ALDH3A2

Based on positive biomarker results observed in adult cohort of Phase 2 clinical trial of ADX-629 in Sjögren-Larsson Syndrome, proposed expansion to include pediatric patients expected to be submitted to the US Food and Drug Administration (FDA) in the first half of 2024 Phase 2 clinical trial of ADX-629 in moderate alcoholic hepatitis initiated; top-line results expected in the second half of 2024 Investigational New Drug (IND) application of ADX-246 submitted to FDA for Phase 1 clinical trial in healthy volunteers expected to be expanded to include patients with atopic dermatitis IND application of ADX-248 expected to be submitted to FDA for Phase 1/2 clinical trial in dry age-related macular degeneration patients with dark adaptation deficit in 2024 Special Protocol Assessment for clinical trial of reproxalap in dry eye disease amended based on FDA feedback LEXINGTON, Mass.--(BUSINESS WIRE)-- Aldeyra Therapeutics, Inc. (Nasdaq: ALDX) (Aldeyra), a biotechnology company devoted to discovering and developing innovative therapies designed to treat immune-mediated diseases, today announced advancement of its RASP modulator platform, including the expected submission to the FDA of a proposed expansion of the Phase 2 clinical trial of the investigational RASP modulator ADX-629 in Sjögren-Larsson Syndrome to include pediatric patients, initiation of a Phase 2 clinical trial of ADX-629 in moderate alcoholic hepatitis, submission of an IND application of the investigational RASP modulator ADX-246 for a Phase 1 clinical trial that is expected to be expanded to include atopic dermatitis patients, anticipated submission of an IND application of the investigational RASP modulator ADX-248 for a Phase 1/2 clinical trial in patients with the dry form of age-related macular degeneration (AMD) and dark adaptation deficit, and initiation of a preclinical program of RASP modulators in metabolic disease. This press release features multimedia. View the full release here: (Graphic: Aldeyra Therapeutics) “With an unparalleled RASP modulator discovery and development platform, Aldeyra remains a leader in the development of RASP modulators for the treatment of immune-mediated disease,” stated Todd C. Brady, M.D., Ph.D., President and Chief Executive Officer of Aldeyra. Sjögren-Larsson Syndrome is a rare inborn error of metabolism due to mutations in fatty aldehyde dehydrogenase, leading to accumulation of fatty alcohols and fatty aldehydes. The disease is characterized clinically by cognitive delay, spasticity, and dermal compromise. There is no FDA-approved therapy for Sjögren-Larsson Syndrome. ADX-629, administered twice daily over 90 days, has completed initial clinical testing in three adult patients in an investigator-sponsored clinical trial. Broad-based normalization of the majority of abnormal metabolomic signatures was observed along with reduction in accumulation of fatty alcohols. A proposed expansion of the clinical trial to include pediatric patients is expected to be submitted to the FDA in the first half of 2024. Moderate alcoholic hepatitis is a common disease