Coating as a Means to Control Drug Release

Figure 1.6 summarises the many ways in which control of drug release has been achieved by "enveloping" drugs as opposed to modifying the form of the drug as discussed later. Early Enteric Coating Materials

The use of keratin-coated pills is reported in a Lancet paper in 1893 [20]. Although the process is credited to the German dermatologist, Dr Paul Unna, who first marketed such products [21], he himself did not claim to have originated the idea of enteric coating. The early alternative to keratin was salol (phenyl salicylate) and the two were compared in a study in 1917; salol was found to be superior in the delivery of emetine bismuth iodide [22]. Cowen [23] states that what made Unna's work "truly revolutionary" was the concept that "the form of the medicament could be used to influence, if not determine, its substantive effects." This is of course the kernel of controlled release formulation with its ability to influence therapeutic outcomes. While Unna himself demonstrated the effect of his coating system in vitro, there were frequently expressed concerns about the quality of such systems, particularly on product aging. An early noninvasive technique - X-ray examination - was used to observe the disintegration in vivo of keratin coated systems in 1938 [24]. This technique has of course been used many times since, showing delayed transit of dosage forms in the esophagus [25], the lack of disintegration of enteric coated tablets of potassium chloride [26], the esophageal retention of barium sulfate tablets [27], and later Channer's work on esophageal transit of formulations [28].

Fig. 1.6 Schematic of the approach to controlled release through enveloping the drug in a carrier either by coating or by preparation of microcapsules, nanoparticles, dendrimers, and nanocon-structs of increasing diversity, implants and films

Ingenuity was shown by those who estimated whether enteric coated pills or tablets actually disintegrated in vivo by determining the presence of drugs or markers such as iodides, and methylene blue in urine. Thomson and Lee [29] suggest, perhaps tongue in cheek, that a foolproof method of determining the lack of disintegration is the recovery of the dosage form intact in the feces [30], but they themselves provide an account of sound methods of ensuring in vitro that enteric coated products were reliable and standardized, with tests of disintegration in acid pepsin, and both acid and alkaline pancreatin [31]. Wax Coatings

A number of formulations appeared comprising granules or beads coated with waxes of varying structures. Glycerides have a greater effect on retarding release in vitro as they become less polar, glyceryl monostearate being less effective than the distearate and the tristearate most effective [32]. The SKF Spansule™ product was one of the early systems to reach the market (circa 1945). The product contained a range of granules or beads coated with different thicknesses of a wax coating, releasing drug over a period of 10-12 h. By the 1950s there was a growing range of such products, not all of which again were beneficial clinically. Nitroglyn™ a preparation of coated granules of nitrogyclerin (but elsewhere described as a porous plastic matrix tablet [33]) gave disappointing results given the "logic behind the product" in alleviating exercise-induced cardiac stress, while a long-acting formulation of pentaerythritol (Peritrate™) provided marked responses for 5-6 h after administration, but only after a latent period of 60-90 min [34]. However, Peritrate lost all of its activity when given with food, early indication of the differences between disintegrating and non-disintegrating controlled release forms and their transit behavior in the gastrointestinal tract. Polymer Coatings and Matrices

Polymer coats are now used widely in modified release coated tablets, materials such as cellulose acetate phthalate (CAP) from 1938 [35], hydroxypropyl cellulose phthalate (HP50 and HP55), and mixtures of ethyl cellulose and hydroxy-propyl methylcellulose (HPMC) [36] whose physicochemical characteristics such as solubility parameters, pH dependency of solubility, solubility in a range of organic solvents, and rheology were reviewed by Rowe [37]. By varying the proportion of ethylcellulose and HPMC, disintegration times varying from 10 min (ratio: 25:75) to 5.75 h (ratio: 75:25) could be obtained. At Smith, Kline and French, Swintosky recalls his contributions after he joined the company in 1953 to the use of hydrogenated castor oil-ethyl cellulose systems for coating pellets and tablets.

The Eudragit™ polymers are copolymers of acrylic acid or methacrylic acids and their esters. They were first marketed by Rohm and Hass in 1953. The properties of these polymers can be adjusted by variations in their chemistry. Eudragit type L and S polymers are copolymers of methacrylic acid and methacrylic esters in different ratios. The ratio of the free carboxylic groups to the ester groups is approximately 1:1 in Eudragit type L and about 1:2 in Eudragit type S. Therefore, Eudragit type L polymer is more acidic than Eudragit type S polymer. Eudragit L 12.5 was available from 1954 and new materials were introduced at intervals, one of the latest being Eudragit FS 30 D in 1999. The Eudragit polymers can be used as tablet coating or as matrix materials.

