The history of the development of our understanding of the means to control the performance of drugs either through manipulation of the drug itself or through choice of modes of delivery can be illuminating for us today. The gradual understanding of the mechanisms of drug absorption following administration of medicines by a variety of routes, and the possible hazards from inappropriate doses and modes of delivery, provides the background for the development of today's varied array of controlled delivery systems. To ignore the history of any subject is to forget the evolution of thought and technique that has led to the inventions of the present, discussed in depth

Professor Emeritus, School of Pharmacy, University of London, London, UK e-mail: [email protected]

C.G. Wilson and P.J. Crowley (eds.), Controlled Release in Oral Drug Delivery, 1

Advances in Delivery Science and Technology, DOI 10.1007/978-1-4614-1004-1_1, © Controlled Release Society 2011

in the chapters that follow. It would be wrong to imagine that the field of controlled drug release is a recent, even twentieth century affair. It may even be surprising to learn of the relatively slow evolution of the discipline. One needs only to consider the time that elapsed between the publication of the Noyes-Whitney equation in 1879 [1] and its utilization in pharmacy. The first studies on the effect of drug particle size on dissolution occurred in the 1950s. Even so, the introduction of dissolution tests into pharmacopeias occurred only in 1970s, after much discussion over the relative merits of disintegration and dissolution tests, which the author observed at first hand as a member at that period of the Chemistry, Pharmacy and Standards Subcommittee of the UK's Committee on Safety of Medicines (CSM). The example alone illustrates the slow advance from empiricism in pharmaceutical technology to the rigor introduced by, for example, Takeru Higuchi and his team some 60 years ago. Clearly, progress in most areas has been dependant on a growing and more precise appreciation of the underpinning technologies and biologies.

There could of course have been few truly oral controlled release delivery systems without the developments, from the nineteenth century onwards, in tabletting. Advances in materials science, especially polymer science has provided scientists with a large and growing range of materials with which to work, amongst which are carbon nanotubes and quantum dots, systems such as gels, hydrogels, films, polymer micelles, liposomes, dendrimers, and the like. Not all can be discussed in this short introduction. Another influence has been the increasing precision of imaging technology that has aided progress towards defining and refining the behavior of delivery systems in vivo. Nevertheless, there was considerable at least implied knowledge of the fate of therapeutic agents and dose forms in the nineteenth century and early part of the twentieth century despite the lack of facile analytical techniques and the virtual absence of the ability to monitor medicines in vivo, apart from X-ray photography.

From the early days of the twentieth century to the mid-1950s it might be claimed that pharmaceutics was concerned primarily with the science and practice of the manufacture of dosage forms at small and large scale and with the preparation of galenicals. However, it would be wrong to conclude that it had no regard for the fate or influence of the dosage form in vivo. It is interesting to note that in the early days of the twentieth century most reports on medicinal product performance emanated from work in human patients or volunteers, before the widespread use of experimental animals. The literature therefore emphasized clinical outcomes or physiological measures. Analytical science rarely allowed the measurement of plasma drug levels, which today remain substitutes for performance.

The 1924 edition of Martindale and Wescott's The Extra Pharmacopeia [2] discusses enteric coating of tablets as a means of minimizing the adverse effects of drugs on the intestinal mucosa, and enhancing action:

Various substances have been proposed for the coating of pills, tablets and capsules to render them insoluble in the stomach but soluble in the intestines, i.e. on reaching the duodenum. Drugs, for example, which irritate the mucous membrane and the administration of which is liable to induce vomiting, and substances intended to act solely on the intestines and the anthelmintic drugs, have been so given. Keratin, as usually employed, seldom brings about the desired effect.

Clinical need

Exploring routes

Challenging drugs

Commercial advantage

Avoidance of ADRs

Prolonging action


Minimising variability

Fig. 1.1 The driving forces for the development of optimized or controlled release systems. Clinical need is key, enabled by new technologies. Curiosity-driven research will provide the seeds of novel ideas, materials, and approaches

Here there is clear concern for the efficacy of formulations and the therapeutic consequences of their properties. Clinical need and clinical benefit are of course the main driving forces for developments in controlled release. But there are other drivers also, not least scientific curiosity, as outlined in Figs. 1.1 and 1.2. The discipline must allow and indeed encourage research which has no obvious and immediate applicability in delivery. The word "novel" is often misused in the titles of papers in the modern literature. Truly novel systems and approaches are nonetheless required to achieve the goal of individualized or personalized medicine, for as Nobel Laureate and physicist Pierre-Gilles de Gennes reminded us: It was not by perfecting the candle that electricity was invented [3].

One of the notable trends in the field has been the move from a certain empiricism to a more theoretical, mathematical, and materials science approach to the design and understanding of drug delivery and drug delivery systems. We have yet to reach the stage where the behavior of controlled release systems, let alone conventional systems, can be predicted by any given equation or mathematical formulation. There is as yet no theory of everything biopharmaceutical, and there probably never will be. The ultimate test of performance will always be determined in individual human subjects.

