Extended-release products

Traditionally, the ideal extended-release product has been conceived as providing essentially stable blood levels over the whole dosing frequency interval. Thus, unlike the saw-edge blood concentration time profile of a non-controlled-release product that may show rather wild fluctuations between sub- and su-pratherapeutic blood levels, the ideal extended-release product avoids both nontherapeutic blood levels and those likely to have an increased frequency of dose-related side effects. However, in recent years con-trolled-release products that deliberately exploit a pulsatile drug release time profile have also attracted attention. 

Initial side effects are often dose related and are worse at peak serum concentrations (1 to 2 hours postdose). Lowering the dose, taking smaller doses with food, using extended-release products, and once-daily dosing at bedtime may help. 

Lithium is usually initiated with low to moderate doses (600 mg/day divided into two to three doses) for prophylaxis, and higher doses (900 to 1,200 mg/day, divided into two to three doses) for acute mania. Immediate-release preparations should be given two to three times daily, whereas extended-release products can be given once or twice daily. After patients are stabilized, many patients can be switched to once-daily dosing. 

The dissolution measurements of the two products (test and reference, pre- and post-change, two strengths) should be made under the same test conditions. The dissolution time points for both the profiles should be the same, e.g., for IR products 15, 30, 45, and 60 min, for extended-release products 1, 2, 3, 5, and 8 hr. 

Figure 1 Stages of extended-release product development and associated questions (panel a) and information available at each stage (panel b).

D. J. Kopacz, C. M. Bernards, H. W. Allen, C. Landau, P. Nandy, D. Wu, and P. G. Lacouture. A model to evaluate the pharmacokinetic and pharmacodynamic variables of extended-release products using in vivo tissue microdialysis in humans Bupivacaine-loaded microcapsules. Anaesth. Analg. 97 124-131 (2003). 

Two relatively new formulations of metformin are available. Glucovance is a combination of metformin and glyburide that may be helpful for diabetics who require both a sulfonylurea and metformin, and Glu-cophage XR is an extended-release product of metformin that may be better tolerated in some patients who are prone to gastrointestinal side effects. Metformin is usually given two to three times a day at mealtimes. 

Preferred analgesic for mild to moderate pain in older adults due to safety profile. More effective in chronic pain when used on a scheduled basis. The extended-release product allows for q8h dosing, which may enhance compliance in patients taking acetaminophen for chronicpain. 

Sustained-release niacin (not the same as extended-release product) Should be avoided ... 

USP Dissolution Apparatus 1 (basket) and 2 (paddle) are commonly used for immediate-release formulations. USP Apparatus 3 (reciprocating cylinders) is the system of choice for testing extended-release products or a dosage form that requires release profiling at multiple pH levels and time points. Low-dose products may require the use of flow-through analysis or other low-volume test techniques (noncompendial 100- or 200-mL dissolution vessels). Once the apparatus is selected and has been shown to be suitable during method development, no further evaluation of another apparatus is required during validation. 

Extended Release Extended release products are formulated to make the drug available over an extended period after ingestion. This allows a reduction in dosing frequency compared to a drug presented as a conventional dosage form (e.g., as a solution or an immediate release dosage form). 

Extended release product Applica-tion/compendial release requirements plus multipoint dissolution profile in three other media (e.g., water, 0.1N HC1, and USP buffer media at pH 4.5 and 6.8). 

Notification of change and submission of updated batch records Stability Three batches accelerated data in suppl. first three production batches LT stability in AR Extended release product Application/compendial release requirements plus multipoint dissolution profile in application/compendial medium for the changed drug product and the biobatch or marketed batch (unchanged drug product). Adequate sampling should be performed (1,2, and 4 hr and every 2 hr thereafter until... 

An NDA can be submitted for a previously unapproved new molecular entity, or for a new salt, new ester, prodrug, or other noncovalent derivative of a previously approved new molecular entity, formulated as a modihed-release drug product. The first modified-release drug product for a previously approved immediate-release drug product should be submitted as an NDA. Subsequent modified-release products that are pharmaceutically equivalent and bioequivalent to the listed drug product should be submitted as ANDAs. BA requirements for the NDA of an extended-release product are listed in 320.25(f). The purpose of an in vivo BA study for which a controlled-release claim is made is to determine if all of the following conditions are met. 

Specifications for extended-release products reflect the intended release profile of the product, which in some cases, may be relatively complex. The drug-release specification for Bupropion Hydrochloride Extended-Release Tablets USP requires 25-45% of the nominal content of drug to have dissolved after one hour, 60-85% after four hours and not less than 80% after eight hours. The specifications for Diltiazem Hydrochloride Extended-Release Capsules USP are even more complex, with 13 different tests being prescribed to cover the various products (Table 1). Other products with multiple profiles include Pentoxifylline Extended-release Capsules USP (10 tests). Lithium Carbonate Tablets USP (4 tests) and Indomethacin Extended-release capsules USP (3 tests). 

Dupuis RE, Cooper AA, Rosamond LJ, Campbell-Bright S. Multiple delayed peak lithium concentrations following acute intoxication with an extended-release product. Ann Pharmacother 1996 30(4) 356-60. 

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