Liposphere local anesthetic timed-release for perineural site application.
OBJECTIVE
This investigation determines the drug delivery capacity of Lipospheres, which are drug-containing solid-filled vesicles made of triglyceride with a phospholipid outer covering, to release local anesthetic in vitro and to produce sustained peripheral nerve block in vivo.


METHODS
The local anesthetic, bupivacaine, was loaded into Lipospheres in several dosage forms, characterized, and measured for in vitro release. In rats, Lipospheres were administered into a large space between muscle layers surrounding the sciatic nerve to assess sensory and motor block in vivo.


RESULTS
The particle size of Lipospheres was determined to be between 5 and 15 microm, with over 90% surface phospholopid. Lipospheres released bupivacaine over two days under ideal sink conditions. Liposphere nerve application produced dose-dependent and reversible block. Indeed, sustained local anesthetic block (SLAB) was observed for 1-3 days in various in vivo tests: a) Hind paw withdrawal latency to noxious heat was increased over 50% for 96 hr period after application of 3.6% or 5.6% bupivacaine-Lipospheres. The 3.6% and 5.6% doses were estimated to release bupivacaine at 200 and 311 microg drug/ hr, respectively, based on release spanning 72 hr. Application of 1.6% bupivacaine-Lipospheres increased withdraw latency 25-250% but for only a 24 hr duration; b) Similarly, vocalization threshold to hind paw stimulation was increased 25-50% for 72 hr following application of 3.6% bupivacaine-Lipospheres; c) Finally, sensory blockade outlasted or equaled corresponding motor block duration for all Liposphere drug dosages.


CONCLUSIONS
Liposphere delivery of local anesthetic drugs may be well suited for site-specific pharmacotherapy of neural tissue to produce SLAB. Dose-dependent effects in duration of action may include lipophilic tissue storage.
Masters
D B
DB
Department of Anesthesiology, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA. Masters.David@Mayo.Edu
Domb
A J
AJ
D000779:Anesthetics, Local / Q000008:administration & dosage*; D000818:Animals; D002045:Bupivacaine / Q000008:administration & dosage; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D004333:Drug Administration Routes; D016503:Drug Delivery Systems; D008081:Liposomes; D008297:Male; D008863:Microspheres; D009407:Nerve Block / Q000379:methods; D010147:Pain Measurement / Q000187:drug effects; D010316:Particle Size; D010743:Phospholipids / Q000008:administration & dosage / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000187:drug effects*; D014280:Triglycerides / Q000008:administration & dosage / Q000737:chemistry
D000779:Anesthetics, Local; D003692:Delayed-Action Preparations; D008081:Liposomes; D010743:Phospholipids; D014280:Triglycerides; D002045:Bupivacaine