIV-positive or a combination thereof. In some embodiments, the subjects are in a modified intent-to-treat (“mITT”) population. In some embodiments, the rate of primary endpoint of microbiological cure in the mITT population at step (c) is higher in the single oral dose of SYM-1219 group than the placebo group.
  • mITT modified intent-to-treat
  • the mITT population includes all randomized patients who are culture positive for T. vaginalis and negative for other sexually transmitted infections.
  • the rate of primary endpoint of microbiological cure in the mITT population at step (c) is at least about 0.5%, about 2%, about 10%, about 50%, about 90%, about 92%, or about 95%.
  • the rate of primary endpoint of microbiological cure in the mITT population at step (c) is in the range of at least about 0.5% (or about 2%, or about 10%, or about 50%, or about 90%, or about 92%) to about 95%; at least about 0.5% to about 2%; at least about 0.5% (or about 2%) to about 10%; at least about 0.5% (or about 2%, or about 10%) to about 50%; at least about 0.5% (or about 2%, or about 10%, or about 50%) to about 90%; or at least about 0.5% (or about 2%, or about 10%, or about 50%, or about 90%) to about 92%.
  • the subjects comprise subjects are HIV-positive.
  • the rate of primary endpoint of microbiological cure in the mITT population at step (c) is at least about 0.5%, about 10%, about 50%, about 90%, or about 100%. In some embodiments, the rate of primary endpoint of microbiological cure in the mITT population at step (c) is in the range of at least about 0.5% (or about 10%, or about 50%, or about 90%) to about 100%; at least 0.5% to about 10%; or at least 0.5% (or about 10% or about 50%) to about 90%.
  • the sexual partner of the subject is a male or a female.
  • Blood was obtained for determination of SYM-1219 plasma concentrations at the following times: pre-dose (within 30 minutes of dosing), and then at 0.25 hour, 0.5 hour, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 18 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, 120 hours, 144 hours, and 168 hours post-dose.
  • Plasma concentrations of SYM-1219 were determined by using validated analytical procedures. The following plasma pharmacokinetic parameters were determined for secnidazole via noncompartmental analysis methods: Cmax, Tmax, area under the plasma concentration curve from time 0 to the last timepoint (“AUCo-t”), area under the plasma concentration curve from time 0 extrapolated to infinity (“AUCo-inf”), half-life (“ti/2”) and apparent terminal rate constant ( z ).
  • FIG. 1 Mean ( ⁇ SD) plasma concentrations of secnidazole by dose and time point are displayed graphically in Figure 1, which illustrates the mean ( ⁇ SD) SYM-1219 plasma concentration for the 1-gram dose and the 2-grams dose over time.
  • the time points plotted in Figure 1 correspond to the sample collection times described above, z.e., pre-dose (within 30 minutes of dosing), and then at 0.25 hour, 0.5 hour, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 18 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, 120 hours, 144 hours, and 168 hours post-dose.
  • Descriptive statistics and secnidazole plasma pharmacokinetic parameters by dose are provided in Table 2 below.
  • the FDA Guidance for Industry recommends that the sample collection should be spaced in such a way that the Cmax of the drug in the blood and terminal elimination rate constant ( z ) can be estimated accurately.
  • the time intervals for sample collection in the method described above are sufficiently spaced that the Cmax of SYM-1219 and U are estimated with reasonable accuracy.
  • Table 2 discloses the plasma pharmacokinetics of SYM-1219 (1 g or 2 g) administered according to methods described in this Example to fasted healthy female subjects.
  • Table 4 discloses the urine pharmacokinetics of SYM-1219 (1 g or 2 g) administered according to methods described in this Example to fasted healthy female subjects.
  • Figure 1 illustrates the mean (+SD) SYM-1219 plasma concentration (ug/mL) for the 1 g dose (circle markers) and the 2 g dose (triangle markers) over time.
  • the PK of SYM-1219 was consistent between individuals, as demonstrated by low coefficients of variation (“%CV”) estimates.
  • Mean maximum concentrations were 22.6 mcg/mL for the 1 g dose and 45.4 mcg/mL for the 2 g dose and were achieved by approximately 4 hrs. in both dose groups.
