患者为中心的产品设计思路:前沿的分散技术

 

如需获取课件或有课程相关问题,欢迎咨询:

华女士,0512-62585188-317,yulan.hua@capsugel.com

 

>>点此下载视频字幕(中英双语)

 

视频简介:

世界人口结构正在发生翻天覆地的变化,催生了新的庞大患者群体,其中以老人和小孩为代表的患者群体最为醒目。相比之下,药物产品的设计、开发和制造,在过去的数十年中并没有发生明显改善,仍然依赖于一刀切的产品理念。
 

人们日益认识到,依从性差、用药错误、换药不当和用药管理问题,造成了药物的安全问题,并使特殊的患者人群疗效较差。了解患者和药物相互影响的关系,以及他们理解和使用药物的方式,这些信息是概念化、设计和开发以患者为中心的药物的关键前提。
 

Sven 博士从人口结构的变化说起,阐述老人和小孩患者群体的特征与需求,在此基础上提出了对应产品设计框架。最后尝试从剂型的角度,帮助我们思考创新剂型与患者为中心产品设计理念的关系。

 

视频字幕(中英文双语对照):

Ladies and gentlemen, welcome, I just want to give you an introduction into patient centric drug product, and specific focusing on sprinkle technology.
女士们,先生们,欢迎大家!今天,我想向大家介绍「以患者为中心」的药品设计技术,尤其是「Sprinkle 技术」。
 
The presentation contains basically 4 chapters, the basic data on the patient population, as we are talking about patient centricity, the frame work of drug therapy in the market, and then advance sprinkle technology before I come to conclusions.
我们今天的话题主要围绕「以患者为中心」展开,分为四个部分:首先我们来了解一下患者族群的基本情况,其次是市场上药物治疗的基本框架,以及领先的「sprinkle 技术」,最后我们进入结论部分。
 
Basic data on patient populations
患者族群的基本数据
 
What you see here is typically patient population which trace from 1917 and from 2006.In 1917, we really had a pyramid, and the pyramid was not because no more people were born, but we died early. What you see here on the right side in 2006 which looks more like a tower, is the demographic pyramid of a healthy society. When we are born, we have high probability to reach 80-85 years. We have a good healthcare system to keep us alive.
这里呈现的是 1917 年至 2006 年的典型患者分布。1917 年,由于人的寿命较短,该分布呈现金字塔型。右边是 2006 年的患者分布,类似塔状,是典型的健康社会的人口金字塔。得益于优良的医疗健康体系,我们这个年代的人,活到 80-85 岁是很常见的事情。
 
If we now look a little bit more in detail, we always found out 65 years as a threshold to become older. What you see here is a big difference between these 2 populations. Now, if we talk about 85 years to 100 years, we suddenly see that the peak beyond 85 is quite new when in 1917, they were just very few people reaching this age, and basically no one reaching 100. In China, I read yesterday in the news that there were a couple with 75 years married and all reach 100 years old. So this is the reality of our society.
综合更多的数据来看,我们一般认为 65 岁是老年人的分界线。这里,我们发现两种患者族群分布有很大的差异。如果说起 85 至 100 岁的患者,在 1917 年,他们几乎是不存在的,因为很少有人能活到 85 岁,更不要说 100 岁了。然而,现代社会已经完全不一样了,昨天我还读到中国的新闻,描述了一对结婚 75 年的夫妇携手迈进 100 岁的门槛。
 
Now let's look into what diseases we are suffering from while we are aged. There will be called DALYs days the disability-adjusted life years, which is a combination of life lost due to premature mortality (YLL) and time we live with diseases. And then when we look into DALYs, which provide a very good understanding about what diseases at what ages we are suffering now.
现在我们来看,当进入老年时,我们会罹患何种疾病。有一个叫做「伤残调整生命年」的指标,包括期望寿命前死亡(YLL),以及伴随疾病的生命年。对 DALYS 的研究,为我们清楚的展现了不同年龄段高发的主要疾病类型。
 
It looks like a very busy slide and I try to walk you through. We have males and females and underneath we have the age, starting from new born and end up with beyond 80 years. And here is the percentage of DALYs of diseases we are suffering from at a certain age. What we see here is that cancer is more in the years of 50 -80, and Cardiovascular disease is very common, like respiratory disease and diabetes. So when we look across these ages, we see any age populations has a very common set of diseases. We are trying to understand better what diseases they are suffering from, and what problem they are facing.
这张片子看起来信息量很大,我来逐一为大家介绍。这里有男性,女性患者,下面横坐标是不同的年龄段,从新生儿开始到 80 岁以上,纵坐标是 DALYs 的比例。从这张图上,我们看到癌症主要侵袭的年龄段为 50-80 岁,心血管疾病、呼吸系统疾病以及糖尿病在这一年龄段也比较常见。一般来说,同一年龄段患者的疾病谱是比较类似的,这让我们更容易了解他们罹患的疾病以及他们面临的问题。
 
