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WO2025147262A1 - Système de dispositif et utilisation pour une infection par hpv et une néoplasie intraépithéliale cervicale - Google Patents

Système de dispositif et utilisation pour une infection par hpv et une néoplasie intraépithéliale cervicale Download PDF

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Publication number
WO2025147262A1
WO2025147262A1 PCT/US2024/010538 US2024010538W WO2025147262A1 WO 2025147262 A1 WO2025147262 A1 WO 2025147262A1 US 2024010538 W US2024010538 W US 2024010538W WO 2025147262 A1 WO2025147262 A1 WO 2025147262A1
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Prior art keywords
compound
retaining device
certain embodiments
vaginal
administered
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PCT/US2024/010538
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Inventor
Oranee DANIELS
Elaine Y. CHIEN
Catherine Marie BEHRENS
Ramakrishna GADIRAJU
Barry Aldous
Sarah Walter
Gail MADERIS
Ankush Argade
Ravichandran Mahalingam
Zhengle ZHAO
Zhaoyang QIN
Siyi Jiang
Runyan LI
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Antiva Biosciences Inc
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Antiva Biosciences Inc
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Priority to PCT/US2024/010538 priority Critical patent/WO2025147262A1/fr
Priority to PCT/US2025/010220 priority patent/WO2025147598A1/fr
Publication of WO2025147262A1 publication Critical patent/WO2025147262A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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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
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/664—Amides of phosphorus acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • 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
    • A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds

Definitions

  • HPV Papillomaviruses are a group of non-enveloped DNA viruses, which in humans infect keratinocytes of skin and mucous membranes including in the cervical area. HPV infections can cause cellular transformations in the human patient that have not yet progressed to cancer but have reached the stage of neoplasia.
  • HPV-induced neoplasia forms include cervical intraepithelial neoplasia (“CIN”), anal intraepithelial neoplasia (“AIN”), perianal intraepithelial neoplasia (“PAIN”), vulvar intraepithelial neoplasia (“VIN”), penile intraepithelial neoplasia (“PIN”) and vaginal intraepithelial neoplasia (“VAIN”).
  • Cancers caused by HPV include cervical, anal, perianal, penile, vaginal, vulvar, and oropharyngeal cancer. Thus, HPV can cause viral infection, neoplasia and cancer.
  • HPV and cervical intraepithelial neoplasia are adjunctive only.
  • Commonly used drug therapies include trichloroacetic acid, 5-fluorouracil, imiquimod and podofilox.
  • Imiquimod (Aldara TM , Zyclara TM ) stimulates the immune system to clear the infection through toll-like receptor signaling and causes redness and swelling.
  • Podofilox (Condylox TM ) destroys tissues by destabilizing microtubules which prevents host cell replication.
  • the cervical epithelium is composed of several layers of tissue and is referred to as stratified squamous epithelium. The layers are the superficial cell layer, the intermediate cell layer, the parabasal cell layer and the basal cell layer.
  • Cervical intraepithelial neoplasia is most often treated by observation (the wait and see approach) or by excision or ablation of the cervical transformation zone.
  • Techniques include cryotherapy, laser therapy, loop electrosurgical procedure (LEEP) and cone biopsy. All of these surgical procedures damage the affected areas and can lead to scarring.
  • LEEP loop electrosurgical procedure
  • Cervical high-grade squamous intraepithelial lesions (cHSIL), sometimes referred to as CIN2 and CIN3, is a disease caused by the abnormal hyperproliferation (dysplasia) of squamous cells in the cervical epithelium (Waxman, A. G., et. al 2012. “Revised terminology for cervical histopathology and its implications for management of high-grade squamous intraepithelial lesions of the cervix”. Obstet Gynecol, 120, 1465-71).
  • Hyperproliferation usually occurs where the simple columnar, endometrial-type epithelium of the endocervix transitions to the stratified squamous epithelium of the ectocervix; this region is referred to as the “transformation zone” (Sellors, J. W. & Sankaranarayanan, R. 2003. An introduction to the anatomy of the uterine cervix. Colposcopy and Treatment of Cervical Intraepithelial Neoplasia: A Beginners' Manual). Cervical HSIL is classified as a pre-cancerous condition because apoptosis is impaired in these hyperproliferating cells, which can lead to the accumulation of genetic alterations that transform the cells into cancer.
  • Artesunate is an artemisinin derivative with cytotoxic activity. Artesunate is a known WHO-approved anti-malarial agent. The cytotoxic agent is delivered in the trial at a dosage, for example, of 50 to 200 mg for a 5-day cycle on weeks 0, 2 and 4. The artesunate vaginal inserts are self-administered at bedtime with a vaginal applicator, followed by use of a tampon, which is removed in the morning. Artesunate has a cytotoxic effect but is not an anti-viral agent, so does not directly stop the HPV replication.
  • artesunate cannot be used to treat patients who have an HPV infection that has not progressed to cervical intraepithelial neoplasia. Also, artesunate does have some systemic exposure under these conditions. See generally Trimble, et al., “A first- in-human proof-of-concept trial of intravaginal artesunate to treat cervical intraepithelial neoplasia 2/3 (CIN 2/3)”, Gynecologic Oncology 157 (2020)188-194 as well as U.S. Patents 6,586,464; 8,394,849; 8,940,787 and 7,989,491.
  • Cidofovir a pyrimidine based acyclic phosphonate nucleoside, which has broad spectrum activity against DNA viruses, is recognized as one of the effective treatments for HPV lesions that have not become cancerous. It is a DNA terminator and causes cell death via apoptosis of HPV transformed cells and regression of HPV-induced tumors. Cidofovir has been tested as a topical treatment of CIN2 and CIN3. See Van Pachterbeke, et al., “Topical treatment of CIN 2+ by cidofovir: Results of a phase II, double-blind, prospective, placebo-controlled study”, Gynecologic Oncology 115 (2009) 69-74.
  • Snoeck, et al “Cidofovir, a New Approach for the Treatment of Cervix Intraepithelial Neoplasia Grade III (CIN III)” Journal of Medical Virology 60:205-209 (2000).
  • Snoeck, et al. except for two patients, patients had at least partial responses and half had a total response. In the partial responses, the transformed cells persisted in the deep tissues that can lead to neoplasia. Therefore, because of imperfect bioavailability, modifications were needed. The clinical trial thus had mixed results and was not progressed through completed clinical trials to an approved product.
  • Patent Nos.10,702,532; 10,213,430; 9,493,493; and 9,801,884, with a priority date of September 15, 2014 PCT/US2015/050202; published as WO 2016/044281
  • U.S. Patent No. 11,014,950 and 10,377,782 with a priority date of September 15, 2015.
  • the drug must be lipophilic enough to pass through the tissue layers and be metabolized if necessary to the active agent in a sufficient concentration to kill the pathogenic cells. It is an object of the present invention to provide an improved method for the treatment of cervical or vaginal HPV infection and related conditions such as HPV-induced cervical or vaginal intraepithelial neoplasia in a female in need thereof, that is effective against the infection or related conditions and also minimize toxicity to nearby tissues and cells.
  • the use of a retaining device is advantageous to minimize potential adverse effects on surrounding tissue that can be uncomfortable or even painful for the patient and possibly damaging to normal tissue.
  • the invention includes a device system and therapeutic use to effectively treat HPV cervical or vaginal HPV infection or cervical or vaginal intraepithelial neoplasia.
  • a particularly advantageous treatment for cervical or vaginal HPV infection or cervical or vaginal intraepithelial neoplasia is achieved by the administration of an effective amount of the PMEG prodrug Compound I or a pharmaceutically acceptable salt thereof such as the monofumarate or hemifumarate salt, or other solid form including in particular Compound II or Compound III, by steps comprising (i) administering an effective amount of the anti-HPV therapeutic agent Compound I (or a pharmaceutically acceptable salt thereof) or Compound II or III, typically in solid tablet form (although semi-solid formulations may also be acceptable), to the cervix using a vaginal applicator and then (ii) inserting a retaining device that is maintained at the base of the cervix or in the vaginal canal for sufficient time to collect the post-treatment leakage of vaginal fluids which may contain, for example, remaining therapeutic agent or its metabolite such as PMEG, in a manner that minimizes toxicity-causing damage to non
  • the lubricant can be coated on the retaining device for ease of placement as well as to help maintain the device in position.
  • a pharmaceutical salt of Compound I below sometimes referred to as “ABI-2280”
  • PMEG a prodrug of PMEG
  • HPV human papillomavirus
  • HSIL high-grade squamous intraepithelial lesions
  • hrHPV high-risk HPV
  • Compound I is an acyclic nucleotide phosphonate that metabolizes to a known potent antiviral compound (PMEG; ((9-[2-phosphonomethyoxy)ethyl)guanine])), but PMEG has poor cellular permeability and use- limiting systemic toxicity. Applicant has discovered how to improve the prodrug to be delivered topically in a manner that it is rapidly taken up into epithelial cells, a challenging task to date and one that ABI-1968 failed.
  • PMEG potent antiviral compound
  • the female patient optionally coats the vagina with a lubricant and then inserts a vaginal tablet into the base of the cervical area with a vaginal applicator (optionally that has been coated with a lubricant), and then removes the vaginal applicator.
  • the female then inserts the retaining device (also which has been optionally coated with a lubricant) and leaves it in place for at least 4-12 hours, such as 6-10 hours or 5-8 hours and typically at least 6 hours. It is advantageous to insert the vaginal tablet and then place the retaining device in the evening and leave it in overnight, for at least 5 or 6 hours or more.
  • retaining device In the morning, the retaining device is removed and cleaned for the next use if reusable, or disposed of if not.
  • the topical medication is allowed to penetrate into the intraepithelial tissue while the patient is in a supine position with little movement, and the retaining device protects surrounding healthy tissue from the PMEG prodrug toxicity.
  • retaining devices are those that are conventionally used for period protection or those normally used for birth control.
  • Nonlimiting examples of retaining devices normally used for period protection are: a menstrual cup, a menstrual disc, and a tampon. These devices are commercially available without a prescription.
  • a menstrual cup is a cup that is placed in the vagina below the cervix that stays in place and normally holds blood flow.
  • menstrual cups are commercially available with different shapes and sizes, and are typically bell-shaped, V-shaped, round or asymmetrical.
  • a menstrual cup is typically made from medical grade silicone or latex rubber. Menstrual cups can typically be used for up to 8 to 12 hours, which is well within the time needed for the Compound I, II, or III or PMEG fluid retainment. It should be thoroughly cleaned between uses, with an antibiotic soap or in boiling water.
  • Some menstrual cups have a tapered shape that can make insertion and removal easy.
  • Nonlimiting examples of current commercially available products include FlexTM, CoraTM, SaaltTM, LenaTM, LummaTM, TampaxTM, ShordyTM and DivaTM.
  • a menstrual disc is a product that is worn inside the vaginal canal that is flat and disc- shaped. It is placed differently in the vaginal canal than a menstrual cup. It is designed to fit at the base of the cervix, where it creates a seal to prevent leaks.
  • the menstrual disc comes is a range of sizes, shapes and materials to fit the comfort of the patient.
  • Menstrual cups sit lower in the vaginal canal than menstrual discs and are usually designed to create a suction.
  • Nonlimiting examples of current commercially available menstrual disc products include, but are not limited to, those made by nixitTM, CoraTM, SaaltTM, LenaTM, LummaTM, ShordyTM and DivaTM.
  • a tampon is a well-known device that is a pocket-sized absorbent material that can optionally have a cardboard or plastic applicator that is inserted into the body normally to collect period fluid. It is normally removed every few hours up to once a day, for example every 4-6 hours. It is sold in many different varieties by many different vendors.
  • Non-limiting birth control devices include, but are not limited to a diaphragm, a cervical cap, and a sponge. The diaphragm and cervical cap devices often need a doctor’s prescription as part of gynecological healthcare for birth control, while sponges do not.
  • a diaphragm is a shallow bendable cup that is placed in the vagina typically as a means for contraception.
  • the separate vaginal applicator and diaphragm can be combined into one device by including a contoured surface in the diaphragm that the vaginal tablet can be placed in.
  • a cervical cap is smaller than a diaphragm and can be left in place longer. It covers the cervix and should be covered with a spermicide.
  • a nonlimiting example of a current commercially available cervical cap product is the FemcapTM.
  • Sponges can also be used according to this invention. They are typically made of polyurethane or natural sea sponges. It is soft, spongy and usually round. It is placed against the cervix and typically contains applied spermicide (when used as a birth control device but not in the present invention). Often it has a loop attached for easy displacement and removal.
  • Nonlimiting examples of products include, but are not limited to, those made by Safe-TTM and Today SpongeTM.
  • a female diagnosed with HPV or cervical or vaginal squamous intraepithelial lesions is treated with a PMEG prodrug, for example, ABI-2280 vaginal tablet in a dose strength of 0.1 mg to 1 mg, for example 0.1, 0.2, 0.3, 0.4 or 0.5 mg, once daily on a schedule of 2, 3 or 4 times a week optionally for 1, 2, 3, 4, 5 or 6 weeks with the use of a retaining device to adequately protect surrounding tissue.
  • the dose strengths in mg used herein refer to the weight of the active acyclic phosphonamidate and do not include the salt in the molecular weight, and thus the total weight in the dosage form.
  • Compound I (or a pharmaceutically acceptable salt thereof), Compound II or Compound III is therefore expected to eliminate HPV infection in productively infected cells typical of low-grade lesions and to induce apoptosis in advanced lesions, which often have integrated HPV genomes and express elevated levels of HPV oncoproteins.
  • Compound I ethyl (((2-(2-amino-6-methoxy-9H-purin-9-yl)ethoxy)methyl)- (benzyloxy)phosphoryl)-L-alaninate) has two chiral centers, one at the phosphorus atom and one in the amino acid moiety, either of which can be in the R or S stereoconfiguration.
  • Compound I exists as four stereoisomers, or two diastereomeric pairs: (R P , S C )/(S P , S C ) and (R P , RC)/(SP, RC). While U.S. Patent Nos. 9,801,884 and 11,344,555 describe Compound I generally, the patents do not address the potential stereochemistry of the phosphorus atom. It has been discovered that the stereoisomer of Compound I with R-stereochemistry at the phosphorus and S- stereochemistry at the amino acid carbon has advantageous properties over the other three stereoisomers.
  • the advantageous salt (for example fumarate) of Compound I is used as a mixture of (R,S) and (S,S) diastereomers, wherein the first R/S designates the stereochemistry at the phosphorus atom and the second S is the stereochemistry of the carbon in the amino acid moiety (corresponding to the L-alanine residue having S-configuration). While any ratio of the diastereomers can be used that provides the desired results, the (R,S) diastereomer stands out. In other embodiments, the ratio is approximately 1:1 of the R to S enantiomer at the phosphorus atom.