  • Exposure estimates (“AUCinf’) were 619 mcg*hr./mL for the 1 g dose and 1331 mcg*hr./mL for the 2 g dose.
  • the pharmacokinetics of SYM-1219 was dose proportional when comparing the 1 g and 2 g doses.
  • the intersubject variability was low ( ⁇ 20% CV) for Cmax and AUC.
  • Urinary excretion of unchanged SYM-1219 accounted for 13.6% (1 g dose) and 15.3% (2 g dose) of the administered dose.
  • the amount excreted into the urine increased in proportion to dose. Renal clearance was similar after 1 g and 2 g doses and the renal clearance is only a small percentage (Y.e., ⁇ 5%) of the glomerular filtration rate typically found in healthy subjects with normal renal function.
  • SYM-1219 was safe and well-tolerated. The most common adverse events were headache and nausea. All adverse events were mild and resolved without sequelae. There were no significant changes in vital signs, electrocardiogram (“ECG”) or laboratory parameters. Table 2: Plasma Pharmacokinetics of SYM-1219 After a Single Oral Dose Administered to Fasted Healthy Female Subjects (Part A)
  • Figure 3 illustrates the mean (+SD) EE2 plasma concentrations (pg/mL) over time when (1) EE2 was administered alone (circle markers) on Day 1 of Period 1; and (2) when 2 grams microgranule formulation SYM-1219 was administered on Day 1 of Period 2 and EE2 was administered on Day 2 of Period 2 (triangle markers) (Group B2).
  • Figure 4 illustrates the mean (+SD) net plasma levels (ng/mL) over time when (1) NET alone was administered on Day 1 of Period 1 (circle markers), and (2) NET followed by 2 grams microgranule formulation of SYM-1219 was administered on Day 1 of Period 2 (triangle markers) (Group Bl).
  • Figure 5 illustrates the mean (+SD) net plasma levels (ng/mL) over time when (1) NET alone was administered on Day 1 of Period 1 (circle markers), and (2) 2 grams microgranule formulation of SYM-1219 was administered on Day 1 of Period 2 and NET was administered on Day 2 of Period 2 (triangle markers) (Group B2).
  • Table 4 below is a summary of the NET plasma pharmacokinetic parameters for Group Bl where (1) EE2/NET was administered on Day 1 of Period 1, and (2) EE2/NET was administered followed by SYM-1219 on Day 1 of Period 2; and Group B2 where (1) EE2/NET were administered on Day 1 of Period 1, and (2) 2 grams microgranule formulation of SYM-1219 was administered followed by on Day 1 of Period 2 and EE2/NET was administered on Day 2 of Period 2.
  • Table 5 below is a summary of the percent of relative bioavailability for EE2 plasma pharmacokinetic parameters Cmax, AUCo-t, and AUCo-® for Group Bl where (1) EE2/NET was administered on Day 1 of Period 1, and (2) EE2/NET followed by 2 grams microgranule formulation of SYM-1219 was administered on Day 1 of Period 2; and Group B2 where (1) EE2/NET was administered on Day 1 of Period 1, and (2) 2 grams microgranule formulation of SYM-1219 was administered on Day 1 and EE2/NET was administered on Day 2 of Period 2.
  • Table 6 is a summary of the percent of relative bioavailability for NET plasma pharmacokinetic parameters Cmax, AUCo-t, and AUCo-® for Group Bl where (1) EE2/NET was administered on Day 1 of Period 1, and (2) EE2/NET followed by 2 grams microgranule formulation of SYM-1219 was administered on Day 1 of Period 2; and Group B2 where (1) EE2/NET was administered on Day 1 of Period 1, and (2) 2 grams microgranule formulation of SYM-1219 was administered on Day 1 and EE2/NET was administered on Day 2 of Period 2.
  • EE2 Cmax was reduced by 29% (90% CI 63.09, 80.05) for Group Bl; no change in EE2 AUC was seen.
  • EE2 PK was not altered for Group B2.
  • NET Cmax and AUC increased (13%) slightly for Group Bl.
  • NET Cmax increased by 16% for Group B2; no change was seen for NET AUC.