A wide range of matrix systems have been developed, from hydrophobic inert polymers such as polyethylene, PVC, ethyl cellulose, and acrylates and their copo-lymers to various lipid matrix systems, and of course hydrophilic matrices and biodegradable matrices.

As will be seen from other chapters in this book, oral controlled release products can be divided into those whose drug release properties are controlled by diffusion, dissolution, erosion of the matrix, osmotic pressure, ion-exchange reactions, or sometimes a combination of processes. The backgrounds to some of these are discussed below. Osmotic Pumps

The application of sound physical chemical principles led to the invention of the ingenious series of capsule and tablet systems whose driving force for drug release was osmotic pressure; semipermeable membranes controlled ingress of water, and a laser-drilled hole a mode of escape of the drug [38]. While Rose and Nelson [39] produced a prototype for veterinary use in 1955, whose driving force was the osmotic pressure difference between a saturated solution of Congo Red against water, it was the work of T. Higuchi and colleagues at Alza who drove the work forward [40, 41] to provide both prototypes and, in 1982 the first product based on an "elementary osmotic pump" for the delivery of indomethacin (Osmosin). This drug seemed a likely candidate for a system which accurately controlled the release of the active, given its propensity to cause serious effects in the small intestine, like many other nonsteroidal anti-inflammatory drugs. An occasional patient suffered from intestinal perforations as a result of long-term intake of NSAIDs [42]. Between December 1982 and the end of June 1983, 400,000 prescriptions had been written for Osmosin in the UK, but there was a high rate of reporting of adverse effects to the UK's Committee on Safety of Medicines (CSM), some 200 by August of that year, amongst them reports of intestinal bleeding and perforation [43]. Two cases of perforation distal to the duodenum (unusual with other NSAIDs) suggested that the Osmosin formulation exposed new areas of the bowel to the drug. The CSM noted that the formulation contained 158 mg of potassium bicarbonate a known irritant. Other reports accumulated in the literature [44, 45]. Of one report it was said [46] that as the two patients concerned were 70 years old, "it is unfortunate that a new drug (sic) should fall into disrepute as a result of inadequate attention to dosage, unwarranted polyphar-macy, or lack of concern for the patient's age." The product was withdrawn from the UK market in 1984. This short life is highlighted here not to diminish the invention, but to emphasize that as Laidler and colleagues [47] pointed out at the time, "new formulations of drugs may have unexpected side effects," a lesson that history tells us and that current experience reinforces. This episode is also a warning that whatever the merits of any dosage form, care has to be taken with its use. Few are panaceas. The effects produced by novel devices and formulations are not always as we anticipate, and sometimes difficult to fathom in hindsight, but in the case of Osmosin the effect of drug and excipient was no doubt exacerbated by the single exit point of the active in some orientations in the GI tract. This is very true of the delivery of endogenous molecules which we seek to insert into cavities that these molecules would never normally see, or accumulate in organs and tissues that the free drug would not. The 30 years of development of osmotic systems and a detailed analysis of the many successful products relying on this and related technology are comprehensively reviewed by Malaterre et al. [48]. Already by 1995 over 240 US patents had been granted [49] for variants and improvements on this initial concept that has spawned a new generation of controlled release devices. Ion-Exchange Resin Complexes

Oral depot therapy with two long-acting dexamphetamine-resin salt formulation (Dexten™ and Barbidex™) was described by Abrahams and Linnell in 1957 [50].

Molecular manipulation

Fig. 1.7 Molecular manipulation of the active to achieve control of release rate from dosage forms, in some cases in increase solubility and thus rate of solution, e.g., by forming nanocrystals

Crystal approaches

Molecular manipulation

Fig. 1.7 Molecular manipulation of the active to achieve control of release rate from dosage forms, in some cases in increase solubility and thus rate of solution, e.g., by forming nanocrystals

Their paper showed in vitro release of the drug from the resin over 12 h using the techniques adopted by Chaudhry and Saunders [51]. With a rather overblown introduction to their paper, Abrahams and Linnell state that the many advantages of sustained release oral therapy "demand no emphasis in recommendation; they include certainty of continuity, no relapse due to forgotten dose, and convenience." While the last is certainly true, one could debate the other points. A forgotten dose is a forgotten dose and more sophisticated means of reminding patients to take their medication at the right time is one of the necessary developments of recent years. Reviews on the pharmaceutical applications of ion-exchange resins are useful in exploring the background and uses of these complexes [52, 53].

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