that leads to significant morbidity and mortality due to hepatic compromise and related complications. There is no FDA-approved therapy for alcoholic hepatitis. In preclinical models of ethanol toxicity, ADX-629 decreased hepatic levels of RASP, triglycerides, and inflammatory cytokines. In a sequence-randomized, double-masked, placebo-controlled crossover Phase 2 clinical trial announced last year, relative to placebo, ADX-629 reduced dermal flushing (P=0.0007), increased Romberg test balance time (P=0.02), and lowered levels of the ethanol RASP metabolite acetaldehyde (P=0.03) following acute exposure to alcohol. The moderate alcoholic hepatitis Phase 2 clinical trial is intended to assess the activity of ADX-629, administered orally twice daily over 90 days, initially in approximately 10 patients. The primary endpoint is safety and tolerability; secondary endpoints include liver function biomarkers, model for end-stage liver disease (MELD) score, hospitalization, and mortality rate. Top-line results from the first patient cohort are expected in the second half of 2024. Atopic dermatitis is a common disease characterized by immune dysregulation that leads to hyperreactivity to endogenous and exogenous factors, potentially including RASP. There is no widely accepted oral therapy for the treatment of patients with mild to moderate atopic dermatitis. Recently announced results from a 90-day, open-label Phase 2 clinical trial of orally administered ADX-629 in eight mild to moderate atopic dermatitis patients demonstrated statistically significant and clinically relevant improvement in investigator-assessed and patient-reported outcomes across a number of different physiological and psychosocial assessments, including complete resolution of affected body surface area observed in one patient and elimination of itching reported by two patients. Based on the results of the clinical trial, an IND application of next-generation investigational RASP modulator ADX-246 for a Phase 1 clinical trial in healthy volunteers has been submitted to the FDA and is expected to be expanded to include clinical testing in patients with atopic dermatitis. The clinical trial is anticipated to be initiated in the first half of 2024, and top-line results are expected in the second half of 2024. AMD is a common disease, the so-called dry form of which is characterized by accumulation of toxic metabolites in the retina and visual deficit, typically beginning with difficulty seeing in low-light settings. Metabolites of RASP are associated with compromise in dark adaptation. Based on data demonstrating that RASP modulation reduces accumulation of toxic metabolites in a preclinical model of AMD, an IND application of next-generation investigational RASP modulator ADX-248 is expected to be submitted in 2024. The Phase 1/2 clinical trial is anticipated to enroll dry AMD patients with dark adaptation deficit. Highlighting the advancement of the RASP platform and the selection of key clinical indications for future development, Aldeyra released a focused pipeline. The previously announced programs