Controlled Drug Release Physiological Considerations in Oral Formulation Development Teaching Notes - Gastrointestinal Tract Characteristic Relevant to Controlled

Drug Release

Physiological Considerations in Oral Formulation Development Gastrointestinal Tract Characteristics Relevant To Controlled Drug Release (CDR) (Functions, pH, Transit Time, and Mucous Membrane) by. Anissa Permatadietha Ardiellaputri (1006661203)

There are many difficulties faced in designing controlled release systems for better absorption and enhanced bioavailability. One of such difficulties is inability to confine the dosage form in the desired area of gastrointestinal tract (GIT).

1.1 GI anatomy and physiological features GI tract is a group of organs joined in a long tube which is divided into several sections, each of that fulfills a specific function. The tract begins with oral cavity, follows pharynx, esophagus, stomach, small intestine and large intestine ending with rectum to anus (Fig 1). Each segment has certain morphological and physiological features, but there is almost a common structure for all parts of GI with muscular walls comprising four different layers: inner mucosa, submucosa, muscularis externa, and the serosa. Seeing as, most of the orally administered drugs display region-specific absorption that could be related to differential drug solubility and stability in different regions of the GI tract as a result of changes in environmental pH, degradation by enzymes present in the lumen of the intestine or interaction with endogenous compounds (Table 1).

1.2 Oral cavity

The principle physiological environment of the oral cavity, in terms of pH, fluid volume and composition, is shaped by the secretion of saliva. Saliva is secreted by three major salivary glands, which are parotid and submaxillary that produce watery secretion, and sublingual glands that produce mainly viscous saliva with limited enzymatic activity.

Controlled Drug Release Physiological Considerations in Oral Formulation Development Teaching Notes - Gastrointestinal Tract Characteristic Relevant to Controlled Drug Release

The main functions of saliva are to lubricate the oral cavity, facilitate swallowing and to prevent demineralisation of the teeth, also allows carbohydrate digestion and regulates oral microbial flora by maintaining the oral pH and enzyme activity.

The volume of saliva constantly available is around 1.1 ml, thus providing a relatively low fluid volume available for drug release from delivery systems compared to the GI tract. Drug permeability through the oral (e.g. buccal/sublingual) mucosa represents another major physiological barrier for oral transmucosal drug delivery (Table 2).

1.3 Esophagus The esophagus is closed at both ends by the upper esophageal sphincter (UES) at the top, and the lower esophageal sphincter (LES) at the bottom. The junction between the esophagus and the stomach is controlled by the lower esophageal sphincter (LES), which remains constricted at all times other than during swallowing and vomiting to prevent the contents of the stomach from entering the esophagus.

1.4 Stomach
The stomach is a J-shaped area of the gastrointestinal (GI) tract that sits in the upper left side

of the abdomen. During the fasting state an interdigestive series of electrical events take place, which cycle through both stomach and intestine every 2 to 3 hours. This is called the interdigestive myloelectric cycle or migrating myloelectric cycle (MMC). MMC divided into following 4 phases (Table 3). After the ingestion of a mixed meal, the pattern of contractions changes from fasted to that of fed state. This is also known as digestive motility pattern and comprises continuous contractions as in phase II of fasted state. These contractions result in reducing the size of food particles (to < 1 mm), which are propelled toward the pylorus in a suspension form.

1.5 Intestine
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Controlled Drug Release Physiological Considerations in Oral Formulation Development Teaching Notes - Gastrointestinal Tract Characteristic Relevant to Controlled Drug Release

It is the longest rout in GI tract (6-7 m long), designed for food digestion and macromolecules assimilation. Intestinal wall is having four layers: mucosa, submucosa, and two outer layers (external muscular layer and serosa). The epithelium, the most exposed part of mucosa, is a glandular epithelium with many goblet cells, that secret mucus, which lubricates the passage of food along and protects it from digestive enzymes.

Villi are folds of the mucosa that increase the surface area of the intestine. It contain a lacteal, a vessel connected to the lymph system that aids in the removal of lipids and tissue fluids. Microvilli are present on the epithelium of a villus and further increase the surface area over which absorption can take place.

1.6 Colon Overall the length of the human colon is approximately 150 cm, but only the last 30 cm is accessible from the anus, since the folding of the splenic flexure resists material entering the transverse colon if rectal delivery of large volume enemas is attempted. Without villi, the absorptive capacity for drugs is therefore markedly reduced but this can be balanced by the long periods of residence in the ascending colon. The major regions of the colon are the right or ascending colon; the transverse colon which is folded in front of the ascending and descending arms by the hepatic and splenic flexures; the descending colon which stores feces and finally the rectum and anus (Fig 6).

