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GI Tract Characteristics Relevant To Controlled Drug Release (CDR) Group A

Controlled Drug Released

Universitas Indonesia 1

Physiological Considerations in Oral Formulation Development

GASTROINTESTINAL TRACT CHARACTERISTICS RELEVANT TO

CONTROLLED DRUG RELEASE (CDR)

(FUNCTIONS, PH, TRANSIT TIME, AND MUCOUS MEMBRANE)

Anissa Permatadietha Ardiellaputri1, 1006661203, Group A

1Bioprocess Technology, Department of Chemical Engineering

Universitas Indonesia

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.

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 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 μm in humans (Fig 7).

Composition of the mucus layer, it varies substantially, depending on the species, the anatomical location and

pathological states (Table 4).

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.

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.1–16

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: 0378-5173.

SVKM‟s 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 217–222.




APPENDIX

Table 1. GI Tract Summary

Oral Cavity Esophagus Stomach (Gastric) Small Intestine Colon (Large intestine)

Anatomy

Comprises the lips, cheek,

tongue, hard palate, soft

palate and floor of the mouth

(Fig 2).

The surface of the

esophagus is a squamous

epithelium with a protective

function as in the mouth and

has few if any glands.

Divided into 3 regions; fundus,

body, and antrum pyrolus (Fig 4)

Consist of duodenum, jejunum and

ileum

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.

Function

To begin the mechanical and

chemical digestion of food and

to start it on its journey

through the gastrointestinal

tract.

To produce a peristaltic

wave which forces a ball of

food (called a bolus) down

and through the LES into

the stomach.

Food reservoir, absorption,

mucus secretion, gastric juice

secretion, churning food,

production of intrinsic factor

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.

General description

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).

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.

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.

pH

5.2 - 6.8 5 - 6 1.2 - 3.5 D J I

7.5 - 8 4.6 - 6 6.3 - 7.3 7.6

Length and Diameter (cm)

15 - 20 10 25 - 40 2.5 20 15 D J I

150 5 25 5 300 5 300 3.5

Transit time (h)

Short Very short

(10 - 14 s) 0.25 - 3

D J I 4 - 20

1-2 - 1-10

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

Tissue Structure Thickness

(μm)

Turnover

time (days)

Surface area

(cm2)

Permeability Residence

time

Buccal NK 500 - 600 5- 7 26.5 ± 2.9 Intermediate Intermediate

Sublingual NK 100 - 200 20 26.5 ± 4.2 Verry good Poor

Gingival K 200 - - Poor Intermediate

Palatal K 250 24 20.1 + 1.9 Poor Very good

NK is non-keratinized tissue (more permeable to water), K is keratinized tissue (relatively impermeable to water)



Universitas Indonesia 5 5

APPENDIX

APPENDIX APPENDIX

Table 3. The migrating myoelectric complex (MMC)

Phase I (basal phase)

It is a quiescent period lasting from 30 to 60 minutes with no contractions.

Phase II

(preburst phase)

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.

Phase III (burst phase)

This is a short period of intense distal and proximal gastric contractions (4–5 contractions per

minute) lasting about 10 to 20 minutes; these contractions, also known as „„house-keeper

wave,‟‟ sweep gastric contents down the small Intestine

Phase IV 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

Components % Amounts

Water 95

Glycoprotein and lipids 0.5 - 3.0

Mineral salts 1.0

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)




APPENDIX

APPENDIX APPENDIX

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)

Figure 4. Stomach

(Source. Badoni et al., 2012)

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




APPENDIX

APPENDIX APPENDIX

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)

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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