Amantadine Hydrochloride

A new Supernus Pharmaceuticals medical device that continuously administers an old Parkinson’s disease drug is now FDA approved, giving patients another way to manage the motor control symptoms that return when the effects of standard treatment for the neurological disease wanes. The drug/device combination product, known in development as SPN-830, will be commercialized under the brand name Onapgo. Supernus said Tuesday it plans to launch Onapgo in the second quarter of this year. In an email, the Rockville, Maryland-based company, which specializes in treatments for central nervous system diseases, said it cannot comment on pricing of products before they become commercially available. The backbone of Parkinson’s treatment is levodopa, a compound that is converted to dopamine in the brain to boost levels of this brain chemical that patients lack. The periods when this medication works are called “on” times. But Parkinson’s patients also experience “off” times when levodopa therapy wears off and motor symptoms return. One treatment option for these off periods is a different drug, apomorphine. presented by sponsored content, Artificial Intelligence What Keeps Healthcare CIOs Up at Night: Balancing Technology Investments with Consumer Expectations When it comes to managing inbound phone calls, underperformance has devastating cost implications. By Stephanie Baum Apomorphine mimics dopamine, binding to receptors responsible for motor control. An FDA-approved injectable version of this drug has been available for more than 20 years for treating the off episodes of Parkinson’s. In 2020, Sunovion Pharmaceuticals’ sublingual film formulation of apomorphine received FDA approval for intermittent treatment of the off episodes of Parkinson’s. Supernus already has a presence in Parkinson’s. Its second-largest product by revenue is Gocovri, a capsule that treats dyskinesia and off time in Parkinson’s patients. The company also already markets apomorphine, dosed as needed via an injection pen product branded as Apokyn. But motor symptoms of Parkinson’s worsen as the disease progresses and off periods can happen at any time. Continuous infusion of apomorphine offers an additional way to manage these unpredictable off times. Supernus sources Apokyn from Britannia Pharmaceuticals, a subsidiary of German company Stada Arzneimittel. Britannia markets both injectable and continuous infusion apomorphine products in Europe. A license and supply agreement with Britannia grants Supernus the right to use and market injectable apomorphine in the U.S. The 2016 pact also covers the joint development of other apomorphine products, including