Formulation for Delivery

New concepts in colonic drug targeting

By Dr. Stephen Brown

Historically the clinical applications of colonic drug delivery have been limited to the local treatment of inflammatory bowel disease with little consideration of the possibility for systemic absorption. The physiology and environmental conditions in the colon — extremely low surface area due to lack of villi and lack of fluid — would seem to support this view. Nevertheless, other local diseases of the large intestine could benefit from topical delivery to the colonic mucosa. The potential of the colon for systemic delivery of drugs including vaccines, proteins and peptides, is gaining renewed interest.

Photo courtesy of Encap Drug Delivery

In spite of the physiological barriers in the colon, some drugs have excellent bioavailability from this region of the gastrointestinal tract, and in some instances higher than that seen in the small intestine. McConnell et al.¹ in their review provide a list of drugs that have been found to have good colonic absorption. It appears that BCS class I-II drugs (high permeability) have a higher permeability in the colon compared to the small intestine when passive diffusion is the predominant transport mechanism.

The colon also offers the advantage of lower efflux transporter levels and lower metabolic enzyme levels which improve bioavailability of some drugs. This has recently been reported for simvastatin, where bioavailability was three times higher when administered to the distal gastrointestinal tract.²

The colon may also provide a suitable site for protein and peptide absorption, as proteolytic levels are significantly lower than in the small intestine and there is a relatively long transit time for drug absorption. Drug and vaccine delivery may also be exploited by the fact that the small intestine and the colon are lymphatic organs.³ Peyer’s patches in the small intestine and lymphoid follicles in the colon can take up antigenic and particulate material, as well as pathogens. This was demonstrated in a recent study which investigated the delivery of a model particulate vaccine (ovalbumin entrapped in PLGA nanoparticles) to the whole colon of mice. Positive and different antibody responses to oral gavage and rectal administration suggest the potential for orally targeted colonic vaccination.³

Formulation Options

There are several systems that are used for colonic drug delivery. Colonic targeting can be achieved by exploiting the luminal pH or by using the metabolic activity of the colonic microbiota. Attempts have also been made to target the colon using time delayed delivery systems which aim to release the drug after a pre-determined lag time following ingestion. Each system has its advantages and disadvantages.

pH-Responsive Polymers

The concept of pH-responsive drug delivery to the intestine is well established. Enteric coatings are commonly used to prevent drug release in the stomach, but allow release as the dosage form enters the small intestine and the pH increases. This concept has been extrapolated to colonic delivery. The pH-responsive colon-specific systems rely on the luminal pH increasing distally along the small intestine, from 6.63 ± 0.53 in the jejunum reaching a peak at the ileocaecal junction (7.49 ± 0.46).⁴ Using polymer coatings that dissolve at these higher intestinal pH values should allow drug release upon reaching the distal small intestine. However, it must be remembered that inter- and intra-subject intestinal pH values can vary greatly even in healthy subjects. The most commonly used polymer is the polymethacrylic acid methyl methacrylate ester co-polymer (Eudragit S), which is designed to dissolve above pH 7. This is widely used in a number of commercial products, including Asacol®, Ipocol®, Mesren®MR, tablets for site-specific delivery of the anti-inflammatory drug mesalazine (mesalamine) to the large intestine for the treatment of ulcerative colitis.

There are reports in the literature¹ of this type of formulation failing to disintegrate in vivo. McConnell et al.¹ reviews data from a number of studies indicating an incidence of non-disintegration of dosage forms in both patients with inflammatory bowel disease and healthy volunteers. The authors suggest that the performance of this type of dosage form may be influenced by other factors in addition to pH, such as residence time at the ileocaecal junction, feeding status and gastrointestinal fluid composition.

Another approach is to use polymers that have a lower pH threshold. For example Eudragit L dissolves at lower pH than Eudragit S (pH > 6) and has been applied as coatings for targeting to the lower intestine. It is used in Salofalk (mesalazine) tablets for the treatment of ulcerative colitis. Combinations of Eudragit polymers can theoretically target any required pH in the range 5.5-7.0 by varying the ratios of polymers. This has been used in some commercial products and in the TARGIT™ technology to coat injection molded starch capsules.

A recent extension of the pH-responsive polymer technique involves the sustained release of an active from an internal lipophillic core (multimatrix, MMX tablet technology). In this case, the release of drug from the core is controlled by a hydrophilic gel layer which forms once an outer gastric resistant pH-responsive film is breached in the small intestine. This technology has been applied to mesalazine (Lialda®, Mesavant®) and budesonide. It seems likely that all such systems relying on pH-responsive polymers will not be truly colon site specific.