We also see that from the communicable diseases, which are infectious diseases, are moving much more to non-communicable diseases which are disease of good lifestyle and chronic disease, like diabetes, hypertension, which is on a growth in the last 20 years between 1990 and 2010. This is a global figures. And in all societies, we see much more chronic diseases coming in place. So we really shift from premature death to life with disability, and the major rise in mental and behavioral disorders, muscoskeletal disorders and diabetes. The DALYs of children are really dropped. Children are very well treated and get healthy.
我们也发现,社会主要的疾病已经从传染性疾病 (感染) 转向非传染性疾病,如由于生活水平提高带来的诸如糖尿病,高血压等慢性疾病。这些疾病在过去的 20 年,从 1990 年至 2010 年,呈上升趋势。这是一份全球数 据,在所有的社会中,我们看到越来越多慢性疾病的发生。因此,我们的患者已经从期望寿命前死亡逐渐转向伴有特定功能障碍的生存。患者身体机能或精神障碍,肌肉骨骼障碍以及糖尿病,呈上升趋势。另一方面,由于医疗体系的完善,儿童的 DALYS 已经有明显的下降。
 
Here are some data about the use of drugs in our society. If we talk from volume standpoint, which are the solid bars here, we see that from the age of 60-65, the major user group of our drug products is coming in place. The volumes between male and female are quite similar. What we see here is the daily doses prescribed to patients which are beyond 60-65 years. The old popularities are majority of our drug users, while there is a very limited number in early ages. In terms of cost, the cost is much higher for the diseases in younger ages, simply for the reasons that these diseases are life threatening, and extremely expensive therapy like cancer therapy and treatment in the early age.
这些数据反映了我们现代社会的用药状况。从用量的角度来说,(就是这里的实心柱),我们看到用量最大的患者群是 60-65 岁,且性别差异不大。这里,从 60-65 岁以上患者的日处方量来看,老年患者是药物的主要服用人群,而年轻患者的用量则非常有限。从费用的角度来看,年轻患者的治疗费用较高主要是因为这一年龄段的疾病谱多为危及生命的重症,需要及其昂贵的治疗,如癌症等。
 
Even though age is not a disease, we see a lot of the dependency and correlations between age and multimorbidity, so having more than 1 chronic diseases. When we look at the chronic diseases and prevalence for multimorbidity with age, we see all the different studies performed, you can see here, all showed very similar pattern that majority of people beyond 60 here from multimorbidity, so they are at least have 1 chronic disease.
即使年龄增长本身并不是一种疾病,其和共存疾病(即患有 1 种以上的慢性疾病)之间存在一定依赖性和相关性。很多机构对慢性疾病以及共存疾病与年龄之间的关系进行了不同的研究,结果表明大多 60 岁以上的患者都患有一种或以上的慢性疾病。
 
Now each chronic disease comes with also some functional impairments, like vision impairment, dexterity impairment. And if we look to these age group, we can see that people with multimorbidity also have some very basic functional impairment, which we have to take into considerations when we design product. For example, vision impairment need to have certain design that people can identify or differentiate between different products. And if we have dexterity issues, meaning you have really not the sensitivity or hands strength anymore, tablet splitting becomes a huge problem and patient are not really able to manage this.
每一种慢性病都或多或少的伴随着一些功能障碍,如视觉障碍,灵敏度下降等。从患者年龄层来看,我们也发现大多数患有共存疾病的患者都呈现某些基本功能的障碍。而这一点,也是我们在药物设计的过程中必须考虑 的现象。举例来说,视觉损伤的患者需要具有明显特征的产品与其他产品进行区分;而对灵敏度下降,即手部的力量和灵敏度都大幅下降的患者来说,切分药片将是非常难于完成的任务。
 
What comes along with the multimorbidity, so having more than just 1 chronic disease, we also see polypharmacy. Any disease needs drug treatment, patient usually takes more than 1 drug, if we take the prescription guideline of doctors for example. We take hypertension, if hypertension is diagnosed, we normally start to prescribe at least 2 different drugs, and if there is a risk of other diseases, we even get 3 drugs prescribed. As you can see, the no. of the drugs prescribed from 1988 to 2010 doubled. And about 40% of patients (in 2010) beyond 65 takes at least 5 different drug products. In 1988, it was only 12 % of the population. Majority of drugs which are prescribed according to the diseases are mainly statins, antihypertensive which are for cardiovascular diseases, antidepressants, et al.
共存疾病,即罹患超过 1 种的慢性病,不可避免的导致多种药物使用。由于任一疾病都需要药物治疗,患者通常同时服用 1 种以上的药物。以医生的处方指南,高血压用药为例,一旦确诊为高血压,患者的处方通常从两种药物合并使用开始,如果同时存在其他疾病风险,3 种及以上药物的同时使用则不可避免。这里我们可以看到从 1988 年到 2010 年,药物的处方量翻了一倍。2010 年,大约 40%,65 岁以上的患者同时服用至少5种不同的药物,而这一比例在 1988 年仅为 12%。根据疾病谱,处方量最大的药物主要是他汀类,抗高血压及其他心血管药物,抗抑郁等。
 
