Teaching Note: Controlled Drug Release Technology Class 2013

Physiological Consideration in Oral Formulation Development

Gastrointestinal Tract (GIT) in Relevance with Controlled Drug Release: Characteristics, Function, pH, Transit Time, Mucus Membrane Farah Fauzia (0906640791) The rate and extent of absorption of drugs is highly depending on the route of administration; the most common for controlled-release: oral administration. The efficiency will be greatly affected by the physiology of gastrointestinal tract (GIT).

GIT Basic Characteristics Long muscular tube (Figure 1); specialized areas for digest and storage [1]. Designed for the absorption of nutrients; involves fluid secretion to ensure optimum environment for enzymes to work [1]. GIT dividing: preparative & primary storage region (mouth & stomach); secretory & absorptive region (mid-gut); water reclamation system and wasteproduct storage system (colon) [1] (summary: Figure 2). Mouth (Oral Cavity) [1, 2] Guard the GIT by moistening the food. Comprises the lips, cheek, tongue, hard palate, soft palate, and floor of the mouth (Figure 3); The lining is oral mucosa, includes buccal, sublingual, gingival, palatal, and labial mucosa. Overall route is in Figure 4. Potential for drug delivery; advantages: bypass the first pass effect of GIT, avoid pre-systemic elimination in GIT; not using GIT route; Oral mucosal drug delivery: 1) local delivery, 2) systemic delivery: by buccal (immobile surface; Figure 5) or sublingual mucosa (more permeable). Roles in drug delivery: pH, fluid volume, enzyme activity, permeability of mucosa; affected by saliva secretion. Saliva: viscous, watery fluid; lubricate oral cavity, facilitate swallowing, prevent teeth demineralization; 1-2 L discharged per day; composition and pH varies with the rate of secretion (Figure 6); favorable for drug release especially from hydrophilic polymer based. Esophagus [1, 3] Approximately 40 cm (in adult); has a surface of squamous epithelium with a protective function. Transit time taking only around 10-14 s; drug shape factors affecting it.

1 Farah Fauzia (0906640791) Bioprocess Engineering Universitas Indonesia

Teaching Note: Controlled Drug Release Technology Class 2013

Stomach (Gastric) [1, 3-5] First GIT organ located in abdomen (Figure 7); one of GIT reservoirs; digest food and deliver chime to the intestine. Volume swells to accommodate meal without mixing; capacity up to 1.5 L, 50-100 ml in fasted state; capacity can affect the absorption. Lined by epithelium covered by impermeable gastric mucus layer; secrete bicarbonate and create pH gradient (key features: Figure 7). Varied pH, with 1 2.5, generally similar as HCl solution of 1, 1.2, or 1.8; favorable for ionized drugs; co-administration of drug with water or food can affect the pH; acidic pH kill most microbes. Supply calories to small intestine by controlling rate of emptying according to food type; classification: (1) liquid, (2) digestible solids, (3) indigestible solids; summary in Figure 9; liquid emptied first, digestible solids are next, and indigestible solids are emptied later in the fasted state through migration myoelectric complex (MMC) process (Figure 10); varied emptying time, 5 min 2 hour, with half emptying time ~80.5 min Intestine [1, 4, 5] 6-7 m long (longest route); designed for food digestion and macromolecules assimilation; primary area for drug absorption (10-20 times of colon). Divided into three parts: duodenum (20-30 cm); jejunum (2.5 m); and ileum (3.5 m); has mucosa with great surface area (~200 m2 in adult), with 5 million of villi which is covered by epithelium (Figure 11). Varied transit time (0.5 9.5 hour); pH range 6.15 7.35; 6.8 7.88 in different region; varied microflora resembles both in stomach and colon). Is the primary area of the GIT for drug absorption (10-20 times of colon). Colon [1, 4, 5] Large intestine; 1.5 m long; a reservoir for reabsorption of water Environment differs along its length (Figure 12); transit time is varied, typically in a range of 6 to 32 hour; pH range of neutral Home to a large concentration of bacterial species, because of near neutral pH; offer opportunity for targeted delivery (example: some polysaccharides which are colon-microflora-biodegradable) GIT Mucus Layer [2, 6, 7] First membrane barriers in GIT to be encountered; constitutes of water, mineral salts, free proteins, lipids, and DNA. Viscoelastic and translucent; secreted throughout the GIT; prevents direct adhesion to the epithelial cells and retards the transport of active molecules Potential for drug and nutrient absorption through adhesion mechanism

