塩酸モルヒネの経鼻吸収および脳内移行に及ぼすシクロデキストリン誘導体の影響

Abstract

The extent of systemic availability of morphine after the nasal administration of morphine hydrochloride in solution was much greater than those when the opioid was given orally in solution and rectally in suppository in rats. The ratio of area under the plasma level-time curve of intact morphine to the main metabolite, morphine-3-glucuronide for the nasal administration was about twice those for the oral and rectal administrations and almost equivalent to that for the intravenous administration. Furthermore, higher levels of morphine in the cerebrospinal fluid were attained after the nasal administration compared with the oral and rectal routes. The nasal administration of morphine produced a dose-dependent analgesic response, as measured by the hot-plate method. The efficacy of morphine to block the hot-plate response increased in the order : oral < nasal < subcutaneous route. The scanning electron microscopic observations and membrane permeability studies using a transport marker, 6-carboxyfluorescein revealed that morphine neither induced noticeable changes in surface morphology of the nasal mucosa nor affected the nasal membrane permeability to the transport marker. Dimethyl-β-cyclodextrin significantly enhanced the rate of nasal absorption of morphine by facilitating the nasal epithelial permeability and consequently increased the entry of the opioid into the cerebrospinal fluid. In contrast, 2-hydroxypropyl-γ-cyclodextrin sustained the plasma levels of morphine, probably through the formation of a complex that was less permeable through membranes. The present results suggest that the nasal cavity is a potential route of administration for morphine to bypass first-pass metabolism and is able to deliver the opioid more effectively into the central nervous system. A proper use of the cyclodextrin derivatives in nasal morphine preparations may provide adequate analgesia for both acute and chronic pain states, thus offering an improvement in patient comfort.