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«Abstract Oral drug delivery remains the mainstay of patient treatment although the candidate drugs of the new millennium are becoming increasingly ...»

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Chapter 2

The Organization of the Gut and the Oral

Absorption of Drugs: Anatomical, Biological

and Physiological Considerations in Oral

Formulation Development

Clive G. Wilson

Abstract

Oral drug delivery remains the mainstay of patient treatment although

the candidate drugs of the new millennium are becoming increasingly difficult to

formulate for good systemic absorption. The area of oral delivery therefore repre-

sents an important area of innovation for pharmaceutical formulation including modulating solubility, exploiting windows of absorption and increasing bioavail- ability in a robust manner to attempt a more predictable outcome.

In order to deliver an active pharmaceutical ingredient to facilitate systemic exposure, the drug must be presented in a dosage unit that contains an accurate dose of a specified active pharmaceutical ingredient which remains intact to the point of

administration. On dosing, the pharmaceutical phase must be undone appropriately:

the drug must be liberated at the correct rate, escaping degradation and metabolism and reach sufficient concentrations in the target tissue. The exposition of the phar- macist’s art is then completed in the lumen of the gut and therefore an understand- ing the organization of the organ system, at a macroscopic level, is of great relevance.

In this chapter, the general integration of anatomy and motility with regard to the interaction of the dosage form will be considered. The biochemical and biophysical elements of absorption of the drug substance will not dealt with in detail in this chapter but by other books in this series.

2.1 Background The gut is primarily designed for the absorption of nutrients which are presented in a complex and varied matrix comprising protein, carbohydrate, fat, minerals and vitamins in different proportions. The components must be extracted by batch C.G. Wilson (*) Institute of Pharmacy & Biomedical Sciences, University of Strathclyde, Glasgow, Scotland, UK e-mail: c.g.wilson@strath.ac.uk 27 C.G. Wilson and P.J. Crowley (eds.), Controlled Release in Oral Drug Delivery, Advances in Delivery Science and Technology, DOI 10.1007/978-1-4614-1004-1_2, © Controlled Release Society 2011 28 C.G. Wilson processing, which involves fluid secretion of liquids providing an optimum milieu for the enzymes to work in a controlled sequence. If a foodstuff is energy rich but difficult to process, motility must be slowed to allow presentation at an appropriate rate with mixing patterns predominating over propulsive activity during digestion.

This has to be achieved in the proximal regions of the gut, particularly the jejunum and ileum. At the end of the ileum, secretion is lower and assimilation is the main physiological activity. Finally in the colon water, salts and remaining nutrients must be extracted to conserve the ionic balance of cellular fluids.

The gut of mammals evolved into specialist herbivores, fairly inefficient carnivores and balanced omnivores who were able to take advantage of high calorific densities in flesh and nuts by processing in the fore-gut and to extract significant nutrients from pulverized and enzyme treated vegetables using bacterial populations of the hind-gut. This diversity required a range of enzymes to be available and control of exposure to allow efficient processing. The early diet contained seeds from berries which were poisonous, and nature has preserved protective functions throughout evolution of the mammals to man. Thus we recognize poisonous alkaloids as bitter by taste and have several protective mechanisms to avoid toxin exposure including, in the last resort, vomiting.

Our earliest medicines were derived from plant stuff, and of varied potency. The poor analytical techniques hampered quality control and thus the medicines were dangerous to use. The replacement of plant extracts by chemically synthesized drugs, which were obtained at high purity, and were single entities, made the materials easier to use as pharmacons. Doses of the chemically derived drugs could be relatively large (those which were more potent and hard to detect were still commonly referred to by the public as poisons) and although knowledge of the importance of hepatic metabolism and renal excretion was well established 60 years ago, we knew little of more subtle defense mechanisms. As pharmacological knowledge was refined and medicines became more potent, scientists became aware of protection at the prehepatic, intestinal level including efflux and drug metabolizing systems, which attempt to avoid exposure to xenobiotic materials.

