Guaifenesin

A pharmaceutical ingredient that’s been a key component in nasal decongestants for decades is having its efficacy called into question, and the FDA is now weighing whether to change the compound’s regulatory status — potentially leading to many widely used over-the-counter cold and allergy products being pulled from pharmacy shelves. But before the FDA takes any action, it wants to hear what the public thinks. The ingredient, oral phenylephrine, by itself and in combination with other active ingredients, is in decongestants sold under numerous brand names, such as Sudafed and Mucinex. All products containing oral phenylephrine continue to be available to consumers for now. But on Thursday, the FDA proposed an order that would remove oral phenylephrine from its non-prescription drugs guidelines, called the OTC Monograph. The regulator emphasized that this proposed order is due to lack of efficacy, not because of safety. At one time, phenylephrine was rare in decongestants because pseudoephedrine was the preferred active ingredient. But that compound can be made into the methamphetamine. Efforts to curb meth production led to the Combat Methamphetamine Act of 2005, which moved pseudoephedrine-containing drugs behind pharmacy counters. Drugmakers responded by making more products with oral phenylephrine, which is not covered by this law. presented by Sponsored Post The Promise of Value-Based Care and MedTech Innovation Monica Vajani, Executive Director for mHUB’s MedTech Accelerator, discusses how mHUB is helping innovators transition healthcare towards value-based care. By Monica Vajani - mHUB Last year, an FDA advisory committee discussed phenylephrine and unanimously voted that current scientific data do not support the ingredient’s efficacy as a nasal decongestant. The committee raised no concerns about the safety of oral phenylephrine when used at the recommended dose. The FDA now says it has conducted a comprehensive review of all available safety and efficacy data for oral phenylephrine as a nasal decongestant, including historical data used to support the compound 30 years ago. Speaking during a conference call with journalists Thursday, Theresa Michele, director of the FDA’s office of nonprescription drugs, said new data had become available since the advisory committee meeting, which the agency also reviewed. “At this point, based on the available data, and taking into account the advice of the advisory committee, we are proposing that oral phenylephrine is not effective to relieve nasal congestion at the recommended dose set forth in the monograph,” Michele said. Phenylephrine is also an ingredient in some nasal spray decongestants. The FDA’s proposal does not extend to such products. The proposed FDA order can be found here. Public comments may be submitted here (use docket number FDA-2024-N-4734 ) through May 7, 2025. After considering the comments, the agency may issue a final order removing oral phenylephrine from its guidelines, which would mean nasal decongestants could no longer contain the compound. Michele said the FDA would then provide manufacturers with time to either reformulate their medicines or remove oral phenylephrine-containing