• The patient is not able to make use of the oral route. This may be the case when the patient has a problem with their gastrointestinal tract, is nauseous or is postoperative (when the patient may be unconscious and not able to take a dosage form orally). Furthermore, several categories of patients, i.e. the very young, the very old or the mentally disturbed, may more easily be treated via the rectal than the oral route.

• The drug under consideration is not well suited for oral administration. This may be the case where oral intake results in gastrointestinal adverse effects, when the drug may be insufficiently stable at the pHs to which it is exposed in the gastrointestinal tract, or when the drug is susceptible to enzymatic degradation in the gastrointestinal tract, or during the first-pass through the liver following absorption. Also, drugs with an unacceptable taste can be administered rectally to the patient. The formulation into suppositories of certain drugs that are candidates for abuse, for instance those likely to be used in suicide, has also been considered.

• Where localized treatment of either the rectum or vagina is required.

Introduction

The rectal route is used in many different therapies, intended either for local or for systemic effect.

Anatomy and physiology of the rectum

Rectal dosage forms are introduced into the body through the anus and are thus brought into contact with the most caudal part of the gastrointestinal tract, i.e. the rectum. Anatomically, the rectum is part of the colon, forming the final 150–200 mm of the gastrointestinal tract.

The rectum can be subdivided into the anal canal and the ampulla, the latter forming approximately 80% of the organ. It is separated from the outside world by a circular muscle, the anus. The rectum can be considered as a hollow organ with a relatively flat wall surface, without villi and with only three major folds – the rectal valves. The rectal wall is composed of epithelium, which is one cell layer thick, and contains cylindrical cells and goblet cells that secrete mucus. A part of the rectal wall and the rectum’s venous drainage are shown in Figure 42.1.

The total volume of mucus is estimated at approximately 3 mL, spread over a total surface area of approximately 300 cm². The pH of the mucous layer is reported as approximately 7.5 (i.e. close to neutral) in adults, and slightly alkaline in most children. Furthermore, there seems to be little buffering capacity. This point is discussed in relation to drug absorption later in this chapter.

Under normal circumstances the rectum is empty and filling provokes a defaecation reflex under voluntary control. Data comparing drug absorption from freshly prepared and aged (and therefore more viscous) suppositories suggest that there is sufficient motility to provoke spreading even of relatively viscous suppositories.

Absorption of drugs from the rectum

Absorption of drug from the rectum is primarily by passive diffusion. Because of inter-individual variations and the venous drainage of the rectum, the bioavailability of drugs following rectal administration is very unpredictable. In general, the rate and extent of drug absorption is lower than the oral route, mainly due to the small surface area for absorption.

Knowledge of the venous drainage from the rectum is important for the understanding of drug absorption. As can be seen from Figure 42.1, there are three separate veins. The lower and middle rectal (inferior and middle haemorrhoidal) veins drain into the interior vena cava, hence this blood goes directly to the heart and into the general circulation. In contrast, the upper rectal (superior haemorrhoidal) vein drains into the portal vein and therefore this blood passes through the liver before reaching the heart.

This means that drug molecules from the rectum can enter the general circulation either directly or by passing through the highly metabolizing liver. Drug absorbed in the middle and lower part of the rectum will pass directly to the general circulation and avoid first-pass metabolism in the liver. Bioavailability from the upper part of the rectum will be low for certain drugs, as much will be metabolized by the liver during its ‘first pass’ and only a proportion of the drug molecules (if they are of the high clearance type) will enter the general circulation intact.

Investigations have shown that avoiding the first-passage through the liver is possible by keeping the dosage form, and thus the released drug, in the lower part of the rectum. Compared to the small intestine, this situation is very favorable as most gastrointestinal veins drain into the portal vein.