  • EE2/NET was administered 1 day after SYM-1219 administration, there was no effect (90% Cis within 80-125%) from SYM-1219 on EE2 Cmax, AUCo-t or AUCo-®.
  • NET Cmax, AUCo-t or AUCo-® were increased by 13-16% and the upper value of 90% Cis were just above 125% when SYM-1219 was administered immediately after EE2/NET administration.
  • EE2/NET was administered 1 day after SYM-1219 administration the NET Cmax, AUCo-t or AUCo-® were increased by 9-16%.
  • the NET upper value of the 90% CI for Cmax was 131% and there was no effect (90% Cis within 80-125%) from SYM-1219 on AUCo-t or AUCo-®.
  • SYM-1219 was safe and well-tolerated when taken alone or in combination with EE2/NET. The most common adverse events were headache and nausea. All adverse events were mild and resolved without sequelae. There were no significant changes in vital signs, ECG or laboratory parameters. Concomitant administration of SYM-1219 with EE2/NET is not expected to have an effect on contraceptive efficacy.
  • MLCs minimal lethal concentrations
  • Low-level resistance was defined as an aerobic MLC of 50 pg/ml to 100 pg/ml, moderate-level resistance as an aerobic MLC of 200 pg/ml, and high-level resistance as an aerobic MLC of >400 pg/ml.
  • the MLCs for metronidazole and secnidazole were analyzed using the Wilcoxon signed-rank test to evaluate the differences between treatments.
  • Each well of a 96-well plate was filled with 150 pL of T. vaginalis suspension in Diamond’s growth media (10 4 trichomonads). Samples were treated with secnidazole (0.2 pg/mL to 400 pg/mL), metronidazole (0.2 tg/mL to 400 tg/mL), CDC control 520 (susceptible), CDC control 252 (resistant), and clindamycin (a drug with no known efficacy against T. vaginalis, 0.03 pg/mL to 32 pg/mL) for 48 hours. Cultures were visually assessed for survival, defined by observation of motility, through a 100X inverted microscope. The MLC of each drug was defined as the lowest treatment concentration that resulted in no motility in all samples tested.
  • 1.6 pg/mL are maintained up to at least 96 hours postdose in men.
  • MLC minimal lethal concentration
  • NR not reported a _
  • the Modified Intent-To-Treat (“mITT”) population (131 patients) included all randomized patients who met all inclusion/exclusion criteria.
  • FDA Food and Drug Administration
  • a treatment-delay study design allows for a finding of superiority of the investigational drug compared to placebo at a time point early in therapy, after which patients randomized to treatment delay receive antibacterial drug treatment.
  • This study design principle was applied to the trichomoniasis indication, which allowed for a placebo comparison and rapid follow-up treatment for patients originally randomized to placebo.
  • Exclusion criteria for this study included: • Is pregnant, lactating, or planning to become pregnant during the study;
  • vaginal symptoms including symptomatic vulvovaginal candidiasis, chlamydia, gonorrhea, or an active genital herpes outbreak;
  • Eligible patients were randomized 1 : 1 to SYM-1219 (2 grams of secnidazole) or matching placebo (as recommended by the FDA). Randomization was stratified by site and clinical symptoms of trichomoniasis (present or absent). Patients were evaluated at a baseline Visit 1(“V1”) and 6-12 days later at Visit 2 (“V2”). The primary efficacy endpoint was microbiology cure by culture at V2 (test-of-cure; TOC).
  • vaginalis were asked to return to the clinic for Visit 3 (“V3”), 7-12 days post V2, for an additional assessment, including determination of need for additional therapy.
  • An additional Visit 4 (7-12 days post V3) was scheduled at the investigator’s discretion if a repeat T. vaginalis culture at V3 was positive. Assessments at Visits 3 and 4 were the same as at V2.
  • the primary endpoint in this clinical efficacy study was microbiological cure, defined as a negative T. vaginalis culture, at the TOC visit. To reduce the possibility of reinfection from unprotected sex after a patient is cured, the TOC visit was specifically selected during Day 6 to Day 12. As required by the FDA, the primary population for efficacy analysis was the modified intent-to-treat (“mITT”) population, defined as all randomized patients who had a positive T. vaginalis culture at baseline as well as a negative chlamydia and gonorrhea NAAT test.
