References 390

This chapter provides basic information on the physicochemical mechanisms of drug absorption and how the processes of absorption are affected by the physicochemical properties of the drug and its formulation, by the interaction of the drug with the aqueous phase and by the nature of the membrane. Oral absorption is discussed in some detail and the influence of the following in determining bioavailability should become clear:

• The extent and rate of dissolution of the drug

• The rate of gastric emptying

• The site of absorption

The pH of the contents of the gastrointestinal tract (GI tract, gut) and the effect of pH on the ionisation of the drug (discussed also in section 5.2.4) are crucial.

The application of the so-called pH-partition hypothesis and its limitations should be understood, so that the effects of the nature of the drug and the medium on absorption can be assessed. In the case of the oral route, the effect of concomitant medication (cimetidine, ranitidine, antacids, etc.), which might alter the pH of the gut contents, can be approximated by calculating the change in the drug ionisation.

Many routes of entry into the body are used for both systemic and local action of drugs. We deal here with the essentials of formulations used by the following routes:

• Buccal and sublingual

• Subcutaneous and intramuscular

• Topical or transdermal

• Respiratory or inhalational

• Intrathecal

Factors affecting drug absorption after delivery of the drug by these routes, often in special formulations designed for the given route, are important, particularly with regard to the comparative advantages and disadvantages of the different routes.

Absorption, whether it be from the gastrointestinal tract, from the buccal mucosa, or from the rectal cavity, generally requires the passage of the drug in a molecular form across one or more barrier membranes and tissues. Most drugs are presented to the body as solid or semisolid dosage forms and obviously these must first release the drug contained within them. Tablets or capsules will disintegrate, and the drug will then dissolve either completely or partially. Many tablets contain granules or drug particles which should preferably deaggregate to facilitate the solution process. If the drug has the appropriate physicochemical properties, its molecules will pass by passive diffusion from a region of high concentration to a region of low concentration across the membrane separating the site of absorption from tissues containing the blood supply. Soluble drugs can, of course also be administered as solutions, e.g. intravenously.

The special features of the different routes of administration are dealt with in separate sections of this chapter, after a brief summary of the general properties of biological membranes and drug transport, a knowledge of which is important in understanding all absorption processes. It is impossible to be comprehensive in this one chapter, but we will concentrate on factors unique to the routes discussed, such as the properties of the vehicle in topical therapy, and the aerodynamic properties of aerosols in inhalation therapy, to give a flavour of the different problems that face formulators. Where attempts have been made to quantify absorption, equations are presented, but the derivations of most equations have been omitted.

9.1 Biological membranes and drug transport

The main function of biological membranes is to contain the aqueous contents of cells and separate them from an aqueous exterior phase. To achieve this, membranes are lipoidal in nature and, to allow nutrients to pass into the cell and waste products to move out, biological membranes are selectively permeable. Membranes have specialised transport systems to assist the passage of water-soluble materials and ions through their lipid interior. Lipid-soluble agents can pass by passive diffusion through the membrane from a region of high concentration to one of low concentration. Biological membranes differ from polymer membranes in that they are composed not of polymers but of small amphipathic molecules,


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