of ADX-629 in chronic cough and idiopathic nephrotic syndrome have been de-prioritized due to regulatory and trial feasibility challenges, respectively. In addition, a new preclinical RASP modulator program in metabolic disease has been announced, supported by a number of clinical trials with ADX-629 that demonstrated a reduction in triglycerides and cholesterol. Based on Special Protocol Assessment feedback received from the FDA last week on reproxalap in dry eye disease, Aldeyra has amended the proposed clinical trial protocol and statistical analysis plan. “With the success achieved in our ADX-629 program, which includes a number of positive, signal-finding clinical results, we are excited to advance our RASP modulator pipeline to systemic and retinal immune-mediated diseases, as well as metabolic diseases, exacerbated by RASP,” stated Dr. Brady. “We anticipate 2024 to provide a variety of clinical-stage catalysts, as Aldeyra continues to progress its novel RASP platform.” About Aldeyra Aldeyra Therapeutics is a biotechnology company devoted to discovering innovative therapies designed to treat immune-mediated diseases. Our approach is to develop pharmaceuticals that modulate immunological systems, instead of directly inhibiting or activating single protein targets, with the goal of optimizing multiple pathways at once while minimizing toxicity. Our product candidates include RASP (reactive aldehyde species) modulators ADX‑629, ADX‑246, ADX‑248, and chemically related molecules for the potential treatment of systemic and retinal immune-mediated diseases. Our pre-commercial product candidates are reproxalap, a RASP modulator for the potential treatment of dry eye disease and allergic conjunctivitis, and ADX-2191, a novel formulation of intravitreal methotrexate for the potential treatment of proliferative vitreoretinopathy and retinitis pigmentosa. About RASP Modulators ADX-629, ADX-246, and ADX-248 ADX-629 is an orally administered RASP modulator currently in development as a signal-finding molecule for the treatment of mass-market immune-mediated diseases. ADX-629 has demonstrated potential activity in clinical trials of patients with psoriasis, asthma, COVID, ethanol toxicity, chronic cough, and atopic dermatitis. In more than 100 healthy volunteers and patients, no consistent adverse events associated with ADX-629 have been identified. An analog of ADX-629, ADX-246 is an orally administered next-generation RASP modulator expected to initiate clinical testing in the first half of 2024 in a Phase 1/2 clinical trial in healthy volunteers and patients with atopic dermatitis. Top-line results from the Phase 1/2 clinical trial are expected in the second half of 2024. ADX-248 is an intravitreally administered RASP modulator in development for the treatment of immune-mediated diseases of the retina, including the dry form of age-related macular degeneration, geographic atrophy, and related diseases. ADX-248 is expected to initiate clinical testing in 2024. Safe Harbor Statement This release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including, but not limited