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罗盖特:如何掌握药物掩味技术?

来源:荣格     发布时间:2022-01-13
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本文根据 罗盖特医药应用实验室经理Bing Xun Tan博士 的采访问答整理

 

Could you please run through the importance of taste-masking as well as the approaches that are currently available to formulators for taste-masking?

能不能给我们介绍一下味觉掩蔽的重要性以及目前配方师可以使用的味觉掩蔽的解决方法

 

Taste is an important aspect when it comes to oral drug products and improving patient compliance, with consequent benefits in overall therapeutic outcomes. Taste-masking solutions can also enable the development of innovative orodispersible dosage forms, which are considered more patient-friendly. In the nutraceuticals market, where consumers can choose from a multitude of commercial offerings, product taste can be a deciding factor when it comes to making their purchasing decision.

口服药物产品的味道是一个非常重要的方面,它会影响患者依从性,从而影响到整体治疗效果另外,味觉掩蔽解决方案还可以使创新的口分散剂型的开发成为可能,让产品更有利于患者。在选择丰富的营养药品市场,产品口味是决定消费者是否购买的因素之一

 

Taste masking of pharmaceutical drug products is generally achieved through one, or a combination, of the following three approaches. The first approach involves chemical modification of the active pharmaceutical ingredient (API) to reduce bitterness. Here, the bitter-tasting APIs are chemically modified to develop prodrug or salt forms with a reduced bitter taste.

药品的味觉掩蔽一般通过以下三种方法中的一种或组合形式来实现。第一种方法是对活性药物成分API进行化学修饰。苦味的原料药经过化学修饰,以开发苦味度降低前药或盐形式。

 

The second approach utilize excipients in formulation to facilitate a direct sweetening effect and/or reduction of the perceived API bitterness. Careful selection of excipients can enable formulation strategies, using flavors, sweeteners (e.g. sugars, polyols, artificial intense sweeteners), and bitter blockers. Pleasant-tasting, highly viscous, or lipophilic vehicles can also provide an effective tastemasking effect.

第二种方法是在配方中使用赋形剂,直接增加甜味效果和/或降低感知到的原料药苦味。制定配方策略时,需要仔细选择辅料,可以使用香料、味剂如糖、多元醇、人工强效甜味剂和苦味阻滞剂。味道愉悦高粘性或亲脂性载体也可以提供有效的味觉掩盖效果

 

Lastly, advanced processing of the API or drug product can help minimize oral solubility and direct

contact with the taste buds. Some common approaches include:

Coating of API particles with a physical barrier

Tablet film coating or sugar coating

Microencapsulation

Embedment of API particles in a matrix via solid dispersion or granulation

Microspheres and liposomes

Complexation of API with cyclodextrins or ion exchange resins

Adsorption of API using insoluble powders

第三种方法,原料药或药物的高级加工可以帮助减少口服溶解度,以及药物与味蕾的直接接触。一些常见的方法包括:

  • API粒子进行物理包衣覆盖

  • 片剂薄膜包衣或糖衣

  • 微型胶囊技术

  • 原料药颗粒通过固体分散或造粒嵌入基质中

  • 微球、脂质体技术

  • API与环糊精或离子交换树脂的络合

  • 不溶性粉末对原料药的吸附

     

    Are there best practices for formulators to follow when approaching taste-masking so that they

    can make the best selection of technique/solution? (Are there certain questions that the

    formulator should ask? Should the formulator approach taste-masking at a certain time point?

    Etc.) 可否分享一下味觉掩蔽的最佳实践或技术?(配方师应该提前思考哪些问题应该在个时间点进行味觉掩蔽等等)

     

    In formulation, the difficulty of taste-masking is increased when the API possesses a strong bitter taste, high solubility in the buccal cavity, or when a high dose of the API is required. These are some of the key factors that should be considered, especially when the oral dosage form is not intended to be immediately swallowed during administration, such as chewable tablets, lozenges, orally-disintegrating tablets and films.

