Esophageal transit and in vivo disintegration of branded risedronate sodium tablets and two generic formulations of alendronic acid tablets: a single-center, single-blind, six-period crossover study in healthy female subjects.

BACKGROUND: Delayed esophageal transit or disintegration of oral bisphosphonate tablets before they enter the stomach may be of concern with respect to iatrogenic complications among patients receiving longterm treatment. Different formulations of generic bisphosphonate tablets meeting regulatory requirements may have substantial differences in pharmaceutical attributes from the branded product that may result in different characteristics during esophageal transit. OBJECTIVE: The primary objective of this study was to evaluate and compare esophageal transit times and in vivo disintegration of 3 bisphosphonate formulations, one branded and the others generic, that are commercially available in Canada and the United Kingdom. METHODS: This was a single-center, randomized, singleblind, 6-period crossover study in healthy postmenopausal women aged >50 years. Each subject received a single oral dose of a branded risedronate sodium 35-mg tablet and 2 generic formulations of alendronic acid 70-mg tablets (Novopharm Limited, Toronto, Canada, and Teva UK Limited, Morley, United Kingdom) in both the erect and semisupine (45 degrees ) positions. Although the products are labeled to be taken in the erect position, the semisupine position was included to simulate dosing in bedridden patients. Subjects took tablets with 30 mL of water in the morning after an overnight fast. The tablets were radiolabeled with technetium-99m ion-exchange resins to enable visualization and measurement of esophageal transit time and disintegration using a gamma camera. Dynamic scintigraphic images were obtained for a total of 10 minutes: 2 images per second for the first 30 seconds and 1 image every 15 seconds for 9.5 minutes. This was a mechanistic study and tolerability was not assessed. RESULTS: The study was conducted in 20 healthy white female subjects with a mean age of 62 years (range, 51-77 years). The effect of body position was statistically significant (P = 0.043), with the estimated hazard ratio (HR) of 0.74 indicating longer transit time in the semisupine position relative to the erect position. There was a statistically significant difference in transit time among the 3 types of tablets (P = 0.007), with the Novopharm tablet (HR = 0.59; P < 0.001) and Teva tablet (HR = 0.71; P = 0.042) having longer transit times compared with the risedronate tablet. In 4 instances, the Novopharm tablet disintegrated and dispersed in the esophagus, once in the erect position and 3 times in the semisupine position. CONCLUSIONS: In these healthy female subjects, esophageal transit was delayed when the tablets were given in the semisupine position. The branded risedronate tablet had a significantly faster transit time than the 2 generic formulations of alendronate tested.

Esophageal transit of the weekly film-coated risedronate (Actonel) placebo tablet in subjects with Kyphosis.

Risedronate sodium is a pyridinyl bisphosphonate of proven effectiveness for the treatment and prevention of osteoporosis and Paget's disease of the bone. The aim of this study was to compare the esophageal transit and gastric emptying of the placebo film-coated risedronate tablet when taken with 50 or 120 mL of water in subjects with Kyphosis. A total of 23 patients with radiologically documented osteoporosis participated in a single-center, open-label, crossover gamma scintigraphy study. The mean esophageal transit times were 15.6 s (50 mL) and 12.0 s (120 mL) and the mean gastric emptying half-times were 20.5 min (50 mL) and 14.3 min (120 mL). There was no relationship between the degree of Kyphosis measured from lateral standing radiographs and the esophageal transit time. This study demonstrated that even when taken with a minimal volume of water the esophageal transit and gastric emptying of the film-coated 35 mg weekly risedronate placebo tablet was similar in kyphotic subjects to previously obtained results from healthy control subjects.

In vitro disintegration studies of weekly generic alendronate sodium tablets (70 mg) available in the US.

BACKGROUND: Bisphosphonates as a class have the potential to cause upper gastrointestinal irritation. Although the generic alendronate sodium tablets are bioequivalent to the branded product, a potential concern is that the pharmaceutical attributes of the various generic formulations my affect the potential for local irritation and tolerability. SCOPE: The in vitro disintegration times were determined using the method described in the US Pharmacopeia 30 (USP 30). The disintegration of three generic alendronate sodium tablets 70 mg available in the United States was compared to that of the branded product. FINDINGS: The mean disintegration times of the generic alendronate sodium tablets ranged from 9 to 10 s for the Barr lots to 108 s for the Watson lot. The disintegration time of the branded product (Fosamax) was 53 s. The three Barr lots and one Teva lot had rapid disintegration times which were similar to the disintegration standards (< 30 s) for orally disintegrating tablets. Since there is no established disintegration time for alendronate sodium tablets there can be no assurance that the generic tablets are equivalent to the branded product in terms of esophageal exposure. However, the in vitro disintegration times have not been correlated with in vivo disintegration performance. CONCLUSIONS: Copies of generic alendronate sodium tablets are approved based on the results of single-dose bioavailability studies in healthy subjects and this is not considered adequate to establish similar disintegration characteristics.

Compatibility of risedronate sodium tablets with food thickeners.

