Compositions and dosage forms for treatment of HPV infection and HPV-induced neoplasia
Inventors
Aldous, Barry • Gadiraju, Ramakrishna • Argade, Ankush • Zhao, Zhengle • JIANG, Siyi • LI, Runyan • Liu, Chao • Liu, Minyan
Assignees
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Publication Number
US-12329768-B2
Publication Date
2025-06-17
Expiration Date
Abstract
A pharmaceutically acceptable salt of an acyclic nucleotide phosphoramidate to treat HPV and related conditions including neoplasia, as well as pharmaceutical compositions, morphic forms and dosage forms thereof.
Core Innovation
The invention provides pharmaceutically acceptable salt forms of acyclic nucleotide phosphoramidate prodrug compounds, including Compound I, Compound II, and related compound salts. It emphasizes enantiomerically enriched stereochemistry, including R chirality at the phosphorus atom and S chirality at the alanine carbon, and describes monofumarate, hemifumarate, sesquifumarate, sulfate, hydrochloride, benzenesulfonate, tosylate, and succinate forms.
A key embodiment is the fumarate salt of (R_P,S_C) ethyl ((2-(2-amino-6-methoxy-9H-purin-9-yl)ethoxy)methyl)(benzyloxy)phosphoryl)-L-alaninate, referred to as Compound II. The disclosure contrasts Compound II with other stereoisomers and with prior art ABI-1968, and describes amorphous or crystalline solid forms with XRPD-based pattern specifications, including Pattern 1 for Compound II.
The document further addresses salt screening and characterization, including stoichiometry, residual solvents/water, purity, bulk stability, solubility across multiple pH media including simulated vaginal fluid, hygroscopicity, polymorph screening, crystallization behavior, and transformations under heating/cooling and mechanical stress. It also reports improved topical tissue penetration in porcine and human vaginal/cervical tissues together with improved physical properties, high crystallinity, low hygroscopicity, nonhygroscopic behavior, and unexpected stability and processability of the monofumarate salt embodiment.
Claims Coverage
The provided independent claims cover compound salts defined by formula and isomeric enrichment at the phosphorus atom. Across the identified independent claims, the main inventive features are greater than 50% R chirality at phosphorus, specified compound-salt formula, and crystalline compound salt form.
Greater than 50% R chirality at phosphorus
A compound salt of the formula, wherein the compound salt is isomerically enriched by greater than 50% by weight with R chirality at the phosphorus atom.
Specified compound-salt formula
A compound salt defined by the specified chemical formula shown in the figures/images.
Crystalline compound salt form
The compound salt is crystalline.
Overall, the claim coverage focuses on compound salts defined by formula and, where specified, on isomeric enrichment with R chirality at the phosphorus atom, with dependent claim coverage narrowing the material form to crystalline compound salts.
Stated Advantages
Improved topical tissue penetration in porcine and human vaginal/cervical tissues.
Improved physical properties including high crystallinity, low hygroscopicity, and nonhygroscopic behavior.
Unexpected stability and processability of the monofumarate salt.
Monofumarate shows superior properties to hemifumarate and monosuccinate and remains the desired salt form.
Documented Applications
Treating HPV infection.
Treating HPV-induced intraepithelial neoplasia, including progression prevention toward cancer.
Treatment context includes high-risk HPV types, including HPV-16/18 and other listed high-risk HPV types.
Topical delivery use cases for treating HPV infection and HPV-induced intraepithelial neoplasia.
Salt screening and characterization for Compound I free base, hemifumarate, and monofumarate, including evaluation of bulk stability, solubility in multiple pH media including simulated vaginal fluid, and hygroscopicity.
Polymorph screening and crystallization behavior characterization for fumarate salts, including identification of additional fumarate salt patterns and observations of transformation under heating/cooling and mechanical stress.
Preparation and characterization of additional compound salts (Compound II/III and others) including stability, solubility, hygroscopicity, XRPD peak list characterization, and single-crystal XRD for Compound II Pattern 1.
Topical treatment of human papillomavirus, including HPV-16 and HPV-18, using therapeutic cycles and topical formulations such as gel, cream, and tablet.
Treatment of vaginal intraepithelial neoplasia, vulvar intraepithelial neoplasia, cervical intraepithelial neoplasia, anal intraepithelial neoplasia, perianal intraepithelial neoplasia, and penile intraepithelial neoplasia.
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