Colonic Microbiota

The gastrointestinal bacterial population increases along the gut. There are relatively low levels in the stomach and proximal small intestine (10² – 10⁴ CFU/g) and a dramatic increase to 10¹¹ – 10¹² CFU/g in the colon. The prodrugs sulfasalazine, olsalazine and balsalazide rely on colonic bacterial enzymes to metabolize the inactive precursor to the active drug mesalazine. By employing polysaccharides which could avoid digestion in the upper gastrointestinal tract but be digested by enzymes produced by the colonic microbiota, coating systems have been developed which can effectively target the colon.⁵

A variety of polysaccharides have been investigated but the most successful has been resistant starch (amylose). It has been demonstrated that the combination of amylose with a water-insoluble polymer (ethylcellulose) produces a film coating that prevents gastric and small intestinal drug release from solid dosage forms but allows a slow sustained drug release once in the colon. The amylose/ethylcellulose coating (COLAL®) has been used to coat pellets containing the corticosteroid prednisolone sodium metasulphobenzoate (COLAL®-PRED) and is undergoing clinical trials for the treatment of ulcerative colitis.

Time-Dependent Colonic Delivery

Time-dependent systems utilize the time delay between dosage form administration and colonic arrival to achieve colon-specific targeting. This is usually achieved by using coating techniques or matrix systems which erode and release the drug over a pre-determined period. Time-based systems work on the assumption that dosage form transit times are reasonable predictable. In reality, dosage form transit through the gastrointestinal tract is highly variable and influenced by a wide range of factors such as gastric emptying, which in turn is influenced by dosage form size, density and food intake. Moreover small intestinal transit time and ileocaecal hold time are also highly variable.⁶ This has meant that site specificity for time-dependent colonic delivery systems has been poor.¹

New Technologies

A new concept in colonic drug targeting, recently described by Ibekwe et al.⁷, uses a combined pH-responsive and bacterially triggered drug delivery technology. The technology combines the bacterial and pH mediated approaches used previously for colonic delivery. The combination of these independent but complementary release mechanisms should overcome the limitations associated with the single trigger systems and improve site specificity. The technology involves the combination of a pH-sensitive polymer with resistant starch. This mixture is used as a film coating matrix, which can be applied to tablets, capsules or pellets. Ibekwe et al.⁷ report the results of testing tablets with the new coating in healthy volunteers to assess the site of disintegration using gamma scintigraphy. In contrast to the performance of the pH-responsive polymer coatings mentioned above, the authors reported that the coated tablets were able to resist breakdown in the stomach and small intestine. Consistent disintegration of the dosage form was observed at the ileocaecal junction/large intestine and this was unaffected by food.

The success of the system was attributed to the role of starch, which is not digestible by mammalian pancreatic amylase but is readily digested by colonic bacterial enzymes. Thus, even if the pH-responsive polymer component of the film remains intact, the colonic bacterial enzymes will still digest the starch component allowing dosage form disintegration. It is claimed that the starch provides a back-up or ‘fail-safe’ for dosage form disintegration.

One of the physiological constraints to the colonic delivery of drugs is the low volumes of fluid available for disintegration of dosage forms and subsequent dissolution.⁸ A combination of the new colonic drug targeting technology with liquid filled hard capsule technology, where the drug is delivered as a solution, suspension or self-emulsifying system, has yet to be investigated, but may well prove to be an ideal platform technology for the delivery of drugs to the colon.

A further enhancement would be the development of formulations that would facilitate the delivery of proteins and peptides to the colon. We have developed proprietary techniques that can allow the incorporation of proteins and peptides in aqueous formulations. These are resistant to photolytic degradation as they pass through the gastrointestinal tract and allow the proteins to be delivered in their optimal conformation for biological activity.

References

1. McConnell, E.L., Liu, F., Basit, A.W. Colonic treatments and targets: issues and opportunities. J Drug Target, 17 (5), 335-363, 2009.
2. Tubic-Grozdanis, M., Hilfinger, J.M., Amidon, G.L., Kim, J.S., Kijek, P., Staubach, P., Languth, P. Pharmacokinetics of the CYP 3A substrate simvastatin following administration of delayed versus immediate release oral dosage forms. Pharm. Res, 25(7), 1591-1600, 2008.
3. McConnell, E.L., Basit, A.W., Murdan, S. Colonic antigen administration induces significantly higher humoral levels of colonic and vaginal IgA, and serum IgG compared to oral administration. Vaccine 26, 639-646, 2008.
4. Evans, D.F., Pye, G., Bramley, R., Clark, A.G., Dyson, T.J., Hardcastle, J.D. Measurement of gastrointestinal pH profiles in normal ambulant human subjects. Gut 29 (8), 1035-1041, 1988.
5. McConnell, E.M., Short, M.D., Basit, A.W. An in vivo comparison of intestinal pH and bacteria as physiological trigger mechanisms for colonic targeting in man. J Cont Release, 130, 154-160, 2008.
6. Fadda, H.M., McConnell, E.L., Short, M.D., Basit, A.W. Meal-induced acceleration of tablet transit through the human small intestine. Pharm. Res. 26(2) 356-360, 2009.
7. Ibekwe, V.C., Khela, M.K., Evans, D.F., Basit, A.W. A new concept in colonic drug targeting: a combined pH-responsive and bacterially triggered drug delivery technology. Aliment Pharmacol Ther 28, 911-916, 2008.
8. McConnell, E.L., Fadda, H.M., Basit, A.W. Gut instincts: Explorations in intestinal physiology and drug delivery. Int J Pharm 364, 213-226, 2008.

Dr. Stephen Brown is chief operating officer/director at Encap Drug Delivery.