dipalmitoyl apomorphine | 42337-33-7

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 原小檗碱生物碱及其衍生物
• 英文名称: dipalmitoyl apomorphine
• 英文别名: Apomorphine palmitate；[(6aR)-11-hexadecanoyloxy-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinolin-10-yl] hexadecanoate
• CAS: 42337-33-7
• 化学式: C₄₉H₇₇NO₄
• 分子量: 744.155
• InChiKey: MAFITCMHQZUUQZ-VZUYHUTRSA-N

物化性质

• 沸点：
  775.8±60.0 °C(Predicted)
• 密度：
  0.997±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  17.2
• 重原子数：
  54
• 可旋转键数：
  32
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  55.8
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  盐酸去水吗啡 、 棕榈酰氯 在 三氟乙酸 作用下， 以72%的产率得到dipalmitoyl apomorphine
  参考文献：
  名称：

  Lipophilic prodrugs of apomorphine I: Preparation, characterisation, and in vitro enzymatic hydrolysis in biorelevant media

  摘要：

  Apomorphine, a subcutaneously administered drug for Parkinson's disease with short half-life requires frequent administration leading to patient non-compliance. This study aimed at synthesising and purifying lipophilic diesters of apomorphine, and investigating their in vitro degradation in biorelevant media before and after incorporating them into self-emulsifying drug delivery systems (SEDDS) for oral delivery.Two apomorphine diester prodrugs were synthesised: dilauroyl apomorphine (DLA) and dipalmitoyl apomorphine (DPA). The in vitro enzymatic hydrolysis of diesters was performed using biorelevant media with pancreatin to catalyse the diester degradation.The synthesised and purified diesters were found to be free from reactants as impurities confirmed by LC/MS and NMR. DLA and DPA were degraded into corresponding monoesters and free apomorphine within 5 min after adding pancreatin, leaving about 4% and 28% of the intact diester, respectively. The incorporation of the diesters into SEDDS reduced the enzymatic degradation of diesters. In addition, the chain length of diester and the type of oil used in formulations affected diester hydrolysis.The lipophilic apomorphine diesters were substrates of lipases present in pancreatin, and the degree of diester degradation can be controlled by selecting suitable lipid excipients. Therefore, diesters of apomorphine are promising prodrugs for oral delivery aiming at lymphatic transport. (C) 2014 Elsevier B.V. All rights reserved.

  DOI：

  10.1016/j.ejpb.2014.12.014

文献信息

• In vivo evaluation of lipid-based formulations for oral delivery of apomorphine and its diester prodrugs
  作者：Nrupa Borkar、René Holm、Mingshi Yang、Anette Müllertz、Huiling Mu

  DOI：10.1016/j.ijpharm.2016.09.024

  日期：2016.11

  In the present study, the differences in oral absorption of apomorphine and its diester prodrugs and the effect of lipid-based formulations on the absorption of apomorphine or its prodrugs were investigated. Apomorphine, dilauroyl apomorphine (DLA) and dipalmitoyl apomorphine (DPA) were orally administered (0.24 mmol/kg) to rats as: DLA-o/w emulsion, DPA-o/w emulsion, apomorphine-o/w emulsion, apomorphine aqueous suspension, DLA-Maisine, DLA-soybean oil, DLA-self-emulsifying drug delivery systems (SEDDS), and DLA-w/o emulsion. The o/w and w/o emulsion consisted of Maisine 35-1 emulsified with water in 1: 3 and 4: 1 ratio, respectively. T-max of diesters was significantly increased (p <= 0.05) compared to apomorphine in o/w emulsion, suggesting that esterification yielded prolonged drug absorption. C-max, AUC and the relative bioavailability of apomorphine after DLA-SEDDS administration was higher (p <= 0.05) than after DLA-w/o administration, indicating that triglycerides and surfactants improved the oral absorption of DLA. Similarly, C-max and AUC after dosing apomorphine-o/w were significantly higher (p <= 0.05) than that of aqueous suspension. This suggested that lipids and lipolysis products possibly aided apomorphine micellar solubilization in intestinal fluids. A combination of prodrug strategy and lipid-based formulations facilitated a higher and prolonged absorption of apomorphine from its diester prodrugs. (C) 2016 Elsevier B. V. All rights reserved.