Alkaline phosphatase formulations
Inventors
WACHER, Vincent • West, J. Blair • Kaleko, Michael • FURLAN FREGUIA, Christian
Assignees
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Publication Number
US-12048735-B2
Publication Date
2024-07-30
Expiration Date
Abstract
The present invention provides, in part, formulations comprising an alkaline phosphatase (AP)-based agent. Particularly, modified-release powder formulations comprising an AP-based agent are provided which release a substantial amount of the AP-based agent in the intestines. Therapeutic uses of the formulations are also provided.
Core Innovation
The invention relates to alkaline phosphatase (AP)-based modified-release pharmaceutical formulations that remain stable in gastric fluid and release substantial AP in the intestines. The disclosure includes AP formulations in powder/matrix systems and enteric-coated tablet/capsule formats, where release behavior is tied to intestinal conditions and gastric exposure.
A compressible tablet formulation is provided comprising an alkaline phosphatase (AP) and hypromellose acetate succinate (HPMCAS) polymer, together with buffer, zinc, magnesium stearate, and a protein stabilizer, wherein the formulation releases the AP in the intestines. The formulation is described as compressible and configured to release the AP in the small intestine, with variants that refine release to the large intestine.
The disclosed AP-based agents include intestinal mammalian IAP and other AP variants, including engineered sequences and pro-enzyme concepts with protease-activated cleavage sites, as well as constructs involving cysteine modifications, GPI-anchor disruption/stop codons for secretion, and Fc fusion extensions. Formulation stabilization is described with components such as zinc, magnesium, and protein stabilizers such as trehalose, together with enteric polymer coatings including HPMCAS/HPMCAS-HF and EUDRAGIT-type coatings, and acid-triggered tablet-to-gel transformation in the presence of stomach acid.
Claims Coverage
The document contains one independent claim directed to a compressible tablet formulation for intestinal AP release, with dependent claims specifying intestinal release location, acid-triggered transformation into a gel, additional polymer inclusion, and more specific weight-percentage composition ranges.
Compressible HPMCAS tablet releasing AP in the intestines
A formulation comprising an alkaline phosphatase (AP) as a compressible tablet that comprises about 1-10% by weight AP, about 80-95% by weight hypromellose acetate succinate (HPMCAS) polymer, about 1-10% by weight buffer, about 0.01-0.1% by weight zinc, about 0.1-1% by weight magnesium stearate, and about 1-10% by weight protein stabilizer, wherein the formulation releases the AP in the intestines.
Small intestine AP release
The formulation is configured so that AP is released in the small intestine.
Acid-triggered tablet to gel transformation
The tablet converts into a gel when exposed to stomach acid.
Additional poly(methacrylic acid, methylmethacrylate) polymer
The tablet formulation further includes a poly(methacrylic acid, methylmethacrylate) polymer.
Defined weight-percent composition for the HPMCAS tablet
The tablet formulation is characterized by specified weight percentages of AP, the HPMCAS polymer, a buffer, zinc, magnesium stearate, and a protein stabilizer.
Overall, the claim set centers on a compressible HPMCAS-based tablet containing an AP with defined excipient ranges to achieve intestinal AP release, with dependent refinements for small-intestine release, stomach-acid tablet-to-gel transformation, optional additional polymer inclusion, and more specific composition constraints.
Stated Advantages
Releases the AP in the intestines while being designed to remain stable in gastric fluid.
Documented Applications
Therapeutic methods for celiac disease symptom treatment and assessment using intestinal permeability and inflammatory outcomes, including LAMA ratio, anti-transglutaminase antibodies, CeD PRO, GSRS/CeD GSRS, and BSFS.
Treatment related to gastrointestinal disorders associated with HIV enteropathy, including addressing intestinal barrier dysfunction and immune activation markers, and references to HIV enteropathy subtypes and gut dysbiosis.
Treatment of gastrointestinal dysfunction and dysbiosis in cystic fibrosis in association with CFTR mutation types.
Prevention and/or treatment of necrotizing enterocolitis (NEC) in pediatric patients, with reference to microbiota restoration goals and Bell et al. staging system.
Broader therapeutic contexts described in the document include metabolic syndrome, obesity, and diabetes (type 1/type 2) with related gastrointestinal dysfunction context.
Treatment or mitigation of microbiome- and GI-related diseases, including dysbiosis, antibiotic-associated adverse effects, and C. difficile-associated disease.
Treatment of metabolic disorders.
Treatment of neurological diseases.
Treatment of sepsis.
Treatment of renal failure.
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