These comments emphasize a couple of important principles which must be always considered. First, the gut is designed to process food and some component of the drug’s absorption profile is likely to be affected by the sequence of meals.

Second, if the drug concentration is sufficiently low, it may be processed by the protective guardians that reduce exposure.

The basic design of the gut is a long muscular tube with specialized areas for digestion and storage. The plan of the gut is illustrated in Fig. 2.1. As shown, the gut is a long tube supplied by arteries and drained by veins and a lymphatic trunk, all of which are supported in a mesentery, which are folds of the peritoneum attached to the abdominal wall. The small intestine is the major site of nutrient and anutrient absorption. Although uptake occurs in stomach tissue, the contribution of direct gastric absorption to bioavailability is small, and slow delivery into the upper gastrointestinal tract is far more important.





In adults the length of the gut is approximately 7 m and the large intestine 1.5 m in length. Differences in length are apparent at death, when inherent tone is lost.

2 The Organization of the Gut and the Oral Absorption of Drugs… 29 Fig. 2.1 Illustration of the plan of the gastrointestinal tract showing arrangement of mucosa and muscles Fig. 2.2 The growth of the human intestine. Measurements made at necropsy. From data of [1] A study of 1,010 small intestines at autopsy by Weaver, Austin and Cole was used to construct the data shown in Fig. 2.2 describing the growth of the small intestine to adulthood [1].

Functionally, the gut is divided into a preparative and primary storage region (mouth and stomach), a secretory and absorptive region (the midgut), a water reclamation system (ascending colon) and finally a waste-product storage system (the descending and sigmoid colon). The whole structure loosely fills the abdomen, with the esophageo-gastric junction just below the diaphragm. The pyloric sphincter area and the cardia provide points of attachment and help fix the ends of the stomach;

however, when posture changes or the stomach is filled with food, organs such as the stomach can change shape and therefore their position in the abdomen. This generates potential differences in emptying patterns in supine, prone and upright positions.

30 C.G. Wilson

2.2 Buccal Delivery

The first port of call to consider in oral drug delivery is the buccal cavity, and buccal delivery remains of interest for a small range of drugs used for cardiovascular control, smoking cessation and pain control. The primary function of the mouth is guarding of the gut by moistening the food to a soft, shaped bolus: the mucosa must therefore be tough and act as protective layer rather than an absorptive membrane.

In areas of maximum abrasive stress, the mucosa will become keratinized. Prolonged exposure to tobacco smoke produces excess keratinization, as does poor dental hygiene. The water inlet channels, which hydrate the digesta, must have high capacity and react instantly: this is the function of the three main sets of glands assisted by minor glands.

Saliva is a viscous, watery fluid which is hypo-osmotic compared to plasma. One to two liters are discharged every day into the mouth and the composition and pH varies with the rate of secretion as illustrated in Fig. 2.3. The pH as shown varies from 7.4 and 6.2; however, the bacterial action can create local pockets where the pH falls below 5 and the tooth enamel starts to demineralize. Saliva acts as a diluent and the bicarbonate component raises pH. In addition, bacteria in the dental plaque metabolize components in saliva and raise the local pH: when this protection is lost a condition known as xerostomia, a diffuse and severe caries results.

The saliva produced by the glands varies. “Serous” saliva contains more protein particularly amylase, is watery and subserves the sense of taste by beginning digestion; the saliva stream also needs to produce mucins to resist drying at rest and to lubricate the structures to allow speech. Taste sensation in the tongue, palate and upper esophagus provide an input to the brain allowing involuntary responses such as gagging, retching and excess salivation to remove material. In the dog, the mouth is also used for thermo-regulation.

The classical routes of buccal delivery are summarized in Fig. 2.4 and specific examples are given in Chap. 16. The access to saliva, the variation in patterns of keratinization and squamous cell thickness, and the abrasive forces associated with speech and chewing are important factors in variation in performance.