to, statements regarding Aldeyra’s future expectations, plans, and prospects, including without limitation statements regarding: the goals, opportunity and potential for reproxalap, ADX-629, ADX-246, and ADX-248, outcome and expected timing of discussions with the FDA on the Special Protocol Assessment, and anticipated clinical or regulatory milestones for reproxalap, ADX-629, ADX-246, and ADX-248. Aldeyra intends such forward-looking statements to be covered by the safe harbor provisions for forward-looking statements contained in Section 21E of the Securities Exchange Act of 1934 and the Private Securities Litigation Reform Act of 1995. In some cases, you can identify forward-looking statements by terms such as, but not limited to, “may,” “might,” “will,” “objective,” “intend,” “should,” "could," “can,” “would,” “expect,” “believe,” “anticipate,” “project,” “on track,” “scheduled,” “target,” “design,” “estimate,” “predict,” “contemplates,” “likely,” “potential,” “continue,” “ongoing,” “aim,” “plan,” or the negative of these terms, and similar expressions intended to identify forward-looking statements. Such forward-looking statements are based upon current expectations that involve risks, changes in circumstances, assumptions, and uncertainties. Aldeyra is at an early stage of development and may not ever have any products that generate significant revenue. All of Aldeyra's development timelines may be subject to adjustment depending on recruitment rate, regulatory review, preclinical and clinical results, funding, and other factors that could delay the initiation, enrollment, or completion of clinical trials. Important factors that could cause actual results to differ materially from those reflected in Aldeyra's forward-looking statements include, among others, the timing of enrollment, commencement and completion of Aldeyra's clinical trials, the timing and success of preclinical studies and clinical trials conducted by Aldeyra and its development partners; delay in or failure to obtain regulatory approval of Aldeyra's product candidates, including as a result of the FDA not accepting Aldeyra’s regulatory filings, or requiring additional clinical trials or data prior to review or approval of such filings; the ability to maintain regulatory approval of Aldeyra's product candidates, and the labeling for any approved products; the risk that prior results, such as signals of safety, activity, or durability of effect, observed from preclinical or clinical trials, will not be replicated or will not continue in ongoing or future studies or clinical trials involving Aldeyra's product candidates in clinical trials focused on the same or different indications; the scope, progress, expansion, and costs of developing and commercializing Aldeyra's product candidates; uncertainty as to Aldeyra’s ability to commercialize (alone or with others) and obtain reimbursement for Aldeyra's product candidates following regulatory approval, if any; the size and growth of the potential markets and pricing for Aldeyra's product candidates and the ability to serve those markets; Aldeyra's