2 Farah Fauzia (0906640791) Bioprocess Engineering Universitas Indonesia

Teaching Note: Controlled Drug Release Technology Class 2013

Mucin molecules Key macromolecular of mucus; large glycoprotein molecule (Figure 13) Govern viscoelastic properties of mucus; negatively charged, hydrophobic, varied structure & arrangement: concentration, pH and temperature dependent Serve as delivery vehicle as lubricant; play major role in adhesion of mucoadhesive drug delivery systems Mucus layer properties Viscoelastic: two types of mucus; different thickness (Figure 14). Hydrophobic: protect epithelium from proton of gastric liquid. Varied acidity: pH gradient across the mucus to ensure neutral pH. Mucosa physiological characteristics are varied (Figure 15). Mucoadhesion Attachment of a carrier to the mucus in bioadhesion; via mucoadhesive system; complex process; potential for improving controlled-release Mucoadhesives polymer: (1) first generation: hydrophilic, non-specific, pHdependent. Examples: chitosan, alginate, CMC; (2) second generation: able to target specific mucosal surface. Examples: lecithin. References 1. Wilson, C.G., The Organization of the Gut and the Oral Absorption of Drugs: Anatomical, Biological and Physiological Considerations in Oral Formulation Development, in Controlled Release in Oral Drug Delivery, C.G. Wilson and P.J. Crowley, Editors. 2011, Springer Science+Business Media: New York. p. 27-48. 2. Patel, V.F., F. Liu, and M.B. Brown, Advances in oral transmucosal drug delivery. J Control Release, 2011. 153(2): p. 106-16. 3. Hejazi, R. and M. Amiji, Chitosan-based gastrointestinal delivery systems. Journal of Controlled Release, 2003. 89(2): p. 151-165. 4. Cook, M.T., et al., Microencapsulation of probiotics for gastrointestinal delivery. J Control Release, 2012. 162(1): p. 56-67. 5. Sinha, V.R. and R. Kumria, Microbially triggered drug delivery to the colon. European Journal of Pharmaceutical Scienes, 2003. 18: p. 3-18. 6. Lafitte, G., Structure of the gastorintestinal mucus layer and implications for controlled release and delivery of functional food ingredients, in Delivery and Controlled Release Bioactives in Foods and Nutraceuticals, N. Garti, Editor 2008, Woodhead Publishing Limited: England. p. 26-47. 7. Madhav, N.V., et al., Orotransmucosal drug delivery systems: a review. J Control Release, 2009. 140(1): p. 2-11.

3 Farah Fauzia (0906640791) Bioprocess Engineering Universitas Indonesia

Teaching Note: Controlled Drug Release Technology Class 2013

Appendix

Figure 1 Illustration of the plan of the GIT showing arrangement of mucosa and muscles [1]

Figure 2 Characteristic of the GIT, showing the pH at the different parts [4]

Figure 3 Schematic representation of the different linings of mucosa in mouth [2]

Teaching Note: Controlled Drug Release Technology Class 2013

Figure 4 Buccal routes of delivery [1]

Figure 5 Schematic diagram of buccal mucosa [2]

Figure 6 The change in saliva pH and osmolality with increasing flow [1]

Figure 7 Diagram of the features of the GIT showing location in the abdomen [1]

Figure 8 Key gastric features [1]

Teaching Note: Controlled Drug Release Technology Class 2013

Figure 9 Emptying of tablet components with a meal. Dissolving drug will follow the liquid emptying curve [1]

Figure 10 The migrating myoelectric complex (MMC) or housekeeper sequence [1]

Figure 11 Structure of intestinal villus [1]

Teaching Note: Controlled Drug Release Technology Class 2013

Figure 12 Schematic of colon transit [1]

Figure 13 Structure and composition of a basic unit of mucin [7]

Figure 14 Thickness of the entire mucus layer in the GIT [6]

Figure 15 Table of comparison of different mucosa [2]