Insertion of a suppository into the rectum results in a chain of events leading to the absorption of the drug. This is represented in a simplified scheme in Figure 42.2. Depending on the character of its vehicle (see later in this chapter), a suppository will either dissolve in the rectal fluid or melt on the mucous layer. Since the volume of rectal fluid is so small, dissolution of the complete vehicle will be difficult and requires extra water. Due to osmotic effects (of the dissolving vehicle) water is attracted, with a resultant unpleasant sensation for the patient. Independent of the vehicle type, drugs dissolved in the suppository will diffuse out towards the rectal membranes. Suspended drugs will first need to leave the vehicle (if it is water immiscible) under the influence of either gravity or motility movements and then begin to dissolve in the rectal fluid.

Dissolved drug molecules will have to diffuse through the mucous layer and then into and through the epithelium forming the rectal wall. The process of absorption will be by passive diffusion, as it is throughout the whole gastrointestinal tract for almost all drugs. Active transport processes, as found in the upper regions of the gastrointestinal tract, have not been shown to be present in the rectal area.

For a generalized discussion on drug absorption, the reader is referred to Part 4 of this book. However, some specific points concerning rectal absorption will be discussed here. Box 42.1 provides a summary of the physiological factors that are important in rectal absorption.

The quantity of fluid available for drug dissolution is very small (approximately 3 mL) spread in a layer of approximately 100 µm thick over the organ. Only under non-physiological circumstances is this volume enlarged, e.g. by osmotic attraction by water-soluble vehicles or during diarrhoea. Thus, the dissolution of poorly water-soluble drugs can easily be the slowest step in the absorptive process.

Properties of the rectal fluid, such as composition, viscosity and surface tension, are essentially unknown and have to be estimated from data available for other parts of the gastrointestinal tract. The pH and the buffering capacity of the rectum have been considered earlier in this chapter. The rectum is usually empty, except temporarily when faecal matter arrives from the colon. This material is either expelled or transported back into the colon, depending on voluntary control of the anal sphincter.

The rectal wall may exert pressure on a suppository present in the lumen by two distinct mechanisms. First, the abdominal organs may simply press on to the rectum, especially when the body is in an upright position. This may stimulate spreading and thus promote absorption. The second source of pressure is the motility of the muscles of the rectal wall, which may originate from the normally occurring colonic motor complexes. These are waves of contractions running over the wall of the colon in a caudal direction and are associated with the presence of food residues in the colon.

In contrast with the upper part of the gastrointestinal tract, no esterase or peptidase activity is present in the rectum, resulting in a much greater stability of peptide-like drugs (thus allowing attempts at their delivery by this route). Administration of these compounds using the rectal or vaginal routes has been satisfactory but only if absorption enhancers, such as surfactants are used concomitantly. All types of surfactants seem to be effective, but polyoxyethylene lauryl alcohol ether seems to have the greatest effect. One major drawback of these enhancers, however, is their irritation of the rectal mucosa in the long term. Less irritating enhancers are thus needed to explore this interesting area of drug delivery in greater depth.

Rectal dosage forms

The advantages and limitations of rectal drug administration are outlined in Box 42.2. Several categories of rectal preparations for drug delivery are available: suppositories, rectal capsules, rectal solutions, emulsions and suspensions, powders and tablets for rectal solutions and suspensions, semi-solid rectal preparations, rectal foams and rectal tampons. Of these, suppositories are the most commonly used and these are discussed first, followed by a briefer description of some of the other rectal dosage forms.

Formulation of suppositories

Suppositories are the primary, but not exclusive, dosage form used for the administration of drugs via the rectal route. Suppositories are single-dose preparations with a shape, volume and consistency appropriate for rectal administration. Administration of other suppository-type products (bougies) through other body orifices, e.g. ear, nose and urethra, is rarely undertaken and is not discussed here. Alternative dosage forms for the rectal route are discussed later.

Rectal suppositories are formulated in different shapes and sizes (usually 1–4 g). They contain one or more active substances dispersed or dissolved in a suitable base that may be soluble or dispersible in water or may melt at body temperature. Excipients such as diluents, adsorbents, surface-active agents, lubricants, antimicrobial preservatives and colouring matter may be added if necessary. Their drug content varies widely from less than 0.1% up to almost 40%.