  • the compound is used with R- stereoconfiguration at the chiral carbon and wherein the R-stereoconfiguration is greater than about 50%, or equal to or greater than about 60%, 70%, 75%, 80%, or even 85% or more.
  • a pharmaceutically acceptable salt of the enantiomerically pure (Rp,Sc, or simply “R,S”) version of Compound I is a principal embodiment in the disclosed therapeutic use device therapy as disclosed herein.
  • An enantiomerically pure Compound II is at least 90% free of the opposite enantiomer.
  • the free base parent compound is an oil, not a solid, and thus would not have been selected as the active ingredient for the topical formulation.
  • Compound II exhibits superior stability properties over its stereoisomer, ethyl ((S)-((2-(2-amino-6-methoxy-9H- purin-9-yl)ethoxy)methyl)(benzyloxy) phosphoryl)-L-alaninate monofumarate (Compound III). This is important for the success of the topical application to the cervix or vagina.
  • the formulation of the dosage form is very important for adequate administration of the active agent into the intraepithelial tissue.
  • Tablet formulation should display the properties of mucoadhesion and substantivity and include excipients that have solubilizing, erosion-generating (for disintegration), porosity (for water uptake) and viscosity enhancing (to keep the drug at the target site) properties.
  • excipients that will cause rapid disintegration of a solid dosage form to cover the cervix or vaginal areas include, but are not limited to mannitol, microcrystalline cellulose, lactose, sucrose, calcium phosphate, sodium phosphate, sodium bicarbonate, citric acid, maleic acid, adipic acid or fumaric acid.
  • excipients that can enhance disintegration and coverage of the affected area include but are not limited to sodium starch glycollate, pregelatinized starch, crospovidone and croscarmellose sodium.
  • Mucoadhesive excipients that are useful in the present invention include but are not limited to microcrystalline cellulose, polycarbophil, hydroxymethyl cellulose, hypromellose, hydroxypropyl cellulose, and PVP.
  • a nonlimiting example of a tablet formulation includes, but is not limited to, microcrystalline cellulose, crospovidone, magnesium stearate, silicon dioxide, polyethylene oxide and mannitol.
  • Another non-limiting example of a tablet formulation has microcrystalline cellulose, magnesium stearate and mannitol.
  • Semi solid dosage forms may include, for example, a mucoadhesive polymer, a solubility/penetration enhancer, a lipophilic solubilizer and a penetration enhancer.
  • the mucoadhesive polymer for example, may be, but is not limited to, a carbomer, polyethylene glycol, crospovidone, hypromellose, polycarbophil and/or hydroxyethyl cellulose.
  • the solubility/penetration enhancer can be, for example, but not limited to, a mixture of polyoxyl 6 stearate Type I, ethylene glycol stearate and polyoxy 32 stearate Type I, cetyl alcohol, stearyl alcohol, polysorbate 80, sodium lauryl sulphate, mono and di-glycerides, sorbitan monostearate, glyceryl isostearate, polyoxy 15 hydroxystearate, poly15 hydroxystearate, polyoxy 40 hydrogenated castor oil, octyl dodecanol, and/or soybean lecithin.
  • Lipophilic solubilizers include, but are not limited to light mineral oil, mineral oil, white wax and silicone fluid.
  • Penetration enhancers include but are not limited to propylene glycol, transcutol, oleic acid, isopropyl myristate, propylene glycol glycerol monooleate, propylene glycol monocaprylate, PEG-8 Bees wax, cetyl alcohol, stearic acid, cetyl palmitate and/or cetostearyl alcohol.
  • a non-limiting example of a semi-solid formulation includes, for example, one or more of a carbomer, propylene glycol, sorbic acid, EDTA and water.
  • a semi solid formulation includes one or more of a carbomer, mineral oil, a mixture of polyoxy 6 stearate Type I, ethylene glycol stearate, polyoxy 32 stearate Type I, parabens, propylene glycol, EDTA and/or water.
  • Films can be produced, for example, with, but not limited to, hypromellose, polyethylene glycol, polymethacrylates, microcrystalline cellulose, xanthan gum, guar gum and/or polyvinylpyrrolidone.
  • a pessary (vaginal suppository) can be formulated with, for example but not limited to, hard fat (such as Ovucire, Witepsol, Supposi-Base), polyethylene glycol, macrogols, cocoa butter and glycerol.
  • hard fat such as Ovucire, Witepsol, Supposi-Base
  • polyethylene glycol such as polyethylene glycol
  • macrogols such as polyethylene glycol
  • cocoa butter and glycerol glycerol
  • a non-limiting example of a pessary can be made from Witepsol H 15 or Ovucire WL 3264.
  • the present invention includes at least the following features: (i) A method to treat a cervical or vaginal HPV-induced infection or an associated condition in a female in need thereof, including but not limited to cervical or vaginal intraepithelial neoplasia, comprising administering to a host in need thereof an effective amount of Compound I or a pharmaceutically acceptable salt thereof such as the monofumarate or hemifumarate, or other solid form, or Compound II or Compound III, in a pharmaceutical composition, in a vaginal tablet or semisolid formulation with a vaginal applicator in combination with the use of a retaining device for sufficient time to collect the post-treatment leakage of vaginal fluids and the therapeutic agent or its metabolite such as PMEG in a manner that minimizes toxicity-causing damage to non- diseased tissue.
  • a method to treat a cervical or vaginal HPV-induced infection, intraepithelial neoplasia, or an associated condition in a human in need thereof comprising (i) administering an effective amount of the anti-HPV therapeutic agent Compound I or a pharmaceutically acceptable salt thereof, such as the monofumarate or hemifumarate, or other solid form or Compound II or Compound III typically in tablet form, to the cervix using a vaginal applicator (which is optionally coated with a lubricant) and then (ii) inserting a retaining device (which is optionally coated with a lubricant) that is maintained at the base of the cervix or in the vaginal canal for sufficient time to collect the post-treatment leakage of vaginal fluids and the therapeutic agent or its metabolite such as PMEG in a manner that minimizes toxicity-causing damage to non-diseased tissue.
  • a vaginal applicator which is optionally coated with a lubricant
  • (xii) The method of (i)- (xi) that provides a dosage form containing of from 0.1 mg to 30 mg, from 0.05 to 0.3 mg, from 0.5 mg to 20 mg, from 1 mg to 20 mg, from 1 mg to 15 mg, from 1 mg to 10 mg of a compound of embodiments (i)-(v) and in certain embodiments about or at least 0.03, 0.05, 0.1 mg, 0.3 mg.0.5 mg, 0.7 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45mg or 50 mg of the active agent.
  • (xiii) The method of (i)-(xi) that provides a dosage form containing from about 0.05 mg to about 1.0 mg, such as 0.1 to 0.5 mg, for example 0.2, 0.3 or 0.4 mg of a compound of embodiments (i)-(v).
  • (xiv) The method of (i)-(xiii) wherein the retaining device is held in place for between 4- 12 hours, 5-10 hours or 6-9 hours and then removed.
  • (xv) The method of (i)-(xiv) wherein the topical formulation with retaining device is administered once a day for one, two, three or four days a week for as long as necessary to achieve the desired results.
  • kits that includes a dosage form with a therapeutic compound as described herein and a retaining device.
  • the kit of (xxiv) that also includes a vaginal applicator.
  • the kit of (xxiv) wherein the retaining device is selected from a menstrual cup, a menstrual disc, a tampon, diaphragm, cervical cap and a sponge.
  • the retaining device is used as both the vaginal applicator and a retaining means.
  • FIG.1A and FIG 1B depict the molecular structure of Compound I monofumarate pattern 1 as determined by the single crystal X-ray diffraction analysis of Example 21. There exists an intermolecular interaction between protonated N5-atom of free base and O7-atom of fumaric acid anion (N(5)–H(5) ⁇ O(7)) in the single-crystal form of Compound II.
  • FIG.2 is an in vitro tissue permeation test in vaginal tissue comparing ABI-2280 fumarate salt to ABI-1968. Bar A shows the tissue penetration of a 0.1% ABI-2280 gel in porcine vaginal tissue. Bars B and C show the tissue penetration of a 0.1% ABI-2280 gel in human cervical tissue.
  • Bar D shows the tissue penetration of a 1% formulation of ABI-1968 in 6% NMP into porcine vaginal tissue.
  • Bar E shows the tissue penetration of a 1% nanosuspension of ABI-1968 in porcine vaginal tissue.
  • Bar F shows the tissue penetration of a 3% formulation of ABI-1968 in 6% NMP into porcine vaginal tissue.
  • Bar G shows the tissue penetration of a 3% formulation of ABI-1968 in 20% NMP into porcine vaginal tissue.
  • ABI-1968 penetrates the tissue to a substantially smaller degree, which hinders the ability of the compound to reach the cells which are infected with HPV. This may be a contributing factor to the performance of ABI-1968 in clinical studies.
  • FIG. 3 shows a flow diagram for the process of preparing a topical cream formulation described in Example 6.
  • FIG. 4 shows a flow diagram for the process of preparing a topical gel formulation described in Example 6.
  • FIG. 5 shows a flow diagram for the process of preparing a tablet formulation described in Example 7.
  • FIG.6 is a bar graph comparing the tissue penetration of a topical gel and a topical tablet dosage form as described in Example 15. The tablet dosage form produces similar tissue penetration to the topical gel, with an average of 58 ng/mg of compound in the tissue.
  • FIG.8 depicts the structure of Compound I monofumarate.
  • the synthesis of Compound I and stereoisomers and pharmaceutically acceptable salts thereof is provided in Examples 1-5.
  • FIG. 9 is a comparison of XRPD diffractograms of Compound I hemifumarate Pattern 1 and Compound I monofumarate Pattern 1 (small scale preparation) obtained in Example 23.
  • FIG.10 is a DSC thermogram of Compound I hemifumarate Pattern 1 obtained in Example 23.
  • FIG.11 is a TGA thermogram of Compound I hemifumarate Pattern 1 obtained in Example 23.
  • FIG. 12A is a DSC thermogram of Compound I monofumarate Pattern 1 (small scale preparation, Example 23), recorder at heating rate of 10°C/min.
  • FIG. 12B is a DSC thermogram of Compound I mono-fumarate Pattern 1 (small scale preparation, Example 23), recorder at heating rate of 2°C/min.
  • FIG. 12C is a DSC cycle of Compound I mono-fumarate Pattern 1 (DSC cycle, 0-150oC, 150-0oC, 0-250oC, 10oC/min) for the small-scale preparation sample (Example 23).
  • FIG.13 is TGA thermogram of Compound I mono-fumarate Pattern 1 for the small-scale preparation sample (Example 23).
  • FIG.14 is a comparison of XRPD diffractograms of Compound I monofumarate Pattern 1 obtained in stability test experiments at 25°C/84%RH (2 days, open container), 25°C/92%RH (1 week, open container), 40°C/75%RH (1 week, open container), and 60°C (1 week, tight container) as described in Example 24 with original sample of Compound I monofumarate Pattern 1 before the test.
  • FIG. 15 is a Dynamic Vapor Sorption (DVS) plot and DVS change in mass plot for Compound I Pattern 1(Example 26).
  • DVDS Dynamic Vapor Sorption
  • FIG.16 is a comparison of XRPD diffractograms of Compound I Pattern 1 before and after DVS study (Example 26).
  • FIG. 17 is a Dynamic Vapor Sorption (DVS) plot and DVS change in mass plot for Compound I hemifumarate Pattern 1 (Example 26).
  • FIG.18 is a comparison of XRPD diffractograms of Compound I hemifumarate Pattern 1 before and after DVS study (Example 26).
  • FIG. 19 is a Dynamic Vapor Sorption (DVS) plot and DVS change in mass plot for Compound I monofumarate Pattern 1 (Example 26).
  • FIG.20 is a comparison of XRPD diffractograms of Compound I monofumarate Pattern 1 before and after DVS study (Example 26).
  • FIG.21A is a comparison of XRPD diffractograms of Compound I monofumarate Pattern 1 obtained in Example 27 (large scale) before and after heating to 106°C.
  • FIG. 21B is a DSC thermogram of Compound I monofumarate Pattern 1 (Example 27), recorded at heating rate of 10°C/min.
  • FIG. 21C is a DSC thermogram of Compound I monofumarate Pattern 1 (large scale preparation, Example 27), recorded at heating rate of 2°C/min.
  • FIG. 21A is a comparison of XRPD diffractograms of Compound I monofumarate Pattern 1 obtained in Example 27 (large scale) before and after heating to 106°C.
  • FIG. 21B is a DSC thermogram of Compound I monofumarate Pattern 1 (Example 27), recorded at
  • 21D is a DSC thermogram of Compound I monofumarate Pattern 1 (obtained in Example 27).
  • FIG.22 is TGA thermogram of Compound I monofumarate Pattern 1 (obtained in Example 27).
  • FIG.23 is a comparison of XRPD diffractograms of Compound I mono-fumarate Pattern 1, hemi-fumarate Pattern 2, hemi-fumarate Pattern 3, Pattern 4 obtained from equilibration experiment in water at 25°C for 2 weeks and fumaric acid pattern (obtained in Example 28).
  • FIG.24 is a comparison of XRPD diffractograms of Compound I Pattern 4 obtained from equilibration experiment in water at 25°C for 2 and 3 weeks (obtained in Example 28).
  • FIG. 25 is a DSC thermogram of Compound I Pattern 4 obtained from equilibration experiment in water at 25°C for 2 weeks (obtained in Example 28).
  • FIG. 26 is a DSC thermogram of Compound I Pattern 4 obtained from equilibration experiment in water at 25°C for 3 weeks (obtained in Example 28).
  • FIG. 27 is a TGA thermogram of Compound I Pattern 4 obtained from equilibration experiment in water at 25°C for 2 weeks (obtained in Example 28).
  • FIG. 28 is a TGA thermogram of Compound I Pattern 4 obtained from equilibration experiment in water at 25°C for 3 weeks (obtained in Example 28).
  • a method to treat a cervical or vaginal HPV-induced infection, intraepithelial neoplasia, or an associated condition in a human in need thereof comprising: (i) administering an effective amount of the compound or pharmaceutical composition for use as described in any one of embodiments 1-42, to the cervix using a vaginal applicator (which is optionally coated with a lubricant); and then (ii) inserting a retaining device (which is optionally coated with a lubricant) that is maintained at the base of the cervix or in the vaginal canal for sufficient time to collect the post- treatment leakage of vaginal fluids and the therapeutic agent or its metabolite such as PMEG in a manner that minimizes toxicity-causing damage to non-diseased tissue.