expectations regarding Aldeyra's expenses and future revenue, the timing of future revenue, the sufficiency or use of Aldeyra's cash resources and needs for additional financing; the rate and degree of market acceptance of any of Aldeyra's product candidates; Aldeyra's expectations regarding competition; Aldeyra's anticipated growth strategies; Aldeyra's ability to attract or retain key personnel; Aldeyra’s commercialization, marketing and manufacturing capabilities and strategy; Aldeyra's ability to establish and maintain development partnerships; Aldeyra’s ability to successfully integrate acquisitions into its business; Aldeyra's expectations regarding federal, state, and foreign regulatory requirements; political, economic, legal, social, and health risks, public health measures, and war or other military actions, that may affect Aldeyra’s business or the global economy; regulatory developments in the United States and foreign countries; Aldeyra's ability to obtain and maintain intellectual property protection for its product candidates; the anticipated trends and challenges in Aldeyra's business and the market in which it operates; and other factors that are described in the “Risk Factors” and “Management's Discussion and Analysis of Financial Condition and Results of Operations” sections of Aldeyra's Annual Report on Form 10-K for the year ended December 31, 2022, and Aldeyra’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2023, which are on the Securities and Exchange Commission (SEC) and available on the SEC's website at . Additional factors may be described in those sections of Aldeyra's Annual Report on Form 10-K for the year ended December 31, 2023, expected to be filed with the SEC in the first quarter of 2024, and Aldeyra’s other filings with the SEC. In addition to the risks described above and in Aldeyra's other filings with the SEC, other unknown or unpredictable factors also could affect Aldeyra's results. No forward-looking statements can be guaranteed and actual results may differ materially from such statements. The information in this release is provided only as of the date of this release, and Aldeyra undertakes no obligation to update any forward-looking statements contained in this release on account of new information, future events, or otherwise, except as required by law.

点击关注，星标CPhI制药在线十二烷基硫酸钠（SLS）是一种常用的药用辅料，它是阴离子表面活性剂，可作为药品的增溶剂、乳化剂、皮肤穿透剂、片剂和胶囊剂的润滑剂、润湿剂等，SLS的应用可能会影响到药品的质量、安全性和有效性。   1   1. SLS基本性质       SLS是一种以十二烷基硫酸钠（C12H25NaO4S）为主的烷基硫酸钠混合物。其易溶于水，在乙 醚和氯仿中几乎不溶；pH值为7.0～9.5（10g/L水溶液）；mp 204～207℃；密度为1.07g/cm-3（20℃）；HLB值（亲水亲油平衡值）约为40；表面张力为25.2mN/m（0.5g/L，30℃的水溶液）；临界胶束浓度为8.2mmol/L（2.365g/L，20℃）。SLS在正常贮藏条件下稳定，在酸性条件下会水解成月桂醇和硫酸氢钠，如在pH2.5或更低pH的水溶液中易发生水解，进而导致SLS有效成分含量下降。SLS应置于密闭容器中，并在阴凉、干燥和远离强氧化剂的地方贮藏。SLS是中等毒 性物质，能对皮肤、眼睛、黏膜、胃、上呼吸道产生刺激等急性毒 性反应。长期、反复使用SLS稀溶液能造成皮肤干裂和接触性皮炎。22. 各国药典SLS质量标准对比       SLS作为常用的药用辅料，各国药典对其质量标准均有不同的规定和描述。例如：美国药典对烷基硫酸钠含量提出了质量控制标准，而中国药典和日本药典没有对此予以要求；美国药典和日本药典对总醇类提出了质量控制，《中国药典》2015版有总醇量的控制指标，但《中国药典》2020版取消了该指标；《中国药典》2020版对脂肪醇组成进行了控制，而美国药典和日本药典均没有予以控制；中国药典和日本药典对SLS水分提出了质量控制，而美国药典没有予以控制；中国药典对重金属含量提出了质量控制标准，美国药典和日本药典并没有予以控制；其他指标基本一致。       