Masters D B, Domb A J
Department of Anesthesiology, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
Pharm Res. 1998 Jul;15(7):1038-45. doi: 10.1023/a:1011978010724.
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.
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.
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.
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.
本研究旨在确定脂质球（由甘油三酯制成、外层包裹磷脂的含药固体填充囊泡）的药物递送能力，以评估其在体外释放局部麻醉药以及在体内产生持续外周神经阻滞的效果。
将局部麻醉药布比卡因制成多种剂型载入脂质球，对其进行表征并测定体外释放情况。在大鼠中，将脂质球注入坐骨神经周围肌肉层之间的大间隙中，以评估体内的感觉和运动阻滞。
脂质球的粒径测定为5至15微米，表面磷脂含量超过90%。在理想的漏槽条件下，脂质球在两天内释放布比卡因。脂质球用于神经产生了剂量依赖性且可逆的阻滞。事实上，在各种体内试验中观察到持续局部麻醉阻滞（SLAB）达1至3天：a）应用3.6%或5.6%布比卡因 - 脂质球后，后爪对有害热刺激的退缩潜伏期在96小时内增加超过50%。根据72小时的释放情况估计，3.6%和5.6%剂量分别以200和311微克药物/小时的速度释放布比卡因。应用1.6%布比卡因 - 脂质球使退缩潜伏期增加25 - 250%，但仅持续24小时；b）同样，应用3.6%布比卡因 - 脂质球后72小时内，后爪刺激的发声阈值增加25 - 50%；c）最后，对于所有脂质球药物剂量，感觉阻滞持续时间长于或等于相应的运动阻滞持续时间。
局部麻醉药的脂质球递送可能非常适合神经组织的位点特异性药物治疗以产生SLAB。作用持续时间的剂量依赖性效应可能包括亲脂性组织储存。