In observing the literature on the development of the discipline of controlled release there are three critical elements: the drug, its formulation, and its route of administration. These are of course intertwined (Fig. 1.3) and can be deconstructed. The target is rightly emphasized now, and at the organ and even cellular level there

Fig. 1.2 A version of Fig. 1.1 listing other ambitions for controlled drug delivery in terms of advanced systems targeting to specific sites in the body, minimizing variation, overcoming barriers, or responding to the need for more personalized medicines/dose forms
Fig. 1.3 The four key elements of drug delivery: the drug, the formulation, the route of administration, the target organ and cellular or intracellular target

are targets within targets. The two elements that can be manipulated technologically are the drug and the formulation, although one can temporarily enhance the permeability of barrier membranes, it is sometimes a risky strategy. More attention certainly needs to be paid to the matching of the active to particular delivery systems and devices. Again the early observation of clinical outcomes has led to the awareness of the formulation and its ability to enhance or indeed sometimes jeopardize outcomes, a subject that has not perhaps had the emphasis it should have had in the pharmaceutical sciences, but which is of course of vital importance to each patient.

In assembling the material for this chapter it has not always been possible to determine the exact date of any invention or development: sometimes the date recorded is the date of the granting of a patent or the publication of a key paper. Sadly, the scientists who are the true inventors and discoverers are not always revealed, especially in clinical papers describing the testing of the delivery system on patients.

Although this book is primarily focused on oral delivery, many technologies cross route boundaries. What is clear is that much of the relevant history of controlled release depends on the early attempts to administer drugs by various routes, and from the clinical study of outcomes. For example, early views that subcutaneous (sc) and intramuscular (i.m) administration of drugs resulted only in local action were dispelled by the Scots physician Benjamin Bell [4], who in the Edinburgh Medical Journal of 1858 opined that "absorption from the enfeebled stomach may not be counted on; we possess in subcutaneous injections a more direct rapid and trustworthy mode of conveying our remedy in the desired quantity to the circulatory blood."

Preliminary studies have frequently led, as in the case of insulin and penicillin to a realization that early formulations were inadequate and that other approaches were needed to overcome either toxicity or short duration of action or both. Hence the history of controlled drug delivery includes those earlier "uncontrolled" or "conventional" systems. While the subject has come far, it has in no way reached its apogee. The plasma level versus time diagram used for explaining the pharmacokinetic advantages of controlled release systems, such as sustained release delivery forms usually purveys an ideal that has not been always been reached in spite of much ingenuity and invention. Figure 1.4 shows a more complex picture for four subjects. The reality is still that inter- and intrapatient variability (in minimum effective dose, maximum tolerated dose, and physiology) is still an issue with some drugs and some delivery systems. The lower diagrams in Fig. 1.4 shows such a situation for oral controlled release nicotine. Data have to be scrutinized with care. Figure 1.5 shows phar-macokinetic data for a transdermal patch studied in a number of human subjects, and the different impression one obtains from such individual data sets, compared to mathematically manipulated data, often plotted logarithmically. When they first became available transdermal patches were implied to offer much tighter control of levels of absorption.

Nicotine concentration 6mg dose


Cotinine concentration 6mg dose

Fig. 1.4 Upper plot: An idealized representation of the plasma concentration-time profiles for a conventional release oral dosage form and a sustained release form, attempting to show four individual responses and the range of minimum effective concentrations (MEC) and maximum tolerated concentration (MTC), both of which vary from patient to patient. The two identical plasma curves could represent two individuals whose MECs and and MTCs differ. The arrows point to different t values. Lower plot: Results from an oral form of nicotine (5 mg dose) designed for release in the colon. Plasma levels of both nicotine and its metabolite cotinine are shown. From Green JT, Evans BK et al. (1999) An oral formulation of nicotine for release and absorption in the colon: its development and pharmacokinetics. Br J Clin Pharmacol 48:485-493 with permission

Fig. 1.4 Upper plot: An idealized representation of the plasma concentration-time profiles for a conventional release oral dosage form and a sustained release form, attempting to show four individual responses and the range of minimum effective concentrations (MEC) and maximum tolerated concentration (MTC), both of which vary from patient to patient. The two identical plasma curves could represent two individuals whose MECs and and MTCs differ. The arrows point to different t values. Lower plot: Results from an oral form of nicotine (5 mg dose) designed for release in the colon. Plasma levels of both nicotine and its metabolite cotinine are shown. From Green JT, Evans BK et al. (1999) An oral formulation of nicotine for release and absorption in the colon: its development and pharmacokinetics. Br J Clin Pharmacol 48:485-493 with permission

