Advanced Drug Delivery Reviews 33 (1998) 265268

Future challenges for drug delivery research 1

D.D. Breimer 2
Leiden /Amsterdam Center for Drug Research, Leiden University, P.O. Box 9502, 2300 RA Leiden, Netherlands Received 26 September 1997; accepted 13 February 1998

Keywords: Drug delivery; Pharmacodynamics; Therapeutic outcome; Future medicines

1. Current research Current research in the elds of drug delivery and drug targeting is blooming in a quantitative sense. This is exemplied by the success of CRS-meetings and the overwhelming increase in research publications on these topics in the international pharmaceutical and biomedical literature over the last ten years. New journals have been established and existing ones have shifted their scopes to accommodate the publication needs of these emerging elds. Relatively few papers on drug delivery or targeting research however appear in the top ranking scientic journals, probably because, most often, the concepts or technologies presented are not recognized as being the most innovative scientically and are rather application-oriented. Indeed, much of the research is technology-driven and most impressive progress has been made in the development of new technologies and their potentially appealing applications. This can clearly be deduced from some excellent recent reviews [13]. However, has the impact in health
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care and the pharmaceutical market in particular also been impressive?

2. Current products and market In 1996, the list of pharmaceutical products based on advanced drug delivery with worldwide sales of ten million U.S. dollars or higher comprised 35 different trade names [4]. This was 11 more than in 1994. In these two years, total sales had increased from 5.5 to 6.5 billion U.S. dollars, which is less than 10% per year. Four products were responsible for more than half of the total number of sales; in 1996, these were NifedipineProcardiaXL, LeuprolideLupron, DiltiazemCardizem and Goserelin Zoladex. Of the whole list, most products have been co-developed and marketed between a DDS-company and a major pharmaceutical rm. Compared to the world market of NCEs, the share of products using advanced drug delivery technology is not impressive. An important question is why the potential value of such technologies is not being exploited to a greater extent and how this could be improved. Improved therapeutic value (outcome) and pharmacoeconomic value have in recent years become

This paper is the summary of the authors key-note lecture at the Annual CRS Congress, Stockholm, June 1997. 2 Tel.: 1 31-71-5274295; fax: 1 31-71-5274277; e-mail: Breimer@LACDRLeidenuniv.nl

0169-409X / 98 / $ see front matter 1998 Published by Elsevier Science B.V. All rights reserved. PII: S0169-409X( 98 )00034-9

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D.D. Breimer / Advanced Drug Delivery Reviews 33 (1998) 265 268

major issues in dening health care priorities under the pressure of cost containment. Only seldomly is it recognized that improvements in drug therapy are a consequence of not only the (new) chemical entity, but of the combination of active substance and delivery system. Clearly, the added value of the latter has to be made more explicit [5].

effects associated with rapidly changing plasma concentrations [7]. For other products, convenience of dosing and better compliance explain their relative success of acceptance in the market place. Delivery pattern-dependent pharmacodynamics translated into improved therapeutic outcome is a major overall challenge for future drug delivery research.

3. Potential value Most drug delivery systems currently applied are capable of rate- and / or time-controlled drug release. The release rate is often of a (semi)zero-order, which gives rise to less uctuating drug levels than with conventional pharmaceutical formulations. The potential therapeutic advantage of such more or less constant delivery rates have been claimed to be severalfold: in vivo predictability of release rate on the basis of in vitro data, minimized peak plasma levels and, thereby, reduced risk of adverse reactions, predictable and extended duration of action, reduced inconvenience of frequent redosing and, hence, improved patient compliance. However, in relatively few cases have such potential advantages in fact proved to be of great therapeutic signicance. Only too often, the major emphasis is placed on the relatively at plasma level prole that is achieved (pharmacokinetics), rather than on the improved drug effect prole (pharmacodynamics in disease state) [6]. It is interesting to note that of the top four products on the 1996 worldwide sales list (previous paragraph), at least three have a strong pharmacodynamic basis, rather than a pharmacokinetic one alone. For the two GnRH agonists (leuprolide and goserelin), the pharmacological mechanism of action dictates that the compounds are administered continuously to suppress (desensitize) GnRH receptors and gonadotrophin secretion in conditions of hormone-dependent cancers. Repetitive (pulsatile) administration would induce a completely different pharmacological series of actions. The success of the nifedipineGITS system is based on a series of pharmacodynamic experiments in man using the rate of change of plasma concentration as a major variable, which showed that a sustained decrease in blood pressure could be achieved without causing an increase in heart rate and the occurrence of other side

