Development of a novel high-concentration galantamine formulation suitable for intranasal delivery
Development of a novel high-concentration galantamine formulation suitable for intranasal delivery
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DOI：
10.1002/jps.20389
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发表时间：
2005-08-01
影响因子：
3.8
通讯作者：
Costantino, HR
中科院分区：
文献类型：
--
作者：
Leonard, AK;Sileno, AP;Costantino, HR
目前这项研究的目标是开发乙酰胆碱酯酶抑制剂加兰他明的鼻腔(IN)配方，加兰他明是治疗阿尔茨海默病的重要疗法。为了能够提供与治疗相关的剂量，有必要大大提高药物的溶解度。为此，研究了各种方法，包括添加共溶剂、环糊精和反离子交换。其中，后者，例如，用乳酸盐或葡萄糖酸盐取代溴离子，导致药物的溶解度显著增加，超过12倍。核磁共振确证了新药盐类的分子结构。采用体外上皮组织模型评价药物通透性和细胞毒性。在体外，乳酸加兰他敏制剂在药物透过上皮膜方面的表现与氢溴酸(HBr)的对应物一样或更好，毒性最小。在大鼠体内的研究比较了不同配方的药代动力学(PK)。体内研究证实，IN加兰他明达到了与传统口服给药相当的全身血液水平。体外和体内数据均支持IN给药的可行性。(C)2005年Wiley-Liss，Inc.
The goal of the current study was to develop an intranasal (IN) formulation of the acetylcholinesterase inhibitor galantamine, an important therapeutic for treating Alzheimer's disease. To allow for delivering a therapeutically relevant dose, it was necessary to greatly enhance drug solubility. Various approaches were examined to this end, including adding co-solvents, cyclodextrins, and counterion exchange. Of these, the latter, for example, replacement of bromide ion with lactate or gluconate, resulted in a dramatic drug solubility increase, more than 12-fold. NMR confirmed the molecular structure of new drug salt forms. An in vitro epithelial tissue model was used to assess drug permeability and cellular toxicity. In vitro, galantamine lactate formulations performed as well as or better than their hydrobromide (HBr) counterparts with respect to drug permeation across the epithelial membrane with minimal toxicity. In vivo studies in rats compared pharmacokinetic (PK) profiles of different formulations. The in vivo studies confirmed that IN galantamine achieves systemic blood levels comparable to those of conventional oral administration. Both the in vitro and in vivo data support the feasibility of IN administration of this important drug. (c) 2005 Wiley-Liss, Inc.