Prolonged-release

Prolonged-release (or slow-release) preparations are useful for water-soluble drugs with short biological half-lives. Hydrophobic CyDs, such as ethylated CyDs, with low aqueous solubilities have been demonstrated to work as slow-release carriers of water-soluble drugs such as isosorbide dinitrate, diltiazem hydrochloride, and 5-fluorouracil [19, 38, 39]. For example, 15 has the most prominent retarding effect for water-soluble molsidomine and diltiazem hydrochloride, after oral administration in dogs. The release of isosorbide dinitrate from 16 film was retarded and the plasma drug level after topical application of the film to rat abdominal skin was maintained at 100 ng mL for about 10 h [41]. 

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In the past, many of the terms used to refer to therapeutic systems of controlled and sustained release have been used in an inconsistent and confusing manner. Although descriptive terms such as timed release and prolonged release give excellent manufacturer identification, they can be confusing to health care practitioners. For the purposes of this chapter, sustained release and controlled release will represent separate delivery processes. Sustained release constitutes any dosage form that provides medication... 

The advantageous effects of liposomal carrier systems include protection of compounds from metabolism or degradation, as well as enhanced cellular uptake. Liposome-mediated delivery of cytotoxic drugs to cells in culture has resulted in improved potency [58,59]. Prolonged release of encapsulated cargo has also been demonstrated [60,61]. More recently, liposomes with extended circulation half-lives and dose-independent pharmacokinetics (Stealth liposomes) [62] have shown promise in delivery of drugs that are normally very rapidly degraded. 

Sustained- and controlled-release devices for drug delivery in the vaginal and uterine areas are most often for the delivery of contraceptive steroid hormones. The advantages in administration by this route—prolonged release, minimal systemic side effects, and an increase in bioavailability—allow for less total drug than with an oral dose. First-pass metabolism that inactivates many steroid hormones can be avoided [183,184],... 

Where an unusual excipient is chosen, or where an established excipient is chosen for a dosage form that results in its administration by a novel route of administration, then additional data will need to form part of the application. In effect, a novel excipient will need to be supported by data similar to those required for a new drug, with full supporting data including composition, function, and safety. Novel excipients include the components of the matrix in prolonged release products, new propellants, and new permeability enhancers. The exception to this need for extensive supporting data would be for a material already approved for food use and administered by the oral route or a material already approved for cosmetic use with a topical route of administration. In all cases the quality of the excipients has to be described adequately and shown to be satisfactory (which will depend on its role). 

There are two specific guidelines on prolonged-release oral dosage forms (3AQ10a, adopted November 1992) and on modified-release products—oral dosage forms and transdermal dosage forms (CPMP/QWP/604/96, adopted July 1999). The advice in the two documents differs in a number of ways. 

The information requirements for products such as prolonged-release oral dosage forms will depend on whether or not it has been possible, during the development of the product, to establish an in vivo-in vitro correlation between clinical data and dissolution studies. In vivo-in vitro correlations should be attempted using product at different stages of development, but bioavailability and pharmacokinetics data from pivotal clinical studies using at least pilot-scale production materials and possibly routine production material are particularly important. Where it is not possible to establish an in vivo-in vitro correlation, additional data will be required to compare the bioavailability of product developed at laboratory scale, pilot scale, and production scale. In the absence of an in vivo-in vitro correlation, the dissolution test will be a quality control tool rather than a surrogate marker for in vivo performance of the product. 

The dissolution specification for prolonged-release dosage forms should cover a minimum of three points one to ensure that dose-dumping does not occur (early, typically 20-30% release), one to confirm compliance with the dissolution curve profile (around 50% release), and one to ensure that the majority of the dose has been released (often more than 80% released). The robustness of the test procedure should be considered (e.g., to temperature, pH, and rotational speed). 

These ideas appear to merit careful consideration. Similarly, the use of nomograms to evaluate the intrinsic absorption rate constants for drugs that may be formulated into oral prolonged-release products may be of value [5],... 

S. C. Dyer and R. E. Notari, A nomogram to evaluate intrinsic absorption rate constants of potential oral prolonged release candidates, Pharm. Dev. Tech., 4, 305 (1999). 

Robertson JF, Harrison MP (2003) Equivalent single-dose pharmacokinetics of two different dosing methods of prolonged-release fulvestrant ( Faslodex ) in postmenopausal women with advanced breast cancer. Cancer Chemother Pharmacol 52 346-348... 

The majority of oral preparations are solid dosage forms. These include tablets and capsules for administration to small farm animals, pastes for horses, and a variety of prolonged-release products for administration to cattle. The drug in solid dosage form must dissolve before it can be absorbed. The dissolution rate de-... 

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