可持续多巴胺能刺激治疗帕金森病的罗替戈汀微球的研究
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摘要
帕金森病(Parkinson’s disease，PD)为中枢神经系统退行性疾病，典型临床症状表现为动作迟缓，肌肉强直及静止性震颤等，左旋多巴多年的临床应用实践证明它是疗效最优且耐受性好的PD症状治疗药物，但是左旋多巴长周期治疗后会导致PD患者的运动并发症（也称为异动症），成为PD治疗面临的难题，也限制了左旋多巴的临床应用。大量的研究提示，运动并发症的产生可能与纹状体多巴胺受体长期受到非生理性或“脉冲样”刺激有关，因而提出了持续多巴胺能刺激理念（continuous dopaminergic stimulation，CDS）治疗PD。研究表明基于CDS理念的治疗可有效减少PD患者运动并发症的发生，近年来受到了广泛关注。目前已有多种实现CDS治疗PD的方式，尽管这些方式可以有效减轻、改善甚至能够逆转由左旋多巴诱导的运动并发症，但是大多数方法或者操作困难，患者依从性差，或者疗效不够充分等。因此很有必要研究开发一种临床效果好，患者依从性高的CDS治疗方式。
罗替戈汀是一种新型的非麦角类选择性多巴胺受体激动剂，通过激动D3／D2／D1而产生抗帕金森作用。为实现罗替戈汀持续多巴胺能刺激治疗PD，本研究采用O/W乳化溶剂挥发法将罗替戈汀包埋于生物可降解的乳酸羟基乙酸共聚物(PLGA)中制备成可持续缓慢释药的微球，并考察了处方及制备工艺对微球包埋率、粒径、体外释放、大鼠体内释放等指标的影响。结果显示，软脂酸可有效降低药物的突释，不同高分子按一定比例组合可获得体内持续平稳释药的微球。PLGA浓度、油水相比、PVA浓度、乳化速度等制备工艺参数对微球的包埋率、粒径及释放等有不同程度的影响。按最优处方及工艺制备的微球的载药量为26.9%，包封率为89.7%，微球体外可持续释放14天，在此基础上进行了罗替戈汀微球体内药代动力学和药效学研究。
以大鼠为模型动物，考察了罗替戈汀微球在体内的释药特点，并采用微渗析技术进行脑内药物浓度的监测，以考察罗替戈汀微球给药后是否能够实现对多巴胺受体的持续刺激。结果发现大鼠肌肉注射罗替戈汀微球后，罗替戈汀在体内持续缓慢释放，血浆浓度在给药后48-72h达峰，Cmax为6.38±0.80 ng/mL，消除缓慢，可以检测到给药后16天，末端消除半衰期约30-40 h。脑内药物浓度监测结果显示，罗替戈汀微球给药后，在60min内即可检测到药物，于给药后第8天达Cmax8.16±0.95 ng/mL(以体内回收率校正)，并维持平稳的药物浓度至14天。结果表明罗替戈汀微球能够提供持续平稳的血浆及脑内药物浓度，可实现对多巴胺受体的持续刺激。
以6-羟基多巴（6-OHDA）致PD大鼠为模型动物，通过观察PD大鼠对侧旋转行为评价罗替戈汀微球的主要药效。PD大鼠肌肉注射罗替戈汀微球后14天内，每天固定时间点检测15分钟大鼠向对侧旋转圈数；并且于第8天的24小时内连续多点观察以考察时效关系。结果显示，肌肉注射罗替戈汀微球（10mg/kg）可显著增加6-OHDA致PD大鼠对侧旋转行为，药效可维持至14天，在第8天连续观察24h的结果显示罗替戈汀微球在24h内药效持续平稳，表明罗替戈汀微球可实现CDS治疗PD。
罗替戈汀微球可用于PD的早期治疗，但是随着PD的进展，需添加左旋多巴以保证抗PD治疗效果，而左旋多巴长期应用会导致异动症的发生，因此研究分别以6-OHDA致PD大鼠和左旋多巴致异动症大鼠为模型动物，考察罗替戈汀和左旋多巴联合治疗后对异动症的影响，同时对其药效进行了考察。由于左旋多巴的强诱导异动症效应，被选用为阳性对照组。以不自主运动（abnormalinvoluntary movements, AIM）评分考察对异动症的影响，通过观察大鼠对侧旋转行为评价治疗效果。结果发现，罗替戈汀（脉冲式或持续式）和左旋多巴联合应用所诱发的对侧旋转行为与单独左旋多巴治疗组无明显差异，表明其在治疗效果方面是相等同的；然而，与单独左旋多巴治疗组相比，罗替戈汀微球和左旋多巴联合治疗后，大鼠AIM评分显著降低，表明罗替戈汀微球和左旋多巴联合治疗可有效降低PD大鼠异动症的发生或者改善异动症大鼠已出现的异动症。而脉冲式罗替戈汀和左旋多巴联合治疗后，可导致与左旋多巴单独治疗相似程度（中-重度）的异动症。
为制备更长释药周期的罗替戈汀缓释制剂，选择原位形成植入体剂型进行初步探讨，主要以体外释放为评价指标，结果显示，原位形成植入体可持续缓慢释放罗替戈汀达4周。
以上研究结果表明，研究制备的罗替戈汀微球注射一次可以维持疗效两周，并维持较稳定的血药及脑内药物浓度，避免了对多巴胺受体的脉冲式刺激，实现持续多巴胺能刺激治疗PD，显著改善患者由于血药浓度波动而出现的“开关”现象，从而避免了运动并发症的发生，可以提高疗效、降低副作用，提高患者的顺应性。罗替戈汀微球与左旋多巴联合治疗可有效降低PD大鼠异动症的发生或改善异动症大鼠已出现的异动症，同时具有较好的抗PD效果，显示出罗替戈汀微球尤其与左旋多巴联合应用在中晚期PD治疗中的优势。
Parkinson’s disease (PD) is a progressive neurodegenerative disorder leading toexpression of motor symptoms characterized by resting tremor, muscular rigidity andbradykinesia. Levodopa (L-DOPA) is highly effective in reversing the motorsymptoms of PD. However, long-term treatment with L-DOPA results in thedevelopment of disabling and troublesome motor complications called dyskinesias, amovement