  • mITT modified intent-to-treat
  • the secondary population for efficacy analysis was the Per-Protocol (“PP”) population, defined as patients in the mITT population who received study medication as randomized, had a TOC visit and had no major protocol violations.
  • PP Per-Protocol
  • the composition of the PP population was finalized and documented in a review of the data conducted prior to unblinding the study database.
  • the PP population was used for supportive efficacy analyses.
  • Intent-to-Treat (“ITT”) population included all randomized patients.
  • Safety analyses including the evaluation of adverse events, physical examinations, pelvic examinations, collection of vital signs (blood pressure, temperature, and pulse), and clinical laboratory assessments (serum chemistry, hematology, and urinalysis) was conducted at all study visits. Adverse event information was also collected on the phone call between study V2 and V3.
  • Microbiological Cure i.e., InPouchTM TV test negative for T. vaginalis
  • CSH Cochran-Mantel-Haesnzel
  • microbiological cure i.e., InPouchTM TV test negative for T. vaginalis
  • the predefined primary efficacy endpoint defined as microbiological cure (i.e., InPouchTM TV test negative for T. vaginalis) at the TOC visit (Day 6-12) in the mITT population (all randomized subjects who were culture positive for T. vaginalis and negative for gonorrhea and chlamydia at baseline), was about 92.2% (59/64) for SYM-1219 (2 grams of secnidazole) versus about 1.5% (1/67) for placebo (p ⁇ 0.001). See Table 8 below.
  • Table 8 Summary of Microbiological Cure at TOC Visit by Treatment in Modified Intent- To-Treat (“mITT”) Population
  • Table 9 Summary of Microbiological Cure at TOC Visit by Treatment in PP Population [218] As shown in Table 10 below, microbiological cure rates were analyzed in each of the two symptom strata (presence/absence of trichomoniasis symptoms at baseline).
  • the microbiological cure rate at the TOC visit was significantly higher in the SYM-1219 (2 grams of secnidazole) group as compared to the placebo group in both baseline clinical symptom strata [92.9% (52/56 patients) vs 0% (0/55 patients) with trichomoniasis symptoms and 87.5% (7/8 patients) vs 8.3% (1/12 patients) without trichomoniasis symptoms in the SYM-1219 (2 grams of secnidazole) group vs placebo group, respectively (p ⁇ 0.001)].
  • Table 10 Summary of Microbiological Cure at TOC Visit by Clinical Symptoms Strata and Treatment (mITT Population)
  • Table 11 Summary of Microbiological Cure at TOC Visit by Clinical Symptoms Strata and Treatment (PP Population)
  • Table 12 Summary of Microbiological Cure at TOC Visit in Patients with HIV or Bacterial Vaginosis (“BV”) - (mITT Population)
  • Table 13 below provides a summary of treatment-emergent adverse events (“TEAEs”) by treatment for this study.
  • Table 13 Summary of Treatment-Emergent Adverse Events by Treatment - (Safety Population)
  • SYM-1219 (2 grams of secnidazole) was evaluated in all 147 patients (74 SYM-1219 (2 grams of secnidazole); 73 placebo) in the safety population. As shown in Table 13 above, the SYM-1219 (2 grams of secnidazole) was well tolerated. Adverse events were lower in the SYM-1219 (2 grams of secnidazole) group compared to the placebo group. All adverse events were mild; none were severe. Only one patient in the SYM-1219 (2 grams of secnidazole) was discontinued due to adverse events (mild nausea and productive cough). The most frequent adverse events were vulvovaginal candidiasis and nausea (each 2.7%).
  • SYM-1219 (2 grams of secnidazole) was safe and had a significantly high microbiological cure, about 92%-95%, compared to placebo, and was effective in treating women with trichomoniasis, including those with HIV or bacterial vaginosis.
  • the analysis of the microbiological cure rate at the TOC visit demonstrated that the SYM-1219 (2 grams of secnidazole) group (59/64 patients; 92.19%) was superior to placebo (1/67 patients; 1.49%) (p ⁇ 0.001).