Now As I told you, there is certain functional impairments, which are associated/correlated with multimorbidity and diseases. Swallowing issues, which is dysphagia. It is a real issue when swallowing nutrition and drugs is quite high dependent on the diseases. 30% of stroke patients developed some kind of swallowing issues. For Parkinson patients, it is up to 80% as well as Alzheimer patients. Institutionalized patients who receiving care have a high probability of having issues with swallowability. If we look to other studies above 70 years old, we see at least 30% of patients have some kind of swallowing issues and we have around 7% patients not only have swallowing issues but also aspiration. The nutrition enters into to lung, due to this, they get pneumonia and serious infections of the lung. Majority of patients died of pneumonia at the end of the day which is originated by swallowing issues.
正如我们前面一直在谈论的,共存疾病伴随着特定的功能障碍。在服用营养素和药物时发生的吞咽问题,即吞咽困难与某些疾病有直接的关系。30% 的中风患者会发生吞咽问题,而对帕金森和阿尔茨海默症患者来说,这一比例上升至 80%;需要照顾的患者存在吞咽问题的比例则更高。对 70 岁以上患者的研究表明,30% 的患者存在不同程度的吞咽问题,约 7% 的患者不仅有吞咽问题,还有呼吸问题。当营养素进入肺部,患者将罹患肺炎以及严重的肺部感染。绝大多数患者最终死于肺炎,而这一切其实都源于吞咽困难。
 
Now, how to do with swallowing issues compared to the drug therapy. If I can’t swallow the nutritional element, can’t swallow the food, I am most likely not able to swallow my drug products. What we see here is the different studies that showed high prevalence of swallowing issues with medications. Because of the swallowing issues of solid oral dosage form, 60% reported they have swallowing issues and 68% either they crush the tablet and mix with food, or omit to take the drugs, so they stop the treatment because it is not suitable for themselves. Other studies here, as you can see from many other studies that they all come to the conclusion that between 25%-30% of patients have problems in swallowing their drug products. This is also for even younger people to have problem in swallowing. The dosage form/drugs are too large which are difficult to swallow.
在药物治疗的同时,我们应当如何处理患者的吞咽问题呢?如果我无法吞咽营养素,无法吞咽食物,那么很大可能性,我也无法顺利的吞咽药物。这里我们看到的不同的研究君表明,吞咽问题与药物治疗之间存在较高的关联性。由于无法顺利的吞咽口服固体制剂,60% 的患者报告过吞咽困难,68% 的患者曾将药品碾碎与食物同服,或者停止服用药物,终止治疗的原因是因为药物无法满足患者的需求。其他的多项研究也得出了类似的结论:即约 25-30% 的患者在吞服药物的过程中存在不同程度的吞咽问题, 而制剂的尺寸过大也会让一些年龄较轻的患者觉得难以吞咽。
 
We see a lot of issues along with the swallowing medications, especially in nursing home where crushing and opening takes place in 80% of nursing homes. They just crush the tablets without really knowing if it is allowed to or it is possible to. Our studies here showed that every 1/4 of drugs are mixed into food or beverages, a lot of them are modified inappropriately. So these tablets are not even supposed to be crushed because it might change the PK/PD profile, efficacy and safety is concerned. At least one medication was altered in 34% of patients, 1/3 of patients. 17% received inappropriate altered drugs. Nearly 60%, these crushing were done in the same vessels, so the next patient can a little bit the drug which made for the 1st patient, and all the spillage lost a lot of drugs. So it is not really the quality of medicines, or safety of medicines due to this fact. It is depend on certain sizes or shapes of the drug. And it is not surprised you find in the internet a lot of these of table crushers which help you to crush tablets for applications.
吞咽困难带来了很多其他的问题,尤其在养老院中。80% 养老院中存在着粉碎或切分药物的行为,甚至在不了解药物是否允许或可以这样服用。 其他的研究表明 1/4 的药物是与食物/饮料混合服用的,这其中很多都未经正确的处理。由于可能改变 PK/PD 表现,造成安全性和有效性问题,有些药物是不能被碾碎或切分的。 34%,也就是 1/3 的患者,至少曾经改变至少一种药物的形状,而 17% 的患者服用了经不恰当形状改变后的药物。近 60% 的药片在同一容器中被粉碎,也就是说患者可能会服用少量上一个患者的药物,同时药物量的损失也是不可避免的。这种现象影响了用药的安全性,但与药物本身的质量无关,而与药物的大小和形状有关。由此,我们在网上能够买到各式各样的分药器也就不奇怪了。
 
We see then all the patients, they not only have swallowing issues, we also need to consider other issues like motoric functions, grip strength, dexterity, mobility, visual impairment (hearing losses). So how do they communicate with health professionals? A lot of these patients with swallowing issues are dehydrated and malnutrition, as well as we have a lot of psychological instability. So when you see sometimes the promotion that you have oral dispersible film that might be very good for swallowing, but it can’t be really handled/ managed by patients. This can be managed by young scientist in the lab when you have this young hands as you can see here. But this is the typically hands of old patients with dexterity issues, grip strength problems, will not able to really mange this kind of product. So any kind of approach should take into consideration that this is more than just 1 issue. And the product needs to be really designed for the patient populations.
这些患者除了存在吞咽问题之外,我们可能还要考虑存在其他肌肉功能的损失,握力,灵敏度,机动性,视力下降,听力损失等。在这种情况下,他们如何能与专业的医务人员进行有效的交流?很多存在吞咽问题的患者伴有脱水和营养不良的症状,同时存在许多心理不稳定性。 因此,当你听到关于口腔分散膜剂的推广时,我们需要了解这种剂型非常有利于吞咽,但患者也可能难于使用。从这两张图上,我们猜想,具有这样一双年轻的手,在实验室研究的年轻科学家可能很容易使用这种产品,而具有这样一双苍老的手的患者,由于灵敏度和握力问题,可能也很难正确使用这种产品。 因此,任何一种药品的设计均应充分考虑到患者可能存在的上述问题。
 
What is the framework of drug therapy?
药物治疗的框架是什么呢?
 