  • a vaginal applicator which is optionally coated with a lubricant
  • a retaining device which is optionally coated with a lubricant
  • the retaining device is selected from a menstrual cup, a menstrual disc, a tampon, diaphragm, cervical cap and a sponge.
  • the retaining device is used as both the applicator and a retaining means to collect the post-treatment leakage of vaginal fluids and the therapeutic agent or its metabolite such as PMEG in a manner that minimizes toxicity-causing damage to non-diseased tissue.
  • the retaining device is a menstrual cup.
  • the retaining device is a menstrual disc. 49.
  • the method of embodiments 43 or 44, wherein the retaining device is a tampon. 50.
  • the method of embodiments 43, 44, or 46, wherein the retaining device is a diaphragm. 51.
  • the method of embodiments 43 or 44, wherein the retaining device is a cervical cap. 52.
  • the method of embodiments 43 or 44, wherein the retaining device is a sponge. 53.
  • the method of embodiment 46, wherein the retaining device used as both an applicator and a retaining means is a diaphragm.
  • the method of any one of embodiments 43-53, wherein the condition caused by a human papillomavirus is atypical squamous cells of undetermined significance (ASC-US). 55.
  • any one of embodiments 43-53 wherein the condition caused by a human papillomavirus is high grade squamous intraepithelial lesions (HSIL). 59. The method of any one of embodiments 43-53, wherein the condition caused by a human papillomavirus is adenocarcinoma in situ (AIS). 60. The method of any one of embodiments 43-53, wherein the intraepithelial neoplasia is cervical intraepithelial neoplasia. 61. The method of embodiment 60, wherein the cervical intraepithelial neoplasia is Grade 1 cervical intraepithelial neoplasia. 62.
  • HSIL high grade squamous intraepithelial lesions
  • the method of embodiment 60, wherein the cervical intraepithelial neoplasia is Grade 2 cervical intraepithelial neoplasia.
  • the method embodiment 60, wherein the cervical intraepithelial neoplasia is Grade 3 cervical intraepithelial neoplasia.
  • 64. The method of any one of embodiments 43-53, wherein the intraepithelial neoplasia is vaginal intraepithelial neoplasia.
  • Isotopic Substitution includes but is not limited to compounds, pharmaceutical compositions, and the use of any of the active compounds described herein in combination with the retaining device, including but not limited to Compound I or a pharmaceutically acceptable salt thereof such as fumarate, Compound II or Compound III, with desired isotopic substitutions of atoms at amounts above the natural abundance of the isotope, i.e., enriched.
  • Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons.
  • isotopes of hydrogen for example, deuterium ( 2 H) and tritium ( 3 H) may be used anywhere in described structures.
  • isotopes of carbon e.g., 13 C and 14 C
  • isotopes of carbon e.g., 13 C and 14 C
  • a preferred isotopic substitution is deuterium for hydrogen at one or more locations on the molecule to improve the performance of the drug.
  • the deuterium can be bound in a location of bond breakage during metabolism (an ⁇ -deuterium kinetic isotope effect) or next to or near the site of bond breakage (a ⁇ -deuterium kinetic isotope effect).
  • Achillion Pharmaceuticals, Inc. (WO/2014/169278 and WO/2014/169280) describes deuteration of nucleotides to improve their pharmacokinetic or pharmacodynamic, including at the 5-position of the molecule.
  • isotopically-labeled refers to an analog that is a "deuterated analog", a " 13 C-labeled analog,” or a “deuterated/ 13 C-labeled analog.”
  • deuterated analog means a compound described herein, whereby a H-isotope, i.e., hydrogen/protium ( 1 H), is substituted by a H-isotope, i.e., deuterium ( 2 H).
  • Deuterium substitution can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted by at least one deuterium.
  • the isotope is 90, 95 or 99% or more enriched in an isotope at any location of interest.
  • a method for the treatment of HPV infection or HPV-induced intraepithelial neoplasia includes (i) administering an effective amount of the anti-HPV therapeutic agent such as ABI-2280 or a pharmaceutically acceptable salt thereof, or other compound or its salt described herein, optionally in morphic form, and typically in tablet form, to the cervix using a vaginal applicator and then (ii) inserting a retaining device that is maintained at the base of the cervix or in the vaginal canal for sufficient time to collect the post- treatment leakage of vaginal fluids and the therapeutic agent or its metabolite such as PMEG in a manner that minimizes toxicity-causing damage to non-diseased tissue as described in detail above.
  • the anti-HPV therapeutic agent such as ABI-2280 or a pharmaceutically acceptable salt thereof, or other compound or its salt described herein
  • the patient can be instructed to remain supine for several hours, for example, 3, 4, 5, 6, 7 or 8 hours with minimal activities and may resume normal activities after that time-period.
  • the patient should repeat this procedure once daily for a total of 2, 3 or 4 applications in a week as instructed. It is preferred to carry out the two step administration process in the evening.
  • Patients typically administer three doses on alternate days over a 1-week period.
  • Patients can optionally be instructed to use the following preventative measures to protect against leakage of drug or metabolite-containing fluid to healthy tissue: • Minimize amount of water-based lubricant (e.g.,KY gel) used for dosing. • Do not bathe the genital area until after the instructed administration dosage time period.
  • water-based lubricant e.g.,KY gel
  • a non-water based barrier gel for example zinc oxide
  • Peripads can be used and can be changed frequently to avoid continued exposure to any leaked drug or metabolite containing fluid.
  • Dosings are preferably initiated and completed prior to anticipated starting date of the period.
  • suitable schedules include days 1, 3, and 5 followed by days 8, 10 and 12, followed by days 15, 17 and 19. Patients can combine this protocol with other standard of care procedures who have screening biopsy results of HSIL (CIN2 or CIN3).
  • the patient may opt to undergo a LLETZ procedure or another procedure described in the Background section above.
  • the Compound I, or a pharmaceutically acceptable salt thereof such as Compound II or Compound III, vaginal tablet is self-administered.
  • one or more doses of the compound are administered by a physician.
  • the first dose is administered by a physician or medical provider and the remaining doses, for example doses on days 3, 5, 8, and 10, are administered at home.
  • a formulation for the treatment of intraepithelial neoplasia is a dosage form that contains from about 0.01 mg to about 10 mg, from about 0.05 to about 5 mg, from about 0.05 to about 0.15 mg, from about 0.15 mg to about 0.45 mg, or from about 0.5 to about 1.5 mg of any of the active compounds described herein including but not limited to Compound I or a pharmaceutically acceptable sale such as a monofumarate, hemifumarate, or other solid form, or Compound II or Compound III.
  • a formulation for the treatment of intraepithelial neoplasia is a dosage form that contains about or at least 0.01, 0.03, 0.05, 0.1 mg, 0.3 mg.0.5 mg, 0.7 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg or 20 mg, of Compound I monofumarate, Compound II or Compound III, optionally in a selected morphic form.
  • the dose strengths in mg used herein refer to the weight of the active acyclic phosphonamidate and do not include the salt in the molecular weight, and thus the total weight in the dosage form.
  • the topical formulation is administered once a day, or several days a week (such as 2 or 3 days a week) in combination with the retaining device, as long as necessary to achieve the desired results. In certain embodiments, the topical formulation is administered on a weekly schedule for one, two, three, four, five, six or more weeks. In certain aspects, the topical formulation is administered on a schedule of three dosages a week for two, three, four, five, or six weeks. In certain embodiments, the compound can be administered in one or more therapeutic cycles comprising a treatment cycle and a rest cycle, wherein the treatment cycle comprises administering the compound as described herein in combination with the retaining device, followed by a rest cycle (comprising a period of no treatment) before the next treatment cycle.
  • the rest cycle is from about one day to about six months. In certain embodiments the rest cycle is one, two, three, four, five, six, seven, eight or more weeks before the next treatment cycle. In certain embodiments, multiple therapeutic cycles are administered, for example one, two, three, four, five, or six therapeutic cycles.
  • Dosage forms which do not adhere well to the target site may be dislodged, interfering with treatment. Dosage forms have been discovered that adhere to the target site and dissolve rapidly in low fluid volumes. Adhesion to the target site also prevents exposure to healthy tissues, which may limit toxicity and side effects. Dosage forms which soften, break down, and/or disintegrate quickly in low fluid volumes are advantageous to cause a rapid release of the active compound to the target tissue.
  • Dosage forms that disintegrate in, for example, less than about 50 ⁇ L, less than about 100 ⁇ L, less than about 125 ⁇ L, less than about 150 ⁇ L, less than about 175 ⁇ L, less than about 200 ⁇ L, or less than about 250 ⁇ L fluid particularly facilitate drug penetration into the target site.
  • the dosage form is a gel.
  • the dosage form is a cream.
  • the dosage form is a tablet.
  • the dosage form disintegrates in about one to about ten seconds. In certain embodiments, the dosage form disintegrates in about ten seconds to one minute. In certain embodiments, the dosage form disintegrates in about one minute to about one hour.
  • the dosage form disintegrates in about one to six hours.
  • the physical dimensions of the dosage form can impact the effectiveness of the dosage form.
  • a tablet that is thinner provides a greater surface area to volume ratio and may degrade quicker and cover the target area better.
  • the dosage form is less than about 6, 5, 4, 3, or 2 millimeters thick in its smallest dimension.
  • the formulation of the dosage form is important for adequate administration of the active agent into the intraepithelial tissue.
  • the formulation for example, can be prepared for use as a tablet, a reconstituted powder, a dry powder, a semi solid dosage form, a film or a pessary (i.e., a vaginal suppository).
  • Some embodiments disclosed herein include the use of an effective amount of Compound I monofumarate, Compound II or Compound III, in the manufacture of a medicament for ameliorating or treating a human papillomavirus infection, wherein the infection can be ameliorated or treated by inhibiting viral replication by inhibiting the synthesis of viral DNA.
  • Other embodiments disclosed herein include the use of an effective amount of any of the active compounds described herein including but not limited to Compound I monofumarate, Compound II or Compound III, for ameliorating or treating a human papillomavirus infection, wherein the human papillomavirus infection can be ameliorated or treated by inhibiting viral replication by inhibiting the synthesis of viral DNA.
  • Certain nonlimiting embodiments disclosed herein include a method for ameliorating or treating a human papillomavirus infection that can include contacting a cell infected with the human papillomavirus in a subject with an effective amount of any of the active compounds described herein including but not limited to Compound I monofumarate, Compound I hemifumarate, or other solid form of Compound I, Compound II or Compound III, wherein the infection is ameliorated or treated by inhibiting the synthesis of viral DNA.
  • Yet still other embodiments disclosed herein include a method for ameliorating or treating a human papillomavirus infection that can include administering to a subject infected with the human papillomavirus an effective amount of Compound I monofumarate, Compound II or Compound III, wherein the human papillomavirus infection can be ameliorated or treated by inhibiting viral replication by inhibiting the synthesis of viral DNA.
  • Some embodiments disclosed herein relate Compound I monofumarate, Compound II or Compound III, for use in ameliorating or treating a human papillomavirus infection, wherein the human papillomavirus infection can be ameliorated or treated by inhibiting viral replication by inhibiting the synthesis of viral DNA.
  • the human papillomavirus can be a high-risk human papillomavirus, such as those described herein.
  • the high-risk human papillomavirus can be selected from HPV-16, HPV-18, HPV-31, HPV-33, HPV-35, HPV-39, HPV-45, HPV-51, HPV-52, HPV- 56, HPV-58, HPV-59, HPV-68, HPV-73 and HPV-82.
  • the human papillomavirus can be HPV-16.
  • the human papillomavirus can be HPV-11.
  • the human papillomavirus can be HPV-18.
  • the human papillomavirus can be one or more of the following high-risk types: HPV-31, HPV-33, HPV-35, HPV-39, HPV-45, HPV-51, HPV-52, HPV-56, HPV-58, HPV-59, HPV-68, HPV-73 and HPV-82.
  • HPV-31, HPV-33, HPV-35, HPV-39, HPV-45, HPV-51, HPV-52, HPV-56, HPV-58, HPV-59, HPV-68, HPV-73 and HPV-82 can be detected using the Papanicolaou test (Pap smear) and/or DNA probe testing (for example, HPV DNA probe testing for one or more high-risk HPV types).
  • an effective amount of Compound I or a pharmaceutically acceptable salt thereof such as a monofumarate, Compound II or Compound III
  • a subject diagnosed with an HPV infection in combination with the retaining device for example a high-risk HPV infection, by a DNA test.
  • an effective amount of Compound I or a pharmaceutically acceptable salt thereof such as a monofumarate, Compound II or Compound III can be provided to a subject diagnosed with an HPV infection, or a disease associated with HPV infection, as identified by a Papanicolaou test.
  • an effective amount of Compound I monofumarate, Compound II, or Compound III may be provided to a subject with a Papanicolaou test result that does not indicate the disease has progressed to cervical cancer.
  • the Bethesda system is a standardized scoring system for reporting pap smear test results and assigns a grade of 1-3 based on severity. Grade 1 CIN (CIN 1) indicates mild dysplasia. Grades 2 and 3 CIN (CIN 2, CIN 3) are more serious and typically require intervention.
  • Compound I monofumarate, Compound II or Compound III is used to treat CIN 1 (Grade 1 cervical intraepithelial neoplasia).
  • Compound I monofumarate, Compound II or Compound III is used to treat CIN 2 (Grade 2 cervical intraepithelial neoplasia) in combination with the retaining device.
  • Compound I monofumarate, Compound II or Compound III is used to treat CIN 3 (Grade 3 cervical intraepithelial neoplasia) in combination with the retaining device.
  • a pharmaceutical composition comprising Compound I monofumarate, Compound II or Compound III, is used in the manufacture of a system for the treatment of CIN 1 (Grade 1 cervical intraepithelial neoplasia) that includes the use of a retaining device, as described further herein.
  • a pharmaceutical composition comprising Compound I monofumarate, Compound II or Compound III, is used in the manufacture of a system for the treatment of CIN 2 (Grade 2 cervical intraepithelial neoplasia) that includes the use of a retaining device as described further herein.
  • a pharmaceutical composition comprising Compound I monofumarate, Compound II or Compound III, is used in the manufacture of a medicament for the treatment of CIN 3 (Grade 3 cervical intraepithelial neoplasia).
