Formulation strategies for the stabilization of tetanus toxoid in poly(lactide-co-glycolide) microspheres.
The development of a single-dose tetanus vaccine based on Poly(Lactic acid) (PLA) or Poly(Lactide-co-Glycolide) (PLGA) microspheres has been complicated due to the instability of tetanus toxoid (TT) inside these systems. Herein we report an attempt to re-design PLGA microspheres by co-encapsulating TT in the dry solid state together with potential protein stabilizers, such as trehalose, bovine serum albumin, alginate, heparin, dextran or poloxamer 188 and by using an appropriate microencapsulation technique. These newly developed PLGA microspheres were able to release in vitro antigenically active TT for at least 5 weeks, the amount released being highly dependent on the stabilizing excipient used. More specifically, results showed that dextran and heparin provided a particularly stabilizing environment for TT inside the microspheres during the polymer degradation process. The efficacy of this strategy was demonstrated by the high, long lasting titers of neutralizing antibodies achieved after in vivo administration of dextran-containing microspheres with a small amount of alum-adsorbed TT, as compared to the commercial adsorbable tetanus vaccine. These findings suggest that future developments in the area of vaccinology depend on ability to combine a detailed knowledge of the microencapsulation technology with a rational choice of stabilizing excipient or combination of excipients.
Sánchez
A
A
Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Santiago de Compostela, 15706, Santiago de Compostela, Spain.
Villamayor
B
B
Guo
Y
Y
McIver
J
J
Alonso
M J
MJ
D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003692:Delayed-Action Preparations; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry; D005260:Female; D007074:Immunoglobulin G / Q000096:biosynthesis; D019344:Lactic Acid / Q000737:chemistry*; D051379:Mice; D008863:Microspheres; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry*; D011134:Polysaccharides / Q000737:chemistry; D012710:Serum Albumin, Bovine / Q000737:chemistry; D012965:Sodium Chloride / Q000737:chemistry; D013501:Surface-Active Agents / Q000737:chemistry; D013745:Tetanus Toxoid / Q000737:chemistry* / Q000276:immunology
D001672:Biocompatible Materials; D003692:Delayed-Action Preparations; D005079:Excipients; D007074:Immunoglobulin G; D011108:Polymers; D011134:Polysaccharides; D013501:Surface-Active Agents; D013745:Tetanus Toxoid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D012710:Serum Albumin, Bovine; D019344:Lactic Acid; D012965:Sodium Chloride