Fig. 2.3 The change in saliva pH and osmolality with increasing flow 2 The Organization of the Gut and the Oral Absorption of Drugs… 31 Fig. 2.4 Buccal routes of delivery The mucosa or inner lining of the mouth is divided into four zones. The first part of the gut has a lining of the squamous epithelium which extends from the mouth to the stomach. The many layers of cells are analogous to dermal tissue and drugs will only penetrate if residence is prolonged. The exception is the tissue under the tongue, as used in sublingual delivery, where the epithelium is thin. The vessels of the face drain directly to the heart and thus avoid the hepatic portal system, which provides a number of obvious advantages.

An important property is mouth feel and taste, since the released drug will be in intimate contact with the tongue. Variability in performance may be associated with changes in saliva flow and movements of the mouth when talking. The marked variation in the thickness and keratinization of the epithelial lining is also exaggerated in rodents, and pig and dog are more suitable models for human buccal tissue.

The characteristics of buccal delivery are summarized in Fig. 2.5.

2.3 The Esophagus

The esophagus is approximately 40 cm long in the adult, passing through the diaphragm at approximately 38 cm. The surface of the esophagus is a squamous epithelium with a protective function as in the mouth and has few if any glands. The morphology changes sharply at the junction with the stomach into secretory epithelium.

After the dosage form leaves the buccal cavity, movement through the esophagus is normally complete within 10 s. The voluntary maneuver is handed over to a complex autonomic sequence in the cricopharynx, followed after swallowing by short secondary peristaltic waves, which serves to attempt to clear the esophagus.

The efficiency of clearance may be influenced by several factors, including the outside surface of the dosage form, the age of the subject and pre-existing disease.

Conditions such as type 1 diabetes reduce the amplitude of peristaltic waves and further exacerbate the problems of esophageal clearance, particularly for solid swallows [2]. The elderly often report problems in attempting to swallow 32 C.G. Wilson Fig. 2.5 General plan of buccal physiology. Note that the tissues at the top of the mouth are much less permeable than the sublingual area. Buccal systems are used along the gum margin and cheeks and are generally sustained delivery systems, whereas sublingual systems are fast release, as they cannot be anchored large objects, in part influenced by previous unsuccessful attempts but influenced by the increased stiffness and lower muscle compliance. The elderly have little “swallowing reserve” but experience fewer problems in clearing a liquid bolus compared to a solid mass. It is a common practice in nursing homes to crush medications for dysphagic patients, despite the fact that controlled release formulations are specifically designed not to be damaged prior to ingestion. Although, large tablets are commonly identified as problematic, small flat and buoyant dosage forms are particularly likely to cause problems in the elderly because of the inability to complete the swallowing maneuver.

The coating of tablets to identify the product, to protect the integrity of the dose or to mask bitterness or appearance is a principal activity in the manufacture of oral formulations. The film coat can be functional as for enteric release products or esthetically pleasing and the mouth feel emphasizes the “swallowability” of the product. Channer and Virjee (1985) showed that the clearance of plain, sugar-coated, enteric-coated and film coated tablets in 34 patients was strongly influenced by coating and by posture [3]. The authors reported 100% clearance of film coated tablets in 13 s; for the plain uncoated formulation full clearance was observed in only 60% of subjects at this time. The findings also confirmed their earlier report that oval coated tablets showed the fastest esophageal transit in the erect position, even when swallowed with low volumes of water [4]. A recent interesting article nicely illustrates the importance of shape factors and organoleptic issues on the swallowing of large dosage forms [5].

2 The Organization of the Gut and the Oral Absorption of Drugs… 33

2.4 The Stomach

The gut contains two reservoirs, in which the tube structure of the gut is modified to accommodate gut contents for longer periods of time. The first, the stomach, allows a regulated supply of calories to the small intestine by control of rate of emptying according to food type. The arrangement of the human gut is illustrated in Fig. 2.6, with the stomach sitting below the diaphragm, nestled by lobes of the liver (removed from the illustration) and the greater curvature of the stomach placed just above the transverse colon. The position of the cardia and the pyloric sphincter are usually fixed but as the stomach is filled, the fundus changes shape by receptive relaxation and on lying down, the proximal stomach falls into the abdomen cavity remaining lower than the distal stomach.



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