4. Pharmacodynamics and therapeutic outcome Drug concentrations in plasma are no more than a surrogate for pharmacological and clinical effects, the relevance of which can only be judged if the relationship between pharmacokinetics and pharmacodynamics (PK / PD) is well established. In other words, only on the basis of quantitative information of this relationship can the desired optimal drug concentration time prole be dened. This is then to be translated into desired characteristics of the drug release prole from the delivery system (feedback). What is needed is pertinent information on the kinetics of drug effects and its (potential) dependence on the rate and time of drug input. This is what controlled drug delivery should be aiming at: improved drug treatment (outcome) through rate- and time-programmed (and sometimes site-specic) drug delivery. Therefore, prior to the phases of conception, design and development of such systems, at least three fundamental questions should be asked and provisionally answered: (a) Which unmet medical need is the product that is aimed at to fulll and is the delivery component expected to be an essential feature of such a product to create added therapeutic value? Delivery may represent features of rate- and timecontrol, site-specicity of administration or targeting. (b) What is the optimal rate, time or site at which the drug should be delivered? This requires clinical pharmacological experimentation with emphasis on pharmacodynamics to obtain essential information on the PK / PD relationship and its dependence on the disease and on the rate- and time-prole and the site of drug input (e.g. continuous versus pulsatile as extremes). (c) Which is the most suitable delivery system that

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can provide the required rate and time specications via the desired site or route of administration? Important features are capacity, exibility, rate and time programming possibilities, production costs, etc. Currently, these questions are often studied in the reverse order, i.e. new drug delivery systems looking for a suitable drug candidate. Ideally, however, once an unmet medical need has been dened, relevant clinical pharmacological studies are undertaken with the drug candidate, looking for the optimal delivery prole to be accommodated by the most suitable delivery system. This does not only hold for existing drugs (line extensions, etc.) but denitely also for NCEs, as will be explained in the next paragraph. Apart from remaining relevant objectives of extension of duration of drug action and avoidance of side effects, opportunities in time programming are related to the avoidance of the development of drug tolerance, to meet circadian variation in the intensity of disease or drug effects, combination therapies, improved compliance, etc. [8]. To dene such time dependencies, it will be helpful in research to use miniaturized sensor technology to continuously monitor body functions and drug effects thereon.

tunities with existing drugs. The big pharmaceutical industry has not (yet) recognized drug delivery as an essential component for future innovation and growth. Even more than in the past, the major emphasis is placed on NCEs as a result of an improved understanding of the molecular mechanisms of diseases and, thereby, the discovery of novel drug targets and classes of medicines. This is further substantiated by the application of new technologies, such as molecular modelling, combinatorial chemistry, high throughput screening and bioinformatics, as the new engineering tools that give rise to numerous novel lead compounds. On November 7 1996, Nature devoted a whole Supplement to Intelligent Drug Design, in which these new trends are reviewed, in recognition of the phenomenal progress being made in a discipline that, as much as any other, is steadily transforming the quality of our lives (quotation from the Editor of Nature) [9]. Future categories of medicinal treatment will comprise the following: mechanism based small molecules (with several new classes of medicines); therapeutic proteins and other macromolecules; gene-regulating medicines (e.g. antisense); gene therapy. It is to be realized, sooner or later, that, for these treatment modalities to become major successes, the delivery of active substance will have to be an essential component and they therefore also represent the major challenges of future drug delivery research. This is best recognized, but so far the least successful, with gene therapy and gene-regulating medicines in terms of the need for cell-specic delivery and targeting. For therapeutic proteins (and peptides), a major challenge will be to make noninjection routes of administration feasible. Although some progress has been made for the oral route, as recently reviewed by Wang [10], the goal of reproducible bioavailability by effective and safe strategies is still far from being reached. More fundamental biological research is required to better understand and reversibly manipulate membrane and (para)cellular transport and trafcking processes. For

