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DOI: 10.1007/s11095-012-0880-8Pages: 627-640

Evaluation of Poly (1, 6-bis-(p-carboxyphenoxy) Hexane-co-sebacic Acid Microspheres for Controlled Basal Insulin Delivery

1. North Dakota State University, Department of Pharmaceutical Sciences College of Pharmacy Nursing, & Allied Sciences

2. Isis Pharmaceuticals, Inc.

Correspondence to:
Jagdish Singh
Tel: +1-701-2317943
Fax: +1-701-2318333
Email: Jagdish.Singh@ndsu.edu

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Abstract

Purpose

To develop poly 1,3-bis-(p-carboxyphenoxy) hexane-co-sebacic acid (p(CPH/SA)) microspheres for controlled basal insulin delivery and evaluate their in vivo efficacy and toxicity.

Methods

A series of CPH/SA copolymers with molar ratios 20/80, 40/60, and 50/50 were synthesized and characterized. The stability of encapsulated insulin and the fraction of insulin released from microspheres were assessed by different analytical techniques. The skin from the injection site of rats was examined microscopically for histomorphological changes.

Results

Increasing the molar ratio of CPH/SA significantly (p < 0.05) improved insulin loading and controlled insulin release. However, dimer aggregates of insulin were observed as CPH/SA molar ratio increased. Co-encapsulation of zinc oxide with insulin inhibited dimer aggregate formation and further controlled insulin release. Insulin was stable after entrapment into microspheres and during in vitro release studies. Administration of microsphere formulations CPH/SA 40/60 and 50/50 with zinc oxide controlled insulin release and maintained basal insulin levels for 42 days in rats. Skin sections showed minimal inflammation with no evidence for histomorphological changes and toxicity.

Conclusions

Insulin-loaded CPH/SA microspheres demonstrated considerable potential as controlled delivery system for insulin. Copolymer microspheres maintained basal insulin levels for 42 days and were biodegradable and biocompatible.

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  • Accepted: Aug 29, 2012
  • Online: Sep 14, 2012

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