[丹麦制药行业的早期成就——8. 灵北公司]
[Early achievements of the Danish pharmaceutical industry--8. Lundbeck].
作者信息
Grevsen Jørgen V, Kirkegaard Hanne, Kruse Edith, Kruse Poul R
出版信息
Theriaca. 2016(43):9-61.
The article series provides a written and pictorial account of the Danish pharmaceutical industry's products from their introduction until about 1950. Part 8 deals with products from Lundbeck. Lundbeck which today is known as a considerable international pharmaceutical company could in 2015 celebrate its 100 years' jubilee. Among the early Danish medicinal companies H. Lundbeck & Co. is in many ways an exception as the company was not originally established as a pharmaceutical company. Not until several years after the foundation the company began to import foreign ready-made medicinal products and later-on to manufacture these medicinal products in own factory and even later to do research and development of own innovative products. When Lundbeck was established in 1915 several Danish medicinal companies, not only the well-known such as Alfred Benzon and Løvens kemiske Fabrik (LEO Pharma), but also Skelskør Frugtplantage, Ferrin and Ferraton, had emerged due to the respective enterprising pharmacy owners who had expanded their traditional pharmacy business and even with commercial success. Other medicinal companies, such as C.R. Evers & Co., Leerbeck & Holms kemiske Fabriker, Chr. F. Petri, Erslevs kemiske Laboratorium, Edward Jacobsen, Th. Fallesen-Schmidt, and yet other companies which were named after the founder had all been established by pharmacists with the primary intention to manufacture and sell medicinal products. Also for the limited companies Medicinalco, Ferrosan, Pharmacia, and GEA the primary task was to manufacture and sell medicinal products, and also in these companies pharmacists were involved in the foundation. Not until 1924, fully 9 years after the foundation, Lundbeck started to be interested in medicinal products and initiated import and sale of foreign medicinal products manufactured by a.o. German and French companies which had not established their own sales companies in Denmark. Almost all contemporary Danish manufacturers of medicinal products could exclusively determine own proprietary names of the articles and could themselves make their own homogeneous and easily recognisable design, a.o. by frequent use of prefixes as Afa, Asa, Gea, Ido, Leo, and Meco which associated to for instance the company name. However, it goes without saying that Lundbeck had to market the articles in commission according to the different contracts with their partners. Consequently their range of products appeared heterogeneously. The international financial crisis and the consequent unemployment in the 1920s and 1930s had in Denmark a.o. resulted in national regulation in order to complicate import of ready-made goods and thus support the domestic manufacture of such articles. This was one of the reasons why Lundbeck decided to initiate its own manufacture of medicinal products in Denmark instead of continuing only with the import business which had been obstructed by the authorities. This article does not mention all Lundbeck's medicinal products which were marketed in Denmark until 1955 where a new Pharmacy Act came into force though undoubtedly a lot of interest can be written about all of them. The products mentioned in this article have been carefully selected, not only because they are representative for Lundbeck's development during the first decades, but also because the Danish Collection of the History of Pharmacy has acquired consumer packages of many of the articles. Several of these packages include patient information leaflets with an instruction for use and/or other information, and especially these leaflets represent a source material which has not previously been given much attention. It does not appear from the available source material whether these earliest medicinal products from Lundbeck were assembled in Danish packages on the production sites, or whether they were repacked in Copenhagen. It is not unlikely that the assembling originally was finalized abroad, and that instructions for the production of packaging material with Danish text were supplied by Lundbeck to the respective manufacturers. However, it