    在配方中,原料药具有强烈的苦味、在口腔中的溶解度高或需要大剂量的原料药时,掩味难度会大大增加。如果你的药物产品又属于咀嚼片、含片、口腔崩解片/等这类无法立即吞下的剂型,那配方师确实需要提前考虑关键因素

     

    It’s best practice to consider taste masking early in the product development process, as major

    regulatory agencies now require new drug product developments to include pediatric trials. For

    example, The Pediatric Research Equity Act (PREA) in the US and Paediatric Regulation in Europe

    require submission of a Pediatric Study Plan (PSP) and Paediatric Investigation Plan (PIP) respectively. As such, pharmaceutical companies are focusing on taste-masking solutions and palatability studies which can aid development and demonstrate patient compliance of the drug product for children. Early consideration of the potential need and solution for taste masking can help advance the pediatric product development, minimizing potential delays later in the process.

    最好的做法是在产品开发过程的早期考虑味觉掩蔽因为目前主要的监管机构要求新药开发包括儿科试验。例如,美国的《儿科研究公平法案》(PREA欧洲的儿童用药法规要求分别提交儿科研究计划PSP儿童药物研发计划PIP。因此,制药公司投入更多精力在味觉掩蔽解决方案和适口性研究,是一件划算的事情,可以同时帮助发展和证明儿童药物依从性。尽早考虑味觉掩蔽的潜在需求和解决方案可以帮助促进儿童产品的开发,最大限度地减少后续过程中的潜在延迟。

     

    Pediatric and geriatric patients are target groups not only for taste-masking solutions but also for more convenient/easier to administer dosage forms, such as orally disintegrating tablets (ODTs). Is the use of alternative and more novel dosage forms, such as ODTs, creating new challenges for taste-masking? If so, how are these challenges being overcome? (Please consider a variety of dosage form solutions, I have just specified ODTs as an example in the question)

    儿童和老年人的药物依从性较低,不仅成为味觉掩蔽的重点目标人群,也促使市场不断开发更方便更容易给药剂型如口腔崩解片ODTs)给到老人和小孩。这些替代剂型新颖的剂型,是否对味觉掩蔽提出了新的挑战如何克服这些挑战

     

    The pharmaceutical industry is actively looking into more patient-centric and age-appropriate dosage forms to cater to the personalized needs of different patient populations. Alternative dosage forms such as orally disintegrating tablets (ODTs) or orally disintegrating films (ODFs) are examples of these developments, to name a few.

    制药行业正在积极研究更加以患者为中心适合不同年龄的剂型,以满足不同患者群体的个性化需求。口腔崩解片ODTs口腔崩解膜ODFs,就是很好的例子

     

    As such products are designed to rapidly disintegrate in the mouth, bitter active pharmaceutical

    ingredients (APIs) can have a prolonged direct exposure to taste buds, which results in poor palatability. Careful selection of excipients in a formulation can therefore be a feasible approach to the taste masking of orally disintegrating dosage forms. For example, the excipients hydroxypropyl-β-cyclodextrin and pea-based maltodextrin have been successfully used to mask ODFs containing dimenhydrinate and loratadine.i,ii

    由于这些产品被设计成在口中迅速分解,苦味的活性药物成分APIs可能会长时间直接暴露在味蕾中,从而导致不良的适口性。因此,在配方中仔细选择辅料是口腔崩解剂型掩蔽味觉的一种可行方法。例如,赋形剂羟丙基-β-环糊精和豌豆麦芽糖糊精已成功用于含有茶苯海明和氯雷他定的ODFs的味觉掩蔽i,ii

     

    Excipients are a widely used method of taste-masking: are there any limitations of the currently available excipients (in terms of taste-masking) and do you believe the new pilot program, launched by CDER, for the review of novel excipients could have a boosting effect on the tastemasking excipient market?

