The utility of 2-hydroxypropyl-beta-cyclodextrin as a vehicle for the intracerebral and intrathecal administration of drugs.
The substituted glucopyranose ring structure 2-hydroxypropyl-beta-cyclodextrin (CDEX) increases the solubility of molecules by inclusion of the agent in the lipophilic interior of the ring. This property is of particular use for the administration of molecules by the intracerebral (ICV) or intrathecal (IT) routes. In concentrations up to 40% w/v (isotonic), this agent (10 microliters) effect upon nociceptive or motor function after IT injection or on EEG and general behavior after ICV injection in rats. Using 20% CDEX, there is no change in the ED50 as compared to saline on the hot plate (HP) after IT injection of morphine, D-Ala2-D-Leu5 enkephalin or Tyr-Aib-Gly-gPhe-mAib-NH2, (Aib: alpha-aminoisobutyric acid) although there is an increase in their respective durations of effect. Cyclic peptide opioids: Tyr-c[D-A2bu-Gly-D-beta Nal(1)-D-Leu] (A2bu: alpha, gamma-diaminobutyric acid; beta-Nal(1): beta-naphthylalanine(1)) or Tyr-c[DA2bu-Gly-beta Nal(1)-D-Leu] are insoluble in saline but are readily dissolved in CDEX, and display a naloxone-sensitive antinociception following spinal administration. In other studies, saline insoluble capsaicin is administered in 25% dimethylsulfoxide (DMSO) or 20% CDEX (15 microliters; 5 mg/ml) which result in a significant reduction in the spinal levels of substance P and calcitonin gene related peptide and an increase in the HP latency. DMSO alone, but not CDEX alone, reduces the levels of the two peptides. These data emphasize the utility of complexation with CDEX for intracerebral drug delivery and compatibility with brain and spinal tissue.
Yaksh
T L
TL
Department of Anesthesiology, University of California, San Diego, La Jolla 92093.
Jang
J D
JD
Nishiuchi
Y
Y
Braun
K P
KP
Ro
S G
SG
Goodman
M
M
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000698:Analgesia; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002211:Capsaicin / Q000008:administration & dosage / Q000494:pharmacology; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology*; D003505:Cyclodextrins; D004121:Dimethyl Sulfoxide; D004569:Electroencephalography; D016308:Enkephalin, Leucine-2-Alanine / Q000008:administration & dosage / Q000494:pharmacology; D007276:Injections, Intraventricular / Q000379:methods*; D007278:Injections, Spinal / Q000379:methods*; D008297:Male; D009020:Morphine / Q000008:administration & dosage* / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D009270:Naloxone / Q000494:pharmacology; D009294:Narcotics / Q000008:administration & dosage* / Q000494:pharmacology; D010146:Pain / Q000503:physiopathology; D014677:Pharmaceutical Vehicles; D051381:Rats; D011919:Rats, Inbred Strains; D012995:Solubility; D013373:Substance P / Q000378:metabolism; D013997:Time Factors; D047391:alpha-Cyclodextrins; D047392:beta-Cyclodextrins; D047408:gamma-Cyclodextrins
D003505:Cyclodextrins; D009294:Narcotics; D014677:Pharmaceutical Vehicles; D047391:alpha-Cyclodextrins; D047392:beta-Cyclodextrins; D047408:gamma-Cyclodextrins; C479658:hydroxypropyl-alpha-cyclodextrin; C479659:hydroxypropyl-gamma-cyclodextrin; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D013373:Substance P; D009270:Naloxone; D016308:Enkephalin, Leucine-2-Alanine; D009020:Morphine; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin; D004121:Dimethyl Sulfoxide