5. The future of drug delivery must meet the challenges of future medicines During the past few years, almost revolutionary changes have occurred in the big innovative pharmaceutical industry, partially under the inuence of cost containment pressures in the health care domain worldwide. Mega-mergers have taken place, as well as take-overs and strategic alliances with smaller companies (in particular in the biotech area), to get access to greater innovation potential. It has become widely accepted that only new treatments that offer improved therapeutic outcome will receive proper reimbursement (not to be determined by the patient or doctor, but by the organization that pays the bill). Interestingly enough, this drive towards innovation through mergers, etc. has left the drug delivery arena almost untouched. Most of the (relatively small) companies in this eld are still on their own and looking for partnerships and niche market oppor-

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D.D. Breimer / Advanced Drug Delivery Reviews 33 (1998) 265 268 Pharma Reports, CONNECT Pharma, Oxford, 1996, pp. 1727. R.H. Guy, M. Powell, J. Fix, K. Park, Controlled release technologies: Current status and future prospects, Pharm. Res. 13 (1996) 17591785. T. Sam, J. Fokkens (Eds.), Innovations in drug delivery. Impact on pharmacotherapy. The Anselmus Foundation, Houten, Netherlands, 1996. Hambrecht and Quist Inc., List of Major Pharmaceutical Products Using Drug Delivery, 1997. M. Powers-Cramer, S.R. Saks, Translating safety, efcacy and compliance into economic value for controlled release dosage forms, Pharmacoeconomics 5 (1994) 482504. D.D. Breimer, An integrated pharmacokinetic and pharmacodynamic approach to controlled drug delivery, J. Drug Target. 3 (1996) 411415. C.H. Kleinbloesem, P. Van Brummelen, M. Danhof, H. Faber, J. Urquhart, D.D. Breimer, Rate of increase in plasma concentration of nifedipine as a major determinant of its haemodynamic effects in humans, Clin. Pharmacol. Ther. 41 (1987) 2630. D.D. Breimer, The need for rate and time programming in future drug delivery. Pharmacokinetic, pharmacodynamic and clinical considerations. In: R. Gurny, H.E. Junginger, N.A. Peppas (Eds.), Pulsatile Drug Delivery Current Applications and Future Trends, Wiss. Verlagsgesellschaft, Stuttgart, 1993, pp. 2540. Nature, Supplement to Volume 384, November 7, 1996, pp 126. W. Wang, Oral protein drug delivery, J. Drug Target. 4 (1996) 195232.

small molecules, all of the problems that still exist at present, such as non-solubility, rapid (non)enzymatic breakdown, suboptimal disposition behaviour, etc., require innovative delivery approaches. It will be important, in particular, that these are considered at the early phase of drug candidate selection and that rapid screening procedures for the properties required for optimal delivery are developed. For all categories of treatment, a major challenge is to dene the optimal dose, time, rate and site of delivery in order to add value to the NCE per se. The research approach, as outlined in the previous paragraph, with emphasis on pharmacodynamics, will have to receive far greater attention in preclinical and clinical drug development. Overall high level expertise in drug delivery and targeting is to become an integral part of pharmaceutical R and D; only then can the future challenges be met that should lead to innovative medicinal treatments of as yet unmet medical needs.

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