1.7 Mucus Layer A translucent and viscid secretion, which forms a thin, continuous gel blanket adherent to mucosal epithelial surface. The mean thickness of this layer varies from about 50-450 m in humans (Fig 7). Composition of the mucus layer, it varies substantially, depending on the species, the anatomical location and pathological states (Table 4).
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Controlled Drug Release Physiological Considerations in Oral Formulation Development Teaching Notes - Gastrointestinal Tract Characteristic Relevant to Controlled Drug Release

The primary function of mucus layer are: protective (resulting particularly from its hydrophobicity and protecting the mucosa from the diffusion of hydrochloric acid from the lumen to the epithelial surface), barrier (constitutes a diffusion barrier for molecules and especially against drug absorption), adhesion (has strong cohesional properties and firmly binds to the epithelial cells surface as a continuous gel layer), and lubrication (mucosal layer keeps the mucosal membrane moist).

1.8 Mucho-adhesive Define the ability of a biological or synthetic material to stick to a mucous membrane, resulting in adhesion of the material to the tissue for a protracted period of time. The formation of non-covalent bonds such as hydrogen bonds and ionic interactions or physical entanglements between the mucus gel layer and polymers provides a good muchoadhesion (Fig 8). The theory behind mucoadhesion is quite complex, though certain elements of the process are clear such as the two main stages. Contact stage, the mucoadhesive polymers must spread over the mucus layer to initiate close contact and to increase the surface area of contact. Consolidation stage, the adhesive joints strengthened and consolidated, leading to a prolonged adhesion A mucoadhesive used in oral drug delivery should meet the following requirements: Adhesiveness with the mucus layer, to provide adequate contact. Ability to swell and allow drug release. Ability to prolong the residence time of the drug at the site of administration. Lack of interaction with the active drug, to allow the drug to be released and absorbed through the mucosal surface. Biocompatibility with the mucosal surface, to avoid cytotoxicity or other irreversible alterations of the mucosal surface. Biodegradability, to allow the physical clearance of the mucosal surface.
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Controlled Drug Release Physiological Considerations in Oral Formulation Development Teaching Notes - Gastrointestinal Tract Characteristic Relevant to Controlled Drug Release

Reference. A. Badhoni, A. Ojha, G. Gnanarajan, P. Kothiyal. (2012). Review on Gastro Retentive Drug Delivery System. The Pharma Innovation, Vol.1, No.8, pp 32-42. C.A. Squier, M.J. Kremer. (2001). Biology of oral mucosa and esophagus. J. Natl. Cancer Inst. Monogr. 29, pp.7-15. Dodou, Dimitra et al,. (2005). Mucoadhesives in the gastrointestinal tract: revisiting the literature for novel applications. European Journal of Pharmaceutics and Biopharmaceutics 60, pp.116 G. Lafitte et al., (2008). 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. Woodhead Publishing Limited: England,
pp. 26-47. Madhav, N.V., et al., Orotransmucosal drug delivery systems: a review. J Control Release, 2009. 140(1): p. 2-11.

McConnell, E. L.; Fadda, H. M. & Basit, A. W. (2008). Gut instincts: explorations in intestinal physiology and drug delivery. Int J Pharm, Vol. 364, No. 2, pp. 213-226, ISSN: 03785173. SVKMs NMIMS. (2002). Muchoahesive drug delivery systems. School of Pharmacy and Technology Management, Mumbai, pp. 6-47 Wilson CG. (2002). Colon drug delivery. In: Rathbone M, Hadgraft J, Roberts M (eds) Modified release drug delivery technology. Swarbrick J (ed) Drugs and the pharmaceutical sciences series. Marcel Dekker, New York, pp 217222.

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Controlled Drug Release Physiological Considerations in Oral Formulation Development Teaching Notes - Gastrointestinal Tract Characteristic Relevant to Controlled Drug Release Table 1. GI Tract Summary

Oral Cavity

Esophagus The surface of the esophagus is a squamous epithelium with a protective function as in the mouth and has few if any glands. To produce a peristaltic wave which forces a ball of food (called a bolus) down and through the LES into the stomach.

Stomach (Gastric) Anatomy

Small Intestine

Colon (Large intestine) Compared to the small intestine it is shorter 1.5 m rather than 5 m and the lumen is wider, without the extra surface area provided by the folds of Kekring and the villi.

Comprises the lips, cheek, tongue, hard palate, soft palate and floor of the mouth (Fig 2).

