Encapsulation of exenatide in poly-(D,L-lactide-co-glycolide) microspheres produced an investigational long-acting once-weekly formulation for type 2 diabetes

Diabetes Technol Ther. 2011 Nov;13(11):1145-54. doi: 10.1089/dia.2011.0050. Epub 2011 Jul 13.

Abstract

Exenatide once-weekly (EQW [2 mg s.c.]) is under development as monotherapy as an adjunct to diet and exercise or as a combination therapy with an oral antidiabetes drug(s) in adults with type 2 diabetes. This long-acting formulation contains the active ingredient of the original exenatide twice-daily (EBID) formulation encapsulated in 0.06-mm-diameter microspheres of medical-grade poly-(D,L-lactide-co-glycolide) (PLG). After mechanical suspension and subcutaneous injection by the patient, EQW microspheres hydrate in situ and adhere to one another to form an amalgam. A small amount of loosely bound surface exenatide, typically less than 1%, releases in the first few hours, whereas drug located in deeper interstices diffuses out more slowly (time to maximum, ~2 weeks). Fully encapsulated exenatide (i.e., drug initially inaccessible to diffusion) releases over a still longer period (time to maximum, ~7 weeks) as the PLG matrix hydrolyzes into lactic acid and glycolic acid, which are subsequently eliminated as carbon dioxide and water. For EQW, plasma exenatide concentrations reach the therapeutic range by 2 weeks and steady state by 6-7 weeks. This gradual approach to steady state seems to improve tolerability, as nausea is less frequent with EQW than EBID. EQW administrations may be associated with palpable skin nodules that generally resolve without further medical intervention. In comparative trials, EQW improved hemoglobin A1c more than EBID, sitagliptin, pioglitazone, or insulin glargine and reduced fasting plasma glucose more than EBID. Weight loss due to EQW or EBID was similar. EQW is the first glucose-lowering agent that is administered once weekly.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adult
  • Blood Glucose / drug effects
  • Capsules
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Exenatide
  • Glycated Hemoglobin A / analysis
  • Humans
  • Hypoglycemic Agents / administration & dosage*
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / pharmacokinetics
  • Injections, Subcutaneous
  • Insulin Glargine
  • Insulin, Long-Acting / administration & dosage
  • Insulin, Long-Acting / adverse effects
  • Lactic Acid / administration & dosage*
  • Lactic Acid / adverse effects
  • Lactic Acid / metabolism
  • Peptides / administration & dosage*
  • Peptides / adverse effects
  • Peptides / pharmacokinetics
  • Pioglitazone
  • Polyglycolic Acid / administration & dosage*
  • Polyglycolic Acid / adverse effects
  • Polyglycolic Acid / metabolism
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Pyrazines / administration & dosage
  • Pyrazines / adverse effects
  • Sitagliptin Phosphate
  • Thiazolidinediones / administration & dosage
  • Thiazolidinediones / adverse effects
  • Triazoles / administration & dosage
  • Triazoles / adverse effects
  • Venoms / administration & dosage*
  • Venoms / adverse effects
  • Venoms / pharmacokinetics

Substances

  • Blood Glucose
  • Capsules
  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Insulin, Long-Acting
  • Peptides
  • Pyrazines
  • Thiazolidinediones
  • Triazoles
  • Venoms
  • hemoglobin A1c protein, human
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Polyglycolic Acid
  • Insulin Glargine
  • Lactic Acid
  • Exenatide
  • Sitagliptin Phosphate
  • Pioglitazone