Degradable compounds and methods of use thereof, particularly with particle replication in non-wetting templates

Inventors

DeSimone, Joseph • Parrott, Matthew • Murphy, Andrew • Petros, Robby A.

Assignees

University of North Carolina at Chapel Hill • Liquidia Technologies Inc

Abstract

The present invention provides compounds that will degrade under specified conditions, methods of using such compounds, and compositions comprising such compounds. The degradable compounds of the invention may be characterized by the labile —Si-A-C— groups present in the compounds (A representing an atom, such as O, N, or S, or a group, such as C═O). The compounds may be incorporated into a composition that further may include a polymeric matrix and/or a cargo component. A wide variety of cargo components may also be used in the present invention. In particular embodiments, the cargo component comprises a drug or other therapeutic agent. Accordingly, the invention particularly provides pharmaceutical formulations and methods of delivering a drug or other therapeutic material.

Core Innovation

The disclosed invention relates to degradable and labile silicon-containing compounds having labile —Si-A-C— groups, where A is O, N, S, or C(O), and to surface-activated microparticles and nanoparticles formed with functionalized labile linkers. The compounds are defined by multiple structural formulas including Formula (1a) and Formula (1b) and derived forms (2)-(6), and the labile linkers include halo-functional and chlorosilyl-type linkers that form pH-sensitive silane bonds between a functionalized silane and a cargo component.

The degradable compounds are stable under defined conditions but degrade under specified triggers, including physiological temperature and acidic or pH conditions, including pH-labile degradation associated with cellular endosome pH. The degradation rate is tuned by the structure of the labile linker, including Si substituents and linker/spacer length, such as PEG spacers and hydroxy-terminated spacers, and the disclosure includes acid-labile degradable dimethyl silane, diethyl silane, and diisopropyl silane.

The disclosed compounds are used as degradable components in compositions, including as crosslinkers or matrix components within a polymeric matrix. In the molded particle context, the degradable compound crosslinks the biodegradable polymer of the matrix, and the molded particle is stable at higher pH and degrades at lower pH; the disclosure also includes silane-protected water-soluble polymers that insolubilize at neutral pH and solubilize under lower pH.

Claims Coverage

The document provides two independent claims. Independent claim 1 covers a molded particle with a degradable, crosslinking silicon-containing compound in a biodegradable polymer matrix, together with defined pH-dependent stability and degradation performance. Independent claim 7 covers a composition containing two different molded particle types, with at least one particle type defined by the same degradable compound and matrix crosslinking relationship and the same pH-dependent stability/degradation requirement.

Overall, the claim coverage centers on pH-responsive molded particles in which a degradable Formula (3) silicon-containing compound degrades under physiological conditions and crosslinks a biodegradable polymer matrix, yielding stability at pH 7.4 or higher for more than 24 hours and degradation in less than 2 hours at pH 5.0 or lower. The second independent claim extends this concept to compositions containing first and second molded particle types that differ from one another while maintaining the same crosslinking and pH-responsive performance requirement for at least one particle type.

Stated Advantages

Documented Applications