Divided into 3 regions; fundus, body, and antrum pyrolus (Fig 4)

Consist of duodenum, jejunum and ileum

Function To begin the mechanical and chemical digestion of food and to start it on its journey through the gastrointestinal tract. The lining of the oral cavity is referred to as the oral mucosa, and includes the buccal, sublingual, gingival, palatal and labial mucosa (Fig 3). 5.2 - 6.8 Food reservoir, absorption, mucus secretion, gastric juice secretion, churning food, production of intrinsic factor General description Just before entering the stomach, the esophagus passes through the diaphragm. The stomach is lined by a secretory epithelium which is covered by a thick, relatively impermeable layer of gastric mucus. pH 5-6 D 4.6 - 6 Length and Diameter (cm) D 20 15 25 5 Transit time (h) 0.25 - 3 D 1.2 - 3.5 J 6.3 - 7.3 J 300 5 J I 7.6 I 300 I 3.5 150 4 - 20
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The small intestine is the main site of digestion and absorption in the body and most of this activity takes place in the duodenum.

To reabsorb water and electrolytes and also degradates food biologically.

The small intestine is adapted to absorb substances across the intestinal mucosa with 200 m2 surface area and 5 million of villi (Fig 5)

Here is the home of large concentration of bacterial species, because of near neutral pH.

7.5 - 8

15 - 20 Short

10

25 - 40

2.5

Very short

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Controlled Drug Release Physiological Considerations in Oral Formulation Development Teaching Notes - Gastrointestinal Tract Characteristic Relevant to Controlled Drug Release

(10 - 14 s)

1-2

1-10

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Controlled Drug Release Physiological Considerations in Oral Formulation Development

Teaching Notes - Gastrointestinal Tract Characteristic Relevant to Controlled Drug Release

Table 2. Anatomical and physiological features of the human GI tract

Tissue Buccal Sublingual Gingival Palatal

Structure NK NK K K

Thickness (m) 500 - 600 100 - 200 200 250

Turnover time (days) 5- 7 20 24

Surface area (cm2) 26.5 2.9 26.5 4.2 20.1 + 1.9

Permeability Intermediate Verry good Poor Poor

Residence time Intermediate Poor Intermediate Very good

NK is non-keratinized tissue (more permeable to water), K is keratinized tissue (relatively impermeable to water) Table 3. The migrating myoelectric complex (MMC)

Phase I (basal phase) Phase II (preburst phase) Phase III (burst phase)

It is a quiescent period lasting from 30 to 60 minutes with no contractions. It consists of intermittent contractions that gradually increase in intensity as the phase progresses, and it lasts about 20 to 40 minutes. Gastric discharge of fluid and very small particles begins later in this phase. This is a short period of intense distal and proximal gastric contractions (45 contractions per minute) lasting about 10 to 20 minutes; these contractions, also known as house-keeper wave, sweep gastric contents down the small Intestine This is a short transitory period of about 0 to 5 minutes, and the contractions dissipate between the last part of phase III and quiescence of phase I.
Table 4. General composition of mucus

Phase IV

Components Water Glycoprotein and lipids Mineral salts

% Amounts 95 0.5 - 3.0 1.0

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Controlled Drug Release Physiological Considerations in Oral Formulation Development

Teaching Notes - Gastrointestinal Tract Characteristic Relevant to Controlled Drug Release

Free protein

0.5 - 1.0

(Source. School of Pharmacy and Technology Management - Mumbai, 2002)

Figure 1. Anatomy of the human gastrointestinal tract (Source. McConnell et al., 2008)

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Controlled Drug Release Physiological Considerations in Oral Formulation Development

Teaching Notes - Gastrointestinal Tract Characteristic Relevant to Controlled Drug Release

Figure 2. Schematic representation of the different linings of mucosa in mouth (Source. Squire and Kremer, 2001)

Figure 3. (right) Buccal routes of delivery, (left) Schematic diagram of buccal mucosa (Source. Wilson, CG., 2011)

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Controlled Drug Release Physiological Considerations in Oral Formulation Development

Teaching Notes - Gastrointestinal Tract Characteristic Relevant to Controlled Drug Release

Figure 4. Stomach (Source. Badoni et al., 2012)

Figure 5. General structure of the intestinal wall (Source. http://en.wikipedia.org )

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Controlled Drug Release Physiological Considerations in Oral Formulation Development

Teaching Notes - Gastrointestinal Tract Characteristic Relevant to Controlled Drug Release

Figure 6. Schematic of colon transit (Source. Wilson CG, 2002)

Figure 7. Thickness of the entire mucus layer in the gastrointestinal tract (Source. Lafitte et al, 2008)

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Controlled Drug Release Physiological Considerations in Oral Formulation Development

Teaching Notes - Gastrointestinal Tract Characteristic Relevant to Controlled Drug Release

Figure 8. The cell layer in contact with mucosal layer and lumen (right), muchoadhesive mechanism (left) (Source. School of Pharmacy and Technology Management - Mumbai, 2002).

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