is not unlikely either that the currency restrictions which were made after 1932 encouraged Lundbeck, where possible, first of all to import raw materials and bulk products and then manufacture the finished products in Valby. This was the case with Anusol, which Lundbeck certainly emphazised in the advertisement. It has to be pointed out that at that time there were no legal requirements regarding dating, neither of the user instructions nor of advertisements. Thus it is not due to mistakes or omissions made by Lundbeck that these materials are undated. The user instructions which Lundbeck had inserted in the packages were made and distributed at a time where no legal restrictions were in force neither regarding form nor content of such. The user instructions for products marketed after 1932 had probably been presented to the Pharmacopoeia Commission as this was statutory. It is, however, uncertain whether the Commission has dealt with the contents and the look of the user instructions. The most important task of the Commission was besides of the work with maintaining the Pharmacopoeia to look after the economic interests of the pharmacies so that only new drug substances could be marketed by the pharmaceutical industry, cf. below. In order to find out whether, and if so to which extent, the Pharmacopoeia Commission has been occupied in evaluating the informative and promoting printed matters of the industry, would require studies of the unprinted files of the Commission, and that is outside the scope of this article. At that time it was not against the law to inform in a user instruction that in case of a longer period of treatment, it would be more economical for the patient to buy a larger package. If you look at these patient information leaflets with today's eyes in the light of the present detailed, comprehensive and rigid regulations which the EU Commission has stated regarding patient information leaflets, you will find that Lundbeck's patient information leaflets were both simple and easy to read. On a free sample of Gelonida meant for the prescribing physician Lundbeck stated, besides of indication, dosage and warnings, also that the article was "Manufactured in Denmark". At that time it was not required to print information of production sites on packaging materials, however, it was not unusual to use this sales promoting claim in times of unemployment. In 1949 the original packaging material for Beatin was modified because certain text elements, the therapeutic indications were removed as it appeared that they since 1933 had violated the Pharmacy Act against advertisements for medicinal products aimed at the public. The packaging material for Beatin is a model example of the possibilities to combine practical information about the use of a medicinal product with sales claims in a reliable way. The above text modification and thus the legalisation of the packaging material took place upon request from the company as the violation of the advertising rules of the Pharmacy Act apparently had not resulted in any legal problems. Studies of unpublished files from the National Board of Health may possibly explain the background of this sequence of events, however, that is outside the scope of this article. The paragraph of the Pharmacy Act of 1932, stating that a medicinal product containing a common commodity as the active ingredient could not be marketed as a proprietary medicinal product, was meant to protect the pharmacies against the increasing competition from the industry. At first the paragraph did put a strain on the industry which from then on either had to manufacture own originator products or to copy other originator products without breaking patents. In the long run it has probably caused that not only Lundbeck, but also other Danish pharmaceutical companies became research-oriented and thus have been able to develop a relatively large number of originator products. In this context a product like Lucamid can hardly be regarded as an example of such a compulsory development of an originator product, an acetylsalicylic acid analogue. There were already such products on the market, but the wish to develop a better active ingredient has probably been bigger. From the three first editions of The Tariff of Medicines from 1935, 1937 and 1939 respectively it appears how Lundbeck's business within the area of medicines developed during the last half of the 1930s. In 1935 Lundbeck had placed 36 different medicinal products on the market, and all of them were in-licensing products. 