    辅料是一种被广泛使用的掩味方法目前现有的辅料在掩味方面是否存在局限性您认为CDER*推出的对新型辅料进行审查的新试点项目是否会对掩味辅料市场产生促进作用*CDERFDA下属药审部门

     

    There are limited excipient options today that may be used to taste-mask APIs, and even fewer for formulations meant for pediatric patients. New pharmaceutical processing techniques used in tastemasked formulations, such as 3D-printing, also require suitable excipients better designed to facilitate these modern processes.iii The new pilot program, launched by CDER, could enable the introduction of novel excipients, which may have a precedence of use and/or research in other industries – such as food – where there is already existing emphasis and expertise in terms of taste.

    目前,用于掩味原料药的辅料选择有限,用于儿配方的辅料选择更少此外,用于味觉掩蔽制剂的新型药物加工技术,如3D打印,也需要设计更好的辅料来跟进这些现代工艺。IiiCDER启动的新试点项目,可以引入新的辅料,这些辅料可能在其他行业如食品有优先的使用和/或研究,从而在口味方面替医药行业提前积累经验知识

     

    Are there any technologies/solutions/approaches/techniques under evaluation or in the pipeline that you believe will hold great promise for taste-masking in the future? (Please elaborate) 有哪些正在评估或还在开发中的新技术,能给味觉掩蔽带来巨大潜力

     

    The pediatric patient population exhibits a high demand for taste-masking solutions that is not fully met today. KLEPTOSE® Linecaps is a pea maltodextrin product from Roquette that is primarily designed for taste-masking and solubility enhancement applications. It is particularly suitable for pediatric formulations, as it is compliant with both pharmaceutical and food regulations, easy to formulate, and generally easy to digest.

    儿童患者群体对味觉掩蔽解决方案的需求很高,但该市场尚未完全满足KLEPTOSE®Linecaps罗盖特Roquette公司的一种豌豆麦芽糊精产品,主要用于味觉掩盖和增强溶解度。它特别适合于儿童配方,因为它符合药物和食品法规,易于制定,容易消化。

     

    The pea maltodextrin can decrease exposure of API to the taste buds through a specific mechanism of action and complements the current range of taste-masking excipients available to formulators. This excipient has been shown to exhibit a taste-masking effect on model APIs, such as loperamide hydrochloride and dextromethorphan hydrobromide.iv It also offers a desirable, cost-effective alternative that caters to the needs and preferences of specific patient or consumer populations.

    豌豆麦芽糊精可以通过一种特定的作用机制减少原料药对味蕾的暴露,并扩充了现有的配方商可用的掩味赋形剂范围。该辅料已被证明对模型API如盐酸洛哌丁胺和氢溴酸右美沙芬良好的味觉掩蔽效应。Iv 它还提供一种可取的、具有成本效益的替代办法,满足特定患者或消费群体的需要和偏好。

     

     

     

    参考文献:

    i Preis M, Pein M, Breitkreutz J. Development of a taste-masked orodispersible film containing dimenhydrinate. Pharmaceutics. 2012 Dec;4(4):551-62.

    ii Foo WC, Zhang C, Zhang HL, Chow KT, Gokhale R. A Multifunctional Orodispersible Film System with Hydroxypropyl-β-Cyclodextrin. AAPS PharmSci 360 (virtual conference); 2020 Oct; Poster #890642.

    iii Wang Z, Li J, Hong X, Han X, Liu B, Li X, Zhang H, Gao J, Liu N, Gao X, Zheng A. Taste Masking Study Based on an Electronic Tongue: the Formulation Design of 3D Printed Levetiracetam Instant-Dissolving Tablets. Pharmaceutical Research. 2021 May;38(5):831-42.

    iv Preis, M., Eckert, C., Häusler, O., & Breitkreutz, J. (2014). A comparative study on solubilizing and taste-masking capacities of hydroxypropyl-β-cyclodextrin and maltodextrins with high amylose content. Sensors and Actuators B: Chemical, 193, 442-450.

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