PURPOSE: The chemical compatibility of commercially available food thickeners used with risedronate sodium tablets is examined. METHODS: Plastic 250-mL disposable beakers were used to prepare solutions for compatibility testing. Two ounces of purified water at room temperature was added to each beaker. One risedronate sodium 35-mg tablet was also added to each beaker and allowed to disintegrate without agitation. After two minutes, the water was stirred with a plastic spoon and an additional 4 oz of water was added to each beaker and stirred briskly for 30 seconds. The recommended amount of each food thickener was then added to each beaker. The control solution contained a tablet in water but no food thickener. Immediately after preparation, a portion of each solution was filtered through a 0.2-microm filter and assayed by high-performance liquid chromatography (HPLC). The solutions sat for 1 hour at room temperature and then were stirred briskly for 30 seconds, filtered, and assayed by HPLC. They then sat for 24 hours at room temperature and then were stirred briskly again for 30 seconds, filtered, and assayed by HPLC. RESULTS: The risedronate tablets alone showed a mean initial concentration of 0.194 mg/mL and a mean recovery of 99.8% after 1 hour and 99.2% after 24 hours. The mean initial concentration for risedronate sodium in each of the five food thickeners ranged from 0.193 to 0.195 mg/mL. All samples ranged from 98.8% to 99.9% of the initial concentration after 1 hour and from 96.7% to 99.2% after 24 hours. CONCLUSION: Risedronate sodium tablets were compatible for 24 hours with five food thickeners.

In vitro disintegration and dissolution studies of once-weekly copies of alendronate sodium tablets (70 mg) and in vivo implications.

OBJECTIVE: The aim of this study was to evaluate the in vitro disintegration and dissolution of 26 alendronic acid tablets (70 mg) on the market in Canada, Germany, the Netherlands, and the United Kingdom compared to the branded product (Fosamax). RESEARCH DESIGN AND METHODS: The disintegration and dissolution times were determined using the methods described in the United States Pharmacopeia 30 (USP 30). The disintegration of four orally disintegrating tablets (non-bisphosphonates) and branded film-coated risedronate sodium tablets were included for comparison. RESULTS: The mean disintegration times of the alendronic acid tablets ranged from 14 s for Pharmachemie (Netherlands) to 342 s (5.7 min) for Betapharm (Germany). The mean disintegration time of the branded product tablets ranged from 43 to 78 s. Six of the 26 companies market alendronic acid tablets with very rapid disintegration times which are similar to those of orally disintegrating tablets (non-bisphosphonates). The alendronic acid tablets with very rapid mean disintegration times are as follows: Pharmachemie (Netherlands), 14 s; Novopharm (Canada), 13-24 s; GRY-Pharma (Germany), 21 s; Juta Pharma (Germany), 30 s; APS/Teva (United Kingdom), 26 and 37 s; and Teva (UK), 14-29 s. Since there is no established disintegration time for alendronic acid tablets there can be no assurance that the copy tablets are equivalent to the branded product in terms of esophageal drug exposure. However, the in vitro disintegration times have not been correlated with in vivo disintegration and performance. The dissolution of all the bisphosphonate tablets was rapid with greater than 80% dissolved in 15 min and all products conformed to the USP 30 specification. CONCLUSIONS: The dissolution of all alendronic acid tablets was rapid and complete and conformed to the established USP 30 specifications which should ensure adequate drug absorption from the copy products. However, copies of alendronic acid tablets are approved based on the results of single-dose bioavailability studies in healthy subjects and this is not adequate to establish similar disintegration characteristics.

Extemporaneous procedures for dissolving risedronate tablets for oral administration and for feeding tubes.

BACKGROUND: Risedronate (Actonel, Procter & Gamble Pharmaceuticals) is commercially available only as film-coated tablets. Extemporaneous procedures for dissolving tablets for feeding tubes and for preparation of an oral liquid have not previously been evaluated. OBJECTIVE: To evaluate procedures for dissolving risedronate sodium tablets for administration in liquid form and drug recovery following dissolution in cups and following passage through different types of feeding tubes. METHODS: Tablets (5 and 35 mg) were individually dispersed in 2 oz of water. After 2 minutes, the solution was stirred for 30 seconds, dispensed, and rinsed with an additional 4 oz of water. The sample was filtered and analyzed by HPLC. Ten replicates were performed using the various cups. Gastrostomy and nasoenteric tubes were flushed with 1 oz of water. Individual tablets were dispersed in 2 oz of water; after 2 minutes, the solution was stirred for 30 seconds and poured through the tube and flushed with 1 oz of water. Samples were filtered and analyzed by HPLC. Ten replicates were performed for each type of feeding tube. RESULTS: For cups, the mean amount of drug recovered ranged from 95.7% to 100.5% of the label claim, with a relative standard deviation (RSD) range of 1.1-6.3%. For gastrostomy and nasoenteric tubes, the mean amount of drug recovered ranged from 98.3% to 101.9% of label claim, with an RSD range of 0.9-3.3%. CONCLUSIONS: A simple and accurate procedure was developed for dissolving risedronate tablets in water to prepare a liquid formulation for administration orally or through feeding tubes.