33. 在药物制剂处方中的应用       3.1增溶作用       SLS是分子中带有性质不同的亲水基和疏水基的两亲结构化合物，是一种在药物制剂中常用的增溶剂和助溶剂。在阿司匹林片剂处方中添加SLS可以起到一定的增溶作用，促进阿司匹林的溶出。在偏碱性条件下，SLS对槲皮素具有增溶作用。但在利托那韦片剂配方中使用了SLS以改善药品的润湿性，结果显示，样品在酸性介质中的溶解度却急剧下降。这是由于形成了难溶的利托那韦-SLS复合物所致。由此可知，SLS虽然是常规的增溶剂，但在不同的药物处方中也有反常情况出现，因此在药物研发过程中应予以关注。       3.2乳化作用       SLS是乳剂中常用的乳化剂，用于配制O/W型乳剂基质。SLS的HLB值约为40，常用量为5～20g/L，而过高的用量对其降低表面张力的作用甚微。常与其他W/O型乳化剂（单硬脂酸甘油酯、脂肪酸山梨坦等）合用调节乳膏体系的HLB值，乳化效果更佳。       3.3抑菌作用       SLS可使细胞膜崩解，它与膜蛋白疏水部分结合并与膜分离。研究表明，高浓度的SLS还能够破坏蛋白质中的离子键和氢键等非共价键，甚至改变蛋白质的构象。SLS对革兰阳性菌具有抗菌作用，对抑制金黄色葡萄球菌更有效。       3.4润滑作用       SLS可在一般固体制剂中作为润滑剂使用，一般用量为10～30g/kg。将适量SLS应用于塞来昔布片剂的药用粉末混合物中，结果显示其润滑效率与硬脂酸镁相当，但不会降低片剂的可压性，此外，与含硬脂酸镁的片剂相比，含SLS的片剂还具有改善体外溶出度的作用。       3.5防静电作用       SLS本身具有防静电能力，适合应用于微丸包衣。在微丸包衣的大部分时间内，微丸表面处于微润湿状态，部分解离的SLS具有一定的导电性，有利于消除静电，一般在包衣液中加入5～10g/L的SLS就可以达到防静电的效果。       3.6改进包衣粉或胶囊壳性能       包衣材料要求性质稳定、无毒、有弹性、不出现裂缝、不影响崩解，在包衣粉中加入SLS有利于改进包衣粉的性能。此外，在明胶中加入SLS可以增加胶囊壳的光泽度。提示在原研处方解析中，如果原研参比制剂处方中含有SLS成分，也有可能是原研参比制剂包衣层或胶囊壳中含有SLS，因此在制剂研究过程中要做综合全面的反向解析。       3.7影响药物吸收       ICH最新指南《基于生物药剂学分类系统的生物等效性豁免》中明确说明SLS可能影响药物的吸收，其影响药物吸收的风险应基于机制进行评估。翻转肠囊法研究了吸收促进剂对小肠吸收苦参碱的作用，结果发现加入2g/kg的SLS可增加苦参碱的离体小肠吸收。但美国FDA发表的一篇文章阐述了14种常用辅料对胃肠道渗透性的影响，其中指出当SLS用量小于50mg时，不会对西咪替丁和阿昔洛韦的吸收产生影响。在研究颊黏膜药物渗透率时发现SLS能够降低咖 啡 因和地 西 泮的通透性。上述研究结果说明SLS是否对药物吸收有促进作用不能一概而论，要具体药物具体分析。     4  4.在药物制剂分析中的应用及检测       4.1对药物溶出度的影响       SLS是药物溶出介质中常用的助溶剂之一，在《普通口服固体制剂溶出度试验技术指导原则》中提到"对于不溶于水或难溶于水的药物，可考虑在溶出介质中加入十二烷基硫酸钠或其他适当的表面活性剂，但需充分论证加入的必要性和加入量的合理性"。推荐使用SLS的质量浓度在0.1～10g/L内依次递增，特殊药品可适度增加用量。在按照中国药典配制pH6.8的磷酸盐缓冲液介质时，加入SLS后会产生沉淀，这是由于钾盐与SLS反应所致。按照日本药典记载的方法配制pH6.8的缓冲盐溶液并采用煮沸法溶解SLS，当温度稍微低于30℃时不产生沉淀，这可能与钾盐的浓度低有关。按照中国药典配制不含钾盐的pH6.8磷酸钠缓冲液，可以避免沉淀的产生。       4.2对药物检测的增敏作用       SLS具有荧光性，在药物检测过程中具有显著的增敏作用。在建立银杏叶片剂中测定槲皮素含量的SLS增敏荧光新方法，结果显示，SLS在碱性（pH=9.12）介质中对槲皮素荧光增敏效果最好，在最大激发波长464nm、最大发射波长542nm处有强荧光发射峰。有报道将沙洛芬与铀酰结合成配合物，然后用SLS为表面活性剂将配合物进行包裹，可以达到增敏检测的目的。       随着仿制药一致性评价工作的深入，药用辅料在制剂中的作用越来越突出，十二烷基硫酸钠在较多仿制药和创新药制剂中多有应用。SLS具有增溶促渗作用，由于其在制剂处方中使用的比例一般不大，在低溶低渗药物中尤其需要定量分析其含量，并且要使用质量较好的SLS，以确保仿制药与原研药物同质同效。SLS作为一种多功能性的辅料，在未来的药学领域中将会得到越来越多的研究和应用。       参考文献：       [1]祝红元,汪家众.固体十二烷基硫酸钠控制及检测[J].广东化工,2022,49(04):198-199+193.       [2]朱雷,何训贵.十二烷基硫酸钠在药学研究领域中的应用[J].中国药剂学杂志,2020,18(06):288-295.       作者简介：沙罗，中药研发工作者，现就职于国内某大型药物研发公司，致力于中药新药的研究开发。       智药研习社8月直播讲座报名速来投稿参与金笔奖征文，稿费丰厚！来源：CPhI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPhI制药在线▼点击阅读原文，进入智药研习社~

点击上方的 行舟Drug ▲ 添加关注药用辅料是指生产药品时处方中使用到的赋形剂和添加剂，是除了活性成分（原料药，API）或前体药物以外，在安全性方面已进行了合理评估的物质。辅料除了赋形、充当载体、提高稳定性外，还具有增溶、助溶、调节药物释放等重要功能，是可能会影响到制剂的质量、安全性和有效性的重要成分。在制剂制备过程中，药用辅料选用是否得当会影响制剂的安全性、有效性、稳定性、经济性和顺应性。本文通过围绕辅料的关键质量属性，通过几个案例展示了辅料功能和性质对制剂研发的影响，并总结了辅料质量属性的分析技术，旨在提示广大研发人员重视辅料的质量研究与控制。1、什么是辅料的关键质量属性（CQA）？辅料可以有多种分类方式，如下图可见，包括有机辅料、无机辅料，每类别根据结构不同都可以分为简单（结构简单、明确）和复杂（结构复杂、不明确）的，根据来源不同，分为合成、半合成、天然的辅料。关键质量属性是物理的、化学的、生物的、微生物的属性和特性，这个属性应被限定在一个适当的限度、范围内，以确保产品的质量。对于原料药而言，可能包括质量标准范围内的，如有关物质、含量、异构体、水分、干燥失重、残留溶剂、溶解性等，还有可能包括与制剂的溶出度、生物利用度、稳定性、工艺等相关的晶型、粒度、晶癖。而对于辅料而言，一般包括杂质、粒度、粘度、pH、分子量分布等特性。与原料不同，辅料的关键质量属性有时很难发现，由于受到API（性质、剂量大小）、处方（组成、比例）、生产工艺等的影响，某种属性（例如粘度）对于某药物可能是关键的，而对另一种药物，或另一个不同剂量的药物而言，可能就不是关键的，也就是说辅料属性的发现和确定是否关键与很多因素有关，如果在研发初期研究不充分、没有发现、没有总结，可能就不会发现辅料的关键质量属性，即使一次通过生物等效性试验（BE），也难保后期放大、持续生产、临床安全性、有效性方面不出问题。