products from the market. Don’t let the autumn sniffles get you down. Here’s a look back at other recent regulatory news, including U.S. and European actions on several novel medications (alas, no new decongestants): Exclusive Heard at HLTH 2024: Insights from Innovative Healthcare Executives Executives from Imagine360, Verily, BrightInsight, Lantern, and Rhapsody shared their approaches to reducing healthcare costs and facilitating digital transformation. By MedCity News Decisions for Drugs and Devices —The FDA needs more time to review Organon drug Vtama as a treatment for atopic dermatitis. The company said the regulator has pushed out the December target date for a decision by three months to March 12, 2025. Vtama is from Roivant Sciences subsidiary Dermavant, which Organon recently acquired for $175 million up front. Under Dermavant, the topical drug won FDA approval in 2022 as a treatment for plaque psoriasis. —Novartis cancer drug Scemblix expanded its FDA-approved uses to include the treatment of newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ PML). The tablet, part of a class of drugs called STAMP inhibitors, initially landed accelerated FDA approval in 2021 as a treatment for advanced cases of Ph+ PML. —The FDA approved Iterum Therapeutics antibiotic Orlynvah. The regulatory decision covers the treatment of uncomplicated urinary tract infections in women who have limited or no oral antibacterial treatment options. The drug, whose main ingredient is sulopenem, is taken as a tablet twice daily for five days. —Astellas Pharma landed FDA approval for zolbetuximab, brand name Vyloy, as a treatment for gastric or gastroesophageal junction adenocarcinoma. It’s the first FDA approval for a drug targeting the cancer protein claudin 18.2 (CLDN18.2). The regulatory decision specifically covers patients whose cancer is negative for a different cancer protein called HER2. Drugs are already available for HER2-positive cancers. —In other Astellas news, the Japanese pharma company withdrew its European Medicines Agency application for geographic atrophy drug avacincaptad pegol. The company said it made the decision after discussions with the agency’s Committee for Medicinal Products for Human Use. The drug, administered as a once-monthly eye injection, won FDA approval in geographic atrophy last year and is marketed in the U.S. under the brand name Izervay. Failure to secure approval in Europe will make it harder for Astellas to recoup the $5.9 billion it spent to acquire Iveric Bio, the company that developed the drug. —Pfizer respiratory syncytial virus vaccine Abrysvo expanded its FDA approval to include adults age 18 through 59, broadening the market for the product. The initial FDA approval of Abrysvo last year covered patients age 60 and older. It’s also approved for use by pregnant individuals as a maternal vaccine; antibodies produced by the mother confer protection against RSV intended to last from the baby’s birth up to six months of age. —Gilead Sciences’ Trodelvy will no longer be available in the U.S. for treating urothelial carcinoma, an aggressive bladder cancer. After discussions with the FDA, the company decided to voluntarily withdraw the product, which