  • SYM-1219 (2 grams of secnidazole)’ s high microbiological cure rate for a single dose treatment is much higher than the 83.2% cure rate for single dose metronidazole for HIV-positive women with trichomoniasis. See Kissinger, et al., “A randomized treatment trial: single versus 7-day dose of metronidazole for the treatment of Trichomonas vaginalis among HIV-infected women,” J. Acquir. Immune Defic. Syndr., 55:565-71 (2010)).
  • Plasma concentrations were summarized by timepoint using descriptive statistics; noncompartmental PK parameters were not calculated.
  • Eligible subject were admitted to the clinical site on Day -1 and were discharged following a safety evaluation on Day 2; the in-house period was approximately 2 days. Randomization occurred after the assessments of Day -1 determined that subjects remained eligible for the study. All subject were asked to return on Day 7 +/2 days for a final study visit. The maximum study duration was approximately 4 weeks to 5 weeks (including the study screening period).
  • the study drug, SYM-1219 was administered in the fasted state (z.e., after an overnight fast of at least 10 hours).
  • Plasma secnidazole concentrations were determined by Celerion, Inc., using validated analytical procedures.
  • the PK analysis for each treatment group (Group A or Group B) consisted of descriptive statistics to assess the secnidazole concentration data as related to SYM 1219 treatment administration. The PK data for these subjects in this study are summarized by gender in Table 14 below.
  • Table 14 Summary of Secnidazole Plasma Concentration (
  • CV coefficient of variation
  • SD standard deviation
  • n or N number of subjects
  • SYM-1219 containing 4 grams of secnidazole was determined to be not tolerated if the subjects in the SYM-1219 group met the following criteria: 1) if > 2 out of 6 subjects experience emesis within 4 hours of dosing (approximately Tmax for secnidazole), 2) if > 2 out of 6 subjects experience the same adverse event (“AE”) that was considered severe in intensity and related to study medication, or 3) if any subject experienced a Serious AE that was considered related to study medication. If any of the above occurred, SYM-1219 containing 2 grams of secnidazole was used in the TQT study.
  • AE adverse event
  • SYM-1219 containing 6 grams of secnidazole was determined to be not tolerated if the subjects in the SYM-1219 group met the following criteria: 1) if > 2 out of 6 subjects experience emesis within 4 hours of dosing (approximately Tmax for secnidazole), 2) if > 2 out of 6 subjects experience the same AE that was considered severe in intensity and related to study medication, or 3) if any subject experienced a Serious AE that was considered related to study medication. If any of the above occurred, SYM-1219 containing 4 grams of secnidazole was used in the TQT study.
  • Plasma concentrations increased from 4 grams to 6 grams of secnidazole and were essentially dose-proportional. The variability in plasma concentrations was approximately 4% to 29% across the limited sampling times in this study. The observed secnidazole plasma concentrations and exposures in males appeared to be slightly lower than those observed in females.
  • TQT study was also conducted.
  • the TQT study was a double-blind, randomized, placebo-controlled, 4-period, single-dose, crossover design in 52 healthy male and female subjects.
  • the primary objective of this study was to demonstrate that SYM-1219 containing 2 grams of secnidazole did not have an effect on the QTc interval exceeding > 10 ms compared to placebo.
  • Subjects were randomized to a treatment sequence that included all four of the following treatments, separated by a washout period:
  • Treatment A SYM-1219 oral microgranules containing 2 grams of secnidazole (therapeutic dose)
  • Treatment B SYM-1219 oral microgranules containing 6 grams of secnidazole (supratherapeutic dose)
  • Treatment C Placebo, matching SYM-1219, oral microgranules
  • Treatment D Moxifloxacin, 400 mg, oral
  • CV coefficient of variation
  • SD standard deviation
  • n or N number of subjects
  • SYM-1219 did not have a clinically meaningful effect on cardiac conduction (z.e., the PR and QRS intervals). SYM-1219 did not have a clinically relevant effect on heart rate or cardiac conduction (PR and QRS intervals). Both the QTc analysis and PK/QTc analysis demonstrate that SYM-1219 does not have aclinically relevant effect on the QTc interval and correspond to a negative TQT study, as defined by the ICH E14 guidance. There were no clinically meaningful trends noted in vital sign measurements or safety electrocardiogram data.