  • Compound I monofumarate, Compound II or Compound III is used to treat a condition selected from the group consisting of atypical squamous cells of undetermined significance (ASC-US), atypical glandular cells (AGC), low-grade squamous intraepithelial lesions (LSIL), atypical squamous cells (cannot exclude high grade squamous intraepithelial lesion) (ASC-H), high grade squamous intraepithelial lesions (HSIL), adenocarcinoma in situ (AIS), and cervical cancer (e.g. squamous cell carcinoma or adenocarcinoma).
  • ASC-US atypical squamous cells of undetermined significance
  • ASC atypical glandular cells
  • LSIL low-grade squamous intraepithelial lesions
  • ASC-H atypical squamous cells (cannot exclude high grade squamous intraepithelial lesion)
  • Compound II is administered in combination with the use of a retaining device twice a week for up to 12 weeks. In certain embodiments, Compound II is administered in combination with the use of a retaining device twice a week for up to 10 weeks. In certain embodiments, Compound II is administered in combination with the use of a retaining device twice a week for up to 8 weeks. In certain embodiments, Compound II is administered in combination with the use of a retaining device twice a week for up to 6 weeks. In certain embodiments, Compound II is administered in combination with the use of a retaining device twice a week for up to 4 weeks. In certain embodiments, Compound II is administered in combination with the use of a retaining device twice a week for up to 2 weeks.
  • Compound I monofumarate or hemifumarate or other solid form is administered in combination with a retaining device three times a week. In certain embodiments, Compound I monofumarate or hemifumarate or other solid form is administered in combination with a retaining device three times a week for up to 12 weeks. In certain embodiments, Compound I monofumarate or hemifumarate or other solid form is administered in combination with a retaining device three times a week for up to 10 weeks. In certain embodiments Compound I monofumarate or hemifumarate or other solid form is administered in combination with a retaining device three times a week for up to 8 weeks.
  • Compound I monofumarate or hemifumarate or other solid form is administered in combination with a retaining device three times a week for up to 6 weeks. In certain embodiments, Compound I monofumarate or hemifumarate or other solid form is administered in combination with a retaining device three times a week for up to 4 weeks. In certain embodiments, Compound I monofumarate or hemifumarate or other solid form is administered in combination with a retaining device three times a week for up to 2 weeks. In certain embodiments, Compound I monofumarate is administered in combination with a retaining device three times a week for up to 1 week.
  • Compound I monofumarate is administered in combination with a retaining device daily. In certain embodiments, Compound I monofumarate is administered in combination with a retaining device daily for up to 12 weeks or indefinitely as instructed by a healthcare provider. In certain embodiments, Compound I monofumarate is administered in combination with a retaining device daily for up to 10 weeks. In certain embodiments, Compound I monofumarate is administered in combination with a retaining device daily for up to 8 weeks. In certain embodiments, Compound I monofumarate is administered in combination with a retaining device daily for up to 6 weeks. In certain embodiments, Compound I monofumarate is administered in combination with a retaining device daily for up to 4 weeks.
  • Compound I monofumarate is administered in combination with a retaining device daily for up to 2 weeks. In certain embodiments, Compound I monofumarate is administered in combination with a retaining device daily for up to 1 week. In certain embodiments, Compound I monofumarate, or other solid form Compound II or Compound III may be administered in combination with a retaining device three, four, five or six times a week. In certain embodiments, Compound I monofumarate, Compound II or Compound III may be administered in combination with a retaining device once per day. In certain embodiments, Compound I monofumarate, Compound II or Compound III may be administered in combination with a retaining device twice per day.
  • Compound I monofumarate, Compound II or Compound III may be administered in combination with a retaining device three, four, or more times per day. In certain embodiments, Compound I monofumarate, Compound II or Compound III may be administered in combination with a retaining device daily. In certain embodiments, the compound can be administered in combination with a retaining device in one or more therapeutic cycles comprising a treatment cycle and a rest cycle, wherein the treatment cycle comprises administering the compound as described herein, followed by a rest cycle (comprising a period of no treatment) before the next treatment cycle. In certain embodiments, the rest cycle is from about one day to about six months.
  • the rest cycle is one, two, three, four, five, six, seven, eight or more weeks before the next treatment cycle.
  • multiple therapeutic cycles are administered, for example one, two, three, four, five, or six therapeutic cycles.
  • a number of compounds have been investigated for the treatment of HPV-induced neoplasia, however none has been approved yet.
  • investigated approaches see Ahn W.S., et al. Protective effects of green tea extracts (polyphenon E and EGCG) on human cervical lesions. Eur. J. Cancer Prev.2003;12:383–390; Ashrafian L,et al.
  • lopimune lopinavir/ritonavir
  • vaginal tablets can be packaged for example in bottles with a desiccant.
  • a desiccant Nonlimiting examples are high density polyethylene bottles with a silica gel desiccant canister and rayon, induction sealed and capped with a child-resistant closure.
  • the vaginal tablet can be administered using the single-use vaginal tablet applicator or retaining device. It is preferred that tablets are stored refrigerated (2-8°C) in bottles with desiccant. Prior to administration, the bottle should be brought to room temperature for at least 30 minutes before opening and removing the tablet. Tablets are typically stored refrigerated (2-8°C) in bottles with desiccant.
  • compositions used in the present invention comprise an anti-HPV effective amount of Compound II described herein, optionally in a morphic form, in combination with a pharmaceutically acceptable carrier, additive, or excipient, further optionally in combination with at least one other antineoplastic agent or antiviral agent, such as an anti-HPV agent in combination with the retaining device.
  • the pharmaceutical composition includes Compound II in combination with a second antiviral drug in combination with the retaining device.
  • the pharmaceutical composition includes Compound II in combination with an anticancer drug in combination with the retaining device.
  • a therapeutically effective amount will vary with the infection or condition to be treated, its severity, the treatment regimen to be employed, the pharmacokinetic of the agent used, as well as the patient or subject (animal or human) to be treated, and such therapeutic amount can be determined by the attending physician or specialist.
  • the prodrug form of the compounds especially including acylated (acetylated or other), and ether (alkyl and related) derivatives, phosphate esters, thiophosphonamidates, phosphonamidates, and various salt forms of the present compounds, may be used to achieve the desired effect.
  • the amount of any of the active compounds described herein including but not limited to Compound I monofumarate, Compound II, or Compound III included within the therapeutically active formulation according to the present invention is an effective amount to achieve the desired outcome according to the present invention in combination with the retaining device, for example, for treating the HPV infection, reducing the likelihood of a HPV infection or the inhibition, reduction, and/or abolition of HPV or its secondary effects, including disease states, conditions, and/or complications which occur secondary to HPV infection.
  • Compound I monofumarate, Compound II, or Compound III may be administered in a gel in combination with the use of a retaining device.
  • the gel contains from about 0.001% to about 10%, from about 0.01% to about 10%, from about 0.05% to about 5%, from about 0.1 to about 3% from about 0.1 to about 2% Compound I or a pharmaceutically acceptable salt thereof such as a monofumarate, Compound II, or Compound III (weight/weight). In certain embodiments the gel contains from about 0.001% to about 0.05% Compound I monofumarate, Compound II, or Compound III. In certain embodiments, the gel contains from about 0.01% to about 0.5% Compound I monofumarate, Compound II, or Compound III. In certain embodiments, the gel contains from about 0.1% to about 5% Compound I monofumarate, Compound II, or Compound III.
  • any of the active compounds described herein including but not limited to Compound I monofumarate, Compound II, or Compound III is administered topically via a tablet, capsule, suspension, liquid, emulsion, implant, particle, sphere, cream, ointment, suppository, pessary, transdermal form, gel, mucosal, and the like in combination with the retaining device.
  • the dosage form may also be a bilayer tablet, in which the full dose of active compound is released one direction (for example towards the target tissue).
  • the dosage form can soften, disintegrate, and/or release the drug in low fluid volumes. In certain embodiments, the dosage form softens and begins to release the drug immediately.
  • the dosage form softens and begins to release the drug gradually. In certain embodiments, the dosage form softens and begins to release the drug within one hour. In certain embodiments, the dosage form softens and begins to release the drug within two hours.
  • the dosage form may be prepared to maximize surface area, facilitating disintegration. In certain embodiments, the dosage form is a round tablet. In certain embodiments, the dosage form is an oval tablet. In certain embodiments, the dosage form is a caplet.
  • the tablet width is the largest dimension, and the tablet thickness is the smaller dimension. In certain embodiments, the dosage form is twice as wide as it is thick. In certain embodiments, the dosage form is three times as wide as it is thick. In certain embodiments, the dosage form is four or more times as wide as it is thick.
  • the dosage form is from about 0.1 mm thick to about 5 mm thick. In certain embodiments, the dosage form is from about 1 mm to about 2 mm thick. In certain embodiments, the dosage form is from about 2 mm to about 3 mm thick. In certain embodiments, the dosage form is from about 3 mm to about 4 mm thick. In certain embodiments the dosage form is from about 4 mm to about 5 mm thick. In certain embodiments the tablet is from about 5 mm to about 15 mm thick. In certain embodiments, the dosage form is less than 5 grams. In certain embodiments, the dosage form is from about 0.05 gram to about 0.15 gram. In certain embodiments, the dosage form is from about 0.1 to about 1 gram.
  • the dosage from about 0.75 grams to about 2 grams. In certain embodiments, the dosage form is from about 1 gram to about 5 grams.
  • the dose strengths in mg used herein refer to the weight of the active acyclic phosphonamidate and do not include the salt in the molecular weight, and thus the total weight in the dosage form. In certain embodiments, the dose form is not easily removed, dislodged, or moved from the target site. These desirable properties may be achieved by inclusion of a mucoadhesive polymer into the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises a mucoadhesive polymer or mucoadhesive excipient.
  • mucoadhesive polymers and excipients include: Hypromellose, lectin, thiolated polymers (e.g. chitosan–iminothiolane, poly(acrylic acid)–cysteine, poly(acrylic acid)–homocysteine, chitosan– thioglycolic acid, chitosan–thioethylamidine, alginate– cysteine, poly(methacrylic acid)–cysteine and sodium carboxymethylcellulose–cysteine), polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidinone, polyacrylic acid (Carbopol®), polyheroxyethyl methacrylate, chitosan, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methylcellulose, sodium carboxymethyl cellulose, aminated corn starch, cellulose derivatives, poly (acrylic acid) polymers, poly (hydroxy(acrylic
  • the pharmaceutical composition comprises from about 0 to about 10% mucoadhesive polymer excipients selected from the list consisting of carbomer, polyethylene glycol, crospovidone, polycarbophil, hypromellose, and hydroxyethyl cellulose. In certain embodiments, the pharmaceutical composition comprises from at least about 0.1% to about 90, about 92%, about 93%, about 95%, about 98% about 97%, about 98%, or about 99% mucoadhesive polymer. In certain embodiments, the pharmaceutical composition comprises from about 0.1% to about 1% mucoadhesive polymer. In certain embodiments, the pharmaceutical composition comprises from about 0.5% to about 5% mucoadhesive polymer.
  • the pharmaceutical composition comprises from about 1% to about 10% mucoadhesive polymer. In certain embodiments, the pharmaceutical composition comprises from about 5% to about 20% mucoadhesive polymer. In certain embodiments, the pharmaceutical composition comprises from about 10% to about 50% mucoadhesive polymer. In certain embodiments, the pharmaceutical composition comprises from about 20% to about 75% mucoadhesive polymer. In certain embodiments, the pharmaceutical composition comprises from about 50% to about 90% mucoadhesive polymer. In certain embodiments, the pharmaceutical composition comprises from about 75% to about 99% mucoadhesive polymer.
  • the pharmaceutical composition comprises about or at least about 0.1, 0.25, 0.5, 0.75, 1, 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95 percent mucoadhesive polymer. In certain embodiments, the pharmaceutical composition comprises no more than about 0.1, 0.25, 0.5, 0.75, 1, 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95 percent mucoadhesive polymer. In certain embodiments, the pharmaceutical composition comprises 0% mucoadhesive polymer. In this instance, the adhesion to the target site is achieved by use of other pharmaceutically acceptable excipients.
  • a therapeutically effective amount of any of the active compounds described herein including but not limited to Compound I monofumarate, Compound II, or Compound III optionally in morphic form according to the present invention is often admixed with a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques to produce a dose.
  • a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques.
  • any of the usual pharmaceutical media may be used.
  • suitable carriers and additives including water, glycols, oils, alcohols, preservatives, and the like may be used.
  • the pharmaceutical composition comprises propylene glycol. In certain embodiments, the pharmaceutical composition comprises carboxypolymethylene. In certain embodiments, the pharmaceutical composition comprises ethylenediaminetetraacetic acid (EDTA). In certain embodiments, the pharmaceutical composition comprises sorbic acid. In certain embodiments, the pharmaceutical composition comprises carbomer. In certain embodiments, the pharmaceutical composition comprises hydroxyethyl cellulose. In certain embodiments, the pharmaceutical composition comprises polyethylene glycol.
  • suitable carriers and additives including starches, sugar carriers, such as dextrose, mannitol, lactose, and related carriers, diluents, granulating agents, lubricants, binders, mucoadhesive polymer, disintegrating agents, and the like may be used.
  • the tablets or capsules may be coated or sustained release by standard techniques. The use of these dosage forms may significantly enhance the bioavailability of the compounds in the patient.
  • the pharmaceutical composition comprises mannitol.
  • the pharmaceutical composition comprises magnesium stearate.
  • the pharmaceutical composition comprises microcrystalline cellulose.
  • the pharmaceutical composition comprises polycarbophil. In certain embodiments, the pharmaceutical composition comprises polyethylene oxide. In certain embodiments, the pharmaceutical composition comprises colloidal silicon dioxide. In certain embodiments, the pharmaceutical composition comprises povidone. In certain embodiments, the pharmaceutical composition comprises isopropyl alcohol. In certain embodiments, the pharmaceutical composition comprises sodium starch glycolate. In certain embodiments, the pharmaceutical composition comprises croscarmellose sodium. In certain embodiments, the pharmaceutical composition comprises crospovidone. In certain embodiments, the pharmaceutical composition comprises hydroxypropylmethylcellulose. In certain embodiments, the pharmaceutical composition comprises lactose.
  • a powder pharmaceutical composition comprises one or more excipient from the group consisting of xanthan gum, microcrystalline cellulose, polyethylene oxide, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose sodium, povidone, mannitol, colloidal silicon dioxide, sodium benzoate, sodium starch glycolate, sodium lauryl sulfate, poloxamer 407, polyoxypropylene- polyoxyethylene copolymers, and the like.