disorder usually designated as L-DOPA induced dyskinesias (LID). It ishard to control and limits the utility of L-DOPA. Substantial evidence hasaccumulated indicating that LID in PD is associated with non-physiological orpulsatile stimulation of striatal dopamine receptors. Therefore, the concept ofcontinuous dopaminergic stimulation (CDS) has been developed and has receivedconsiderable attention for treatment of PD. There are a variety of methods that canachieve CDS treatment in PD. Although these methods can reduce, improve and evenreverse the motor complications, many of these methods either have inadequatetherapeutic benefit or are difficult to operate with poor compliance. Therefore, it iscrucial to develop a more convenient and practical means of achieving CDS andapplying to the most of the PD patient groups.
To achieve continuous dopaminergic stimulation for the treatment of PD rotigotinewas entrapped into biodegradable poly (lactic-co-glycolic acid) (PLGA) microspheresby an oil-in-water emulsion/solvent evaporation method. Several rotigotine loadedmicrospheres were prepared and their characteristics (size, drug encapsulationefficiency and drug release profiles) were evaluated. We found that palmitic acid caneffectively reduce the burst release of drug and a smooth release within 14 days wasachieved by blends of polymer. The effects of processing parameters, such as polymers concentration, PVA concentration, the ratio of oil to water, and thehomogenization rate on the characteristics of microspheres were also investigated.The drug loading of rotigotine loaded microspheres achieved by the optimized processwas 26.9% and the encapsulation efficiency was 89.7%. The in vitro drug releasesustained for 14 days.
The pharmacokinetics of rotigotine loaded microspheres in both blood and brain (bymicrodialysis) in rat was investigated. The plasma concentration of rotigotine reachedCmaxof 6.38±0.80 ng/mL at 48-72h after the administration of rotigotine loadedmicrospheres. It can be detected on 16th day after administration and the eliminationwas slow. The brain extracellular drug concentration monitored by microdialysisshowed that rotigotine can be detected in the dialysate in the first 1 h after theadministration and a peak concentration of 8.16±0.95 ng/mL (corrected by in vivorecovery) was obtained on day 8 and a constant and stable level of extracellularrotigotine was maintained at 3.94±2.06 ng/mL. The results suggested that rotigotineloaded microspheres can provide a continuous stimulation on the dopamine receptors.
