Sustained-release oral formulations

Doses of 0.3-10 mg of the immediate-release formulation orally given once nightly have been tried. The lowest effective dose should be used first and may be repeated in 30 minutes up to a maximum of 10-20 mg. Sustained-release formulations may be used but currently do not appear to offer any advantages over the immediate-release formulations. Sustained-release formulations are also more costly. 

Dosages and routes of administration Dihydrocodeine is mostly used in the form of immediate or sustained release oral formulations (Lloyd et al., 1992). For pain treatment the dose range is 30-80 mg, for cough inhibition doses are in the range of 10 mg. 

Because faster onset of action is associated with higher potential for abuse, abuse-liability assessment should include consideration of whether a formulation can be altered to increase the speed of onset. There are numerous examples of abuse of a medication by a route other than that intended by the manufacturer. The sustained-release oral form of oxycodone, designed to deliver an initial rapid dose followed by slow release, has been widely abused by chewing the tablet, thus releasing the entire content of the tablet at once.65 There is also evidence for intravenous use of sublingual buprenorphine tablets.66 Transdermal systems developed to deliver medication slowly for extended periods of time have been prime targets for misuse,67 as discussed below in the case study of fentanyl. 

To study the bioavailability of ketotifen from sustained-release oral formulations, deutera-ted ketotifen (N-CD,) was used. The kinetic profiles of ketotifen in the plasma and in the urine shows that any isotopic effect due to the presence of deuterium is lacking (13). 

The challenge of developing successful delivery technologies for gene therapy is a world removed from the simple, sustained-release oral formulations which were the achievements of the first pharmaceutical scientists to specialize in advanced drag delivery technology. The potential, in commercial terms and in terms of human well-being, is too vast to estimate. 

Sustained-release (oral) preparations can reduce the frequency of medication to once a day, and compliance is made easier for the patient. Most long-term medication for the elderly can now be given as a single morning dose. In addition sustained-release preparations may avoid local bowel toxicity due to high local concentrations, e.g. ulceration of the small intestine with potassium chloride tablets, and may also avoid the toxic peak plasma concentrations that can occur when dissolution of the formulation, and so absorption of the drug, are rapid. Some sustained-release formulations also contain an immediate-release component to provide rapid, as well as sustained, effect. 

Theophylline is relatively insoluble and it is formulated either as a salt with choline (choline theophyllinate) or complexed with EDTA (amino-phylline). Aminophylline is sufficiently soluble to permit i.v. use of theophylline in status asthmaticus. There are numerous sustained-release oral forms for use in chronic asthma. These are not bioequivalent and patients should not switch between them once they are stabilised on a particular preparation. It has also been used in the past for the emergency treatment of left ventricular failure (see p. 518). At high therapeutic doses some patients... 

Sodium alginate is used in a variety of oral and topical pharmaceutical formulations. In tablet formulations, sodium alginate may be used as both a binder and disintegrant it has been used as a diluent in capsule formulations. Sodium alginate has also been used in the preparation of sustained-release oral formulations since it can delay the dissolution of a drug from tablets, capsules, and aqueous suspensions. ... 

There are approximately a dozen calcium channel antagonists marketed in the United States for the treatment of hypertension, certain dysrhythmias, and some forms of angina (see Chaps. 13,15, and 17). The calcium channel blockers are classified by their chemical structure as phenylalkylamines (e.g., verapamil), benzothiapines (e.g., diltiazem), and dihydropyridines (e.g., amlodipine, felodipine, nicardipine, and nifedipine). Several of these agents, namely, diltiazem, nicardipine, nifedipine, and verapamil, are formulated as sustained-release oral dosage forms or have a slow onset of action and longer half-life (e.g., amlodipine " ), allowing once-daily administration. 

Clinical Uses As previously noted, nitroglycerin is available in several formulations (Table 12-2). The standard form for treatment of acute anginal pain is the sublingual tablet, which has a duration of action of 10-20 minutes. Oral (swallowed) normal-release nitroglycerin has a duration of action of 4-6 hours. Sustained-release oral forms have a somewhat longer duration of action (Table 12-2). Transdermal formulations (ointment or patch) can maintain blood levels... 

By definition, sustained release formulations differ pharmaceutically and pharmacokinetically from the innovator drug. Delayed or sustained release oral formulations are used for chronic therapy, and may have two principal advantages (a) reduction in dose frequency (and thus, hopefully, improved compliance see Chapter 21) and (b) reduction of Cmax for a standard AUC, which can improve tolerability when adverse events are plasma concentration-related. The demonstration of bioequivalence usually hinges on the following factors (a) equivalence of AUC to an innovator drug at steady state (b) the absence of any chance of dose dumping (c) consistency of performance from dose to dose [see 21CFR320.25(f)]. 

Improvements in asthma treatment include the development of more effective, safer formulations of known dmgs. The aerosol adrninistration of P2-agonists or corticosteroids results in a decrease in side effects. Also, the use of reUable sustained release formulations has revolutionized the use of oral xanthines which have a very narrow therapeutic index (see Controlled release technology). For many individuals, asthma symptoms tend to worsen at night and the inhaled bronchodilatots do not usually last through an entire night s sleep (26,27). 

A. Yacobi and E. Halpetin-Walega, eds.. Oral Sustained Release Formulations Design and Evaluation, Pergamon Press, New York, 1988. 

Sustained-release formulations can produce stable serum concentrations with once or twice daily dosage. Therapeutic effects occur at blood levels > 5 mg/1, and side effects increase considerably at levels > 15 mg/1. Smoking, alcohol, anticonvulsants, and rifampicin induce the drug-metabolizing enzyme system in liver and reduce the half-life of theophylline. On the other hand, heart and liver failure, sustained fever, old age and drugs such as cimeti-dine, ciprofloxacin, and oral contraceptives reduce theophylline clearance and thereby increase serum concentrations. 

Improvements in theophylline preparations have come from alterations in the physical state of the drugs rather than from new chemical formulations. For example, the increased surface area of anhydrous theophylline in a microcrystalline form facilitates solubilization for complete and rapid absorption after oral administration. Numerous sustained-release preparations (see Preparations Available) are available and can produce therapeutic blood levels for 12 hours or more. These preparations offer the advantages of less frequent drug administration, less fluctuation of theophylline blood levels, and, in many cases, more effective treatment of nocturnal bronchospasm. 

If disturbances of gastrointestinal function prevent the use of oral sustained-release morphine, the fentanyl transdermal system (fentanyl patch) can be used over long periods. Furthermore, buccal transmucosal fentanyl can be used for short episodes of breakthrough pain (see Alternative Routes of Administration). Administration of strong opioids by nasal insufflation has been shown to be efficacious, and nasal preparations are now available in some countries. Approval of such formulations in the USA is growing. In addition, stimulant drugs such as the amphetamines have been shown to enhance the analgesic actions of the opioids and thus may be very useful adjuncts in the patient with chronic pain. 

Thus polymers serve as key excipients in oral and parenteral CR formulations. Other excipients used in sustained release dosage forms have been covered in other chapters within this book. For example, parenteral CR dosage forms involving polymers would still have other excipients as discussed in the chapter on injectable excipients (Chapter 16). Similarly oral dosage forms will require consideration of other excipients depending on the nature of the drug, as discussed in Chapter 12. This chapter reviews some of the promising polymers used in this application. 

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