Diblock Terpolymers Are Tunable and pH Responsive Vehicles to Increase Hydrophobic Drug Solubility for Oral Administration

Swapnil Tale, Anatolii A. Purchel, Molly C. Dalsin, Theresa M. Reineke

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Synthetic polymers offer tunable platforms to create new oral drug delivery vehicles (excipients) to increase solubility, supersaturation maintenance, and bioavailability of poorly aqueous soluble pharmaceutical candidates. Five well-defined diblock terpolymers were synthesized via reversible addition-fragmentation chain transfer polymerization (RAFT) and consist of a first block of either poly(ethylene-alt-propylene) (PEP), poly(N-isopropylacrylamide) (PNIPAm), or poly(N,N-diethylaminoethyl methacrylate) (PDEAEMA) and a second hydrophilic block consisting of a gradient copolymer of N,N-dimethylacrylamide (DMA) and 2-methacrylamidotrehalose (MAT). This family of diblock terpolymers offers hydrophobic, hydrophilic, or H-bonding functionalities to serve as noncovalent sites of drug binding. Drug-polymer spray dried dispersions (SDDs) were created with a model drug, probucol, and characterized by differential scanning calorimetry (DSC). These studies revealed that probucol crystallinity decreased with increasing H-bonding sites available in the polymer. The PNIPAm-b-P(DMA-grad-MAT) systems revealed the best performance at pH 6.5, where immediate probucol release and effective maintenance of 100% supersaturation was found, which is important for facilitating drug solubility in more neutral conditions (intestinal environment). However, the PDEAEMA-b-P(DMA-grad-MAT) system revealed poor probucol dissolution at pH 6.5 and 5.1. Alternatively, at an acidic pH of 3.1, a rapid and high dissolution profile and effective supersaturation maintenance of up to 90% of the drug was found, which could be useful for triggering drug release in acidic environments (stomach). The PEP-b-P(DMA-grad-MAT) system showed poor performance (only ∼20% of drug solubility at pH 6.5), which was attributed to the low solubility of the polymers in the dissolution media. This work demonstrates the utility of diblock terpolymers as a potential new excipient platform to optimize design parameters for triggered release and solubilizing hydrophobic drug candidates for oral delivery.

Original languageEnglish (US)
Pages (from-to)4121-4127
Number of pages7
JournalMolecular pharmaceutics
Volume14
Issue number11
DOIs
StatePublished - Nov 6 2017

Bibliographical note

Funding Information:
We gratefully thank The Dow Chemical Company for funding this project. We thank Dr. Steven Guillaudeu, Dr. Robert Schmitt, and Dr. William Porter III at The Dow Chemical Company for helpful discussions and feedback. Further, we thank Dr. Ligeng Yin for providing the PEP-CTA macro-CTA for polymer synthesis. Also, we thank Jeff Ting for helping to create the TOC image for this paper. Parts of this work were carried out in the Characterization Facility at the University of Minnesota, a member of the NSF-funded Materials Research Facilities Network via the MRSEC program.

Publisher Copyright:
© 2017 American Chemical Society.

Keywords

  • Diblock terpolymers
  • hydrophobic drug solubility
  • oral administration
  • pH responsive

MRSEC Support

  • Shared

PubMed: MeSH publication types

  • Journal Article
  • Research Support, U.S. Gov't, Non-P.H.S.

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