Design of dosage forms

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Design of dosage forms

Peter York

Chapter contents

Principles of dosage form design

Drugs are rarely administered as pure chemical substances alone and are almost always given as formulated preparations or medicines. These can vary from relatively simple solutions to complex drug delivery systems through the use of appropriate additives or excipients in the formulations. The excipients provide varied and specialized pharmaceutical functions. It is the formulation additives that, amongst other things, solubilize, suspend, thicken, preserve, emulsify, modify dissolution, improve the compactability and flavour drug substances to form various medicines or dosage forms.

The principal objective of dosage form design is to achieve a predictable therapeutic response to a drug included in a formulation which is capable of large-scale manufacture with reproducible product quality. To ensure product quality, numerous features are required: chemical and physical stability, with suitable preservation against microbial contamination if appropriate, uniformity of dose of drug, acceptability to users, including both prescriber and patient, as well as suitable packaging and labelling. Ideally, dosage forms should also be independent of patient-to-patient variation, although in practice, this feature remains difficult to achieve. However, recent developments are beginning to accommodate this requirement. These include drug delivery systems that rely on the specific metabolic activity of individual patients and implants that respond, for example, to externally applied sound or magnetic fields to trigger a drug delivery function.

Consideration should be given to differences in the bioavailability of drugs and their bio-fate in patients between apparently similar formulations and possible causative reasons. In recent years, increasing attention has therefore been directed towards eliminating variation in bioavailability characteristics, particularly for medicinal products containing an equivalent dose of a drug substance, as it is recognized that formulation factors can influence their therapeutic performance. To optimize the bioavailability of drug substances, it is often necessary to carefully select the most appropriate chemical form of the drug. For example, such selection should address solubility requirements, drug particle size and physical form and consider appropriate additives and manufacturing aids coupled to selecting the most appropriate administration route(s) and dosage form(s). Additionally, suitable manufacturing processes, labelling and packaging are required.

There are numerous dosage forms into which a drug substance can be incorporated for the convenient and efficacious treatment of a disease. Dosage forms can be designed for administration by alternative delivery routes to maximize therapeutic response. Preparations can be taken orally or injected, as well as being applied to the skin or inhaled, and Table 1.1 lists the range of dosage forms which can be used to deliver drugs by the various administration routes. However, it is necessary to relate the drug substance to the clinical indication being treated before the correct combination of drug and dosage form can be made, since each disease or illness often requires a specific type of drug therapy. In addition, factors governing choice of administration route and the specific requirements of that route which affect drug absorption need to be taken into account when designing dosage forms.

Table 1.1

Dosage forms available for different administration routes

Administration route Dosage forms
Oral Solutions, syrups, suspensions, emulsions, gels, powders, granules, capsules, tablets
Rectal Suppositories, ointments, creams, powders, solutions
Topical Ointments, creams, pastes, lotions, gels, solutions, topical aerosols, foams, transdermal patches
Parenteral Injections (solution, suspension, emulsion forms), implants, irrigation and dialysis solutions
Respiratory Aerosols (solution, suspension, emulsion, powder forms), inhalations, sprays, gases
Nasal Solutions, inhalations
Eye Solutions, ointments, creams
Ear Solutions, suspensions, ointments, creams

Many drugs are formulated into several dosage forms of varying strengths, each having selected pharmaceutical characteristics which are suitable for a specific application. One such drug is the glucocorticoid prednisolone used in the suppression of inflammatory and allergic disorders. Through the use of different chemical forms and formulation additives, a range of effective anti-inflammatory preparations is available, including tablet, enteric-coated tablet, injections, eye drops and enema. The extremely low aqueous solubility of the base prednisolone and acetate salt makes these forms useful in tablet and slowly absorbed intramuscular suspension injection forms, whilst the soluble sodium phosphate salt enables a soluble tablet form and solutions for eye and ear drops, enema and intravenous injection to be prepared. The analgesic paracetamol is also available in a range of dosage forms and strengths to meet the specific needs of the user, including tablets, dispersible tablets, paediatric soluble tablets, paediatric oral solution, sugar-free oral solution, oral suspension, double-strength oral suspension and suppositories.

In addition, whilst many new drugs based on low molecular weight organic compounds continue to be discovered and transformed into medicinal products, the development of drugs from biotechnology is increasing and the importance of these therapeutic agents is growing. Such active compounds are macromolecular and of relatively large molecular weight, and these include materials such as peptides, proteins and viral components. These drug substances present different and complex challenges in their formulation and processing into medicines due to their alternative biological, chemical and structural properties. Nevertheless, the underlying principles of dosage form design remain applicable. At present, these therapeutic agents are principally formulated into parenteral and respiratory dosage forms although other routes of administration are being considered and researched. Delivery of these biotechnologically-based drug substances via these routes of administration imposes additional constraints upon the selection of appropriate formulation excipients.

It is therefore apparent that before a drug substance can be successfully formulated into a dosage form, many factors must be considered. These can be broadly grouped into three categories:

High-quality and efficacious medicines will be formulated and prepared only when all these factors are considered and related to each other. This is the underlying principle of dosage form design.