had won accelerated approval in this indication in 2021. In May, the company reported Trodelvy failed its confirmatory Phase 3 test in advanced urothelial carcinoma. The withdrawal in urothelial carcinoma does not affect drug’s approved uses in breast cancer. —After previous regulatory setbacks, AbbVie finally landed FDA approval for Vyalev, a Parkinson’s disease drug/device combination product that provides 24 hour subcutaneous infusion of the medications foscarbidopa and foslevodopa. Last year, the regulator turned down the product’s application, asking for more information about the pump in the device. The FDA did not raise any questions about safety or efficacy, nor did it ask for another clinical trial. This past June, the agency again turned down AbbVie’s application for issues at the product’s third-party manufacturer. —There’s a new Pfizer drug for both hemophilia A and B. The FDA approved the antibody drug marstacimab for preventing or reducing frequency of bleeding episodes in patients 12 and older. Pfizer will market the drug under the brand name Hympavzi. As a once-weekly injectable medication, Hympavzi will provide an alternative to IV-infused hemophilia therapies. —The FDA needs more time to review Intercept Pharmaceuticals’ application seeking full regulatory approval of Ocaliva, which had received accelerated approval in 2016 for the rare liver disease primary biliary cholangitis. Intercept, now a subsidiary of Alfasigma, said the agency did not provide a new date for a regulatory decision. —Alzheimer’s disease drug Leqembi hit a regulatory obstacle in Australia, where the Therapeutic Goods Administration decided against registering the medication. Eisai said it will request a reconsideration as permitted under Australian law. It’s the second setback for the drug in recent months. Over the summer, the drug received a negative opinion from a European Medicines Agency committee concerned about the risk of severe side effects and limited benefit. Leqembi has approvals in the U.S., Japan, China, and several other markets. —The FDA approved a Thermo Fisher Scientific companion diagnostic to Voranigo, a Servier Pharmaceuticals’ drug approved over the summer for treating patients whose glioma is driven by mutations to IDH1 or IDH2 enzymes. The diagnostic, called Ion Torrent Oncomine Dx Target Test, identifies patients whose cancer carries the genetic signature making them eligible for treatment with the Servier drug. —Advanced cases of non-small cell lung cancer can now be treated with a wearable device. The FDA approved Novocure’s Optune Lua, a wearable technology that kills cancer cells with electrical signals administered via electrodes placed on the skin. Novocure’s “tumor-treating field” technology was first approved in 2011 as a treatment for a recurrent type of brain cancer. —The FDA rejected Zealand Pharma’s dasiglucagon, a drug developed to prevent and treat hypoglycemia in children who have the rare disease congenital hyperinsulinism. According to the Copenhagen-based biotech, the regulator cited issues at a third-party manufacturer. The FDA did not raise any concerns about the drug’s clinical data or safety. Advisory Committee Outcomes —An FDA advisory