The major pharmacodynamics of rotigotine loaded microspheres was evaluated on6-OHDA-lesioned rats. A significant increase in rotation activity of PD rats suggestedthat rotigotine loaded microspheres can produce stable and steady efficacy in the PDrats and the efficacy lasted for about 14 days. The results of continuous observationfor 24h on the 8th day showed that the efficacy was constant and stable within 24h.The results indicated that rotigotine loaded microspheres can provide CDS for thetreatment of PD.
Although RoMS could be effective in the therapy of early PD, L-DOPA was still aninevitable supplementation for most patients with PD. Therefore, in this study weinvestigated both the therapeutic benefit and inducibility of AIMs of continuousrotigotine administration combination with L-DOPA on 6-OHDA-leisioned rats. Wefound that: 1) There is no significant difference of the therapeutic benefit between theconcomitant treatment of continuous (or pulsatile) rotigotine and L-DOPA andmono-treatment with L-DOPA (p>0.05). 2) Pulsatile L-DOPA induced marked AIMs, while the concomitant treatment of rotigotine microspheres and L-DOPA cansignificantly decrease the inducibility of dyskinesia whether dyskinesia was alreadyestablished or not comparing to mono L-DOPA treatment. However, the concomitanttreatment of pulsatile rotigotine and L-DOPA induced marked AIMs too. The resultssuggest that L-DOPA in combination with continuous stimulation of dopaminergicreceptors by rotigotine has lower propensity to induce dyskinesia in this experimentalmodel. In conclusion, this study highlights the potential advantages that rotigotineloaded microspheres could be used especially in combination with L-DOPA in mid tolate stage PD to reduce dyskinesia development whether dyskinesia has beenpreviously established or not.
In situ forming implant (ISFI) was studied to obtain longer sustained-releaseformulation for rotigotine. The results showed that ISFI could provide a sustaineddrug release for 4 weeks.
In conclusion, rotigotine loaded microspheres can provide a continuous delivery ofrotigotine with small fluctuations of drug levels in plasma and brain striatum duringdosing intervals in rats and can also produce stable and steady efficacy in the PD ratswhich lasts for about 14 days, those results enabled rotigotine loaded microspheres tobe a potent alternative of CDS in the treatment of early PD. Rotigotine loadedmicrospheres and pulsatile L-DOPA combination treatment could reduce thedyskinesia development and the intensity of the established dyskinesia and maintaintherapeutic efficacy compared to pulsatile L-DOPA monotherapy. The resultsindicated the potential advantage of the combination treatment on the mild andadvanced PD.
