Extended release drugs

Bailey DG, Arnold JM, Bend JR, Tran LT, Spence JD. Grapefruit juice-felodipine interaction reproducibility and characterization with the extended release drug formulation. Br J Clin Pharmacol 1995 40(2) 135-140. 

Modified Release Dosage Forms Dosage forms whose drug-release characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as a solution or an immediate release dosage form. Modified release solid oral dosage forms include both delayed and extended release drug products. 

Typically, coatings (e.g., enteric coatings) are intended to delay the release of medication until the dosage form has passed through the acidic medium of the stomach. In vivo tests for delayed-release drug products are similar to those for extended-release drug products. In vitro dissolution tests for these products should document that they are stable under acidic conditions and that they release the drug only in a neutral medium (e.g., pH 6.8). 

This guidance recommends that the following BA studies be conducted for an extended-release drug product submitted as an NDA ... 

BE studies are recommended when substantial changes in the components or composition and/or method of manufacture for an extended-release drug product occur between the to-be-marketed NDA dosage form and the clinical trial material. 

Mauger DT, Chinchilli VM. In vitro-in vivo relationships for oral extended-release drug products. J Biopharm Statist 1997 7(4) 565-578. 

Hydromorphone is primarily conjugated in the liver. Its metabolites are dihydroisomorphine and dihydromorphine. Excretion via the kidneys occurs up to 13% as unchanged parent compound, and 22-51% as conjugated hydromorphone. Total body clearance is 1.66 L/min. The elimination half-life is about 2.5 hours for the immediate-release compound and the intravenously administered drug, and about 19 hours for the extended-release drug [1,4]. 

Modified Release In this type of release dosage forms include both delayed and extended - release drug products. Delayed release is defined as the release of a drug at a time other than immediately following administration, while extended release products are formulated to make the drug available over an extended period after administration [114]. 

ER, extended-release FDA, Food and Drug Administration HDL, high-density lipoprotein IR, immediate-release LDL, low-density lipoprotein SR, sustained-release. 

Divalproex sodium is comprised of sodium valproate and valproic acid. The delayed-release and extended-release formulations are converted in the small intestine into valproic add, which is the systemically absorbed form. It was developed as an antiepileptic drug, but also has efficacy for mood stabilization and migraine headaches. It is FDA-approved for the treatment of the manic phase of bipolar disorder. It is generally equal in efficacy to lithium and some other drugs for bipolar mania. It has particular utility in bipolar disorder patients with rapid cycling, mixed mood features, and substance abuse comorbidity. Although not FDA-approved for relapse prevention, studies support this use, and it is widely prescribed for maintenance therapy. Divalproex can be used as monotherapy or in combination with lithium or an antipsychotic drug.31... 

In this work we will focus on the use of the cubic phase as a delivery system for oligopeptides - Desmopressin, Lysine Vasopressin, Somatostatin and the Renin inhibitor H214/03. The amino acid sequences of these peptides are given in Table I. The work focuses on the cubic phase as a subcutaneous or intramuscular depot for extended release of peptide drugs, and as a vehicle for peptide uptake in the Gl-tract. Several examples of how the peptide drugs interact with this lipid-water system will be given in terms of phase behaviour, peptide self-diffusion, in vitro and in vivo release kinetics, and the ability of the cubic phase to protect peptides from enzymatic degradation in vitro. Part of this work has been described elsewhere (4-6). 

E Allemann, JC Leroux, R Gurny, E Doelker. In vitro extended-release properties of drug loaded poly (dl-lactic acid) nanoparticles produced by a salting-out procedure. Pharm Res 10(12) 1732—1737, 1993. 

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. 

Extensions of BCS beyond the oral IR area has also been suggested, for example to apply BCS in the extended-release area. However, this will provide a major challenge since the release from different formulations will interact in different ways with in vitro test conditions and the physiological milieu in the gastrointestinal tract. For example, the plasma concentration-time profile differed for two felodipine ER tablets for which very similar in vitro profiles had been obtained, despite the fact that both tablets were of the hydrophilic matrix type based on cellulose derivates [70], This misleading result in vitro was due to interactions between the gel strength of the matrix and components in the dissolution test medium of no in vivo relevance. The situation for ER formulations would be further complicated by the need to predict potential food effects on the drug release in vivo. 

Abrahamsson, B., Johansson, D., Torstensson, A., Wingstrand, K., Evaluation of solubilizers in the drug release testing of hydrophilic matrix extended-release tablets of felodipine, Pharm. Res. 1994, 2 2, 1093-1097. 

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