committee voted 11 to 3 that the benefits of Lexicon Pharmaceuticals’ sotagliflozin do not outweigh its risks when used as an adjunct to insulin to treat adults with type 1 diabetes and chronic kidney disease. But some committee members expressed support for use of the drug in subpopulations of patients. Sotagliflozin, given the brand name Zynquista, is expected to receive an FDA decision by Dec. 20. Sotagliflozin was approved last year for the treatment of heart failure and is marketed as Inpefa in this indication. —The European Medicine Agency’s Committee for Medicinal Products for Human Use yet again recommended against renewing the marketing authorization for Translarna, a PTC Therapeutics drug for Duchenne muscular dystrophy. Translarna received conditional marketing authorization in 2014. After the drug failed its Phase 3 study, the committee twice recommended against renewing the authorization. The latest opinion comes after the EMA directed the committee to reconsider, taking into account “the totality of evidence.” The committee said its reassessment “concluded that the effectiveness of Translarna has not been confirmed.” —Stealth BioTherapeutics moved a step closer to potential approval of the first drug for Barth syndrome. An FDA advisory committee voted 10 to 6 that Stealth’s drug, elamipretide, was effective at treating the ultra-rare mitochondrial disorder. The committee vote follows several regulatory setbacks, including a 2021 refuse-to-file letter in which the FDA pointed out that elamipretide failed its clinical trial. Stealth maintains there was improvement in a subgroup of patients and the short duration of treatment is the reason for the trial failure. An FDA decision is expected by Jan. 29. What’s New in Covid-19 —The European Commission granted marketing authorization to Novavax’s updated Covid-19 vaccine, Nuvaxovid. Authorization for the protein-based vaccine covers its use in those age 12 and older. The FDA authorized the updated version of Novavax’s Covid-19 vaccine in September. —In other Novavax Covid-19 news, the FDA pressed pause on the company’s plans for late-stage testing of a combination flu/Covid-19 vaccine as well as a standalone influenza vaccine. According to Novavax, the clinical hold stems from a report of motor neuropathy in a single patient outside the U.S. who received the combination vaccine in a Phase 2 study. The trial was completed in July 2023 and the serious adverse event was reported in September. Novavax said previous Covid-19 and influenza trials showed no signs of motor neuropathy. The company’s standalone Covid-19 vaccine is unaffected by the clinical hold. —In Covid-19 and flu testing news, the FDA granted marketing authorization to a Healgen Scientific over-the-counter, at-home test for both pathogens. The OTC Healgen Rapid Check Covid-19/Flu A&B Antigen Test uses a sample from a nasal swab. The authorization covers use of the product by people age 14 and older within five days of the start of symptoms. For children as young as 2, the sample must be collected by an adult.