  • the pharmaceutical composition comprising an effective amount of a fumarate salt of any of the active compounds described herein including but not limited to Compound I, further comprises a pharmaceutically acceptable excipient selected from the list consisting of Acacia, agar, alginic acid, ascorbyl palmitate, bentonite, benzoic acid, butylated hydroxyanisole, butylated hydroxytoluene, butylene glycol, calcium acetate, calcium hydroxide, canola oil, carob bean gum, carrageenan, castor oil, cellulose, corn starch, disodium edetate, erythorbic acid, ethyl lactate, ethylcellulose, glycerin, glyceryl behenate, glyceryl monooleate, glyceryl monostearate, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hypromellose, lactic acid, lauric acid, lecithin, lin
  • the pharmaceutical composition comprises pharmaceutically acceptable excipients for use as a pessary.
  • the pharmaceutical composition comprising any of the active compounds described herein, including but not limited to Compound I or a pharmaceutically acceptable salt thereof such as a monofumarate, Compound II or Compound III further comprises up to 99.9% pessary excipient selected from the group consisting of hard fat, PEG, macrogols, cocoa butter, and glycerol.
  • Non limiting examples of hard fat include Ovucire® (mono-, di- and triglyceride esters of fatty acids (C 10 to C 18 ), the triester fraction being predominant and ethoxylated fatty alcohols), Witepsol® (glycerol esters of vegetable saturated fatty acids, such as lauric acid), and Supposi-baseTM (a blend of saturated polyglycolysed glycerides).
  • Ovucire® mono-, di- and triglyceride esters of fatty acids (C 10 to C 18 ), the triester fraction being predominant and ethoxylated fatty alcohols
  • Witepsol® glycerol esters of vegetable saturated fatty acids, such as lauric acid
  • Supposi-baseTM a blend of saturated polyglycolysed glycerides
  • the pharmaceutical composition comprising an effective amount of any of the active compounds described herein, including but not limited to Compound I or a pharmaceutically acceptable salt thereof such as a monofumarate, Compound II or Compound III further comprises a pharmaceutically acceptable excipient that enhances the penetration, disintegration, film forming and/or controlled release properties of the composition.
  • the pharmaceutical composition comprising any of the active compounds described herein, including but not limited to Compound I or a pharmaceutically acceptable salt thereof such as a monofumarate, Compound II or Compound III further comprises a penetration enhancing excipient.
  • the penetration enhancing excipient is selected from the group consisting of oleic acid, eucalyptol, Caprylol, Labrafil, Labrasol, Lauroglycol, diethylene glycol monomethyl ether (Transcutol), propylene glycol, sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide, poloxamer (231, 182, 184), Tween 20, 40, 60, 80, fatty acids and fatty acid esters, isostearic acid, glycerin, and chitosan.
  • the pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt thereof such as a monofumarate or Compound II or Compound III contains from 0% to about 20% penetration enhancing excipients selected from the group consisting of cetyl alcohol, propylene glycol, transcutol P, oleic acid, isopropyl myristate, propylene glycol dicaprylate, glyceryl monooleate, propylene glycol monocaprylate, PEG-8 bees wax, cetyl alcohol, stearic acid, cetyl palmitate, and cetosteryl alcohol.
  • penetration enhancing excipients selected from the group consisting of cetyl alcohol, propylene glycol, transcutol P, oleic acid, isopropyl myristate, propylene glycol dicaprylate, glyceryl monooleate, propylene glycol monocaprylate, PEG-8 bees wax, cetyl alcohol, stearic acid, cetyl palmitate, and
  • the pharmaceutical composition comprises from about 0 to about 25% penetration enhancing excipients selected from the list consisting of stearyl alcohol, polysorbate 80, sodium lauryl sulfate, mono and diglycerides, sorbitan monostearate, glyceryl isostearate, polyoxyl 15 hydroxystearate, polyoxyl 40 hydrogenated castor oil, octyl dodecanol, and soybean lecithin.
  • the pharmaceutical composition comprising any of the active compounds described herein, including but not limited to Compound I or a pharmaceutically acceptable salt thereof such as a monofumarate or Compound II or Compound III further comprises a film forming excipient.
  • the pharmaceutical composition comprising any of the active compounds described herein including but not limited to Compound I or a pharmaceutically acceptable salt thereof such as a monofumarate or Compound II or Compound III contains from 0% to about 99% film forming excipients selected from the group consisting of hypromellose, polyethylene glycol, polymethacrylates, microcrystalline cellulose, guar gum, xanthan gum, and polyvinylpyrrolidone.
  • the pharmaceutical composition comprising any of the active compounds described herein, including but not limited to Compound I or a pharmaceutically acceptable salt thereof such as a monofumarate or Compound II or Compound III further comprises and excipient which allows for controlled release of the active compound.
  • the controlled release pharmaceutical composition comprises ethylcellulose, hypromellose, microcrystalline wax, polycarbophil, beeswax. Percentage ranges of excipients and other components of the pharmaceutical composition are given as a percent by weight, unless otherwise specified.
  • the pharmaceutical composition comprising any of the active compounds described herein, including but not limited to Compound I or a pharmaceutically acceptable salt thereof such as a monofumarate or Compound II or Compound III further comprises a disintegration enhancing excipient.
  • the disintegration enhancing excipient is selected from the group consisting of cellulose, guar gum, crospovidone, polyplasdone, soy polysaccharides, calcium silicate, gelatin, cation exchange resins, bentonite, citrus pulp, alginic acid, calcium alginate, methylcellulose, microcrystalline cellulose, sodium carboxymethylcellulose, croscarmellose, solka floc, corn starch, sodium starch glycolate (Explotab, Primojel), glycine, hydroxypropyl starch, and starch 1500.
  • the pharmaceutical composition comprises up to about 99% disintegration enhancing excipient such as mannitol and/or microcrystalline cellulose.
  • the pharmaceutical composition comprises from about 0 to about 70% disintegration enhancing excipients selected from the list consisting of lactose, sucrose, and calcium phosphate. In certain embodiments, the pharmaceutical composition comprises from about 0 to about 50% disintegration enhancing excipients selected from the list consisting of sodium bicarbonate, citric acid, maleic acid, adipic acid, and fumaric acid. In certain embodiments, the pharmaceutical composition comprises from about 0 to about 20% disintegration enhancing excipients selected from the list consisting of sodium starch glycollate, pregelatinized starch, crospovidone, and croscarmellose sodium.
  • the pharmaceutical composition comprising any of the active compounds described herein including but not limited to Compound I or a pharmaceutically acceptable salt thereof such as a monofumarate or Compound II or Compound III further comprises from 0 to about 70% mannitol, including but not limited to any amount that achieves the desired results, for example up to about 5%, about 10%, about 20%, about 30% about 40%, about 50%, about 60% or about 70%.
  • the pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt thereof such as a monofumarate or Compound II or Compound III further comprises from 0 to about 70% lactose, including but not limited to any amount that achieves the desired results, for example up to about 5%, about 10%, about 20%, about 30% about 40%, about 50%, about 60% or about 70%.
  • the pharmaceutical composition comprising any of the active compounds described herein, including but not limited to Compound I or a pharmaceutically acceptable salt thereof such as a monofumarate or Compound II or Compound III further comprises from about 0 to about 70% sucrose, including but not limited to any amount that achieves the desired results, for example up to about 5%, about 10%, about 20%, about 30% about 40%, about 50%, about 60% or about 70%.
  • the pharmaceutical composition comprising any of the active compounds described herein, including but not limited to Compound I or a pharmaceutically acceptable salt thereof such as a monofumarate or Compound II or Compound III further comprises from about 0 to about 70% microcrystalline cellulose, including but not limited to any amount that achieves the desired results, for example up to about 5%, about 10%, about 20%, about 30% about 40%, about 50%, about 60% or about 70%.
  • the pharmaceutical composition comprising any of the active compounds described herein, including but not limited to Compound I or a pharmaceutically acceptable salt thereof such as a monofumarate or Compound II or Compound III further comprises from 0 to about 20% sodium starch glycolate, including but not limited to any amount that achieves the desired results, for example up to about 1%, about 2%, about 3%, about 5% about 7%, about 10%, about 12%, about 15% or about 20%.
  • the pharmaceutical composition comprising any of the active compounds described herein, including but not limited to Compound I or a pharmaceutically acceptable salt thereof such as a monofumarate or Compound II or Compound III further comprises from about 0 to about 20% pregelatinized starch, including but not limited to any amount that achieves the desired results, for example up to about 1%, about 2%, about 3%, about 5% about 7%, about 10%, about 12%, about 15% or about 20%.
  • the pharmaceutical composition comprising any of the active compounds described herein, including but not limited to Compound I or a pharmaceutically acceptable salt thereof such as a monofumarate or Compound II or Compound III further comprises from about 0 to about 20% crospovidone, including but not limited to any amount that achieves the desired results, for example up to about 1%, about 2%, about 3%, about 5% about 7%, about 10%, about 12%, about 15% or about 20%.
  • the pharmaceutical composition comprising any of the active compounds described herein, including but not limited to Compound I or a pharmaceutically acceptable salt thereof such as a monofumarate or Compound II or Compound III further comprises from about 0 to about 20% croscarmellose sodium, including but not limited to any amount that achieves the desired results, for example up to about 1%, about 2%, about 3%, about 5% about 7%, about 10%, about 12%, about 15% or about 20%.
  • the pharmaceutical composition comprising any of the active compounds described herein, including but not limited to Compound I or a pharmaceutically acceptable salt thereof such as a monofumarate or Compound II or Compound III further comprises from 0 to about 50% xanthan gum, including but not limited to any amount that achieves the desired results, for example up to about 5%, about 10%, about 15%, about 20% about 25%, about 30%, about 35%, about 40% or about 45%.
  • the pharmaceutical composition comprising any of the active compounds described herein, including but not limited to Compound I or a pharmaceutically acceptable salt thereof such as a monofumarate or Compound II or Compound III further comprises from 0 to about 50% polycarbophil, including but not limited to any amount that achieves the desired results, for example up to about 5%, about 10%, about 15%, about 20% about 25%, about 30%, about 35%, about 40% or about 45%.
  • the pharmaceutical composition comprising any of the active compounds described herein, including but not limited to Compound I or a pharmaceutically acceptable salt thereof such as a monofumarate or Compound II or Compound III further comprises from 0 to about 50% polyethylene oxide, including but not limited to any amount that achieves the desired results, for example up to about 5%, about 10%, about 15%, about 20% about 25%, about 30%, about 35%, about 40% or about 45%.
  • the pharmaceutical composition comprising any of the active compounds described herein, including but not limited to Compound I or a pharmaceutically acceptable salt thereof such as a monofumarate or Compound II or Compound III further comprises from 0 to about 50% hydroxyethylmethyl cellulose, including but not limited to any amount that achieves the desired results, for example up to about 5%, about 10%, about 15%, about 20% about 25%, about 30%, about 35%, about 40% or about 45%.
  • the pharmaceutical composition comprising any of the active compounds described herein, including but not limited to Compound I or a pharmaceutically acceptable salt thereof such as a monofumarate or Compound II or Compound III further comprises from 0 to about 50% hypromellose, including but not limited to any amount that achieves the desired results, for example up to about 5%, about 10%, about 15%, about 20% about 25%, about 30%, about 35%, about 40% or about 45%.
  • a tablet used to treat, prevent, or delay an HPV infection or a secondary disease state, condition, or complication of HPV comprising any of the active compounds described herein, including but not limited to Compound I or a pharmaceutically acceptable salt thereof such as a monofumarate or Compound II or Compound III further comprises about 250 mg of microcrystalline cellulose, about 20 mg of crospovidone, about 5 mg of magnesium stearate, about 5 mg of silicon dioxide, about 5 mg of polyethylene oxide, and about 100 mg of mannitol.
  • a tablet used to treat, prevent, or delay an HPV infection or a secondary disease state, condition, or complication of HPV further comprises about 155 mg microcrystalline cellulose, about 1.75 mg of magnesium stearate, and about 17.5 mg of mannitol.
  • a semi-solid formulation used to treat, prevent, or delay an HPV infection or a secondary disease state, condition, or complication of HPV comprising any of the active compounds described herein, including but not limited to Compound I or a pharmaceutically acceptable salt thereof such as a monofumarate or Compound II or Compound III further comprises about 15 mg of carbomer, about 50 mg of propylene glycol, about 10 mg of sorbic acid, about 5 mg of EDTA, and about 920 mg of water.
  • a semi-solid formulation used to treat, prevent, or delay an HPV infection or a secondary disease state, condition, or complication of HPV comprising any of the active compounds described herein, including but not limited to Compound I or a pharmaceutically acceptable salt thereof such as a monofumarate or Compound II or Compound III further comprises about 20 mg of carbomer; about 70 mg of mineral oil; about 80 mg of a mixture of polyoxyl 6 stearate Type I, ethylene glycol stearates and polyoxyl 32 stearate type 1; about 5 mg parabens; about 60 mg propylene glycol; about 5 mg EDTA; and about 760 mg water.
  • a dry powder for reconstitution is used to treat, prevent, or delay an HPV infection or a secondary disease state, condition, or complication of HPV comprising any of the active compounds described herein, including but not limited to Compound I or a pharmaceutically acceptable salt thereof such as a monofumarate or Compound II or Compound III further comprises about 15.5 mg xanthan gum, about 19.8 mg mannitol, about 5 mg silicon dioxide, and about 0.5 mg sodium benzoate.
  • Compound I or a pharmaceutically acceptable salt thereof such as a monofumarate or Compound II or Compound III further comprises about 15.5 mg xanthan gum, about 19.8 mg mannitol, about 5 mg silicon dioxide, and about 0.5 mg sodium benzoate.
  • cryotherapy laser therapy
  • loop electrosurgical procedure LEEP
  • cone biopsy cone biopsy. All of these surgical procedures damage the affected areas and can lead to scarring.
  • LEEP loop electrosurgical procedure
  • the treatments described herein in combination with the retaining device are used to lessen, ameliorate or substitute for the use of these conventional practices.
  • the treatments described herein can be used in combination with a surgical technique.
  • a patient in need thereof can receive surgery before, during and/or after administration of an effective amount of a compound described herein.
  • the compound is administered in combination with the retaining device about or less than about 8 months, 6 months, 4 months, 3 months, 2 months, or 1 month prior to surgery. In certain embodiments, the compound is administered in combination with the retaining device about or at least about 1 month, 2 months, 3 months, 4 months, 6 months, or 8 months after surgery.
  • the surgical procedure can be an excision of the target and/or diseased tissue, including but not limited to loop electrosurgical excision procedure (LEEP), large loop excision of the transformation zone (LLETZ), knife conization, cold knife conization, knife cone biopsy, or laser conization.