4 years later, in 1939 Lundbeck had placed 40 different medicinal products on the market, and the number of in-licensing products had been reduced to 18 and 22 products were Lundbeck products. However, the increased focus on the development of own new medicinal products as Epicutan and Klianyl did not stop the in-licensing activities. Varex which Lundbeck brought on the market in 1942 came from a German pharmaceutical company with which Lundbeck had not previously collaborated. In Denmark Lundbeck had the intention to market 4 of Goedecke's 6 different medicinal products which all had Gelonida as part of the proprietary name. However, only one of these products got a longer life and with a simplified name, namely Gelonida. The fixed combination with three compounds of acetylsalicylic acid, phenacetin and codeine was without doubt effective, however, already at the end of the 1950s concern was raised about the safety of phenacetin. The Card Index of Medicines is a primary source of knowledge of how Lundbeck marketed the earliest medicinal products to the prescribing physicians. (ABSTRACT TRUNCATED)
该系列文章以文字和图片形式介绍了丹麦制药行业从产品推出至1950年左右的情况。第8部分讲述了伦贝克公司(Lundbeck)的产品。伦贝克如今是一家颇具规模的国际制药公司,在2015年庆祝了其成立100周年。在丹麦早期的医药公司中,H. 伦贝克公司(H. Lundbeck & Co.)在许多方面是个例外,因为该公司最初并非作为制药公司成立。直到成立几年后,公司才开始进口外国现成药品,后来在自己的工厂生产这些药品,甚至更晚才开展自主创新产品的研发。1915年伦贝克公司成立时,丹麦已经出现了几家医药公司,不仅有知名的如阿尔弗雷德·本松公司(Alfred Benzon)和莱奥制药公司(Løvens kemiske Fabrik,即LEO Pharma),还有斯凯尔斯科尔水果种植园公司(Skelskør Frugtplantage)、费林公司(Ferrin)和费拉顿公司(Ferraton),这些公司都是由有进取心的药剂师业主扩展其传统药房业务而来,并且都取得了商业成功。其他医药公司,如C.R. 埃弗斯公司(C.R. Evers & Co.)、莱尔贝克与霍尔姆化学工厂(Leerbeck & Holms kemiske Fabriker)、克里斯蒂安·F. 彼得里公司(Chr. F. Petri)、埃斯莱夫化学实验室(Erslevs kemiske Laboratorium)、爱德华·雅各布森公司(Edward Jacobsen)、托马斯·法勒森 - 施密特公司(Th. Fallesen-Schmidt)以及其他以创始人命名的公司,都是由药剂师成立的,主要目的是生产和销售药品。对于有限责任公司Medicinalco、Ferrosan、Pharmacia和GEA来说,主要任务也是生产和销售药品,并且在这些公司的成立过程中也有药剂师参与。直到1924年,即公司成立9年后,伦贝克才开始对药品感兴趣,并开始进口和销售德国和法国等公司生产的外国药品,这些公司在丹麦没有设立自己的销售公司。几乎所有当时的丹麦药品制造商都可以独家确定其产品的专有名称,并能自行设计出统一且易于识别的包装,例如经常使用与公司名称相关的前缀,如Afa、Asa、Gea、Ido、Leo和Meco等。然而,不言而喻的是,伦贝克必须根据与合作伙伴的不同合同委托销售产品。因此,他们的产品系列显得参差不齐。20世纪20年代和30年代的国际金融危机以及随之而来的失业问题,在丹麦导致了国家监管,以使成品进口变得复杂,从而支持国内此类产品的生产。这就是伦贝克决定在丹麦开始自行生产药品而不是仅继续从事被当局阻碍的进口业务的原因之一。本文并未提及直到1955年新的《药房法》生效前在丹麦销售的伦贝克所有药品,尽管毫无疑问可以就所有这些药品写出很多有趣的内容。本文所提及的产品是经过精心挑选的,不仅因为它们代表了伦贝克最初几十年的发展历程,还因为丹麦药学历史收藏馆收藏了许多此类产品的消费者包装。其中一些包装包括带有使用说明和/或其他信息的患者信息传单,特别是这些传单代表了一种此前未得到太多关注的原始资料。从现有的原始资料中无法看出伦贝克这些最早的药品是在生产地用丹麦包装组装的,还是在哥本哈根重新包装的。很有可能最初组装是在国外完成的,伦贝克向各自的制造商提供带有丹麦文字的包装材料生产说明。然而,也有可能1932年后实施的货币限制促使伦贝克在可能的情况下首先进口原材料和散装产品,然后在瓦尔比生产成品。“安那索”(Anusol)就是这种情况,伦贝克在广告中肯定强调了这一点。必须指出的是,当时对于使用说明和广告都没有关于标注日期的法律要求。因此,这些材料没有标注日期并非伦贝克的错误或疏忽所致。伦贝克插入包装中的使用说明是在当时既没有关于其形式也没有关于其内容的法律限制的情况下制作和分发的。1932年后销售的产品的使用说明可能已提交给药典委员会,因为这是法定要求。然而,不确定委员会是否处理了使用说明的内容和外观。委员会除了维护药典的工作外,最重要的任务是照顾药房的经济利益,以便只有新药物质才能由制药行业销售,详见下文。为了弄清楚药典委员会是否以及在多大程度上参与评估该行业的信息性和促销性印刷品,需要研究委员会未公开的档案,而这超出了本文的范围。当时在使用说明中告知患者如果治疗时间较长,购买大包装对患者更经济并不违法。从当今欧盟委员会对患者信息传单规定的详细、全面和严格的法规角度来看这些患者信息传单,你会发现伦贝克的患者信息传单既简单又易于阅读。在一份给开处方医生的“吉洛尼达”(Gelonida)免费样品上,伦贝克除了注明适应症、剂量和警告外,还声明该产品“丹麦制造”。当时并不要求在包装材料上印刷生产地点信息,然而,在失业时期使用这种促销声明并不罕见。1949年,“贝丁”(Beatin)的原始包装材料进行了修改,因为某些文本元素,即治疗适应症被删除了,因为自1933年以来它们似乎违反了《药房法》中关于针对公众的药品广告的规定。“贝丁”的包装材料是一个很好的例子,展示了如何以可靠的方式将药品使用的实际信息与销售宣传相结合。上述文本修改以及包装材料的合法化是应公司要求进行的,因为违反《药房法》的广告规则显然并未导致任何法律问题。对国家卫生局未公开档案的研究可能会解释这一系列事件的背景,然而,这超出了本文的范围。1932年《药房法》的条款规定,含有普通商品作为活性成分的药品不能作为专有药品销售,这旨在保护药房免受行业日益激烈的竞争。起初,这一条款给行业带来了压力,从那时起,行业要么必须生产自己的原创产品,要么在不侵犯专利的情况下复制其他原创产品。从长远来看,这可能不仅促使伦贝克,也促使其他丹麦制药公司转向以研究为导向,从而能够开发出相对大量的原创产品。在这种背景下,像“鲁卡米德”(Lucamid)这样的产品很难被视为这种强制开发原创产品(一种乙酰水杨酸类似物)的例子。当时市场上已经有此类产品,但开发更好活性成分的愿望可能更强烈。从1935年、1937年和1939年分别出版的前三版《药品关税目录》中可以看出伦贝克在20世纪30年代后半期在药品领域的业务发展情况。1935年,伦贝克在市场上推出了36种不同的药品,且所有这些都是引进许可产品。4年后,即1939年,伦贝克在市场上推出了40种不同的药品,引进许可产品的数量减少到18种,有22种是伦贝克自己的产品。然而,对自主新药产品如“依匹库坦”(Epicutan)和“克利阿尼尔”(Klianyl)的开发投入增加,并没有停止引进许可活动。伦贝克于1942年推出的“瓦雷克斯”(Varex)来自一家此前未与其合作过的德国制药公司。在丹麦,伦贝克打算销售戈德克公司(Goedecke)6种不同药品中的4种,这些药品都将“吉洛尼达”作为专有名称的一部分。然而,这些产品中只有一种寿命较长且名称简化了,即“吉洛尼达”。乙酰水杨酸、非那西丁和可待因三种化合物的固定组合无疑是有效的,然而,在20世纪50年代末就有人对非那西丁的安全性提出了担忧。《药品卡片索引》是了解伦贝克如何向开处方医生销售最早药品的主要信息来源。