drug administered as a continuous infusion. Supernus must pay Britannia royalties on net sales for products covered by the agreement. Britannia retains rights to its drug outside of the U.S. Onapgo, a device secured to the body by an elastic band worn around the waist, has had a rocky regulatory journey leading up to its FDA nod. Supernus applications seeking regulatory approval were turned back by the FDA in 2022 and again last April, as the agency asked for more information about various aspects of the drug/device combination product candidate. Last August, the FDA accepted Supernus’s resubmitted application and set a Feb. 1 target date for a regulatory decision. presented by Health IT Transforming Patient Care: The Role of AI-Powered Assistants The progress in artificial intelligence (AI) is reshaping patient care, across various dimensions, from facilitating faster discharge to curating treatment plans and suggesting lifestyle changes. By IT Medical The long-awaited FDA approval is based on the results of a placebo-controlled Phase 3 test that evaluated Onapgo for 12 weeks. Results showed that patients who received the Supernus treatment experienced a 2.6-hour reduction in daily off time compared to 0.9 hours for those who received a placebo. Patients who received the Supernus treatment also experienced an increase in on time for their Parkinson’s medications — 2.8 hours for the Onapgo arm compared to 1.1 hours for the placebo group. The most common adverse events reported in the study included infusion-site reactions, nausea, sleepiness, dyskinesia, headache, and insomnia. In Supernus’s announcement of the product approval, Dr. Rajesh Pahwa noted the 30-year history of continuous subcutaneous apomorphine infusions in Europe. Pahwa, a professor of neurology at the University of Kansas School of Medicine, director of the Movement Disorder Program at The University of Kansas Health System, and an investigator for Onapgo’s clinical trial, pointed to the significant reduction in off time and increase in on time for patients treated with the Supernus product. “Today’s approval of Onapgo means patients in the U.S. who are not responding well to their current treatment regimen, including levodopa, will now have the option of using a small and lightweight wearable device to deliver a continuous infusion without the need for an invasive surgical procedure,” Pahwa said. Photo by Supernus Pharmaceuticals