  • the surgical procedure can be ablation, including but not limited to laser ablation or cryoablation.
  • the efficacy of a drug against an HPV infection or neoplasia may be prolonged, augmented, or restored by administering the compound in combination or alternation with another, and perhaps even two or three other, antiviral compounds that induce a different mutation or act through a different pathway, from that of the principal drug.
  • the pharmacokinetic, biodistribution, half-life, or other parameter of the drug can be altered by such combination therapy (which may include alternation therapy if considered concerted).
  • combination therapy with anticancer therapeutics can provide better outcomes for patients.
  • the disclosed Compound I or a pharmaceutically acceptable salt thereof such as a monofumarate or Compound II or Compound III are DNA Polymerase inhibitors, it may be useful to administer the compound to a host in need thereof in combination with, for example: a) a protease inhibitor; b) another DNA polymerase inhibitor; c) an inhibitor of E6 or E6AP such as MEDI0457, luteolin, CAF-24 or gossypetin; d) an inhibitor of E7; e) an inhibitor of E1 or E2, including inhibitors of the E1-E2 protein interaction; f) L2 lipopeptides; g) an inhibitor or degrader of L1 or L2; h) an HDAC inhibitor such as vorinostat; i) degraders of tetraspanins such as CD9, CD63 or CD151; j) immunotherapeutics such as T-cell therapies (including adoptive T-cell therapies) and checkpoint inhibitors; k) anti-proliferative drugs
  • Solid-State Forms Any of the materials described herein that include Compound I in any stereochemical designation, or mixtures thereof, along with one or more additional compounds in any selected ratio, such as but not limited to an acid as described herein or water (or other solvent) in a solid form, can be used for HPV anti-viral or intraepithelial neoplasia therapy.
  • Such solid forms when they contain Compound I so described and one or more additional compounds, may be considered multicomponent solids and, when crystalline, multicomponent crystalline forms.
  • “crystalline A B” would be considered a multicomponent crystalline form of compounds A and B.
  • a salt is an example of a multicomponent solid, and a crystalline salt is a multicomponent crystalline form.
  • Salts typically exhibit proton transfer between an acid and a base.
  • Other multicomponent crystalline forms include cocrystals.
  • a cocrystal is typically a crystalline solid of two or more neutral species. Because charge balance is not necessary for neutral species, the stoichiometry of cocrystals cannot be determined based on charge balance.
  • one component is typically an active drug or prodrug and the other (or others) is usually termed a coformer, and it interacts nonionically with the active drug or prodrug in the crystal lattice.
  • the solid form may be both a salt and a cocrystal.
  • the active drug or prodrug may be in the form of a salt with a counterion and interact nonionically with a coformer.
  • a solid form would be a multicomponent solid and, when crystalline, a multicomponent crystalline form.
  • cocrystals when the coformer is volatile includes solvates.
  • a solid form may exist in a single crystalline solid form or be polymorphic where more than one crystalline form of the same solid form exists. Polymorphism is typically determined by use of x-ray powder diffraction.
  • Other examples of multicomponent solids are hydrates and solvates.
  • a hydrate is a solid form that includes water in the solid form.
  • the water may form part of the unit cell of the crystal in which case it is often a stoichiometric hydrate.
  • a solvate is a solid form that includes one or more solvent molecules and, when crystalline, may form part of the unit cell of the crystal in which case it is often a stoichiometric solvate.
  • a hydrate or a solvate can also be used in the therapy described generally herein.
  • the solid form may be partially crystalline, disordered, or amorphous..
  • any of the solid forms described above that comprise Compound I can be used in an effective amount in the treatment of HPV infection or cervical or vaginal intraepithelial neoplasia in a patient in need thereof, as generally taught herein.
  • a multicomponent crystal comprising Compound I can include a salt form of Compound I, a cocrystal form of Compound I and/or a mixture of a salt and cocrystal form of Compound I.
  • the solid form formed can be a function of the synthesis and crystallization or solidification conditions used, among other factors.
  • an effective amount of a multicomponent crystal comprising Compound I and a pharmaceutically acceptable coformer is used in the treatment of cervical or vaginal intraepithelial neoplasia in a patient in need thereof. In certain embodiments, an effective amount of a multicomponent crystal comprising Compound I and a pharmaceutically acceptable coformer is used in combination with a retaining device to treat cervical or vaginal intraepithelial neoplasia in a patient in need thereof.
  • the crystalline form formed by addition of about 1 equivalent of fumaric acid to a solution of Compound I optionally in isopropyl alcohol and heptane, optionally in a pharmaceutically acceptable carrier, is used in the treatment of cervical or vaginal intraepithelial neoplasia, optionally in combination with a retaining device.
  • Any solid form based on desired properties that includes Compound I can be used in an effective amount with or without a retaining device to deliver therapy to the HPV-infected patient in need thereof.
  • the dose strengths in mg used herein refer to the weight of the active acyclic phosphonamidate and do not include the salt in the molecular weight, and thus the total weight in the dosage form.
  • Example 1 Preparation of Fumarate Salts
  • Compound I Hemifumarate About 200 mg of Compound I free base was added to 0.5 mL of EtOH. While stirring, 0.5 molar amount of fumaric acid was added at 50°C and the mixture was stirred for 2 hours. A clear solution was obtained. The solution was then cooled to 25°C within 1 hour. Hemi-fumarate seeds of Sample RC13 (Example 5, Table 7) were added, followed by addition of 2.5 mL of heptanes to induce precipitation. An oil was obtained and stirred at 25°C for about 4 days. After 4 days, the resulting suspension was cooled to 5°C.
  • Mono-fumarate seeds of Sample RC 18 (Table 7) were added to the mixture, followed by addition of 4 mL of heptanes as an antisolvent. The mixture was stirred at 25°C for 4 days. The precipitated material was collected by filtration and dried at 40°C under vacuum for about 2 hours. As a result, 208 mg of mono- fumarate solids were obtained in yield of 69%.
  • Example 2 Large Scale Preparation of Mono-Fumarate About 4.16 g of Compound I free base was dissolved in 11 mL of IPA. Then, 1.0 eq. of fumaric acid was added to the yellow clear solution under stirring at 50°C. After about 1 hour, some solids precipitated out.
  • Step 1 Preparation of diethyl-((2-(2-amino-6-chloro-9H-purin-9-yl)-ethoxy)-methyl)- phosphonate (3) g, 0.296 mol, 1 equiv.), Cs 2 CO 3 (96.37 g, 0.296 mol, 1 equiv.) and DMF (250 mL) under N 2 atmosphere at room temperature. To this at room temperature and under stirring was added diethyl 2- chloroethoxymethyl phosphonate 2 (74.85 g, 0.325 mol, 1.1 equiv.) in a drop-wise manner.
  • the reaction was stirred at 40-50°C for 0.5 to 1.5 hours, heated to 60-70°C and stirred for 0.5-1.5 hours, and then stirred at 75 to 85°C for 18-24 h. After bringing the reaction temperature to 20- 30°C, the reaction mixture was filtered and the resulting cake was washed with DMF (100 mL x 2). The combined filtrate was concentrated to a half volume below 70°C, diluted with n-heptane (250 mL) and again concentrated to a half volume below 75°C. The resulting solution was poured into DCM (1 L), stirred at 20 to 30°C for 20-40 min., then aqueous 10% Na2SO4 solution ( ⁇ 100 mL) was added.
  • the resulting bi-phasic solution was stirred for 20-40 minutes then filtered through diatomite and the wet cake was washed with DCM ( ⁇ 100 mL). From the filtrate, the aqueous phase was separated and the organic phase was again washed with aqueous 10% Na 2 SO 4 solution ( ⁇ 100 mL). The combined aqueous phases upon washing (back extraction) with DCM (200-300 mL), the organic phases were combined and concentrated. The resulting crude product 3 was then purified by silica gel column chromatography using DCM to 1% MeOH in DCM. The fractions containing products were combined and the solvent was evaporated below 40°C.
  • the solid product 3 was treated with the repeated dilution with MTBE and concentration (up to 1/3 rd volume). The resulting slurry was then diluted with MTBE (400-500 mL) and agitated at 40-50°C for 4-6 h and at 15-25°C for 8-15 h. The suspension was filter and washed with MTBE and dried at 35-40°C for 15-20 h to afford the desired product, diethyl-((2-(2-amino- 6-chloro-9H-purin-9-yl)-ethoxy)-methyl)-phosphonate 3 in 43.4% (48.66 g) isolated yield with 91.8 % purity by HPLC.
  • Step 4a Preparation of a mixture of (R,S)- and (S,S)-ethyl-2-((((2-(2-amino-6-methoxy-9H- purin-9-yl)-ethoxy)-methyl)-(benzyloxy)-phosphoryl)-amino)-propionate (8)
  • Example 4 Preparation of (+)-Compound I Monofumarate ((+)-(2S)-Ethyl-2-((((2-(2- amino-6-methoxy-9H-purin-9-yl)-ethoxy)-methyl)-(benzyloxy)-phosphoryl)-amino)- propionate monofumarate) (9) To a solution of (+)-(2S)-ethyl-2-((((2-amino-6-methoxy-9H-purin-9-yl)-ethoxy)- methyl)-(benzyloxy)-phosphoryl)-amino)-propionate (Compound I) 8 (29.72 g, 0.06 mol, 1 equiv.) in IPA was added a solution of fumaric acid (7.66 mol, 1.1 equiv.) in IPA through a filter at 45-55°C and stirring was continued for 1-2 h.
  • the stereoisomers are separated using HPLC or SFC with achiral or chiral stationary phases.
  • chiral stationary phases which may be used include Chiralpak AD, Chiralpak AS, Chiralcel OG, and Chiralcel OJ.
  • the individual isomers can be synthesized asymmetrically.
  • asymmetric synthesis of phosphonamidates see Numan, A et al. “Asymmetric Synthesis of Stereogenic Phosphorus P(V) Centers Using Chiral Nucleophilic Catalysis”, Molecules 2021, 26, 3661 and Ambrosi, A. et al.
  • Step 1b Chiral Separation of (R,S)-ethyl-2-((((2-(2-amino-6-methoxy-9H-purin-9-yl)- ethoxy)-methyl)-(benzyloxy)-phosphoryl)-amino)-propionate and (S,S)-ethyl-2-((((2-(2- amino-6-methoxy-9H-purin-9-yl)-ethoxy)-methyl)-(benzyloxy)-phosphoryl)-amino)- propionate Separation of (R,R)-ethyl-2-((((2-amino-6-methoxy-9H-purin-9-yl)-ethoxy)-methyl)- (benzyloxy)
  • Step 1c Chiral Separation of (R P )-ethyl-2-((((2-(2-amino-6-methoxy-9H-purin-9-yl)- ethoxy)-methyl)-(benzyloxy)-phosphoryl)-amino)-propionate and (SP)-ethyl-2-((((2-(2- amino-6-methoxy-9H-purin-9-yl)-ethoxy)-methyl)-(benzyloxy)-phosphoryl)-amino)- propionate Separation of (RP)-ethyl-2-((((2-(2-amino-6-methoxy-9H-purin-9-yl)-ethoxy)-methyl)- (benzyloxy)-phosphoryl)-amino)-propionate and (SP)-ethyl-2-((((2-(2-amino-6-methoxy-9H-purin-9-yl)-ethoxy)-methyl)-(benzyloxy
  • Step 2a Preparation of (R,S)-ethyl-2-((((2-(2-amino-6-methoxy-9H-purin-9-yl)-ethoxy)- methyl)-(benzyloxy)-phosphoryl)-amino)-propionate monofumarate (Compound II)
  • n-heptane ⁇ 30 mL
  • stirring was continued for another 8-15h at 20-30°C and 0-5°C for 8-15h.
  • the solid observed was filtered and the wet cake was washed with a mixture of IPA/n-heptane (1/3, v/v, ⁇ 5 mL).
  • Step 2b Preparation of (S,S)-ethyl-2-((((2-(2-amino-6-methoxy-9H-purin-9-yl)-ethoxy)- methyl)-(benzyloxy)-phosphoryl)-amino)-propionate monofumarate (13), also referred as Compound III
  • the seeds of the compound 13 were added to the reaction mixture and stirring was continued for 1-2 h at 45-55°C. After allowing the reaction mixture to settle at 20-30°C for 4-6 h, a drop-wise addition of n-heptane ( ⁇ 30 mL) was performed and stirring was continued for another 8-15h at 20-30°C and 0-5°C for 8-15h. The solid observed was filtered and the wet cake was washed with a mixture of IPA/n-heptane (1/3, v/v, ⁇ 5 mL).
  • Step 2c Preparation of (R,R)-ethyl-2-((((2-(2-amino-6-methoxy-9H-purin-9-yl)-ethoxy)- methyl)-(benzyloxy)-phosphoryl)-amino)-propionate monofumarate and (S,R)-ethyl-2-((((2- (2-amino-6-methoxy-9H-purin-9-yl)-ethoxy)-methyl)-(benzyloxy)-phosphoryl)-amino)- propionate monofumarate Synthesis of (R,R)-ethyl-2-((((2-(2-amino-6-methoxy-9H-purin-9-yl)-ethoxy)-methyl)- (benzyloxy)-phosphoryl)-amino)-propionate monofumarate and (S,R)-ethyl-2-((((2-(2-amino-6- methoxy-9H-pur
  • Step 2d Preparation of (R P )-ethyl-2-((((2-(2-amino-6-methoxy-9H-purin-9-yl)-ethoxy)- methyl)-(benzyloxy)-phosphoryl)-amino)-propionate monofumarate and (SP)-ethyl-2-((((2- (2-amino-6-methoxy-9H-purin-9-yl)-ethoxy)-methyl)-(benzyloxy)-phosphoryl)-amino)- propionate monofumarate - - - - - (benzyloxy)-phosphoryl)-amino)-propionate monofumarate and (S P )-ethyl-2-((((2-(2-amino-6- methoxy-9H-purin-9-yl)-ethoxy)-methyl)-(benzyloxy)-phosphoryl)-amino)-propionate monofumarate can be
  • a topical cream formulation can be prepared, for example, by emulsifying an oil phase and an aqueous phase along with an active pharmaceutical ingredient.
  • the oil phase of the cream was prepared by mixing light mineral oil, propylparaben and Tefose® 63.
  • the aqueous phase of the cream was prepared by mixing water, EDTA, methylparaben, and Carbopol®974P.
  • the oil and water phases were then emulsified.
