Sustained-release transdermal formulations

To help avoid nitrate tolerance, clinicians should employ the smallest effective dose and administer the compound infrequently. A daily nitrate-free period is also recommended, particularly with use of the transdermal patches or ointment. A better understanding of the pharmacokinetic profile achieved with these sustained-release formulations should result in more effective dosing regimens. 

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. 

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. 

There are diverse formulations and delivery systems for macrocylic lactones in ruminants, including injectable, oral, sustained-release bolus and transdermal ("pour on") products. In Europe, it is popular clinical practice to administer injectable solutions of ivermectin intravenously (i.v.) to horses. This constitutes extra-label (unlicensed) use and there are no objective data to support the perceived improved efficacy following administration by this route. Specifically, in relation to hypobiotic cyathostome larvae, Klei et al (1993) reported no increase in efficacy when horses were administered 10 pg/kg, which is five times the recommended dose rate. 

Sustained release forms are available to provide prophylactic action against angina attacks these are formulated into transdermal patches. 

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... 

Clonidine hydrochloride is used in the treatment of grades of hypertension. The usual initial dose of clonidine hydrochloride is 50 to 100 pg orally thrice daily increased every second or third day according to the response of the patient. The usual maintenance dose is 0.3 to 1.2 mg daily but doses of up to 1.8 mg or more daily may be required. To reduce side effects a similar dose of clonidine may be given in conjunction with a thiazide diuretic but combination with a 13-blocking agent should be avoided where possible clonidine may also be given in a sustained-release formulation which enables twice-daily dosage, or by a transdermal delivery system which is applied once a week and delivers 100-300 pg daily at a constant rate (4). 

Application of SCF is now the subject of increasing interest especially in the pharmaceutical industry and there are three aims increasing bioavailability of poorly soluble molecules designing sustained-release formulations and formulation of active agents for new types of drug delivery that are less invasive than parental delivery (oral, pulmonary, transdermal). The most complex challenge is related to therapeutic delivery, as it is extremely difficult to obtain a satisfactory therapeutic delivery effect due to biomolecule instability and very short half-life in vivo. 

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