Hydrophobic molecule-induced branched polymer aggregates and their use
Inventors
Qin, Dujie • Yin, Ray • Pan, Jing • Zhang, Yubei
Assignees
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Publication Number
US-10688048-B2
Publication Date
2020-06-23
Expiration Date
Abstract
Symmetrically and asymmetrically branched homopolymers are modified at the surface level with functional groups that enable forming aggregates with water insoluble or poorly water soluble pharmaceutically active agents (PAA). The aggregates formed are specifically induced by interaction of PAA and homopolymer and are different from aggregates that are formed by the polymer alone in the absence of the PAA or by the PAA alone in the absence of the polymer. Such aggregates can be used to improve drug solubility, stability, delivery and efficacy.
Core Innovation
The invention relates to a lyophilized aggregate in which a poorly water soluble or water insoluble pharmaceutically active agent is made to be water soluble. The lyophilized aggregate is produced by forming an aggregate from the pharmaceutically active agent and a water soluble polyoxazoline that is surface modified with a hydrophobic surface group comprising hydrocarbons, aromatic hydrocarbons, or combinations thereof.
The pharmaceutically active agent is located at or in the hydrophobic surface group. The process yields a lyophilized aggregate that, upon dilution in an aqueous solution, releases the pharmaceutically active agent at a controlled rate.
The described making method includes mixing the pharmaceutically active agent with the hydrophobically surface-modified water soluble polyoxazoline, forming the aggregate, collecting it by removing the solvents to yield a collected aggregate, dissolving the collected aggregate in an aqueous solution to form a dissolved aggregate solution, and lyophilizing to form the lyophilized aggregate.
Claims Coverage
The provided claim set contains one independent claim. Across the dependent claims, the claim coverage adds refinements to solvents, the hydrophobic surface group composition, polyoxazoline modification, handling steps, and additional formulation options.
Lyophilized aggregate with PAA at hydrophobic surface group and controlled release
A method of making a lyophilized aggregate by forming an aggregate from a water insoluble or poorly water soluble PAA and a water soluble polyoxazoline modified with a hydrophobic surface group, wherein the PAA is located at or in the surface group; the lyophilized aggregate is water soluble and releases the PAA at a controlled rate upon dilution in an aqueous solution.
Aggregate formation using specified solvent system and water-miscible/organic solvents
Mixing the PAA dissolved in a solvent miscible with water or a chloroform/ethanol mixture with the water soluble polyoxazoline modified with a hydrophobic surface group dissolved in an organic solvent to form an aggregate.
Collection by solvent evaporation to remove miscible and organic solvents
Collecting the aggregate by evaporating to remove the solvent miscible with water or the chloroform/ethanol mixture and to remove the organic solvent to yield a collected aggregate.
Controlled release retention after aqueous dissolution and lyophilization
Dissolving the collected aggregate in an aqueous solution to form a dissolved aggregate solution and lyophilizing the dissolved aggregate solution to form the lyophilized aggregate with the PAA at or in the hydrophobic surface group and controlled rate release upon aqueous dilution.
Solvent refinement for water-miscible solvent selection
The water-miscible solvent comprises acetone.
Hydrophobic surface group refinement to aromatic group
The surface group includes an aromatic group.
Hydrophobic surface group refinement to saccharide
The hydrophobic surface group includes a saccharide.
Polyoxazoline modification refinement with an additional amine group
The method further includes modifying a polyoxazoline so it contains an additional amine group.
Handling/processing refinement via filtering prior to lyophilizing
Filtering the dissolved aggregate solution from the aqueous dissolved aggregate step before the lyophilizing step.
Overall, the independent claim coverage centers on making a water soluble lyophilized aggregate by associating a poorly water soluble or water insoluble PAA with a hydrophobically surface-modified water soluble polyoxazoline, then dissolving and lyophilizing so that, on aqueous dilution, the PAA is released at a controlled rate. The dependent claims refine solvent choice, hydrophobic surface group composition, additional polyoxazoline functionalization, and a filtering step prior to lyophilization.
Stated Advantages
Provides a lyophilized aggregate that is water soluble.
On dilution in an aqueous solution, releases the pharmaceutically active agent at a controlled rate.
Documented Applications
Improved cytotoxicity and increased maximum tolerated dose versus Taxol in an in vivo xenograft model.
Tumor growth inhibition in a xenograft model.
Camptothecin aggregation versus CPT-11, with associated cytotoxicity outcomes.
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