因此，在研究过程中，我们还应该把更多的精力放在系统研究辅料特性上，细致思考和观察，把辅料的CQAs与成品的处方组成、生产工艺和CQAs结合起来，找到其中的因果关系。2、辅料性质差异从何而来？不难理解，与API一样，辅料的理化性质、机械性质的差异也是由其生产工艺决定的，不同的生产工艺（或参数）会生产出不同性质的辅料。如果辅料生产的起始物料、生产工艺（如全合成、半合成、发酵）、生产设备、生产规模、工艺参数等发生了变化，那么辅料中也就可能产生新的工艺杂质，也可能导致某些理化性质发生变化，甚至引起机械性质、粉体学性质的变化，例如不同pH、不同粒度等。一般来讲，对于通过发酵、降解工艺生产的辅料，其发生质量差异的可能性比全合成的辅料要大。因为前两者的生产工艺有时较复杂，工艺参数控制往往较宽，而后者如果起始物料不变，工艺参数调整的空间较小。在原辅料相容性过程中，在不同厂家辅料的筛选中，在稳定性的放样考察中，要特别注意研究和总结不同性质的辅料对有关物质、含量、溶出等CQA的影响，然后去分析辅料的哪些属性会引起这种结果，是水分、pH、杂质、过氧化物、粒度还是其他。对于特殊工艺制备的制剂（如缓释制剂），特殊BCS分类的药物（如BCS II或IV类）来讲，辅料的特性研究更加关键。研发中，要关注不同供应商来源的同种辅料、相同厂家的不同批次辅料之间的差异，尽可能多了解辅料的生产工艺。辅料CQA能否发现，与人员水平有关、工艺有关、还与所选择检测方法和技术有关。3、影响制剂CQA的辅料特性辅料对制剂成品质量属性、生产工艺的影响是通过辅料的功能、辅料的质量以及辅料与辅料、辅料与药物的相互作用来实现的。辅料的性质可分为物理性质和化学性质两大类。在物理性质中，常见的性质例如粉体学性质（流动性、可压性、粒度分布、形态等）；化学性质中，常见的性质例如化学结构式、取代度、杂质等。目前有非常多的关于辅料特性差异的报道，作者仅仅列出几个案例来说明问题，其他代表性案例，读者可自己可通过文献查找，不再一一列举。案例1：不同粉体学性质辅料对直压工艺产品质量的影响Parteck®M200、M100 直压甘露醇和直压甘露醇C、D 这四种不同型号的甘露醇与主药相容性好，但不同型号的甘露醇之间还是存在一些差异[1]。表1. 粉体学测定结果一般来说，卡式指数在25%以下时流动性较好，卡式指数越小，粉体的填充性越好，相反卡氏指数较大，可压性好。通过表1可以看出除Parteck® M100 直压甘露醇外的3 种型号甘露醇及其混合药物后测得的卡式指数均小于20%，而Parteck® M100 直压甘露醇及其混粉的卡式指数也不大于25%，在填充性和可压性方面各有所长。然而，在不同溶出介质中的溶出曲线表明，在水中，含Parteck® M200、M100直压甘露醇的模型药物吲达帕胺的溶出结果优于直压甘露醇C、D，而在其他3 种溶出介质中的4条溶出曲线趋势一致，说明药物与Parteck® M200、M100 直压甘露醇混合压片后的溶出度具有一定优势。图1. 片剂在水（A）、0.1mol/L 盐酸（B）、pH 4.5 醋酸缓冲液（C）和pH 6.8 磷酸缓冲液（D）中的溶出曲线通过这个案例可知，相同种类辅料不同型号、不同粉体学性质的辅料在特定处方、工艺条件下，对制剂成品的关键质量属性影响不同，因此对于粉末直压工艺而言辅料的粉体学指标是一个关键因素。案例2：不同粒度甘露醇对成品含量的影响采用粒径较大的物料甘露醇200SD和氯雷他定混合粉压片，发现压片过程中的硬度、厚度、重量差异等均符合要求，但压片结束时片子的含量偏高，是什么原因呢？原来200SD在混合粉中先从料斗中流出，而粒径较小的主药粘在料斗壁上，最后流出，导致压片结束时饲料器及片子含量偏高。当换用粒度较小的甘露醇100SD 时，由于100SD的粒径和主药差异不大，因此并没有出现分层的现象，示意图如图2 所示[2]。图2. 粉体在压片过程中料斗内的流变学作者在对压片过程中模孔和片子的数据进行分析时发现，甘露醇100SD和200SD混合粉体表现出了相同的现象：模孔内的含量均比同时间的片子含量偏高。产生这种现象的原因是什么呢？作者认为，对于直接压片工艺，粉末并未经过制粒过程，粉末分子间仅有微弱的范德华力连接，很容易受到外界的影响，上冲在压模孔里的物料时，造成了粒径较小的主药飞散出模孔而使最终片子的含量相对偏低。通过这个案例可知，相同种类不同粒度的辅料，在特定药物、处方、工艺条件下，对成品的生产工艺和关键质量属性的影响不同，因此“粒度”是一个关键因素，在一个选定的制剂工艺条件下，需要对辅料提出“特殊要求”。案例3：不同来源SLS对制剂工艺的影响在设计难溶性药物口服固体制剂时，制剂人员面临着极大的挑战，特别是高剂量药物。提高溶出度和/或溶出速率是提高难溶解性药物口服生物利用度的必要条件。目前有许多方法可以提高溶出，如采用酸化剂或碱化剂调节pH值、络合物、固体分散体、制备成无定型药物、减小粒度以及使用表面活性剂等。表面活性剂可以在提高药物溶解度方便发挥一种或多种作用，如改善药物的润湿性和溶解性，并减少或防止药物沉淀。从生产角度而言，使用表面活性剂提高溶解度比其他非常规剂型（如固体分散体）更适合生产与降低成本。十二烷基硫酸钠（SLS）是一种很常用的阴离子型表面活性剂，具有很强的增溶能力，用在固体口服制剂中提高难溶性药物的溶解度。除了上述作用之外，SLS还会影响口服固体制剂的生产过程。不同来源的SLS含有不同含量的表面活性杂质，其中大部分是同源的醇类，其表面活性在SLS的两个数量级以上（见表2）。这些已知或未知的杂质可能有助于表面活性剂的功能，并改变SLS在溶出介质或固体口服制剂中提高药物溶解性时的增溶作用。不同来源的SLS可能具有不同的物理性质，如熔点、粒度、微观形态，这可能影响药物的溶出和生产过程[3]。表2. 不同来源的SLS检测结果不同来源的SLS的扫描电镜图如下所示，Spectrum公司SLS大多数颗粒具有更少的球形形状，长度大于25μm，一些聚集体大于150μm。Cognis公司的SLS大多数颗粒是较大、多孔、不规则的聚集体。Sigma公司的SLS颗粒呈薄片状，表面有层状结构，颗粒的直径约为2μm至数百微米。三个公司的SLS粒度分布测定结果差异很大。图3. Spectrum公司的SLS扫描电镜图图4. Cognis公司的SLS扫描电镜图图5. Sigma公司的超纯SLS扫描电镜图图6. Spectrum、Cognis、Sigma公司的SLS粒度分布图（未微粉、微粉）在湿法制粒中，不同来源和不同粒度的SLS所需的水量和制粒时间也不同。含有SpectrumSLS的辅料制粒时的用水量比其他两个来源的SLS少。因此在固定制粒时间时制粒所需的水量与SLS的表面张力的顺序相同：Spectrum < Cognis < Sigma（超纯）。表3. 不同来源和不同粒度的SLS所需的水量和制粒时间根据上述案例可见，在进行含有SLS的制剂处方工艺研究中有必要研究不同来源SLS的性质、粒度分布等性质，必要时制定辅料的内控标准。案例4：辅料化学结构式与功能的相关性某药物的片芯辅料之一为all-rac-α-Tocopherol，中文名为α-生育酚，结构式中含有酚羟基，作为抗氧剂使用。但有时研发人员误将其认为是维生素E而使用了中国药典中的原料药维生素E作为抗氧剂使用，从结构式中可见由于药典中的维生素E为α-生育酚的醋酸酯，因此已没有抗氧化作用了。