Fig. 1.5 Plasma concentrations of fentanyl delivered from a Cygnus™ patch showing individual data on the upper diagram and the mean data below. The results shown here are not to critique the particular product but to demonstrate strikingly how controlled release products do not always behave for one reason or another as designed to do. The data above are from [5]. The variability has been confirmed in other studies including evidence of toxicity

1.1.1 Terminology of Controlled Release

The vocabulary used in the controlled release field to describe delivery systems is paradoxically uncontrolled: it is diverse, flexible, and overlapping. An attempt at a lexicon follows:

• Controlled release: suggests true control of drug release rates

• Sustained release: suggests prolonged release and prolonged plasma levels

• Prolonged release: as above

• Modified release: suggests release rates which are different from fast release, but it is not a precise descriptor

• Pulsatile release: means the release of more than one dose of drug from a given system

• Timed release: suggests release of drug after a specified period of time

• Triggered release: applies to systems from which drug release is stimulated by an external or endogenous signal

In the following sections, the history of various approaches to controlled release, in its broadest sense, is discussed. Judah Folkman who made significant contributions to the field was, however, wrong to state in the abstract to his reminiscences in 1990 [6] that "the first controlled release system was developed in 1962." No doubt he meant that the first silicone implant system for the release of drugs and proteins was. Allan Hoffman's excellent review of the origins and evolution of controlled release drug delivery systems [7] also takes this as a starting point, but here we take the story back at least 130 years to emphasize the step-wise growth of the subject. Hoffman's account, well illustrated and detailed, highlights key players in the field as it developed thereafter. The majority of us are the laborers, contributing a few bricks here and there, usually as a result of the work of research students.

Given that the oral route is not only the most widely used route but that this book is devoted to oral systems, this account begins with oral delivery systems. But, as stated earlier, the history of other routes cannot be ignored for there are some general principles to be derived from them.

1.1.2 Oral Delivery Systems

Writing in 1961, Lazarus and Cooper [8] stated that the possibility of favorably modifying the therapeutic response of drugs administered by mouth "provide a powerful stimulus to research workers in pharmacy and medicine. Here was an open sesame of scientific opportunity further triggered by vistas of economic rewards." But they added trenchantly that the speed with which pharmaceutical laboratories jumped on the bandwagon resulted in "a plethora of ideas and products, many of which should have remained unborn." Some, simply put had no real clinical benefit. Approximately, 180 different prolonged release products were available in the USA in 1961. There was and is indeed a problem with the prescribing and dispensing of (generic) prolonged release products of the same active [9], as while the drug release rate from conventional release tablets can be defined within a narrow range, modified release products, such as with theophylline legitimately provide a spectrum of rates of delivery; because of their different physical compositions there is a risk of quite different pharmacokinetics due to potential differences in GI transit or the effect of food [10, 11]. Of course the variety of release rates provides overall a palette from which clinicians can choose, but the appropriate pharmacokinetic information is not always available to prescriber or pharmacist to allow reasoned choices. The recent trend for the pharmaceutical industry to introduce controlled release products at or near the end of the patent life for their original invention sullies the field, by the introduction of products whose purpose is to protect a brand name and to outwit generic manufacturers. Why, one asks, was there no clinical need for such a product in the previous decade of product life, when suddenly it becomes an advance of great benefit to all concerned?

Considerable ingenuity has been demonstrated in the development of oral controlled release systems over the years with much overall benefit to patients.

Early work to alter the rate of release and the duration of action of products depended very much on coating pills, capsules, and latterly tablets when these emerged from the compression process invented by Brockedon [12]. His invention not initially intended for pharmaceutical use, but was soon recognized by Brockedon himself, who contacted the Pharmaceutical Journal about potential products from it [13]. The advent of tablets seemed to have raised some opposition, especially in France according to Pariente [14] where they were given the epithet of "barbarismes pharmaceutiques" - engendered in part by the failure of some products to disintegrate, the sarcastically named comprimé

perpetual. Soon the technical problems in compressing powders became evident and Dunton obtained a patent in 1875 [15], in which he suggested the processing of materials by drying before compression and the use of lubricants to reduce cohesion between powder and die. Dunton states that the forces of adhesion are often greater than the forces of cohesion such that the mass breaks up readily without lubricant. Another patent by Sauter employed starch as a disintegrant, and as early as 1878 we have a patent on coating tablet cores by compression, so "that the powder covering holds by cohesion, thus producing a seamless coated medicament [16]." The coat was designed to protect the active, to disguise unpleasant tastes without changing the solubility of the drug. It is a small step to the incorporation of a second drug in the outer compressed coat to be released at a faster rate. The stage was set for more developments.

First we survey of the use of coatings to change the performance of formulations for oral use. Early alternative inventions included Ellzey's drug-containing capsule placed inside a larger capsule with an intervening alkaline material [17], perhaps a forerunner of capsules containing mini-tablets? There were some diversions into gelatin tablets [18, 19] which may in retrospect have been a useful advance, perhaps as a future platform for pediatric and geriatric formulations.

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