Compositions of 5-ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine
Inventors
McWherter, Charles A. • Martin, Robert Louis • Karpf, David B. • Roberts, Brian K. • Lorenz, Douglas Alan • Ketner, Rodney James
Assignees
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Publication Number
US-9241924-B2
Publication Date
2016-01-26
Expiration Date
Abstract
This invention relates to the field of pharmaceutical chemistry and, more specifically, to pharmaceutical formulations as well as to intermediates used to prepare such formulations and to methods for manufacturing such formulations.
Core Innovation
The disclosure relates to a pharmaceutical solid dispersion and related pharmaceutical formulations that include 5-ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine free base and a water soluble, biologically compatible polymer. The polymer is cellulose acetate phthalate, and the drug portion is non-crystalline to a defined extent.
The solid dispersion is characterized by from about 25% to about 100% by weight of the 5-ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine being non-crystalline, with compositions including about 25% by weight free base and about 75% by weight cellulose acetate phthalate. The disclosure also includes pharmaceutical formulations comprising a pharmaceutically inert carrier and the solid dispersion.
The solid dispersion is described in forms such as spray-dried dispersion or hot-melt extrudate, with additional quantitative limits on drug loading and particle dimensions. The document states that the non-crystalline dispersions provide improved dissolution and increased exposure relative to crystalline drug.
Claims Coverage
The independent claims in the provided set cover three claim areas: the composition of a non-crystalline solid dispersion using cellulose acetate phthalate, a specific quantitative drug-to-polymer composition within that solid dispersion, and a pharmaceutical formulation containing the solid dispersion in a pharmaceutically inert carrier. Across these independent claims, the inventive features center on the non-crystalline drug fraction and the use of cellulose acetate phthalate as the water soluble, biologically compatible polymer.
Non-crystalline solid dispersion with cellulose acetate phthalate polymer
A solid dispersion consisting of from about 10% to about 50% by weight of 5-ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine free base and a water soluble, biologically compatible polymer, wherein from about 25% to about 100% by weight of the 5-ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine is non-crystalline, and wherein the water soluble, biologically compatible polymer is cellulose acetate phthalate.
Quantified 25 wt% non-crystalline drug / 75 wt% cellulose acetate phthalate solid dispersion
A solid dispersion, comprising about 25% by weight 5-ethyl-2-{4-[4-(4-tetrazol-1yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine free base and about 75% by weight of cellulose acetate phthalate, wherein from about 25% to about 100% by weight of the 5-ethyl-2-{4-(4-tetrazol-1yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}pyrimidine is non-crystalline.
Pharmaceutical formulation with inert carrier and non-crystalline cellulose acetate phthalate solid dispersion
A pharmaceutical formulation comprising a pharmaceutically inert carrier and a solid dispersion, the solid dispersion consisting of from about 10% to about 50% by weight of 5-ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine free base, and a water soluble, biologically compatible polymer, wherein from about 25% to about 100% by weight of the 5-ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine is non-crystalline and wherein the water soluble biologically compatible polymer is cellulose acetate phthalate.
Across the independent claims, the key scope is directed to a solid dispersion of the specified free base with a water soluble, biologically compatible polymer wherein the drug portion is non-crystalline and the polymer is cellulose acetate phthalate, optionally expressed in specific quantitative composition and incorporated into a pharmaceutical formulation with a pharmaceutically inert carrier.
Stated Advantages
Improved dissolution and enhanced drug exposure relative to crystalline drug, including increased Cmax and AUC.
Improved solubility/bioavailability is achieved when at least part of Compound A is in a non-crystalline form.
Documented Applications
Treatment methods for type I diabetes, type II diabetes, and metabolic syndrome are described in the document.
GPR119-mediated cellular activity is described, including intracellular Ca2+ increase in GPR119-expressing cells.
Insulin/glucose-dependent insulin secretion is described, including incretin production (GLP-1 and GIP) and insulin production in pancreatic/islet/beta cells as well as intestinal endocrine L/K cells.
Phase 1 clinical study design/outcomes including pharmacokinetics and pharmacodynamic effects on fasting glucose and OGTT/MMTT.
Tablet formulation and film-coated tablets with sink dissolution comparisons.
Solid-dispersion drug-product development including in vitro dissolution and in vivo dog exposure comparisons for non-crystalline versus crystalline drug.
Formulations for a diabetes/metabolic-disorder active compound using pharmaceutical formulations of Compound A with pharmaceutically inert carriers and solid dispersions.
Solid-dispersion intermediates comprised of a non-crystalline Compound A solid dispersion.
Solid-dispersion physical forms including a spray-dried dispersion or a hot-melt extrudate.
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