Normally, after look into the patients, and then the patient research we are performing, when we have a patient with certain disease, patient suffers, then a drug is prescribed, and the patient needs to interface with the drug product. So they need to see a product, understand a product and be able to manage a product by themselves. They do this in their own environment which means that in homes, you do not have a really clean table, you do not have the perfect light. So they manage their drug therapy somewhere in between their daily life structure. Then on this, we have culture and education, we have healthcare system with reimbursement, we also have relatives and care givers might advise the patients, and indeed, we have social status can people afford to buy a drug. These are all around the patient centric approach that we look at. So we are trying to take reality check in how patient perceive, how patient use drugs in their own home. 好了,我们对患者的基本情况以及一系列针对特定疾病患者进行的调研结果有所了解。当一个患者患有特定的疾病时,患者感觉到痛苦,随后获得药物处方,患者与药品之间应当有正确的交互。患者需要能清楚的看到产 品,了解产品并依靠自己使用产品。 他们通常在各自的环境,多半是家里服用药物,而患者的家里可能没有符合要求的清洁台面,符合要求的灯光等等,患者的用药过程是主要存在于其正常的生活中的。 除此之外,我们有文化,教育,有医疗卫生报销体系,有亲戚和护理人员可能给患者相关的建议,而社会医疗保障体系也确保患者能够支付所需的药物,这些都是「以患者为中心」的各个不同的方面。 因此,我们试图认真的去了解患者的感受,以及他们在家中如何使用这些药物。
 
Beside the price, we have this microergonomics, microergonomics is the design of the product. What we see when we look into a lot of tables, they really look one like the other. And it is very difficult to differentiate between them. Here are 2 case studies. The one was only once weekly and the other was daily. Patients have mixed up, came to a critical safety issue and ended up in a hospital, because it was not really able to differentiate the 2 forms. Then Macroergonomics, as they said in the home and environment, this is not a perfect laboratory, we have drug storages, like in cartons and in bags, but people more or less try to figure out what drug to take. This surroundings is important when we look into how we develop the concept that patients can really understand the difference. So drug is more than just simple individual part, it is really the sum of all those little pieces, starting from swallowing, identification, handling and managing of the drug. This is what we try to address Capsugel as a whole concept, not only just the technology.
除此之外,微观人因工程,也就是药品的设计也非常重要。当一堆药片在你面前时,由于外观差异较小,你可能很难区分它们。图片中有两种药片,左边的是一周一次,右边的是每天一次,患者可能因为很难区分这两者的外观差异,用错药而导致严重的安全性问题,以至于入院接受治疗。 宏观人因工程,也就是患者的家或周边环境,这并不是一个理想的实验室,我们会把药物储存于各种容器中,如盒子,袋子等,然后试图从中辨别出应当服用的药物。在药品开发的过程中,我们也应当充分考虑患者所处的环境,以及是否能够准确的区分不同的产品。 因此,药品研发并不简单,我们需要从吞咽,辨识,使用和处理药物等不同细节考虑。 这也是 Capsugel 倡导的整理方案的理念,而非某一个或一些单纯的技术。
 
So we see here the different types of patients, that we have pregnant woman, newborns, toddlers, children, adults, and geriatrics, and end up with frail patient. So all of them have specific needs and specific designs.
这里,我们看到患者是多种多样的,从孕妇,新生儿,青少年,儿童,成年人到老人,均有可能成为脆弱的患者。然而,他们都有不同的需求,也需要具有不同设计的产品。
 
Now they are commonalities and differences between pediatric and geriatric as an extreme. In a pediatric form, we are in developmental stage, which means it is a growth stage. While in geriatric, it is differential. What does it means is that I go through very precise development stages, from 1 year to 2 years to 3 years. With the age we do not have the same, every patient is different and every person’s aging is different. We treat more acute disease in young age, and more chronic disease in the late stages. We normally have single disease, while we deal with multimorbidity and multiple disease in older patient. We have single drug vs polypharmacy as a result of multimorbidity. We have in child, we have young care giver, a mother, who is really ambitious in helping their child. When in the old age, it is normally self-managed by the older patient, which is significantly different if you have somebody takes care or supervise you, and on the other hand, you know you have to manage yourself. As I gave very common diseases in the younger age group is more infection. And we have very common disease in the old ages, but they are different.
作为两个极端情况,儿童和老人的用药有很多异同点。儿童时期,身体处于生长发育阶段,而老年人则是完全不同的。如何理解其中的意义?我们来精确的看不同的研发时间段,从一年到两年到三年,即便处于相同的年龄段每个患者都是不同的,每个患者的老化过程也是不同的。年轻的患者多以急性病为主,而年老的患者面临的主要是慢性病。 年轻患者通常患有较为单一的疾病类型,而老年患者多为共存疾病,多重疾病同时存在。因此,用药方面也有单纯的用药,或者针对共存疾病的多种药物同时应用的情况。儿童患者多有监护人照顾,比如妈妈通常很努力的照顾她们的孩子,而老人可能以独居为主,或者由年纪更大的人来照顾,这两者是完全不同的。年轻的患者多发感染类疾病,而老年患者也有其多发的疾病种类,但两者亦完全不同。
 