罗替戈汀是一种新型的非麦角类选择性多巴胺受体激动剂，通过激动D3／D2／D1而产生抗帕金森作用。为实现罗替戈汀持续多巴胺能刺激治疗PD，本研究采用O/W乳化溶剂挥发法将罗替戈汀包埋于生物可降解的乳酸羟基乙酸共聚物(PLGA)中制备成可持续缓慢释药的微球，并考察了处方及制备工艺对微球包埋率、粒径、体外释放、大鼠体内释放等指标的影响。结果显示，软脂酸可有效降低药物的突释，不同高分子按一定比例组合可获得体内持续平稳释药的微球。PLGA浓度、油水相比、PVA浓度、乳化速度等制备工艺参数对微球的包埋率、粒径及释放等有不同程度的影响。按最优处方及工艺制备的微球的载药量为26.9%，包封率为89.7%，微球体外可持续释放14天，在此基础上进行了罗替戈汀微球体内药代动力学和药效学研究。
以大鼠为模型动物，考察了罗替戈汀微球在体内的释药特点，并采用微渗析技术进行脑内药物浓度的监测，以考察罗替戈汀微球给药后是否能够实现对多巴胺受体的持续刺激。结果发现大鼠肌肉注射罗替戈汀微球后，罗替戈汀在体内持续缓慢释放，血浆浓度在给药后48-72h达峰，Cmax为6.38±0.80 ng/mL，消除缓慢，可以检测到给药后16天，末端消除半衰期约30-40 h。脑内药物浓度监测结果显示，罗替戈汀微球给药后，在60min内即可检测到药物，于给药后第8天达Cmax8.16±0.95 ng/mL(以体内回收率校正)，并维持平稳的药物浓度至14天。结果表明罗替戈汀微球能够提供持续平稳的血浆及脑内药物浓度，可实现对多巴胺受体的持续刺激。
以6-羟基多巴（6-OHDA）致PD大鼠为模型动物，通过观察PD大鼠对侧旋转行为评价罗替戈汀微球的主要药效。PD大鼠肌肉注射罗替戈汀微球后14天内，每天固定时间点检测15分钟大鼠向对侧旋转圈数；并且于第8天的24小时内连续多点观察以考察时效关系。结果显示，肌肉注射罗替戈汀微球（10mg/kg）可显著增加6-OHDA致PD大鼠对侧旋转行为，药效可维持至14天，在第8天连续观察24h的结果显示罗替戈汀微球在24h内药效持续平稳，表明罗替戈汀微球可实现CDS治疗PD。
罗替戈汀微球可用于PD的早期治疗，但是随着PD的进展，需添加左旋多巴以保证抗PD治疗效果，而左旋多巴长期应用会导致异动症的发生，因此研究分别以6-OHDA致PD大鼠和左旋多巴致异动症大鼠为模型动物，考察罗替戈汀和左旋多巴联合治疗后对异动症的影响，同时对其药效进行了考察。由于左旋多巴的强诱导异动症效应，被选用为阳性对照组。以不自主运动（abnormalinvoluntary movements, AIM）评分考察对异动症的影响，通过观察大鼠对侧旋转行为评价治疗效果。结果发现，罗替戈汀（脉冲式或持续式）和左旋多巴联合应用所诱发的对侧旋转行为与单独左旋多巴治疗组无明显差异，表明其在治疗效果方面是相等同的；然而，与单独左旋多巴治疗组相比，罗替戈汀微球和左旋多巴联合治疗后，大鼠AIM评分显著降低，表明罗替戈汀微球和左旋多巴联合治疗可有效降低PD大鼠异动症的发生或者改善异动症大鼠已出现的异动症。而脉冲式罗替戈汀和左旋多巴联合治疗后，可导致与左旋多巴单独治疗相似程度（中-重度）的异动症。
为制备更长释药周期的罗替戈汀缓释制剂，选择原位形成植入体剂型进行初步探讨，主要以体外释放为评价指标，结果显示，原位形成植入体可持续缓慢释放罗替戈汀达4周。
以上研究结果表明，研究制备的罗替戈汀微球注射一次可以维持疗效两周，并维持较稳定的血药及脑内药物浓度，避免了对多巴胺受体的脉冲式刺激，实现持续多巴胺能刺激治疗PD，显著改善患者由于血药浓度波动而出现的“开关”现象，从而避免了运动并发症的发生，可以提高疗效、降低副作用，提高患者的顺应性。罗替戈汀微球与左旋多巴联合治疗可有效降低PD大鼠异动症的发生或改善异动症大鼠已出现的异动症，同时具有较好的抗PD效果，显示出罗替戈汀微球尤其与左旋多巴联合应用在中晚期PD治疗中的优势。
Parkinson’s disease (PD) is a progressive neurodegenerative disorder leading toexpression of motor symptoms characterized by resting tremor, muscular rigidity andbradykinesia. Levodopa (L-DOPA) is highly effective in reversing the motorsymptoms of PD. However, long-term treatment with L-DOPA results in thedevelopment of disabling and troublesome motor complications called dyskinesias, amovement disorder usually designated as L-DOPA induced dyskinesias (LID). It ishard to control and limits the utility of L-DOPA. Substantial evidence hasaccumulated indicating that LID in PD is associated with non-physiological orpulsatile stimulation of striatal dopamine receptors. Therefore, the concept ofcontinuous dopaminergic stimulation (CDS) has been developed and has receivedconsiderable attention for treatment of PD. There are a variety of methods that canachieve CDS treatment in PD. Although these methods can reduce, improve and evenreverse the motor complications, many of these methods either have inadequatetherapeutic benefit or are difficult to operate with poor compliance. Therefore, it iscrucial to develop a more convenient and practical means of achieving CDS andapplying to the most of the PD patient groups.