在药物分析工作中，常常会遇到极性较强的化合物，使用液相色谱法或液相色谱串联质谱法对这些化合物进行分析时，会遇到很多困难。 如果采用传统的反相色谱柱，有些极性化合物常常较早时间就被流动相洗脱，甚至在死时间流出，不能与杂质分离；与串联质谱联用，依赖于质谱的定性技术，可以对这些物质进行定性，但流动相中高比例的水相会抑制此类物质在电喷雾离子源中的的电离，造成灵敏度下降，影响准确定量。在一些分析中，如果目标化合物较早被流动相洗脱，柱效也难以达到标准要求。 有些极性化合物含有碱性基团，会与反相色谱柱中装填的硅胶颗粒产生次级保留作用，在色谱图上表现为拖尾峰，影响准确定量；有些化合物甚至在色谱图上不出峰。 为应对这些问题，本文提出几种液相色谱方法，以期对大家的工作有所帮助，起到抛砖引玉的作用。 1.采用改性C18色谱柱分析极性较强的化合物 改性的C18色谱柱或保留硅胶表面活性的-OH基团，或接枝极性基团如氨基甲酸酯等，这些基团使得硅胶颗粒表面形成了“富水层(Rich Water Layer)”，对极性化合物产生保留作用，目标化合物与干扰组分之间能够得到有效的分离，同时，对于改善目标化合物峰形，也有一定的帮助。 以天麻素(β-Gastrodin，4-羟甲基苯基-β-D-吡喃葡萄糖苷)为例，其结构如图1所示，ACD/LogP为-1.85，具有较强的极性。 图1天麻素结构图 分析中成药中天麻素含量，为增强其在C18色谱柱上的保留，多以低有机相含量的乙腈水溶液作为流动相，如乙腈-水(1:100)，流动相流速1 mL/min，等度 洗脱，使用紫外检测器，检测波长为220 nm，色谱图如图2所示。 图2 C18色谱柱分析天麻素色谱图 使用传统C18色谱柱分析天麻素时，色谱峰宽约为1 min，天麻素轴向扩散较为严重，如果以改性C18（T3）色谱柱分析天麻素，采用同样的流动相及流速。色谱峰宽约为0.2 min，如图3所示，峰形更为尖锐，对称，对于准确定量和提高柱效有很大帮助。 在日常工作中，可以先大致了解物质物化性质，如查询logP以了解物质极性。使用常规C18色谱柱不能达到分析需求时，尝试更换改性C18色谱柱。 图3 T3色谱柱分析天麻素色谱图 2.使用亲水相互作用色谱柱 亲水相互作用色谱法(HILIC)是对反相色谱法的有利补充，对于极性化合物，既提供了与正相色谱法相同的出峰顺序和选择性，又避免了使用正己烷等有机流动相。同时亲水相互作用色谱法中高比例的乙腈流动相非常有利于待测物质在电喷雾离子源中的电离，因此亲水相互作用色谱法和串联质谱联用，非常适合极性化合物的分析。 以核苷和碱基为例介绍亲水相互作用色谱柱的使用方法。核苷和碱基分子中含多个N，O原子，分子结构不对称，分子有较大的偶极矩，极性较强，难以溶解于普通有机溶剂，在普通C18色谱柱上几乎没有保留，定性定量分析存在较大困难。 以金水宝胶囊中核苷及碱基分析为例，如果使用传统C18色谱柱，为了增强各物质保留，需要维持流动相中高比例水相相当长的时间，色谱分析时间长，同时，流动相使用纯水，会使得C18碳链卷曲，降低色谱柱柱效。 使用C18反相色谱柱，柱温为25°C。以甲醇-0.02mol/L磷酸二氢钾水溶液为流动相，梯度洗脱，流速为1 mL/min，检测器为紫外检测器，检测波长260 nm，色谱图如图4所示，5种化合物全部洗脱时间约为30 min。 图4使用C18色谱柱分析5种化合物 考虑到此类化合物多含有碱性基团，可采用具有两性基团的亲水相互作用色谱柱进行分离，如ZIC-cHILIC色谱柱，其功能基团为磷酸胆碱，与待分析化合物之间可能存在亲水相互作用，电荷相互作用等，可以快速有效分离核苷及碱基等碱性物质。 使用ZIC-cHILIC色谱柱，柱温40°C，以乙腈-100 mmol/L甲酸铵水溶液为流动相(90：10)，流速0.4 mL/min，等度洗脱，检测器为紫外检测器，检测波长为263 nm。色谱图如图5所示，15 min内即可完成5种化合物的分析分离。 图5使用ZIC-cHILIC色谱柱分析5种化合物 使用C18色谱柱分析上述碱性化合物，具有非常好的分离度，但用时较长，如果使用ZIC-cHILIC色谱柱，柱效低于C18色谱柱，但是分析速率大大提高，适用于快速分离分析。 对于胺类化合物，也可以采用氨基色谱柱进行分析，氨基色谱柱同样为亲水相互作用色谱柱。 3.使用耐碱的C18色谱柱 耐碱的C18色谱柱可以使用较高pH的流动相，达到抑制碱性物质电离的目的，为分离多个碱性化合物混合物的分离提供了非常好的解决方案。 抗病毒药物有三环胺类和核苷类等，均属于碱性化合物。无论是三环胺类还是核苷类，几乎都含有N原子和不对称结构，因此具有较强的极性。 使用液相色谱方法或液相色谱-串联质谱方法分析三环胺类抗病毒药物，如金刚烷胺，金刚乙胺，美金刚等，可以采用C18色谱柱，也可以采用亲水相互作用色谱柱。分析核苷类抗病毒药物，如阿昔洛韦，奥司他韦等一般采用亲水相互作用色谱柱，如氨基柱。分析美金刚和金刚乙胺两种化合物的混合物时，无论采用C18色谱柱还是采用氨基柱，两者都不能得到有效分离。 金刚乙胺和美金刚是一对同分异构体，结构式分别如图6，图7所示， 图6金刚乙胺分子结构图 图7美金刚分子结构图 使用液相色谱串联质谱法对上述金刚乙胺和美金刚进行检测时，监测的离子对分别为180>163，180>121和180>163，180>107。如果采用亲水相互作用色谱柱如氨基色谱柱进行分析，流动相为乙腈-5mmol/L乙酸铵和0.2%甲酸水溶液，两者同时出峰，180>163离子对色谱峰相互重叠，为定性带来诸多不便，色谱图如图8所示。如果使用普通C18色谱柱，以甲醇-0.1%甲酸为流动相，两者亦同时出峰。 图8使用氨基柱分析金刚乙胺和美金刚混合物总离子流色谱图 根据二者结构的细微差别，如果能充分抑制-NH2的电离，C18色谱柱应能提供一定选择性，实现二者的分离，但是一般C18色谱不能使用pH过高的流动相，否则会造成硅胶颗粒溶解。这种情况下可以选择可以耐受高pH的C18色谱柱，如BEH C18，HPH C18或EVO C18。使用BEH C18色谱柱，以甲醇-0.1%氨水溶液(pH=10)为流动相，电喷雾离子源，液相色谱-串联质谱法分析金刚乙胺和美金刚，色谱图如图9所示，可见，美金刚和金刚乙胺得到有效分离。 图9使用BEH C18分析金刚乙胺和美金刚混合物总离子流色谱图 在药物分析工作中，对于遇到的极性化合物，如果采用常规C18色谱柱分析难以满足需求，可以根据化合物极性，酸碱性等性质，转换思路，选择改性C18色谱柱或亲水相互作用色谱柱进行分析，验证是否满足需求。 参考文献 [1] 中华人民共和国药典（2020年版）； [2] Patrik Appelblad, etc.亲水作用色谱HILIC实用指南.SeQuant AB出版 [3] 刘向国,等.在线二维液相色谱法测定发酵虫草菌粉(Cs-4)中6种活性物质[J].中国药物评价,2023,40(01):65-70. 药事纵横征稿启事