  • To the emulsified mixture was added the active pharmaceutical ingredient and propylene glycol. The mixture was pH adjusted and then filled into tubes.
  • a topical gel formulation can be prepared, for example, by mixing an aqueous gel carrier with an active pharmaceutical ingredient.
  • the aqueous phase of the topical gel was prepared by mixing water, EDTA, methylparaben (or sorbic acid) and Carbopol®974P.
  • the active pharmaceutical ingredient and propylene glycol was added to this solution, mixed and pH adjusted, then filled into tubes.
  • from about 0.001% w/w to about 10% w/w active pharmaceutical ingredient is added to the semisolid formulation.
  • from about 0.0025% w/w to about 2.5% w/w such as 0.003%, 0.01%, 0.03%, 0.1%, 0.3% or 1%.
  • Blend the active and the excipients, and screen to remove chunks Take 49.5 grams of the excipients blend and add 2.12 grams of Compound I monofumarate 3. Blend the active and the excipients, and screen to remove chunks 4. To this blend add 148.5 grams of the excipients blend 5. Blend the active blend and the excipients and screen to remove chunks 6. To this blend add 247.5 grams of the excipients blend 7. Blend the active blend and the excipients and screen to remove chunks 8. To this blend add the remaining 495 grams of the excipients blend 9. Blend the active blend and the excipients and screen to remove chunks Final Blending 10. Add magnesium stearate to the diffusion blender and mix the contents. 11. Discharge and reconcile blend. Compression 1.
  • Packaging 1. Package bulk tablets into double lined re-closable clear PE bags with desiccants between the bags and further into an aluminum foil pouch with desiccant and heat sealed.
  • Illustrative excipients for a vaginal tablet formulation Tablet formulations are optionally selected to display the properties of mucoadhesion and substantivity and include excipients that have solubilizing, erosion-generating (for disintegration), porosity (for water uptake) and viscosity enhancing (to keep the drug at the target site) properties.
  • excipients that will cause rapid disintegration to cover the cervix or vaginal areas include, but are not limited to mannitol, microcrystalline cellulose, lactose, sucrose, calcium phosphate, sodium phosphate, sodium bicarbonate, citric acid, maleic acid, adipic acid or fumaric acid.
  • excipients that can enhance disintegration and coverage of the affected area include but are not limited to sodium starch glycollate, pregelatinized starch, crospovidone and croscarmellose sodium.
  • Mucoadhesive excipients that are useful in the present invention include but are not limited to microcrystalline cellulose, polycarbophil, hydroxymethyl cellulose, hypromellose, hydroxypropyl cellulose, and PVP.
  • a tablet formulation may for example comprises the active pharmaceutical ingredient, microcrystalline cellulose and may contain mannitol.
  • the tablet formulation comprises one or more excipients selected from the rapid disintegrant category (left column of Table 3).
  • the tablet formulation comprises one or more excipients selected from the disintegration enhancement category (middle column of Table 3).
  • the tablet formulation comprises one or more excipients selected from the mucoadhesive excipient category (right column of Table 3). Table 3. Excipients for Tablets Rapidly disintegrating To Enhance Mucoadhesive polymers d i t t Dii t ti d e o Example 8. Illustrative excipients for a reconstitution powder or dry powder formulation A reconstitution powder or dry powder formulation may improve the shelf stability of a pharmaceutical agent or formulation. In certain nonlimiting embodiments, the dry powder formulation may be mixed with saline, propylene glycol or other aqueous carrier shortly before it is administered, minimizing the time for degradation.
  • the dry powder formulation is mixed with an oil, cream, or other nonaqueous carrier shortly before it is administered.
  • the reconstitution powder or dry powder formulation rapidly covers the infected or diseased tissue in the cervix, vulva or vagina.
  • Excipients which enhance the rapid coverage of the cervix, vulva or vagina include but are not limited to mannitol, lactose, sucrose, calcium phosphate, and microcrystalline cellulose.
  • the excipient for rapid coverage of the cervix, vulva or vagina is mannitol.
  • the reconstitution powder or dry powder formulation has good coverage of the cervix, vulva or vagina.
  • Nonlimiting examples of excipients which enhance the coverage of the cervix, vulva or vagina include sodium starch glycollate, pregelatinized starch, crospovidone, and croscarmellose sodium.
  • the reconstitution powder or dry powder formulation contains mucoadhesive properties once it has been reconstituted. This prevents smearing of the dosage form or otherwise exposing healthy tissues to the active pharmaceutical ingredient.
  • the dry powder or reconstitution powder formulation comprises one or more excipients selected from the rapid coverage category (left column of Table 4). In certain non-limiting embodiments, the dry powder or reconstitution powder formulation comprises one or more excipients selected from the coverage enhancement category (middle column of Table 4). In certain non-limiting embodiments, the dry powder or reconstitution powder formulation comprises one or more excipients selected from the mucoadhesive excipient category (right column of Table 4). Table 4. Excipients for Reconstitution Powders of Dry Powder Dosage Forms Rapidly covering To Enhance coverage Mucoadhesive polymers PVP (0 to 50%) e Example 9.
  • the formulation for a vaginal tablet dosage form comprises the ingredients in Table 7.
  • the formulation for a tablet dosage form comprises the ingredients in Table 7.
  • An illustrative process for combining these ingredients into a tablet dosage form can be found in Example 7.
  • Table 7. Example Tablet Formulation Material Amount in tablet Table 8.
  • Illustrative semisolid formulations In certain non-limiting embodiments, the formulation for a gel semisolid dosage form comprises the ingredients in Table 9.
  • the formulation for a cream semisolid dosage form comprises the ingredients in Table 10. An illustrative process for combining these ingredients into a cream or gel semisolid dosage form can be found in Example 6 above.
  • In-vitro cytotoxicity testing Compounds Three compounds (Compound I, Compound II and Compound III) were solubilized at 40 mM in DMSO and stored at -20°C. The test compounds were evaluated using a high test concentration of 50 ⁇ M. Serial half-logarithmic dilutions were performed for the in vitro cytotoxicity assays. Tamoxifen citrate was purchased from Sigma-Aldrich (St. Louis, MO).
  • Tamoxifen citrate was solubilized in DMSO at 40 mM and used as a positive control compound at a high test concentration of 100 ⁇ M for the cytotoxicity assays.
  • In Vitro Cytotoxicity Evaluations Cells listed in Table 13 were enumerated by Trypan Blue Dye exclusion method and seeded in the interior wells of a 96 well flat bottom microtiter plate at 100 ⁇ L/well. Proliferating cells were incubated overnight at 37°C/5% CO2 to allow the cells to adhere to the plates at approximately 70% confluency. Tissue culture medium was removed and replaced with 100 ⁇ L/well of fresh medium.
  • Table 70 lists the cell line, type of cell, source of cell stock, base tissue culture medium supplemented with 10% fetal bovine serum, 2 mM L-glutamine, 100 U/mL penicillin and 100 ⁇ g/mL streptomycin, and microtiter plate seeding density.
  • Table 13 Cell Culture for in vitro Cytotoxicity Cell Seeding Cell Line Cell Type Cell Source C lt D ity l) 4 Cytotoxicity XTT: Following incubation at 37°C in a 5% CO2 incubator for five days, the test plates were stained with the tetrazolium dye XTT (2,3-bis(2-methoxy-4-nitro-5- sulfopheny1)-5- [(phenylamino)carbonyl]-2H-tetrazolium hydroxide). XTT-tetrazolium was metabolized by the mitochondrial enzymes of metabolically active cells to a soluble formazan product. XTT solution was prepared daily as a stock of 1 mg/ml in RPMl1640.
  • Phenazine methosulfate (PMS) solution was prepared at 0.15 mg/ml in PBS and stored in the dark at - 20°C.
  • XTT/PMS stock was prepared immediately before use by adding 40 ⁇ L of PMS per ml of XTT solution. Fifty microliters of XTT/PMS were added to each well of the plate and the plate was reincubated for 4 hours at 37°C. Plates were sealed with adhesive plate sealers and shaken gently or inverted several times to mix the soluble formazan product and the plate was read spectrophotometrically at 450/650 nm with a Molecular Devices Vmax plate reader. Data Analysis and Evaluation: Microsoft Excel 2010 was used to analyze and graph the raw data.
  • CCso 50% reduction in cell viability values are tabulated and provided.
  • Raw data for cytotoxicity with a graphic representation of the data are provided in a printout summarizing the compound effect on cell viability.
  • In Vitro Cytotoxicity Evaluations Compounds I, II, and III were evaluated for cytotoxicity to proliferating Hs27, HeLa, C33A and HEK293 cells by measuring cell viability using XTI tetrazolium dye following five days in culture (Table 14). The CC 50 values calculated from these assays are summarized in the below tables. Tamoxifen citrate was evaluated in parallel as a control compound.
  • CC50 value for tamoxifen citrate in proliferating C33A, HeLa, Hs27, and HEK293 cells was 17.2, 19.9, 21.2 and 21.3 ⁇ M, respectively. Compound I and its two isomers were similarly cytotoxic when evaluated in parallel against each of the four cell lines.
  • CC50 values for the three test compounds ranged from approximately 0.1 to 0.28 ⁇ M in C33A cells. In HeLa cells, CC50 values for the three test compounds ranged from 15.1 to 18.6 ⁇ M. The CC 50 values for the three test compounds ranged from approximately 7.62 to 23.2 ⁇ M in Hs27 cells. In HEK293 cells, CC50 values for the three test compounds was approximately 0.1 ⁇ M.
  • Example 15 In vitro Cytotoxicity Data Compound C33A HeLa Hs27 HEK293 )
  • Example 15 Ex Vivo permeation and penetration of antiviral drugs across porcine vaginal tissue Preparation of Porcine Vaginal Tissue Freshly harvested porcine vaginal tissue was procured from local slaughterhouse in an ice box. The vaginal tissue was cut open to expose the mucosal surface and tissue was cleaned by gentle flow of PBS pH 7.4. The porcine vaginal tissue was cut into circular portions (approximately 2 cm 2 ) with help of a telemetric punch.
  • Porcine vaginal tissue mounted on Franz diffusion cells
  • the circular portion of tissue was sandwiched between two chambers of a Franz diffusion cell with an active diffusion area of 1 cm 2 , and the mucosal layer was exposed to the donor chambers.
  • the resistance across porcine vaginal tissue was measured using a wave form generator to ensure the integrity of the tissue segment used for the permeation study.
  • Porcine vaginal tissue with resistance of ⁇ 3 K ⁇ .cm 2 was used for study.
  • the receiver chamber was filled with 8 ml of 5% solutol PBS 7.4 pH, which was stirred at 600 rpm with a 3 mm magnetic stir bar and the temperature was maintained at 37 °C with a circulating water bath.
  • the tissue was minced into smaller pieces on a dish with a precooled surgical blade.
  • the minced tissue was transferred to sample tubes and dish was rinsed with 1 ml of 5% solutol in PBS 7.4 pH and transferred to same tissue sample tube. These tubes were stored in -70 ⁇ C until analysis.
  • Preparation of receptor fluid for analysis The samples stored at -20 °C was removed and thawed at room temperature for 30 min.
  • the drug from receptor fluid was centrifuged at 13000 rpm for 5 min and to 200 ⁇ L of supernatant equal volume of extraction solvent was added. These samples were centrifuged at 13000 rpm for 5 min and supernatant was transferred into vials for analysis.
  • Vagina and Cervix Many animals, including sham and placebo controls, had microscopic infiltrates of a mixed cell population noted within the lamina intestinal of sections of vulva and vagina after repeated administration of Compound I vaginal tablets. Within the vagina, microscopic findings in the two studies included minimal to mild epithelial degeneration, mixed cell inflammation and luminal exudate in animals administered tablets ⁇ 0.03 mg Compound I. In the first study, two cases of minimal arterial degeneration/necrosis were seen at the 2.9 mg dose, which was characterized by disruption of the arterial wall with karyorrhectic (nuclear) debris and/or fibrinous change. In addition, one animal treated at 2.9 mg had moderate ulceration in the middle portion of the vagina.
  • Compound I administered by the IV route in safety pharmacology studies evaluated the potential for adverse effects on the respiratory, cardiovascular, and central nervous systems. No adverse effects were observed.
  • Single-dose IV toxicity studies were also conducted to describe potential systemic toxicity. In rabbits, single doses of 0 (vehicle control), 0.03, 0.3 and 3.0 mg/kg Compound I were given intravenously and animals were monitored for 7 or 23 days before sacrifice for necropsy and microscopic examination of tissues. Compound I was well tolerated with no signs of toxicity at any dose and all animals survived to the scheduled termination. There were no changes in chemistry or coagulation parameters.
  • Karyomegaly is an enlargement of the cell nucleus that has been proposed to be a response to chemical/drug exposure or insult (Hard, 2018). As indicated, the NOAEL for this study was 0.3 mg/kg which is approximately 12-fold greater exposure (by AUC) than the plasma exposure in rabbits dosed intravaginally at the 0.29 mg dose strength. Genotoxicity A standard battery of genotoxicity studies to assess the potential mutagenicity of Compound I was completed. A bacterial reverse mutation (Ames) study was negative. A mammalian chromosomal aberrations study was positive in the presence of metabolic activation at the highest concentration tested; however, there was no evidence of mutagenicity in an in vivo micronucleus assay.
  • Part B consisted of 2 multiple ascending dose cohorts administering Compound I vaginal tablet at 0.1 mg and 0.3 mg or placebo (3 doses over 1-week period). The study completed in June 2023. A total of 35 subjects were enrolled in the study: 19 subjects in Part A (13 received Compound I; 6 received placebo) and 16 subjects in Part B (12 received Compound I; 4 received placebo). In Part A and the 0.1 mg dose cohort of Part B, Compound I was safe and well tolerated. No dose limiting toxicities (DTLs) were reached or serious adverse events (SAEs) reported. All AEs were mild or moderate in severity. After review of safety data, it was determined that DLT at the 0.3 mg dose in Part B was reached.
  • DTLs dose limiting toxicities
  • SAEs serious adverse events
  • Compound I vaginal tablets can be administered with a vaginal applicator, followed by application of a retaining device. In certain embodiments, Compound I vaginal tablets can be administered with a diaphragm or menstrual cup.
  • Example 19 Exemplary Instructions For Self-Administration Of Compound I vaginal tablets With Vaginal Applicator Tablet administration is preferably carried out at bedtime to reduce displacing medication that may occur when standing or walking. 1. Place all supplies on a clean flat surface 2.