Now, let’s all to some common themes that you know we, from drug development point of view can use the same approaches. In pediatric, as well as geriatrics, we need to have individualization of dosage, dosing flexibility. Excipient safety is an issue in pediatric and also in geriatrics, but because of different origin. [0:20:43]We have exposure to certain excipient which are instrumental to pediatrics because of improvement of metabolism. In older patients with polypharmacy, so if I say I take an excipient, like Polyethylene Glycol, this might be OK for one drug, but in polypharmacy, this Polyethylene Glycol can build up so that they get in the end of 5 drugs, at the toxical level. So here we are talking about the single excipient issue and issues caused by multiple dosing. And palatability, swallowability is the issue in pediatrics because of inmature swallowing reflex, and in geriatric because swallowing reflex already impacted by certain diseases of ages. And issue in dealing with complexity is the same for pediatrics and geriatrics. It should not be underestimated that how complex the drug therapy can get for a patient who is lay person and do not understand technology. So as long as it is only swallowing, taking out from the package and swallowing it is easy, but if some manipulation has been done, like measuring the liquids, then it became a very difficult tasks for them.
接下来,我们来看两者的一些共同点,从研发的角度来看,我们可以采用相同的策略来应对。儿科用药和老年人用药都需要剂量的个性化和灵活性。辅料的安全性在两个领域均非常重要,只是原因不尽相同。 由于代谢促进作用,有些辅料对儿科用药来说是非常重要的。对于同时服用多种药物的患者来说,某一种辅料,如聚乙二醇,可能在单一药物处方中的用量合理,但在同时服用5种药物的情况下,其累积量可能已经超过了毒性计量。 因此除了考虑单一用药的安全性之外,我们还需同时考虑多重用药下的安全问题。儿童的吞咽反射发育并不完全,而老年患者的吞咽反射可能受到某些疾病的侵害,因此药物的口味和可吞咽性对两类患者来说都非常重要。 药物治疗对一个卧床的患者或不懂技术的患者来说,其复杂程度是不可小视的,仅仅是从包装中取出药物后吞服还不算复杂,如果还有其他的操作要求,比如说量取液体药物,其复杂程度就会相应增加。
 
So, older patients are dealing with multiple physiological issues simultaneously, one solution for one single problem might not be the solution for the patient. Like this ODT, it might be good, but if we consider this patient is dehydrated, they might not be able even to dissolve and swallow this ODT because saliva production is significantly reduced.
老年患者同时存在多种生理上的问题,因此,针对某一种问题的方案可能并不能解决患者的所有问题。比如说 ODT,它可能是解决吞咽困难的好方案,但对于脱水患者来说,由于唾液分泌量显著下降,他可能没有足够的唾液来溶解药物后吞咽。
 
We might have once daily. We say that is easier to manage because it only need to take once a day, but if this once daily become into a large tablet size, it counterbalance by the facts that people cannot swallow anymore. So I reduce the dose and but I prevent the dose from not being swallowed.
我们常说每日一次的用药方式很方便,因为每天只需要服药一次。然而,如果每日一次的结果是药片体积过大,则会造成吞咽难度的增加。因此,我们需要降低单片的大小,以确保药物可以被顺利的吞服。
 
Before, technology solutions address some physiological issues, it is not really relevant to the safety and efficacy, because twice daily or once daily, sometimes, it is easier for patient to do one in the morning and one in the evening rather than have 1 tablet in the morning and another product in the evening. Then they might make medication errors because they mix up the products.
以前,技术性解决方案通常着眼于药物的理化性质,与药物的安全性和有效性无关。比如说每天一次还是每天两次的设计,有时早晚各一粒比早上一粒A药,晚上一粒B药更容易避免用药错误。
 
And then, we have different settings which we also need to consider, like in the hospital, we have very professional staff who knows to deal with drug and provide the drug, in care room, we have some kind of professions so they can help and assist patient to taka a drug. But then we also have drugs at home, where we have really a lay person, somehow with no experience with drug product and cannot take decisions with drug products, even if I have a good label in my box.
此外,我们还用不同的用药环境需要综合考虑: 在医院,我们有专业的医护人员,他们非常了解药物以及如何给药;在养老院,我们也设有专业的人员帮助患者用药,而在家里或者对于卧床患者来说,没有用药经验和必要的知识,即使给他一张完美的说明书,他也无法正确的使用药物。
 
First of all, they might not be able to read the label then they don’t understand healthcare information and their health conditions which is very poor. So we should not think that I can write down how patient should take any healthcare decision if they are not educated at all for taking some decision.
首先,他们可能无法阅读说明书,无法了解医疗相关的信息术语或者健康状况非常差。因此,千万不要假设患者都接受过恰当的教育,能够准确的了解说明书的内容,并准确用药。
 