  • the overall incidence rate of TEAEs was higher after administration of SYM-1219 (24.0% and 20.0% for 6 grams and 2 grams treatments, respectively) compared to the controls (8.3% and 4.3% for the placebo and Moxifloxacin treatments, respectively).
  • Table 16 Overview of Plasma PK Data of SYM 1219 After a Single Oral Dose Administered to Fasted Healthy Males and Females
  • the methods and uses described herein also involve a pharmaceutical composition comprising a plurality of microgranules containing secnidazole as shown in Table 17 below.
  • the experimental microgranule composition described in Table 17 allow for increased drug loading (70%) versus drug loading a conventional secnidazole-coated sugar sphere formulation (about 49%) described in Table 18 below.
  • a therapeutic dose of a nitroimidazole compound for example, 2 grams of secnidazole
  • a composition with a substantially reduced mass about 3,315 mg
  • the mass of a secnidazole-coated sugar sphere formulation about 4,600 mg
  • a 2-gram dose as in Table 17 can be incorporated into a 4 size “00” capsule compared with 6 size “00” capsules for the secnidazole-coated sugar sphere formulation of Table 18.
  • drug loading of the microgranules may exceed 70%, such as, for example, 90% drug loading in which case, a 2-gram dose of secnidazole may be incorporated into about 4 size “0EL” capsules.
  • the pharmaceutical compositions described herein comprise the secnidazole microgranules may exhibit a similar PK profile as a secnidazole-coated sugar sphere formulated as shown in Table 18 below.
  • Specific modes of administration of the pharmaceutical compositions described herein depends on the indication.
  • the selection of the specific route of administration and the dose regimen may be adjusted or titrated by the clinician according to methods known to the clinician to obtain the optimal clinical response.
  • the amount of nitroimidazole compound, such as secnidazole may be that amount that is therapeutically effective.
  • the dosage to be administered may depend on the characteristics of the subject being treated, e.g., the particular animal or human subject treated, age, weight, body mass index, body surface area, health, types of concurrent treatment, if any, and frequency of treatments, and can be determined by one of skill in the art (e.g., by the clinician).
  • the therapeutically effective amount of a nitroimidazole compound may be administered in a pharmaceutical composition.
  • a pharmaceutical composition may be used in any of the methods or dosage regimens described herein.
  • administering a therapeutically effective amount of a nitroimidazole compound may include administering a nitroimidazole compound or a pharmaceutically acceptable salt thereof in a controlled release form.
  • the coating described herein may delay disintegration and absorption in the gastrointestinal tract and thereby providing a controlled and/or sustained action over a longer period than an immediate release composition. Additionally, such coatings may be adapted for release of a nitroimidazole compound in a predetermined pattern (e.g., in order to achieve a controlled release composition) or it may be adapted not to release the active compound until after passage of the stomach (enteric coating).
  • Suitable coatings encompassed by such embodiments may include, but not limited to, sugar coating, film coating (e.g., hydroxypropyl methylcellulose, methylcellulose, methyl hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose, acrylate copolymers, polyethylene glycols and/or polyvinylpyrrolidone), or an enteric coating (e.g., methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, shellac, and/or ethyl cellulose).
  • film coating e.g., hydroxypropyl methylcellulose, methylcellulose, methyl hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose, acrylate copolymers, polyethylene glycols and/or polyvinylpyrrolidone
  • enteric coating e.
  • a time delay material such as, for example, glyceryl monostearate or glyceryl distearate may be incorporated into the coatings of some embodiments.
  • the coating may be adapted to protect the composition from unwanted chemical changes, for example, to reduce chemical degradation prior to the release of the active drug substance.
  • the active ingredients may be contained in such compositions with pharmaceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water-soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives and the like.
  • pharmaceutically acceptable diluents fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water-soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives and the like.
