Reproducibility of neutron activated Sm-153 oral dose formulations intended for human administration.

Neutron activation of Sm-152 offers a method of radiolabeling for the in vivo study of oral dose formulations by gamma scintigraphy. Reproducibility measurements are needed to ensure the robustness of clinical studies. 204 enteric-coated guaifenesin core tablets (10mg of Sm(2)O(3)) were irradiated by thermal neutrons to achieve 1 MBq at 48 h. Administered activities were 0.86±0.03 MBq. Good reproducibility (CV=3.5%) was observed over 24 weeks ensuring that volunteer doses were within the dose reference level of 0.8 mSv.

Development and evaluation of extended release bioadhesive sodium fluoride tablets.

Localized fluoride delivery to the oral cavity is important in caries prevention. However, no current marketed dosage forms deliver fluoride for an extended period. This work describes the effect of poly (methyl vinyl ether-co-maleic anhydride) mixed calcium/sodium salt (Gantrez MS), sodium carboxymethylcellulose (NaCMC), polyethylene glycol 8000 (PEG8000) and Carbopol 934 (C934) on the in vitro dissolution and ex vivo bioadhesion of sodium fluoride matrix tablets. Dissolution was studied using USP Apparatus 2 and a low volume (3.1 ml), low flow (0.5 ml/min) dissolution apparatus. In both apparatus, the percent drug dissolved at 2, 4 and 8 h was found to be statistically dependent on the fractions of Gantrez MS and NaCMC. The interaction term was significant at 2 and 4 h (probability > (t) of less than 0.05). Ex vivo bioadhesion was studied using excised bovine gingiva and a TA.XT2i Texture Analyzer. Peak bioadhesive force and work of bioadhesion were found to be statistically dependent on the fractions of Gantrez MS and NaCMC with no interaction (probability > (t) of less than 0.01). Results indicate that bioadhesive matrix fluoride tablets of these mixtures can be designed to exhibit both bioadhesive and extended release properties.

The use of scintigraphy to demonstrate the rapid esophageal transit of the oval film-coated placebo risedronate tablet compared to a round uncoated placebo tablet when administered with minimal volumes of water.

As our population ages, and the consumption of pharmaceutical products rises, the incidence of solid oral dosage forms lodging in the esophagus is likely to increase and may be formulation dependent. The aim of this study was to compare the esophageal transit of the commercial film-coated risedronate tablet and a round uncoated tablet resembling the alendronate 10 mg tablet which is reported to cause esophagitis if ingested with little to no water. Water volumes of 30 ml and 50 ml were selected as these volumes can detect formulations prone to esophageal adhesion and a habits and practice study showed that these volumes are within the range preferred by women (7-385 ml). A total of 28 healthy postmenopausal women completed the four-way crossover scintigraphy study. For both volumes of water, the film-coated placebo risedronate tablet had a statistically significant faster esophageal transit time than the uncoated placebo tablet (P=0.002 for 30 ml water and P<0.001 for 50 ml water). Among those taking the round, flat, uncoated tablet, five subjects had esophageal stasis (transit >20 s) and in three subjects the tablet remained in the esophagus at the end of the 10-min imaging period. No stasis was observed for the oval film-coated placebo risedronate tablet. This study demonstrates that tablet size, shape and coating are pharmaceutical parameters which can be controlled to minimize esophageal contact of a dosage form with esophageal tissue.

The effects of packaging on the stability of a moisture sensitive compound.

Packages that provided stability (less than a 10% loss in potency) of a moisture sensitive compound (PGE-7762928) in tablet form at accelerated conditions for 6 months were identified. The equilibrium moisture content of the tablets at 25 degrees C/60%RH, 30 degrees C/60%RH and 40 degrees C/75%RH were 2.3,2.4, and 2.9%, respectively. The tablet equilibrium moisture content, degradation rate of unpackaged product, and the moisture barrier properties of the packages were used to predict the stability of the packaged product. The physical and chemical stability (HPLC assay) of the products were measured after 2,4,6,8,12, and 24 weeks at ICH conditions. The Containers-Permeation(1) of polyvinyl chloride blisters, cyclic olefin blisters, aclar blisters, cold-form aluminum blisters was 0.259, 0.040, 0.008 and 0.001 mg per blister per day, respectively. At 6 months at 40 degrees C/75%RH, the percent active was 84% in polyvinyl chloride blisters, 91% in cyclic olefin blisters, 97% in aclar blisters, 100% in cold-form aluminum blisters and 99% in an high density polyethylene bottle with a foil induction seal. The stability results for the packaged product were fairly consistent with the predictions based on the moisture sensitivity of the product and the moisture barrier properties of the respective package. To gain a better prediction, the flux value determined by the Containers-Permeation procedure was adjusted for the internal moisture concentration of the blister.

