Physiological Consideration in Oral Formulation Development Gastrointestinal Tract (GIT) in Relevance with Controlled Drug Release.pdf

7/29/2019 Physiological Consideration in Oral Formulation Development Gastrointestinal Tract (GIT) in Relevance with Controlled Drug Release.pdf

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Teaching Note: Controlled Drug Release Technology Class 2013

1 Farah Fauzia (0906640791) Bioprocess Engineering Universitas Indonesia

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 ofadministration; the most common for controlled-release: oral administration.

The efficiency will be greatly affected by the physiology of gastrointestinaltract (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 waste-

product 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 ofmucosa; 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 releaseespecially from hydrophilic polymer based.

Esophagus [1, 3]

Approximately 40 cm (in adult); has a surface of squamous epithelium with aprotective function.

Transit time taking only around 10-14 s; drug shape factors affecting it.


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Stomach (Gastric) [1, 3-5]

First GIT organ located in abdomen (Figure 7); one of GIT reservoirs; digestfood 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; secretebicarbonate 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 tofood 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

min2 hour, with half emptying time ~80.5 min

Intestine [1, 4, 5]

6-7 m long (longest route); designed for food digestion and macromoleculesassimilation; 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 indifferent 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 neutralpH; 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 directadhesion to the epithelial cells and retards the transport of active molecules

Potential for drug and nutrient absorption through adhesion mechanism


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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 ofmucoadhesive 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 mucoadhesivesystem; complex process; potential for improving controlled-release

Mucoadhesives polymer: (1) first generation: hydrophilic, non-specific, pH-dependent. 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 andControlled 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.


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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]


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Figure 4 Buccal routes of delivery [1] Figure 5 Schematic diagram of buccal mucosa [2]

Figure 6 The change in saliva pH and Figure 7 Diagram of the features of the GIT

osmolality with increasing flow [1] showing location in the abdomen [1]

Figure 8 Key gastric features [1]


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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]


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Figure 12 Schematic of colon transit [1]

Figure 13 Structure and composition Figure 14 Thickness of the entire mucus layer

of a basic unit of mucin [7] in the GIT [6]

Figure 15 Table of comparison of different mucosa [2]

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Physiological Consideration in Oral Formulation Development Gastrointestinal Tract (GIT) in Relevance with Controlled Drug Release.pdf