Introductory Remarks and Historical Development

Traditionally, the clinical applications of oral colonic drug delivery have been limited to the local treatment of inflammatory bowel disease (IBD). Enteric coatings, sustained release systems, and bacterially triggered treatments have all been used to deliver anti-inflammatory molecules to the colon to treat this debilitating condition. However, for many years the treatment of colonic cancer has been postulated as an ideal candidate for colonic drug delivery but little has been delivered in this field although there are some potential avenues which are starting to be explored. Also, there are other local diseases of the large intestine which could benefit from topical delivery to the colonic mucosa, and the potential of the colon for systemic

The 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, Advances in Delivery Science and Technology, DOI 10.1007/978-1-4614-1004-1_18, © Controlled Release Society 2011

Bile acids 115 mM

[5| Short-chain ^ fatty acids 30.9 mM

Osmolality 81 mOsm/kg

Surface tension 42.7 mN/m

Nk Fluid *Vk187mL (total) 13mL (free)

Bile acids 115 mM

[5| Short-chain ^ fatty acids 30.9 mM

Osmolality 81 mOsm/kg

Surface tension 42.7 mN/m

Nk Fluid *Vk187mL (total) 13mL (free)

Transit vj 1->24h

Fig. 18.1 The colonic environment: some physiological features of the colon

Transit vj 1->24h

Fig. 18.1 The colonic environment: some physiological features of the colon drug delivery should not be ignored. Applications for colonic delivery, old and new, are constrained by the physiological difficulties of targeting this distal site and the environmental barriers presented by the colon. There are, however, some overlooked factors which could prove beneficial for colonic drug delivery. This book chapter considers how the colonic physiology and local environment can affect the success or failure of traditional and novel strategies for delivery to the large intestine, local and systemic, and examines some of the up-to-date issues in colonic drug delivery.

The biggest issue affecting the success or failure of colonic drug delivery is the colonic environment (Fig. 18.1), and the difficulties it presents to dosage form design for such delivery. For example, there is a distinct lack of fluid, and that which is present is heterogeneously distributed and very little of it free to solubilize a drug. On the colonic mucosa and mixed in with the colonic fluid and solids are the colonic microbiota. These microorganisms (bacteria, yeasts, and fungi) number 10111012 cfu/g of material in the colon, and there may be as many as 3,000 different species residing here [1]. They digest polysaccharides, proteins, and even drugs. To date, over 30 drugs have been identified and published as substrates for colonic bacteria [2] and many more are expected to be uncovered. This can have significant consequences for drugs exposed to the intestinal bacteria; they could potentially be activated, inactivated, or made toxic.

Drug absorption in the colon can be influenced by colonic residence time. The colon shows variations in transit; the residence of a dosage form in the colon can be from around 1 h up to several days [3] and this can affect drug bioavailability [4]. Dosage form factors influence colonic transit; tablets (25 x 9 mm) move ahead of pellets (0.5-1.8 mm) in the ascending colon [5] in a process known as streaming (due to solid and liquid material moving at different rates). Transit in the colon is also nonuniform; dosage forms are often at rest spending up to 30 min periods with no or minimal propagation [6]. In general, however, the transit time is relatively long compared to the upper gastrointestinal tract and this could confer significant advantages for drug delivery to this site.

Colonic drug delivery has its origins in the 1950s when the prodrug sulfasalazine was introduced as a treatment for rheumatoid arthritis and later IBD. However, the mechanism of action of sulfasalazine was not appreciated until studies in the 1970s. This prodrug consists of sulfapyridine azo-bonded to a molecule of 5-aminosali-cylic acid (5-ASA, mesalazine, mesalamine). This can pass through the stomach and small intestine intact, being cleaved by colonic bacteria to release the active moiety (mesalamine). This was the standard of care for IBD (besides steroid treatments) until the 1990s when several new drugs were developed and approved: olsalazine (1990) and new mesalamine formulations (Asacol [1992], Pentasa [1993]). Olsalazine is another prodrug in which two linked mesalamine molecules are cleaved by colonic bacteria to the two active moieties. Asacol and Pentasa are modified release formulations; Pentasa controls release via an ethylcellulose coat whereas Asacol has a pH-triggered release via a coating which dissolves at >pH 7. In 2000, balsalazide (Colazol) was approved. This is cleaved to release mesalamine and an inactive molecule (4-aminobenzoly-beta-alanaine). After this, focus turned to developing new formulations rather than new drug molecules and further mesala-mine formulations were released in 2007 (Lialda) and 2008 (Asacol HD and Apriso). Lialda has a pH-triggered mechanism of release combined with a slow release mechanism.

Apriso is another delayed/extended release formulation based on pH-triggered release. The recent shift in clinical prescribing towards higher doses of anti-inflammatory medications has fuelled the development of high dose products, such as Lialda and Asacol HD (Fig. 18.2). Beyond the mesalamine-based drugs, steroid treatments have also been targeted to the colon. An example is Entocort which uses pH and water-insoluble polymers to control the release of budesonide in the gastrointestinal tract [7]. A further budesonide product is Budenofalk which consists of pellets with pH responsive polymer coatings. These latter two products are multi-unit systems and illustrate the shift away from single unit dosage forms due to the latter's inconsistency and susceptibility to failure as modified release preparations [8, 9]. Many other colonic drug delivery systems have been developed, or are in clinical trials, and some of these are discussed in this chapter.

Fig. 18.2 Historical development of mesalamine formulations in the US

1950

Sulfasalazine

AZULFIDINE

[AZULFIDINE EN

1990

Osalazine

DIPENTUM

1992

Mesalamine

1993

Mesalamine PENTASA

2000

Basalazide

COLAZAL

2007

Mesalamine

2000

Basalazide

COLAZAL

2007

Mesalamine

2008

Mesalamine

2008

Mesalamine

ASACOL HD

2010

APRISO

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