So that is when we talk about the advance of sprinkle technology because it might overcome several of the challenges actually. 那么,接下来,我们来探讨一下「Sprinkle 技术」,因为其可能帮助我们解决这些问题。 First of all, the key themes for pediatric is palatability, swallowability and acceptability, that is what make drug administration safe. I can take a drug with no problem. Then I need to say this individual dose adaptation related to my age, my multimorbidity and my polypharmacy where I have drug-drug-interaction. How I make this dosing quite flexible?
首先,儿童药物最重要的是口味,可吞咽性以及接受度,这些都和用药安全有关,也就是我可以顺利的服用药物,不存在任何问题。然后,我需要个性化的剂型调整,即药物剂量适合于我的年龄,我的共存疾病以及我的多重用药,即药物之间发生反应的问题。那么,我如何设计药物剂量才具有最大的灵活性呢?
 
Now sprinkle technology is using very common technology, which is known and not any rock science. These are mono-dose multiparticulate, so every of these small little multiparticulate contains very distinct and precise dose. They are stable in liquids like orange juice, or semi solid food like yogurt that is something we need to establish because it might be mixed the sprinkles with food or beverages. Now we are talking about the multiparticulates bellow 2 mm, the potential target can be modified release or fixed dose combinations. So you can really combine these multiparticulates with each other without really comprising on size. Multiparticulates can also be oral disintegrating mini-tablets which has been developed. So you just put these small tablets under the tongue, it might dissolve. And you can provide in sachets or capsules, and also some bottles which you put them in, but you need a dosing device which makes it too complex for patient to get it precisely. So this is the concept of sprinkles, and it is well known since many years.
我们的 Sprinkle 技术建立在多种常见技术之上,而非特别高端的科学技术。这些是单剂量多微粒体系,每个小微粒中含有清楚准确的药物量,其在液体,如橙汁,和半固体,如酸奶中非常稳定,可与食品饮料混合服用。说起直径小于 2 mm 的微粒,潜在的研发目标是缓控释或固定剂量合并用药。 你可以灵活合并这些微粒,而不必担心形状问题。口腔崩解微片也可以成为这些微粒中的一种,将这些微片置于舌下,即可迅速溶解。小袋,胶囊,甚至瓶子都可以用来包装这些微粒,但如果需要通过辅助装置用来准确给药的话,患者用药的复杂程度将增加。这就是 Sprinkle 的概念,也是为行业所熟知的技术和理念。
 
How do we develop these multiparticulates, we have different technologies, fluid bed, melt spray congeal, extrusions technology. You can make it as mini-tablets or you can really layout the multiparticulates either with different drugs or with different release coats, that you can have immediate release, modified release, slow release whatever. And they can be used for taste masking, which is a very important theme for a drug product. And we also have the solubilization enhancement enters into amorphous system that dissolve fast.
如何开发这些多种微粒呢?我们通常可选择的技术很多,如流化床,熔喷凝,挤出技术等。你也可以将其制成微片,或采用不同的药物或不同的包衣层实现速释,控释,延迟释放等。这些技术也可应用于对药品设计至关重要的掩味领域;同时还可以应用采用增溶技术达到快速溶解的目的。
 
And then we can have some buccal administration, or we have in the stomach release or in the intestine. And we have different release dynamics we can build into these multiparticulates, that is the specialties we have in our DFS, so that we can develop multiparticulates that commodity to right dosing.
此外,我们还可以实现在不同部位释放,如口颊,胃部或肠道等。同时,我们也可以通过不同的制剂体系实现不同的药物释放行为。这些都是 Capsugel 的 DFS 部门所具备的技术能力,以帮助开发不同需求的制剂产品。
 
So again, you have different release profile, different ways of coating, we have controlled release, delayed controlled release, we can have different releasing profile. That is how we can be very flexible, using same technology for the different clinical targets we want to achieve.
通过不同的包衣方法,我们还可以实现不同的释放行为,如控释,延迟释放等。而将相同的技术灵活应用,使我们有能力针对不同的临床需求研发合适的产品。
 
And again, we have taste masking capabilities, end targeting, so you can combine different things, like BA enhancement, or through enteric form. Plenty of ways how to play with it and that is normally defined by the targeted product profile. I know my patients, I know clinical targets, then I can go to more personalization of medicine or more patient centric.
这里又再提到,我们还具备掩味技术,定位释放的研发能力,可以灵活组合,比如改善生物利用度,或通过肠溶实现等。有很多种方式综合利用多种技术,我们就可以实现不同的释放要求。 我们了解了患者,了解了临床要求,我们就可以研发出更具个性化的药物或「以患者为中心」的药物。
 
So let’s take the hypothesis that multiparticulates and mini-tablets show evidence of ease of swallowing, that is very well established. We have very good possibility to differentiate dose because multiparticulates containing very distinct dose, can be combined by the no. of the pellets, or by volume that can be filled. So that is very high dose flexibility, specifically when we have modified release. It is important that these modified release drugs can be in a wide range without changing really the formulation. So tableting is not becoming an issue, you just fill different type of pellets. And pellets leaves the stomach through pylorus, so we don’t have this residence time in the stomach due to a single unit.
充分的证据表明,多种微粒或微片可以使吞咽变得更加容易。由于微粒中含有清楚的剂量,通过改变微粒的数量,我们就能够更好的区分不同的药品了,也因此具备了更高的用药灵活性,尤其在控释制剂中。在不改变处方的情况下,具有更广的应用领域对这些控释制剂来说是非常重要的。压片不再成为一种问题,你可以使用不同的微丸,这些微丸可以顺利的通过幽门,而消除单一单位药物带来的胃部滞留时间。
 