干法制粒工艺即：先将药物和辅料投到料斗混合机中混合均匀，然后转至干法制粒机料斗中下料，在无外加液体粘合剂的情况下，经上下两只辊轮将松散的粉末压缩团聚成片状，然后将压实的粉末粉碎、整粒形成颗粒，从而使粉末的流动性得到改善的工艺过程。它的工艺优点是在整个制粒过程中无需水或其他有机溶剂参与，尤其对于那些对湿、热比较敏感的药物更为适合。另外，粉末压缩方式有辊压和非辊压方式，其中辊压干法制粒技术是制粒行业的主流。在辊压制粒工艺中，一般可分为三个区域：进料区、辊压区、成粒区。接下来我们主要一起探讨影响干法制粒颗粒收率、脆碎度及性质的一些因素：包括干法制粒的不同工艺参数设定、物料特性等。 不同工艺参数设定影响： 1）进料区：物料经料斗下料，被进料螺杆推入挤压区，在进料区内，物料粉体内粒子间经历重排，粒子间空隙变小，物料间的空气被排出。进料速度会对干法制粒制得的颗粒产生一定影响，一般来说，对于流动性较好的物料，进料速度可适当降低一点。而遇到用干法制粒机制备流动性不好的物料，可以加快制粒机送料的速度，并且减慢压轮的速度，使物料能顺利形成类似云片糕状的条状。 2）辊压区：在该区域内，物料与压轮表面的移动速度保持一致，在咬合区经过上下两只辊轮的一定间距和压力作用下，物料经历弹性和塑性形变最终被压实，被压成一定厚度的片状。在该区域内影响干法制粒工艺的几个变量因素包括：压轮转速、压轮压力、压轮间距、物料特性。 变量之一——压轮转速：压轮转速会影响物料在辊轮咬合区的受压时间，随着压轮转速的变大，物料在辊轮间受压的时间缩短，粉体粒子塑性形变减小，一方面可能有些粉末尚未压制成饼就随着辊轮滚动而泄露，另外受压时间短，形成的饼状颗粒结构疏松从而导致颗粒的收率下降。 例如在以下文献研究中，制备板蓝根泡腾片颗粒时，考察辊轮转速分别为6、9、12、15、18Hz，由结果可知辊轮转速在6~15Hz变化时，颗粒得率下降幅度不大，但当转速增至18Hz时，颗粒得率急剧下降，且颗粒脆碎度也会随着辊轮转速增加呈缓慢增加趋势。 变量之二——压轮压力：压轮压力会直接影响到压饼的压实程度。压轮压力过小，压出的大片易碎，容易造成细粉量较多，细粉量较多的情况下，可以考虑适当增加压轮压力或者提高送料速度。当然，压轮压力并非越大越好，在一段压轮压力范围内，压饼密度会随着压力增大而线性增加，而当达到一定压力值后，再增加压轮压力，粉体密度增加幅度会显著放缓。压力达到选择要基于原料的稳定性、颗粒粒径分布、成品崩解溶出等，例如如果压轮压力过大，则压制得到的颗粒会越硬，导致颗粒的可压性下降，压片时需要较大压力才能压制成形，最终会影响片剂的崩解和溶出。以下文献在制备板蓝根泡腾片颗粒时，将压轮压力设置为：0.5、1.0、1.5、2.0、2.5MPa，分析结果知随着压力增大，其中压力从0.5~1.5MPa时，颗粒得率显著升高，而1.5~2.5MPa，颗粒得率增加速率趋于平缓，究其原因应该是压力增加粒子间排列更紧密，颗粒硬度增加，在压饼破碎过程中细粉减少，从而增加了颗粒的得率。另外因压力增大导致物料粒子间发生塑性形变程度增加，粒子间结合更加牢固，因此结果证实颗粒的脆碎度随着压力增加而呈直线下降趋势。 变量之三——压轮间距：压轮间距即指两个压轮之间的最近点距离，它会影响压饼的片厚。当然，该参数也与压轮间物料所受的压力以及所通过物料数量密切相关。这也就是为什么有时候会出现：明明设置的2mm间隙，压片厚度却比1mm和3mm小，即压辊间隙与片状物厚薄不成正比，究其原因那就是因为输料转速，压轮转速和液压压力三个参数没有匹配好导致的。我们一般压片厚度选择2.0mm左右，大部分物料压片的厚度区间一般也就在1.5mm~2.5mm区间。 3）成粒区：即将压制成一定厚度的压饼通过粉碎室的切割刀将大片进行粉碎，然后经过整粒室内不同尺寸筛网进行整粒处理。如果所得到的颗粒粒径比较大，可以将破碎整粒速度适当减慢一点，只要不堵塞筛网孔径即可。有时候干法制粒得到的颗粒圆整度也较低，从而会影响颗粒的流动性。在制粒过程中可以通过改变片的厚度来提高颗粒的圆整度，一般可以根据颗粒大小来适当调节所压的片的厚薄，这样经整粒后颗粒的圆整度要好一点，或者和厂家沟通改进整粒器的结构来控制颗粒的圆整度。 物料属性影响： 除了以上制粒工艺参数可能会影响到干法制粒颗粒性质外，另外物料本身特性本身也会对颗粒性质造成很大影响。物料特性包括物料的可压缩性、流动性、热敏性以及物料本身的湿度、含水量等。这些因素会直接决定该物料是否适合该干法制粒工艺，所以在选用干法制粒工艺前，有必要去充分了解物料的特性。 1）选用可压性、流动性更好的辅料。如果物料的可压性较差，会导致制粒后颗粒的细粉量较多。例如物料流动性不好有可能是乳糖、微晶纤维素选用的型号的问题，如果用200目的乳糖，用量又大，流动性肯定不好，建议可使用其它流动性较好的直压型乳糖或微晶纤维素；此外也可以加入一些胶态二氧化硅和硬脂酸镁，也能起到改善流动性的作用。例如由愈创木酚甘油醚与氢溴酸右美沙芬组成的愈美颗粒剂干法处方筛选中，筛选了三种辅料包括：直压甘露醇、微晶纤维素和乳糖对颗粒流动性的影响，结果得出在该处方中颗粒流动性优劣顺序为：直压甘露醇＞乳糖＞微晶纤维素，制得颗粒的收率高低顺序为：直压甘露醇＞乳糖＞微晶纤维素，综合考量选择直压甘露醇为本处方中的最适用辅料。 2）选用粘合剂不同种类：由于干法制粒、压片整个工艺过程中需要经历二次压制，所以可压性和脆碎度是该工艺面临的两大挑战，而粘合剂由于对其可压性和脆碎度起着重要的作用，所以它也是干法制粒压片工艺中非常重要的一个功能性辅料，另外粘合剂种类或用量选用不当，也会造成颗粒细粉量较多。有文献研究比较了羟丙纤维素（HPC）、共聚维酮（PVP/VA）、羟丙甲纤维素（HPMC）、聚维酮（PVP）和乙基纤维素（EC）五种粘合剂在干法制粒压片中的表现，韧性测定结果分别为：HPC(4581)、PVP/VA(1102)、 HPMC(388)、 PVP(652) 、EC(725)，即HPC的韧性最好，更加容易承受外界应力，易发生塑性形变而不易发生脆性断裂。由不同粘合剂在盐酸二甲双胍片和扑热息痛片制备过程中的密度和流动性可知：当粘合剂用量不大时，不同种类粘合剂对颗粒密度和卡尔指数的影响均较小，干法制粒的颗粒密度主要还是与压制的大片密度有关，而大片密度主要受单位时间内流入辊轮间隙的物料量影响。由粒径结果知HPC和PVP/VA为粘合剂时细粉量较少，且在不同主压力下，HPC赋予片剂较好的可压性。 3）物料含水量及润滑剂用量：保证物料的含水量在一定适宜范围，可以保证干法制粒的颗粒收率大幅提高，同时颗粒的脆碎度会有所下降，因为适宜的物料含水量可以保证在粉体压缩过程中产生较好的粘性，相邻颗粒间形成的“固体桥”更加牢固。当然，物料含水量过多或者润滑度不够会容易导致干法制粒过程黏压辊现象的发生。尤其对于那些吸湿性较强的物料，很容易引起该情况的发生。如果在制粒过程中发生黏压辊现象，可以适当增加润滑剂如MS的用量，MS作为边缘润滑剂，主要当其受到设备（压辊、冲头类似）挤压时，形成一层软膜，从而起到润滑作用，但应当注意润滑剂的总用量，一般情况会选择润滑剂如MS一半用量内加，一半用量外加，在解决黏压辊问题的前提下，润滑剂用量标准即能少加就少加。例如在制备板蓝根泡腾片颗粒时，浸膏粉含水量分别控制在1.0%、1.5%、2.5%、3.5%、4.5%，其结果可以看出：随着浸膏含水量升高，颗粒的收率增加、脆碎度降低。 参考文献： [1] 干法制粒机原理工艺流程图解 [2] 干法制粒工艺及其在研发中QBD思维的运用 [3] 干法制粒技术探讨：压辊间隙与片状物不成正比问题 [4] 姚丽娜，愈美颗粒干法制粒工艺研究[J].中国科技期刊数据库， [5] 如何保证干法制粒机产品的圆整度 [6] 冯维峰，干法制粒及设备的特点与影响干轧效果因素的简述 [7] 罗晓健等，板蓝根泡腾片干法制粒工艺研究[中国中药杂志].2008，33（12）. [8] 王如意，干法制粒中粘合剂的比较[中国现代应用药学].2016，33（12）. 药事纵横征稿启事