PHResponsive Delivery

pH dependent systems targeting the lower bowel utilize polymers sensitive to the pH gradient along the intestinal tract. This approach represents the majority of commercial products formulated for colonic delivery (other examples being prod-rugs, i.e., drug specific approaches). Targeting the colon with such polymers is conceptually sound, but can be difficult. Polymers that avoid dissolution at the low pH of the stomach and the pH of the small intestine (6.6 ± 0.5 in the proximal) are used. These then need to dissolve at the higher, near neutral pH of the distal gut (7.5 ± 0.4 in the distal small intestine). pH is maximal around the ileocecal junction [13] but can fall on entry to the colon due to the production of short-chain fatty acids by resident microbiota. Intersubject pH at a specific GI site can also span a range of up to 2 pH units [14]: Intraindividual variability is also considerable [15]. However, pH responsive approaches to colonic delivery have provided successful commercial products.

Fig. 18.3 Strategies for colon targeting via the oral route

Luminal pH

Mouth to caecal lag time

Luminal pH

Mouth to caecal lag time

Colonic microbiota

pH responsive/ enteric polymers (EUDRAGIT S) (EUDRAGIT L)

Combination of pH responsive polymers (ASAMAX, TARGIT)

1980s

Time release systems (PULSINCAP, TIMECLOCK)

Bacteria triggered pH+time systems release system (COLAL) (CODES)

pH responsive+ sustained-release multi-matrix system (MMX)

pH+bacteria triggered (PHLORAL)

2010

Fig. 18.4 Evolution of colonic delivery system design

A methacrylic acid/methyl methacrylate copolymer (EUDRAGIT S), with a dissolution threshold of pH 7 was first used to target the colon in the 1980s [16]. A number of commercially available tablet dosage forms were then developed based on this principle. These were employed to deliver mesalamine to the distal gut for the oral treatment of IBD. However, failure to disintegrate in vivo has been noted with some tablets and similar preparations [8, 9] possibly due to intraindividual variability and lower colonic pH in IBD patients [17, 18]. Thus, precise site specificity remains elusive with such coated formulations.

Other approaches to pH-responsive drug delivery to the distal gut include using polymers which have a lower pH threshold. EUDRAGIT L dissolves at lower pH (>6) and has also been applied as coatings for colonic targeting. Salofalk is a EUDRAGIT L-coated mesalamine tablet for the treatment of ulcerative colitis, although more likely to deliver to the mid- to distal small intestine. Combinations of two methacrylic acid copolymers EUDRAGIT S and EUDRAGIT L or EUDRAGIT S and EUDRAGIT L 100-55 (pH >5.5) can be used to manipulate drug release profiles within the pH range of 5.5-7.0 by changing the polymer ratios [19]. Such systems can theoretically deliver drug to any desired region of the GI tract. A gastro resistant mesalamine tablet formulation (Asamax) utilizes a EUDRAGIT L/S mixture as coating material [20]. An in vivo gamma scintigraphy study showed that initial tablet disintegration occurred at the ileocecal junction and the ascending colon. TARGIT™ technology uses EUDRAGIT L/S (3:1) mixture to coat injection-molded starch capsules which form a continuous unit between the lid and the body for easy application of coatings [21].

One recent development for improved colonic delivery has been the multimatrix or MMX™ system. The concept of MMX is based on pH-triggered drug release combined with a diffusion-based release mechanism to achieve sustained release; the technology has been designed to release drug throughout the colon. The system is based on a tablet formulation in which the active ingredient is dispersed in an inner lipophilic matrix and covered by an outer hydrophilic matrix generated by in situ hydration of selected polymer chains. A gastric resistant, pH-dependent film coat is applied. When the coat dissolves and fluid is imbibed into the core, a viscous gel mass forms through which drug diffuses and is released. The technology was applied to mesalamine and budesonide, and is now being applied to other drug molecules (e.g., heparin) albeit still in early development. The mesalamine formulation was first evaluated by pharmaco-scintigraphy study; initial erosion or disintegration was apparent in the ascending and the transverse colon [22]. However, absorption of mesalamine commenced in the small intestine and ileum and before relevant tablet erosion could be identified from scintigraphic images. This suggested that such a mode of delivery still lacks true site specificity [23].

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