Fix dose combinations, we can combine easily different type of products either for certain disease or with certain release profile. And it is also very effective manufacturing. The basic concept is that instead of swallowing the entire capsule, you can also open the capsule and sprinkle the content on food or beverages. Then patient takes his food with drug. This is really the flexibility we have with our dosage form that you can use it either as a capsule or as inner content.
我们可以将不同的药物进行固定剂量组合,用于特定的疾病治疗或特定的释放行为,而其生产过程也非常高效。我们最初的想法是,与其吞服整粒胶囊,我们也可以打开胶囊,将内容物喷洒于食物或饮料上。患者在进食的过程中同时服用药物。这是胶囊剂型可以提供的灵活性,你既可以作为胶囊服用,也可以直接服用其内容物。
 
When we use the normal Coni-snap capsules, the difficulties is how to open such a capsule because for purely oral form, they need to stick together very tightly. So we have developed new capsule which is called coni-snap sprinkle capsule which facilitate opening. It is specifically designed to be easy to open by patient by low pre-lock force.
当我们使用常规的 Coni-snap 胶囊时,由于单纯的口服制剂要求胶囊体帽套合后具有良好的附着性,想要打开这些胶囊,患者可能面临一些困难。 因此,我们研发了一种叫做「Coni-snap Sprinkle 胶囊」,通过特殊设计早就较低的锁合力,使得患者更容易打开。
 
So the development was clearly defined on what we want to have, we want to have easy-to-open capsules which maintaining closure during manufacture. During the transportation, they should have no dimensional changes so that the processability can be used and the equipment can be used in the same way and the machineability performance should not be impacted by the sprinkle design. So we came up with very specific design. We have very different design options in our development phase, and here are the data of pre-lock force with significantly reduced when the opening force we need to apply.
在研发阶段,我们清楚的界定了新产品的特点,它需要很容易被打开,在生产过程中保持套合状态,在运输过程中不会发生尺寸变化,因此以前的生产流程和设备的使用都无需变化,而其上机率不应受到任何影响。随后,我们进行了不同的设计选择,在研发过程中,我们也确实有多种设计方案,这张图显示的是产品的预锁力显著下降从而显著降低打开时所需的力量。
 
Then, we did a study. Instead of saying it is easy to open for me, we say let’s judge patients. We did a study with 25 patients, we have parents of young children, nurses and elderly people, and give them 3 different options, that was in our development, we had 3 different coni-snap sprinkle types developed, so you don’t really see the diference from the visual point of view. The sprinkle capsules is small design change which have significantly impact on the opening. So we tested 3 different design of capsules.
随后,我们进行了一项实验: 与其说这种设计对我来说很容易打开,我们说让患者来说话吧。我们选取了 25 名患者进行了测试,其中包括孩子的父母,护士和老年人。我们给予受试者三种不同设计的产品,这三种设计是我们在研发的三种方案。从外观上,你可能看不出任何差异,因为 Sprinkle 胶囊与常规的胶囊产品之间仅有微小的设计差异,但在打开的难易程度上有显著的差别。
 
With the patient, we found out that 90% of patient open the capsules in a horizontal position, that is natural, so you opening in a horizontal position and the simple thing is that we need to require patient to do it over the food or the drinks. And it will go to the right area. Sprinkle capsule design No. 2 was better than No. 1 and 81% confirm they are very easy to open, so based on the study of the patient, we selected the design No. 2 as our sprinkle design. It is interesting that 1/3 of patient said they can open normal capsule. So even this is feasible. We really want to have it easy to open, so we take our design which is most preferred and develop this further into product.
实验中,我们发现 90% 的受试者采用水平方式打开胶囊,这是很自然的方式,如果以水平方式打开胶囊,唯一需要提醒患者的就是在他们的食物或饮料上进行这种操作,以便内容物进入正确的地方。Sprinkle 的 2#设计由于 1#设计,有 81% 的受试者确认其非常容易打开,因此,根据受试者的反馈,我们选取了 2#设计。非常有趣的是,有 1/3 的受试者反馈说他们也可以打开常规的胶囊,即使这也是可行的,我们仍希望产品更容易被打开,因此,我们选取了受试者最喜欢的设计,并进而研发成最终产品。
 