  • gloves for administration vaginal tablet applicator, water-based lubricant (such as KY Jelly, Surgilube or similar), and bottle of Compound I monofumarate vaginal tablets are assembled. 3. Wash and dry hands, and put on gloves. 4. Remove the applicator from its packaging. 5. Remove the Compound I monofumarate vaginal tablet from the bottle and place it into the end of the applicator. 6. To load the tablet into the applicator, retract the plunger slightly and insert the tablet into the barrel of the applicator until it is securely seated. Illustrations of the tablet placed in the barrel of the applicator are shown in FIG 7A. If loaded properly, the tablet will be firmly in the barrel and will not drop even when the applicator is held with tablet facing down.
  • water-based lubricant such as KY Jelly, Surgilube or similar
  • the tablet can be released by pushing in the plunger. 7.
  • a small amount about a teaspoon, which should be enough to cover/coat the tablet and applicator
  • the lubricant may be provided in individual packets if available; in that case, open the packet and dispense the entire amount of lubricant onto the Compound I monofumarate vaginal tablet.
  • the female can position her body in one of two ways: a. Stand upright (standing with her feet apart and her knees bent). It may also be helpful to raise one leg up on a chair or the bed. b. Lie on her back with her knees bent and legs slightly apart. 9.
  • the diaphragm should be a flexible device that is created to be inserted through the vagina and placed to cover the cervix.
  • the retaining device is used to help prevent leakage from the dissolved Compound I monofumarate vaginal tablet.
  • the device will form a seal against the cervix.
  • the diaphragm with the vaginal tablet is inserted, and then removed approximately 5-10 hours after insertion, and more typically 5-8 hours, for example around or at least 6 hours.
  • vaginal tablet administration should be preferably done at bedtime to reduce displacing medication that may occur when standing or walking.
  • FIG.7B Prior to self-administration, remove the Compound I monofumarate vaginal tablet from the bottle and place it inside the diaphragm first (FIG.7B) 5. Place a small amount (about a teaspoon or 5 mL) of water-based lubricant into the diaphragm to cover the Compound I monofumarate vaginal tablet.
  • the lubricant may be provided in individual packets if available; in that case, open the packet and dispense the amount of lubricant onto the Compound I monofumarate vaginal tablet (FIG.7C). 6. Hold the diaphragm with one hand by placing the thumb and index finger on the grip dimples along the rim. The arrow should point towards her body. See FIG.7D. 7.
  • the vaginal tablet will be located on either the left or right side of the fold (See FIG.7E). 8. Alternatively, if the lubricant and vaginal tablet rise up too close to the rim when folding, and appear to be coming out, the patient can push down on the diaphragm dome while folding to allow for one big fold (See FIG.7F). 9. For insertion of the diaphragm the patient can position her body in one of three ways: kneeling down in a sitting position; lying down with legs bent; or standing with one leg elevated. 10. Using her free hand, spread the labia.
  • Example 21 Single-Crystal X-Ray Diffraction (SC-XRD) study of Compound II Pattern 1
  • SC-XRD Single crystals of Compound II Pattern 1 suitable for SC-XRD study were obtained in a temperature cycling experiment in MeOH.
  • Example 22 Synthesis of Salts of Compound I Compound I Sulfate Two methods were used to synthesize the sulfate salt of Compound I. Method A To a solution of Compound I (0.049 g, 0.1 mmol) in dry THF (1 mL) at 0-10°C was added a solution of sulfuric acid (1N in THF) slowly.
  • Compound I sesquifumarate salt can be synthesized by washing Compound I sesquifumarate salt with additional MTBE and drying under high vacuum.
  • Compound I Pattern 1 is an anhydrate and has a melting peak at T onset of 75.0°C with an enthalpy of about 64 J/g. It shows about 0.3% weight loss at about 70°C. KF shows it contains about 1.7% of water. About 0.7% of MTBE (by weight) residue was detected by 1 H NMR.
  • Compound I hemifumarate Pattern 1 is an anhydrate. The stoichiometry of free form: fumaric acid is about 1:0.5 based on 1 H NMR result. It has a melting peak at Tonset of 85.2°C with an enthalpy of about 37 J/g. It shows about 1.0% weight loss at about 85°C. KF shows it contains about 1.7% of water.
  • Compound I monofumarate Pattern 1 is an anhydrate.
  • the stoichiometry of free form: fumaric acid is about 1:1.0 based on 1 H NMR result. It has a melting peak at T onset of 107.2°C with split peaks and with an enthalpy of about 78 J/g.
  • the two thermal events cannot be resolved with 2 K/min and 0.5 K/min heating rate by DSC as well. It shows about 0.3% weight loss at about 107°C.
  • KF shows it contains about 1.2% of water.
  • About 0.7% of IPA and 2.2% of heptanes (by weight) residue was detected by 1 H NMR.
  • Compound I hemifumarate Pattern 1 tends to degrade more than Compound I monofumarate Pattern 1 in the two conditions mentioned above.
  • Table 19 Bulk stability of Compound I free base Pattern 1, Compound I monofumarate Pattern 1 and Compound I hemifumarate Pattern 1 Compound I Compound I Compound I Compound I Compound I Storage Conditions free base Hemifumarate Monofumarate Example 25. Solubility of Compound I free base Pattern 1, Compound I Monofumarate Pattern 1 and Compound I Hemifumarate Pattern 1 About 4 mg of Compound I Pattern 1 was added into 2 mL of buffer solution.
  • Solubility of Compound I free base Pattern 1, Compound I monofumarate Pattern 1 and Compound I hemifumarate Pattern 1 Compound I free base
  • Compound I Compound I Pattern 1 Hemifumarate Monofumarate Solubility was tested in five media, pH 3.0 citrate buffer, pH 4.5 acetate buffer, pH 6.8 phosphate buffer, water, simulated vaginal fluid (pH 4.2) at 37°C for 0.5 h and 2 h. All the three candidates are highly soluble in the media (>2 mg/mL).
  • Example 28 Polymorph Screening Study of Compound I fumarate salts The polymorph screening study was performed for fumarate salts of Compound I (mixture of diastereomers). Their polymorphic behaviors were investigated by equilibration, precipitation by addition of antisolvent, slow cooling, fast cooling and slow evaporation experiments.
  • Table 32 Results of equilibration with IPA/toluene (1:1 v/v) for Compound I monofumarate Pattern 1 at 25°C for 2 weeks and 3 weeks Exp. XRPD Additional XRPD Additional (Solvent) (2 weeks) test (2 weeks) (3 weeks) test (3 weeks) XRPD diffractogram is shown in FIG.35.
  • Table 33 Results of equilibration with IPA/MTBE (1:3 v/v) for Compound I monofumarate Pattern 1 at 25°C for 2 weeks and 3 weeks Exp. XRPD Additional XRPD Additional (Solvent) (2 weeks) test (2 weeks) (3 weeks) test (3 weeks) XRPD diffractogram is shown in FIG.35. Table 34.
  • Solvent XRPD 1 Acetone Pattern 1 with medium crystallinity Crystallization from hot saturated solutions by slow cooling About 30 mg of Compound I monofumarate Pattern 1 was dissolved in the minimal amount of selected solvents at 50°C. Obtained solutions were cooled to 5°C at the rate of 0.1°C/min. Precipitates were collected by filtration. The solid part (wet cake) was investigated by XRPD. When differences were observed, additional investigations were performed (e.g., NMR, DSC, TGA). If no precipitation was obtained, the solutions were put in a -20°C freezer for crystallization. After storing in -20°C freezer for about 5 days, no precipitation was obtained, heptane was added as antisolvent.
  • Precipitates were collected by filtration.
  • the solid part (wet cake) was investigated by XRPD. Results are presented in Table 42. XRPD diffractograms are shown in FIG. 50 and FIG. 51. Table 42. Crystallization from hot saturated solutions by slow cooling Exp. Solvent XRPD Comments Residual solvent: 2.0% (by weight) ACN solvent DSC onset (enthal ): 740°C (89 J/ ) at N ar ar Crystallization from hot saturated solutions by fast cooling About 30 mg of Compound I monofumarate Pattern 1 was dissolved in the minimal amount of selected solvents at 50°C. Obtained solutions were put into an ice bath and agitated. Precipitates were collected by filtration.
  • the solid part (wet cake) was investigated by XRPD. When differences were observed, additional investigations were performed (e.g., NMR, DSC, TGA). If no precipitation was obtained, the solutions were put in -20°C freezer for crystallization. After storing in -20°C freezer for about 7 days, no precipitation was obtained, heptanes was added as antisolvent. Precipitates were collected by filtration. The solid part (wet cake) was investigated by XRPD. Results are presented in Table 43. XRPD diffractograms are shown in FIG. 52 and FIG. 53. Table 43. Crystallization from hot saturated solutions by fast cooling Exp.
  • Cycle 2 0°C to 130°C at 10°C /min; 130°C to 0°C at 10°C /min; reheat from 0°C to 250°C at 10°C /min.
  • Table 44 Behavior of Compound I monofumarate Pattern 1 under heating and cooling Exp. Heating rate Thermal events 1 Cycle 1: 0°C to 106°C at 10°C/min; 106°C Heating: Behavior under compression About 10 mg of Compound I monofumarate Pattern 1 was compressed for 5 minutes at 10 MPa with a hydraulic press. XRPD characterization was performed to investigate the polymorphic behavior under compression. According to the XRPD, no form change was observed.
  • Pattern 1 used in the study was prepared from Compound I free base according to Example 7.
  • the initial form of monofumarate used in the polymorph study described below (Pattern 1) is an anhydrate of monofumarate with HPLC purity of about 99.3%.
  • the ratio of free form and fumaric acid is about 1: 0.96 by 1 H NMR. It has two melting peaks with Tonset of about 98.5°C with an enthalpy of about 14 J/g and 109.6°C with an enthalpy of about 25 J/g, as measured by differential scanning calorimetry (DSC).
  • Pattern 1 shows about 0.5% weight loss at about 98°C and 0.6 % weight loss from 98°C to 140°C. About 1.0% (by weight) heptanes and 0.2% (by weight) IPA residue were detected by 1 HNMR. Karl Fischer titration shows it contains about 1.3% water. During the polymorph study, four new patterns were identified. Although monofumarate was used as initial physical form obtained new patterns showed different stoichiometric ratio. Pattern B, Pattern C and Pattern E are hemifumarate salts, and Pattern D is a degradation product. Pattern B is an anhydrate of hemifumarate with HPLC purity of about 99.6%.
  • the ratio of free base form to fumaric acid is about 1: 0.52 by 1H-NMR. It has two thermal events with T onset of about 77.4°C with an enthalpy of about 71 J/g and 88.4°C with an enthalpy of about 18 J/g. It shows about 0.7% weight loss at about 77°C and 4.2% weight loss from 77°C to 130°C. About 4.6% (by weight) MEK residue was detected by 1 H NMR.
  • Pattern C is not a monofumarate. It has two thermal events with T onset of about 74.0°C with an enthalpy of about 89 J/g and T onset of about 90.6°C with an enthalpy of about 15 J/g. It shows about 0.4% weight loss at about 73°C and 2.1% weight loss from 73°C to 144°C.
  • Pattern D is a degradation product with HPLC purity of about 0.2%. It was obtained in water by equilibration experiment experiments. It has two thermal events with T onset of about 41.4°C with an enthalpy of about 67 J/g and Tonset of about 72.1°C with an enthalpy of about 29 J/g. It shows about 0.6% weight loss at about 41°C and 8.5% weight loss from 41°C to 178°C.
  • Pattern E is an anhydrate of hemifumarate with HPLC purity of about 98.9%. It was obtained in acetone/toluene by equilibration experiment.
  • the ratio of free base form to fumaric acid of the mixture is about 1: 0.69 by 1 H NMR. It has two thermal events with Tonset of about 53.1°C with an enthalpy of about 33 J/g and T onset of about 96.5°C with an enthalpy of about 34 J/g. It shows about 1.0% weight loss at about 53°C and 3.6% weight loss from 53°C to 96°C. About 0.6% (by weight) acetone residue was detected by 1 H NMR. Results of the study on Compound I mono- and hemifumarate polymorphs are summarized in Table 45 below.
  • the salt ratio is the ratio between Compound I free base and the salt counterion.
  • AS indicates the form can be prepared by antisolvent addition, using the solvent/antisolvent pairs listed in the table.
  • EQ indicates the form can be prepared through equilibration in the listed solvent.
  • SC indicates the form can be prepared by slowly cooling a solution of Compound I monofumarate in the listed solvent.
  • FC indicates t the form can be prepared by quickly cooling a solution of Compound I monofumarate in the listed solvent. Table 45. Summary of identified Compound I fumarate salt Patterns A, B, C, and E Melting Polymorph Salt Temperatures Salt ratio Preparation E th l s, Example 29: Preparation of Compound II Pattern 1 Experiment 1.
  • XRPD diffractogram of Compound II Pattern 1 is shown in FIG.56.
  • Large-scale preparation Three grams of R P Compound I free base and 9 mL of IPA were added into a glass vial. To it was added 1.0 equiv. of fumaric acid and the resulting mixture was stirred at 50°C for 5 min. About 21 mg of Compound II Pattern 1 seeds from Experiment 1 were added into the mixture.30 mL of heptanes was added into the mixture.
  • Example 30 Preparation of Compound III Pattern 1 SP Compound I free base (100 mg) and 0.3 mL of IPA were added into a glass vial. To it was added 1.0 equiv. of fumaric acid and the mixture was stirred at 50°C for 15 min, most of the material was precipitated out.

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Abstract

La présente invention concerne un sel pharmaceutiquement acceptable d'un phosphonamidate de nucléotide acyclique pour traiter le PVH et des états associés comprenant la néoplasie, ainsi que des compositions pharmaceutiques, des formes morphiques et des formes posologiques de ceux-ci.
PCT/US2024/010538 2024-01-05 2024-01-05 Système de dispositif et utilisation pour une infection par hpv et une néoplasie intraépithéliale cervicale Pending WO2025147262A1 (fr)

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PCT/US2025/010220 WO2025147598A1 (fr) 2024-01-05 2025-01-03 Système de dispositifs et utilisation pour une infection par pvh et une néoplasie intraépithéliale cervicale

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US20160083407A1 (en) * 2014-09-15 2016-03-24 The Regents Of The University Of California Nucleotide analogs
US20210246153A1 (en) * 2015-09-15 2021-08-12 The Regents Of The University Of California Nucleotide Analogs

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160083407A1 (en) * 2014-09-15 2016-03-24 The Regents Of The University Of California Nucleotide analogs
US20210246153A1 (en) * 2015-09-15 2021-08-12 The Regents Of The University Of California Nucleotide Analogs

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