To achieve continuous dopaminergic stimulation for the treatment of PD rotigotinewas entrapped into biodegradable poly (lactic-co-glycolic acid) (PLGA) microspheresby an oil-in-water emulsion/solvent evaporation method. Several rotigotine loadedmicrospheres were prepared and their characteristics (size, drug encapsulationefficiency and drug release profiles) were evaluated. We found that palmitic acid caneffectively reduce the burst release of drug and a smooth release within 14 days wasachieved by blends of polymer. The effects of processing parameters, such as polymers concentration, PVA concentration, the ratio of oil to water, and thehomogenization rate on the characteristics of microspheres were also investigated.The drug loading of rotigotine loaded microspheres achieved by the optimized processwas 26.9% and the encapsulation efficiency was 89.7%. The in vitro drug releasesustained for 14 days.
The pharmacokinetics of rotigotine loaded microspheres in both blood and brain (bymicrodialysis) in rat was investigated. The plasma concentration of rotigotine reachedCmaxof 6.38±0.80 ng/mL at 48-72h after the administration of rotigotine loadedmicrospheres. It can be detected on 16th day after administration and the eliminationwas slow. The brain extracellular drug concentration monitored by microdialysisshowed that rotigotine can be detected in the dialysate in the first 1 h after theadministration and a peak concentration of 8.16±0.95 ng/mL (corrected by in vivorecovery) was obtained on day 8 and a constant and stable level of extracellularrotigotine was maintained at 3.94±2.06 ng/mL. The results suggested that rotigotineloaded microspheres can provide a continuous stimulation on the dopamine receptors.
The major pharmacodynamics of rotigotine loaded microspheres was evaluated on6-OHDA-lesioned rats. A significant increase in rotation activity of PD rats suggestedthat rotigotine loaded microspheres can produce stable and steady efficacy in the PDrats and the efficacy lasted for about 14 days. The results of continuous observationfor 24h on the 8th day showed that the efficacy was constant and stable within 24h.The results indicated that rotigotine loaded microspheres can provide CDS for thetreatment of PD.
Although RoMS could be effective in the therapy of early PD, L-DOPA was still aninevitable supplementation for most patients with PD. Therefore, in this study weinvestigated both the therapeutic benefit and inducibility of AIMs of continuousrotigotine administration combination with L-DOPA on 6-OHDA-leisioned rats. Wefound that: 1) There is no significant difference of the therapeutic benefit between theconcomitant treatment of continuous (or pulsatile) rotigotine and L-DOPA andmono-treatment with L-DOPA (p>0.05). 2) Pulsatile L-DOPA induced marked AIMs, while the concomitant treatment of rotigotine microspheres and L-DOPA cansignificantly decrease the inducibility of dyskinesia whether dyskinesia was alreadyestablished or not comparing to mono L-DOPA treatment. However, the concomitanttreatment of pulsatile rotigotine and L-DOPA induced marked AIMs too. The resultssuggest that L-DOPA in combination with continuous stimulation of dopaminergicreceptors by rotigotine has lower propensity to induce dyskinesia in this experimentalmodel. In conclusion, this study highlights the potential advantages that rotigotineloaded microspheres could be used especially in combination with L-DOPA in mid tolate stage PD to reduce dyskinesia development whether dyskinesia has beenpreviously established or not.
In situ forming implant (ISFI) was studied to obtain longer sustained-releaseformulation for rotigotine. The results showed that ISFI could provide a sustaineddrug release for 4 weeks.
In conclusion, rotigotine loaded microspheres can provide a continuous delivery ofrotigotine with small fluctuations of drug levels in plasma and brain striatum duringdosing intervals in rats and can also produce stable and steady efficacy in the PD ratswhich lasts for about 14 days, those results enabled rotigotine loaded microspheres tobe a potent alternative of CDS in the treatment of early PD. Rotigotine loadedmicrospheres and pulsatile L-DOPA combination treatment could reduce thedyskinesia development and the intensity of the established dyskinesia and maintaintherapeutic efficacy compared to pulsatile L-DOPA monotherapy. The resultsindicated the potential advantage of the combination treatment on the mild andadvanced PD.
引文
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