So we did the design also to investigate the impact of imprint, how do I make it visually clear for patient what to do. So we said we need to have imprint and we did another design and another study to verify/validate different imprint. We have 8 subjects and results showed with this imprint of 2 arrows like this, nobody choose it as favorite. Then we have this top up, only 1 patient said yes, it could be something. And we have 2 out of 8 patients said these arrows give them the information they need. And last we have the simple straight pull apart and 5 of 8 patients said it is the imprint which tells them intuitively how to use the capsule. So we really went not only from capsules, but also from how patient interface, how patient use these capsule and could demonstrate these difference, and we could found out what is the best option, the best design for the product.
除了设计,我们仍希望了解不同的印字图案的作用,我如何能更清楚的告知患者应该如何使用?我们设计了不同的印字图案以及实验方案去验证其效果。我们的实验有 8 位受试者,结果显示第一组图案,两个这样的箭头,没有人喜欢它,第二组有「Top Up」字样的设计,仅有 1 位患者认可;第三组设计,8 位受试者中有 2 位认为这样的箭头足以提供所需的信息,而最后一组设计,直接向两边的箭头获得了 5 位受试者的认可,他们认为这样的方式非常直接的告诉他们应当如何使用这种胶囊。 在设计产品的过程中,我们不仅仅是从胶囊本身,还通过了解患者如何使用这些胶囊以及如何体现其差别等方面来寻找产品最佳的选择。
 
So conclusion 好了,我们到了结论的部分 Patient centric drug products are increasingly required to enhance drug safety and effectiveness. So what we want our patient do not start to crush tablets, and do not just open capsule like they would like to do. They do not stop medication because they can’t swallow then we have poorly effects. So it is all about improving or enhancing the safety and effectiveness of our drug product.
加强药品的安全性和有效性越来越多的需要「以患者为中心」的药品设计。我们希望患者不要切分药片,不要随意的打开胶囊,不会因为难以吞服而终止治疗从而导致疗效下降。因此,这一切都是为了提高药片的安全性和有效性。
 
Secondly, we see there are many different distinct patient populations like pediatrics and geriatrics, and we cannot make these patients fit to our drugs, we need to make our drugs fit to the patient because we can’t assume that our patient can really understand what to do that is where medication errors and safety issues occurred.
其次,我们也注意到存在不同的患者族群,如儿童和老人。我们不能要求患者来满足药物,而必须使得 我们的药品满足患者的要求,因此假设患者能够理解如何用药是最容易发生用药错误以及安全问题的。
 
Thirdly, the multiparticulates are very known, this is a traditional technology which are established around the world, which is known for the flexibility [Second video] and ease of dose adjustment and administration by the patient where we can also do a lot of targeted drug delivery.
第三,多微粒设计已经是全球范围内非常成熟和传统的技术,具有高度的灵活性,并大幅增加患者用药以及剂量调整的便利性,同时也便于多种靶向给药的设计。
 
Sprinkle capsules are dedicated to contain precisely pre-measured mono-doses or multiparticulates can be opened and sprinkle on the food. But you might also include mini-tablets into these sprinkle capsules and advice patients to take 3 or 4 of these mini-tablets.
Sprinkle 胶囊是为了装载预定的单剂量或多微粒而设计的,可以被轻松打开将内容物喷洒于食物上。但你也可以将微片置于 sprinkle 胶囊中,并建议你的患者服用 3-4 片微片。
 
The sprinkle technology is based on the existing technology that is very important that we use standard encapsulation and standard technology to make those products as globally available as possible and also at an affordable cost. This is very important. If you can use the standard technology and formulation that is the easiest way how can you get to the market quickly and in affordable cost.
Sprinkle 技术是建立在多种现有技术之上的,这一点非常重要,因为采用标准的充填过程,常规的技术和处方,是我们能够在合理的成本下最快上市产品最便捷的途径。
 
Again you know we Capsugel, we deal with different angles, different areas. We have our end of capsule knowledge, we’ve developed very specific sprinkle capsule and we have our DFS dept. which can do any kind of multiparticulates for sprinkle applications. And together with certain collaborations we have with specifically into patient centricity, we work with patients, we do researches with patients to understand how they perceive the drug product.
最后,作为 Capsugel, 我们尝试从不同的角度,不同的领域来看待产品。我们拥有胶囊产品的知识,研发了非常独特的 Sprinkle 胶囊,我们的 DFS 部门能够针对 Sprinkle 的应用开发任何形式的多微粒体系。我们与「以患者为中心」的研究领域的进行合作,与患者一起进行研究以便了解他们如何看待一种药物产品。
 
I would like to thank very much for your attention. Thank you. 最后,非常感谢大家的关注!谢谢!
 
苏州胶囊有限公司是 Capsugel 与中国国药集团合资建立的生产基地。二十多年来,苏州胶囊采用 Capsugel 最先进的胶囊制造技术,遵循 Capsugel 全球严格的 质量体系,致力于为国内制药和保健品企业提供优质、安全的胶囊产品和专业的服务,引领中国空心胶囊产业的发展。 需要更多讨论,请联系:苏州胶囊有限公司,电话:0512-62585188-317,邮箱:yulan.hua@capsugel.com

活动留言

  • Sven Stegemann, Ph. D.
  • CAPSUGEL全球业务发展总监
  • 格拉兹技术大学药学教授

 

关于苏州胶囊:

苏州胶囊有限公司是 Capsugel 与中国国药集团合资建立的生产基地。二十多年来,苏州胶囊采用 Capsugel 最先进的胶囊制造技术,遵循 Capsugel 全球严格的质量体系,致力于为国内制药和保健品企业提供优质、安全的胶囊产品和专业的服务,引领中国空心胶囊产业的发展。