Diane R. Guinta

In Vitro and In Vivo Evaluation of a Once-Daily Controlled-Release Pseudoephedrine Product

The functionality of a once‐daily, osmotic dosage form—gastrointestinal therapeutic system (pseudoephedrine HCl) or GITS (PeHCl)—was studied in vitro and in vivo. The in vitro release profiles were close to identical from pH 1 to 7.5 and between USP apparatus 2 and 7, independent of paddle speeds from 50 to 200 rpm; GITS also released drug at the normal rate in aqueous media after incubation in bile salts or fatty media. Both strengths of GITS (PeHCl)—240 and 120 mg—were then compared with a commercially available pseudoephedrine solution given every 6 hours and a timed‐release 12‐hour pseudoephedrine capsule given every 12 hours in a randomized 4‐way crossover study in 24 healthy men. All four formulations were equivalent in total drug absorbed. Both GITS treatments had AUCinf values equivalent to those of PeHCl solution and capsules, and Cmax values equivalent to PeHCl capsules. Cmax for GITS and capsule treatments were each significantly lower than for solution, but the differences were small (14–17%). A one‐to‐one correlation was shown between rate of absorption and in vitro release profiles for the GITS products, indicating that drug release from GITS controls absorption. Insensitivity to conditions of in vivo release accounts for the close in vitro/in vivo correlation of release rates. In a second randomized crossover trial (12 men), the effect of a high‐fat breakfast on GITS performance was evaluated. Mean pseudoephedrine concentrations in plasma were close to identical with or without the breakfast, and the treatments were bioequivalent. The validity of the in vitro/in vivo correlation was confirmed in a bioequivalence study in which GITS with similar in vitro release rate profiles, but manufactured under different conditions (batch size, quantitative core composition, manufacturing equipment, and manufacturing site), were shown to be bioequivalent.

Multiple-Dose Pharmacokinetics and Pharmacodynamics of OROS and Immediate-Release Amitriptyline Hydrochloride Formulations

The pharmacokinetics and pharmacodynamics of amitriptyline hydrochloride after oral administration of an OROS osmotic system, which provides controlled drug delivery, and an immediate‐release (IR) tablet, were evaluated in 24 healthy volunteers after repeated administration for 14 days. Each morning, subjects received either 75 mg of the OROS (amitriptyline HCl) controlled‐release formulation or the 75 mg IR amitriptyline tablet for 14 days on two separate occasions with a washout period of 21 days according to a randomly assigned sequence. Serial blood samples were collected for a period of 58 hours after the day 14 dose, then these samples were analyzed by the gas chromatography method for amitriptyline and nortriptyline. Subjective ratings of dry mouth and drowsiness were collected at specific times throughout each treatment period. Administration of the OROS formulation resulted in much more consistent plasma concentrations of the drug and metabolite compared with the IR formulation at steady state. The mean maximum concentration (Cmax) of amitriptyline was significantly lower after administration of OROS than the IR formulation. Mean values for area under the concentration—time curve (AUC0–24) for the OROS and IR formulations were 1,265 and 1,393 ng·hr/mL, respectively. The drug‐to‐metabolite ratio was found to be similar for both treatments, suggesting that there was no difference in metabolism between treatments. Incidence and severity of the anticholinergic effects were similar for the two treatments. A clockwise hysteresis between baseline‐corrected drowsiness and drug concentration suggests development of tolerance of the anticholinergic effects after both treatments. Using a hypothetical anatagonist metabolite model to explain tolerance development, the shape of the hysteresis curves of the two treatments could be explained by differences in dosing frequency.

Controlled-release dosage forms and gastrointestinal blood loss : four clinical studies

Abstract Four clinical studies were conducted to assess gastrointestinal (GI) blood loss during use of the OROS® dosage form. These were open-label, randomized, parallel studies of 176 healthy volunteers 18–78 years of age. Blood loss was measured using the 51 Cr red blood cell tagging method and stool guaiac tests. GI blood loss from a drug associated with GI irritation, indomethacin [as OROS (sodium indomethacin) or as immediate-release indomethacin], was greater than that from lactose placebo but less than that from aspirin. GI blood loss following ingestion of the OROS dosage forms containing cold/allergy drugs - a combination of pseudoephedrine hydrochloride and brompheniramine maleate, chlorpheniramine maleate, or pseudoephedrine hydrochloride - was statistically indistinguishable from that of marketed reference slow-release cold/allergy products or placebos. Blood loss in volunteers 50 years of age or older was similar during use of OROS (mannitol) placebo or oral lactose placebo tablets. Baseline GI blood loss in all four studies was age-invariant. In these studies, GI blood loss, when present, was associated with specific drugs, aspirin and indomethacin, and not with a particular OROS dosage form.