Biopharmaceutical aspects of dosage form design

Biopharmaceutics can be regarded as the study of the relationship between the physical, chemical and biological sciences applied to drugs, dosage forms and drug action. Clearly, understanding the principles of this subject is important in dosage form design, particularly with regard to drug absorption, as well as drug distribution, metabolism and excretion. In general, a drug substance must be in solution before it can be absorbed via absorbing membranes and epithelia of the skin, gastrointestinal tract and lungs into body fluids. Drugs are absorbed in two general ways: by passive diffusion and by carrier mediated transport mechanisms. In passive diffusion, which is thought to control the absorption of many drugs, the process is driven by the concentration gradient existing across the cellular barrier, with drug molecules passing from regions of high to low concentration. Lipid solubility and degree of ionization of the drug at the absorbing site influence the rate of diffusion. Recent research into carrier mediated transport mechanisms has provided much information and knowledge, providing guidance in some cases for the design of new drug molecules. Several specialized transport mechanisms are postulated, including active and facilitated transport. Once absorbed, the drug can exert a therapeutic effect either locally or at a site of action remote from the site of administration. In the latter case, the drug has to be transported in body fluids (as shown in Fig. 1.1).

When the dosage form is designed to deliver drugs via the buccal, respiratory, rectal, intramuscular or subcutaneous routes, the drug passes directly into the circulation blood from absorbing tissues, whilst the intravenous route provides the most direct route of all. When delivered by the oral route, onset of drug action will be delayed because of required transit time in the gastrointestinal tract prior to absorption, the absorption process and factors associated with hepatoenteric blood circulation. The physical form of the oral dosage form will also influence absorption rate and onset of action, with solutions acting faster than suspensions, which in turn generally act faster than capsules and tablets. Dosage forms can thus be listed in order of time of onset of therapeutic effect (see Table 1.2). However, all drugs irrespective of their delivery route remain foreign substances to the human body and distribution, metabolic and elimination processes commence immediately following drug absorption until the drug is eliminated from the body via the urine, faeces, saliva, skin or lungs in unchanged or metabolized form.

Table 1.2

Variation in time of onset of action for different dosage forms

Time of onset of action Dosage forms
Seconds Intravenous injections
Minutes Intramuscular and subcutaneous injections, buccal tablets, aerosols, gases
Minutes to hours Short-term depot injections, solutions, suspensions, powders, granules, capsules, tablets, modified-release tablets
Several hours Enteric-coated formulations
Days to weeks Depot injections, implants
Varies Topical preparations

Routes of drug administration

The absorption pattern of drugs varies considerably between individual drug substances as well as between the different administration routes. Dosage forms are designed to provide the drug in a suitable form for absorption from each selected route of administration. The following discussion considers briefly the routes of drug administration and whilst dosage forms are mentioned, this is intended only as an introduction since they will be dealt with in greater detail later in this book.

Oral route

The oral route is the most frequently used route for drug administration. Oral dosage forms are intended usually for systemic effects resulting from drug absorption through the various epithelia and mucosa of the gastrointestinal tract. A few drugs, however, are intended to dissolve in the mouth for rapid absorption or for local effect in the tract due to poor absorption by this route or low aqueous solubility. Compared with other routes, the oral route is the simplest, most convenient and safest means of drug administration. However, disadvantages include relatively slow onset of action, possibilities of irregular absorption and destruction of certain drugs by the enzymes and secretions of the gastrointestinal tract. For example, insulin-containing preparations are inactivated by the action of stomach fluids.

Whilst drug absorption from the gastrointestinal tract follows the general principles described later in this book, several specific features should be emphasized. Changes in drug solubility can result from reactions with other materials present in the gastrointestinal tract, as for example the interference of absorption of tetracyclines through the formation of insoluble complexes with calcium, which can be available from foodstuffs or formulation additives. Gastric emptying time is an important factor for effective drug absorption from the intestine. Slow gastric emptying can be detrimental to drugs inactivated by the gastric juices and can delay absorption of drugs more effectively absorbed from the intestine. In addition, since environmental pH can influence the ionization and lipid solubility of drugs, the pH change occurring along the gastrointestinal tract, from a pH as low as 1 in the stomach to approximately 7 or 8 in the large intestine, is important to both the degree and site of drug absorption. Since membranes are more permeable to unionized rather than ionized forms and since most drugs are weak acids or bases, it can be shown that weak acids, being largely unionized, are well absorbed from the stomach. In the small intestine (pH from around 4 to 6.5), with its extremely large absorbing surface, both weak acids and weak bases are well absorbed.

The most popular oral dosage forms are tablets, capsules, suspensions, solutions and emulsions. Tablets are prepared by compaction and contain drugs and formulation additives which are included for specific functions, such as disintegrants which promote tablet break-up into granules and powder particles in the gastrointestinal tract, facilitating drug dissolution and absorption. Tablets are often coated, either to provide a protective barrier to environmental factors for drug stability purposes or to mask unpleasant drug taste, as well as to protect drugs from the acid conditions of the stomach (enteric coating). Increasing use is being made of modified-release tablet products such as fast-dissolving systems and controlled, delayed or sustained-release formulations. Benefits of controlled-release tablet formulations, achieved for example by the use of polymeric-based tablet cores or coating membranes, include reduced frequency of drug-related side-effects and maintaining steady drug-plasma levels for extended periods; important when medications are delivered for chronic conditions or where constant levels are required to achieve optimal efficacy, as in treating angina and hypertension.

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