Drug Targeting Organ-Specific Strategies

168 6 A Practical Approach in the Design of Colon-specific Drug Delivery Systems
6.5 Concluding Remarks
All the methods for colon-specific drug delivery presented in this overview are more or less
susceptible to changes in the physiological environment (diet, disease state, medication, etc.).
This may affect reliability and reproducibility of the delivery systems. However, most of the
systems described have already been investigated in vivo with regard to colon specificity.
Methods such as planar γ-scintigraphy [86,97,107] and three-dimensional magnetic marker
monitoring [108,109] appear to be the methods of choice for dynamic visualization of the
dosage form in the GI tract and the determination of the location and time of onset of drug
release. In animal models, the measurement of blood and intestinal tissue concentrations of
the perorally administered drug in order to quantify the reduction in the systemic exposure,
is an additional approach [110]. However, most formulations are tested in healthy humans or
animals in spite of the fact, that pathological conditions such as inflammatory bowel disease
may have a significant influence on gut physiology.As yet, little is known regarding the effect
of disease states on the intestinal transit time, GI tract motility, luminal pH, intra-luminal
colonic pressure and composition of colonic microflora. It appears that time-controlled drug
release systems, which rely on a constant transit time through the small intestine, are the most
promising colon-specific delivery systems, as this transit time is only marginally influenced by
pathological events in the GI tract. pH-controlled systems are reliable only if there is a significant
difference in the luminal pH between the small and the large intestine. Under physiological
conditions this pH difference is often too small. In certain pathological conditions
such as inflammatory bowel disease however, a significant decrease in pH in the affected GI
tract regions may be observed, and this has led to the development of novel pH-controlled
delivery systems. Enzyme-controlled delivery systems are dependent on the activity of the
microbial enzymes in the large intestine, which are susceptible to many environmental factors,
particularly diet and medication. The reliability of pressure-controlled delivery systems
is expected to be highly dependent on variations in intestinal peristalsis despite promising in
vivo data.
References
[1] Simon GL, Gorbach SL, Gastroenterology 1984, 86, 174–193.
[2] Drasar BS, Hill MJ, In: Human Intestinal Flora, pp. 103-123. Academic Press, London, 1974.
[3] Bragger JL, Yazaki E, Evans DF, Pharm. Res. 1997, 14 (11 Suppl.), S656–S657.
[4] Mitsuoka T, Intestinal Bacteria and Health. Harcourt Brace Jovanovich, Tokyo, 1978.
[5] Evans DF, Pye G, Bramley R, Clark AG, Dyson TJ, Hardcastle JD, Gut 1988, 29, 1035–1041.
[6] Shameem M, Katori N, Aoyagi N, Kojima S, Pharm. Res. 1995, 12, 1049–1054.
[7] Haeberlin B, Friend DR, In: Oral Colon-Specific Drug Delivery (Ed. Friend DR), pp. 1–43. CRC
Press, Boca Raton, 1992.
[8] Zeitz M, Digestion 1997, 58 (Suppl. 1), 59–61.
[9] Bhatti MA, Hodgson HJF, Int. J. Exp. Pathol. 1995, 76, 309–315.
[10] Morteau O, Bueno L, Gastroenterol. Clin. Biol. 1995, 19, 204–214.
[11] Warren BF, Watkins PE, J. Pathol. 1994, 172, 313–316.
[12] Pories SE, Ramchurren N, Summerhayes I, Steele G, Arch. Surg. 1993, 128, 647–653.
[13] Fix JA, J. Pharm. Sci. 1996, 85, 1282–1285.
[14] Ashford M, Fell JT, Attwood D, Woodhead PJ, Int. J. Pharm. 1993, 91, 241–145.
[15] Ashford M, Fell JT, Attwood D, Sharma H, Woodhead PJ, Int. J. Pharm. 1993, 95, 193–199.
[16] Dew MJ, Ryder REJ, Evans N, Evans BK, Rhodes J, Br. J. Clin. Pharmacol. 1983, 16, 185–187.