  • the means and methods for administration are known in the art and an artisan can refer to various pharmacologic references for guidance. For example, Modem Pharmaceutics, G.S. Banker & C.T. Rhodes, 4 th Edition, CRC Press (2002); Goodman & Gilman's The Pharmaceutical Basis of Therapeutics, L.L. Brunton, R.
  • Blending and Curing The coated spheres are blended with talc in a V- blender and cured in a tray dryer at 40° C. for 24 hours.
  • Table 19 Experimental High Drug Loading Core Specification and Characteristics
  • any of the terms “comprising,” “consisting essentially of,” and “consisting of’ may be replaced with either of the other two terms in the specification.
  • the methods and processes illustratively described herein suitably may be practiced in differing orders of steps, and that they are not necessarily restricted to the orders of steps indicated herein or in the claims.
  • the patent Under no circumstances may the patent be interpreted to be limited to the specific examples or embodiments or methods specifically disclosed herein. Under no circumstances may the patent be interpreted to be limited by any statement made by any Examiner or any other official or employee of the Patent and Trademark Office unless such statement is specifically and without qualification or reservation expressly adopted in a responsive writing by Applicant.
  • titles, headings, or the like are provided to enhance the reader’s comprehension of this document, and should not be read as limiting the scope of the invention. Any examples of aspects, embodiments or components of the invention referred to herein are to be considered non-limiting.

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Abstract

L'invention concerne un procédé de traitement ou de prévention d'une infection par trichomonase ou T. vaginalis chez un sujet en ayant besoin, le procédé comprenant l'administration au sujet d'une quantité thérapeutiquement efficace de secnidazole ou d'un sel pharmaceutiquement acceptable dans une formulation de microgranules, la formulation de microgranules comprenant une pluralité de microgranules. Le sujet peut également avoir souffrir de vaginose bactérienne, est positif au VIH, et/ou est atteint de trichomonase résistante au métronidazole et/ou de trichomonase résistante au tinidazole. Le sujet peut également être un partenaire sexuel d'une personne atteinte de trichomonase. La formulation de microgranules peut également être administrée avec de la paromomycine, du tinidazole, du métronidazole, de l'acide borique ou une combinaison de ceux-ci. L'invention concerne également des compositions pharmaceutiques et des utilisations pour le traitement ou la prévention de la trichomonase ou de l'infection par T. vaginalis chez un sujet en ayant besoin.
PCT/US2020/052032 2020-09-22 2020-09-22 Procédé et composition pharmaceutique pour le traitement ou la prévention de la trichomonase et leurs utilisations WO2022066146A1 (fr)

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Citations (4)

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US20160346252A1 (en) * 2015-06-01 2016-12-01 Symbiomix Therapeutics, Llc Novel nitroimidazole formulations and uses thereof
US20190008784A1 (en) * 2017-07-07 2019-01-10 Symbiomix Therapeutics, Llc Novel secnidazole soft gelatin capsule formulations and uses thereof
US20200071279A1 (en) * 2018-09-05 2020-03-05 Lupin Inc. Deuterated secnidazole for use in the treatment of bacterial vaginosis and methods and uses thereof
US20200206192A1 (en) * 2014-09-05 2020-07-02 Lupin Inc. Secnidazole for use in the treatment of bacterial vaginosis

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Publication number Priority date Publication date Assignee Title
US20200206192A1 (en) * 2014-09-05 2020-07-02 Lupin Inc. Secnidazole for use in the treatment of bacterial vaginosis
US20200289470A1 (en) * 2014-09-05 2020-09-17 Lupin Inc. Secnidazole for use in the treatment of trichomoniasis
US20160346252A1 (en) * 2015-06-01 2016-12-01 Symbiomix Therapeutics, Llc Novel nitroimidazole formulations and uses thereof
US20190008784A1 (en) * 2017-07-07 2019-01-10 Symbiomix Therapeutics, Llc Novel secnidazole soft gelatin capsule formulations and uses thereof
US20200071279A1 (en) * 2018-09-05 2020-03-05 Lupin Inc. Deuterated secnidazole for use in the treatment of bacterial vaginosis and methods and uses thereof

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