所以，使用辅料时应注意辅料的化学结构和其作用的关系。案例5：辅料中的活性杂质辅料中也有很多类活性杂质，这类杂质可以与API发生反应。以过氧化物为例，聚山梨酯、聚乙烯吡咯烷酮（PVP）、聚乙二醇（PEG）、羟丙基纤维素（HPC）等是含有过氧化物的辅料，如果根据文献报道或研究发现API容易被氧化，由于不同的API对氧化的敏感性可能不同，那么在处方筛选阶段就需要设计相应的实验来研究论证这些辅料中不同过氧化物含量对制剂中杂质的影响，根据数据结果来确定该辅料中过氧化物需要控制在什么限度才能保证制剂的质量和稳定性，保证杂质在整个货架期内的增加趋势不高于原研制剂。辅料中的过氧化物包括过氧化氢(H2O2)，氢过氧化物(ROOH)，有机过氧化物(ROOR’)等。过氧化物常用于聚合物的生产，在纯化过程中很难被完全去除，此外，在聚合物的降解时也可能会产生过氧化物。不同的生产条件、纯化工艺、不同存放时间、不同生产厂家、以及相同厂家不同批次之间，过氧化物的含量都可能存在较大差异。过氧化物可以通过以下三种途径与API发生氧化反应：亲核加成、亲电取代、金属存在下的自由基反应。如果发现API中的氧化杂质增加，且处方中包括上述辅料应进行有针对性的研究和控制。醛类、有机酸（如甲酸、乙酸等）、还原糖、元素杂质等辅料中活性杂质的控制综见美国基因泰克公司的综述[4]。  4、辅料CQA的分析技术从上述案例中可见，辅料变异有时会显著影响自身的性质和功能，也会对制剂的关键质量属性和工艺的选择重要有影响。我国仿制药一致性评价申报资料中的P.4部分就要求对辅料的控制进行研究和说明。因此，在仿制药研发中，不但制剂人员应该对辅料有深入了解，分析人员也应该掌握评价辅料特性的分析方法，以促进对QbD药品研发先进理念的理解。从上文分析可知，辅料差异的来源包括：source to source，site to site，batch to batch， supplier to supplier，year to year等。为了表达这些差异，我们可以从“微观”和“宏观”两个角度进行分析。辅料的微观属性分析技术。X射线粉末衍射法、DCS法、TGA法、NIR法、固态核磁SSNMR、KFT或干燥失重法、pH测定法等方法常用来对辅料的微观属性进行分析，如结构式、晶型或无定型、熔点、水分、酸碱度等。其中，SSNMR法区分辅料化学结构、NIR法在区分辅料批间差异方面具有重要应用。辅料的宏观属性分析技术。辅料粉体学特性的测定方法，如流动性、堆密度、压缩指数、粒度分布、扫描电镜（SEM）等指标都有相关的检测技术，详见USP<1174> POWDER FLOW粉体流动性等其他检测技术章节。当辅料的来源、生产工艺、稳定性等发生变化时，采用上述分析技术进行综合分析，往往可以发现辅料性质的差异，当然辅料的检测方法也是需要进行方法学验证的。5、辅料质控相关的指导原则和质量标准ICHM7和ICHQ3D大家经常会用于成品的质量控制，如原料药或制剂。但是，对辅料的质量控制而言，也有特殊规定。例如ICHM7规定对已上市药品中使用的辅料、香精、着色剂等可不进行基因毒性杂质的有关研究，然而对于新辅料而言，ICHM7要求对首次在制剂中使用到的辅料进行安全风险评估，因此这类辅料需要关注遗传毒性杂质的控制。ICHQ3D用于原料药和制剂的金属杂质控制，对于辅料而言，也可能引入金属杂质，如Pt、Pd等，ICHQ3D同样适用于辅料的金属杂质研究，常用的方法为ICP-MS。此外，EP、USP-NF、JP等国外药典标准也经常收载ChP没有收载的辅料标准，在对辅料标准进行分析研究时，应考察将其汇总对比，详细标准检测方法和限度，根据对制剂产品关键质量属性的影响，制定相应的控制指标和控制方法、限度标准，从物料的源头上来确保产品质量的稳定性和均一性。6、QbD研发理念与辅料控制QbD理念通过ICHQ8、Q9、Q10指导原则进行了表达，QbD强调对制剂处方、工艺的理解和控制，其中重点概念包括目标产品质量概括QTPP、关键质量属性CQA、关键物料属性CMA、设计空间DS等。因此应该对原料、辅料、包材、工艺、设备、分析方法等进行充分的研究与理解，对今后可能出现变异进行提前判断。对于辅料的选择，是药品研发中一个很重要的环节，辅料的选择影响生物利用度（BA）或生物等效性（BE）、药物稳定性以及生产重复性。有时，辅料选择时往往需要综合考虑很多问题，如为了提高生物利用度、生物等效性而牺牲一定程度的药物稳定性，这时就需要选择合理的包材或制定合理的控制策略来实现和保证。把辅料的CQAs与制剂成品的QTPP联系起来，只要制定了辅料控制策略就能够保证产品符合要求，而为了完成这种“过程中的控制策略”，首先需要结合国内外药典标准对辅料的基本检测指标进行分析；其次需要结合辅料的厂家报告和自检结果分析存在的差异；第三需要结合制剂处方工艺研究寻找辅料的CQAs并制定适用于特定药物的内控标准。辅料虽然无药理活性，但却是制剂的重要组成部分，缺少辅料制剂的性能是无法实现的。药品中使用到的辅料的性质往往是发生变化的，这些变化往往来源于生产工艺的变化。辅料的某种特性的变化会影响到制剂的性能和功能，应充分理解了这些变化对制剂关键质量属性的影响。多种辅料的分析检测技术为评估这些变化提供了方法，应注意积累和总结。此外，辅料的包装、贮藏条件对辅料质量的影响，例如光、氧、湿、热等因素都会促进辅料中过氧化物的形成，聚维酮等辅料使用中需注意包装的合理性和完整性。可以预见，随着我国仿制药一致性评价工作的深入开展，人们对辅料关键质量属性的研究和控制将会得到前所未有的重视。 参考文献[1] 白璐,王博,吴疆,任晓文.不同型号甘露醇对吲达帕胺直接压片的影响研究[J].现代药物与临床,2014,29（4）：338-341[2] 赵存婕.探讨不同粒度的甘露醇对于直接压片产品的影响[J].黑龙江医药,2014,27(3):559-562[3] Dongmei Qiang, Jocelyn A.Gunn, Leon Schultz & Z. Jane Li.Evaluation of the impact of sodium lauryl sulfate source variability on solid oral dosage form development [J]. Drug Development and Industrial Pharmacy, 2010; 36(12): 1486–1496.[4] Kelly Zhang, Jackson D.Pellett, Ajit S. Narang, Y. John Wang, Yonghua Taylor Zhang. Reactive impurities in large and small molecule pharmaceutical excipients-A review [J]. Trends in Analytical Chemistry,101 (2018) 34-42.文章信息源于公众号药品研发驿站，登载该文章目的为更广泛的传递行业信息，不代表赞同其观点或对其真实性负责。文章版权归原作者及原出处所有，文章内容仅供参考。本网拥有对此声明的最终解释权，若无意侵犯版权，请联系小编删除。学如逆水行舟，不进则退；心似平原走马，易放难收。行舟Drug每日更新 欢迎订阅+医药大数据|行业动态|政策解读