Oesophageal transit, disintegration and gastric emptying of a film-coated risedronate placebo tablet in gastro-oesophageal reflux disease and normal control subjects.

BACKGROUND: Risedronate sodium is a pyridinyl bisphosphonate, proven effective for the treatment and prevention of postmenopausal osteoporosis and glucocorticoid-induced osteoporosis and Paget's disease of the bone. AIM: To compare the oesophageal transit, disintegration and gastric emptying of the commercial film-coated risedronate tablet in subjects with gastro-oesophageal reflux disease (GERD) and normal control subjects. METHODS: A total of 30 subjects, 15 patients with GERD and 15 age- and sex-matched, normal control subjects, participated in a single-centre, open-label, comparative gamma scintigraphy study. The GERD subjects had active erosive oesophagitis within 4 weeks prior to dosing. RESULTS: The mean oesophageal transit (GERD, 4.4 s; controls, 3.1 s), mean disintegration (GERD, 21.8 min; controls, 19.2 min) and mean gastric emptying (GERD, 15.9 min; controls, 15.0 min) were similar in the two subject groups. The oesophageal transit is rapid and given the rapid disintegration and gastric emptying, oesophageal contact occurring via reflux of risedronate was unlikely since most, if not all, of the dosage form exited from the stomach within 30 min. CONCLUSIONS: The oval shape and film-coating on the commercial risedronate tablet promotes rapid oesophageal transit and minimizes oesophageal contact, even in the high-risk GERD population.

Esophageal transit of risedronate cellulose-coated tablet and gelatin capsule formulations.

Risedronate sodium is an orally active antiresorptive agent and a member of the pyridinyl class of bisphosphonates. It has been approved for the treatment of Paget's disease of the bone and is under development as a chronic therapy for the treatment and prevention of osteoporosis. A novel cellulose film-coated tablet formulation was developed to optimize esophageal transit of this bisphosphonate. The aim of the present study was to compare the esophageal transit of the film-coated tablet formulation of risedronate with its original gelatin capsule dose form. A total of 25 elderly, healthy volunteers (mean 66 years), who were dysphagia-free, participated in this randomized cross-over study. On separate occasions, volunteers swallowed radiolabeled placebo formulations with 50 ml water. Dynamic images with participants in a sitting position were recorded for 10 min using a gamma camera. Scintigraphic imaging showed a delay in esophageal transit (greater than 15 s) in 28% of patients in the capsule group but in none of the tablet group (P<0.05). The mean transit times of the capsules and tablets were 23.8 and 3.3 s, respectively. Esophageal transit of film-coated tablets was faster than gelatin capsules, suggesting that film-coated tablets would be the appropriate formulation for all pivotal trials with risedronate and for subsequent commercialization.

Reduced tetracycline bioavailability caused by magnesium aluminum silicate in liquid formulations of bismuth subsalicylate.

RATIONALE: Bismuth subsalicylate, tetracycline hydrochloride, and metronidazole are widely used in combination for the treatment of Helicobacter pylori infections. As a result, there is renewed interest in the interaction between tetracycline and bismuth subsalicylate. OBJECTIVE: To determine whether the observed decrease in tetracycline bioavailability is due to the active drug bismuth subsalicylate via complexation, or to magnesium aluminum silicate (Veegum), an inactive excipient present only in the liquid formulation of bismuth subsalicylate, which might adsorb the tetracycline, rendering it unavailable for systemic absorption. METHODS: Eleven healthy volunteers participated in a randomized three-period, three-treatment complete crossover study with a 7-day washout interval between treatments. After an overnight fast, subjects received a 500-mg capsule of tetracycline hydrochloride with either tap water, 30 mL of bismuth subsalicylate (525 mg) liquid containing Veegum (Pepto-Bismol), or 30 mL of a specially formulated bismuth subsalicylate (525 mg) liquid without Veegum. Blood was collected for 24 hours after each dose of tetracycline. Serum was assayed for tetracycline concentration by HPLC. In addition, standard in vitro ultraviolet spectrophotometric methods were used to determine the capacity for complexation of bismuth with tetracycline and for adsorption of tetracycline to Veegum. RESULTS: Compared with the reference treatment of tetracycline hydrochloride with water, the liquid formulation of bismuth subsalicylate containing Veegum decreased the maximum serum concentration (Cmax) of tetracycline by 21% and the serum tetracycline AUC by 27% (p < 0.001). The bismuth subsalicylate formulation without Veegum resulted in decreases in Cmax and AUC of 11% and 13%, respectively (p > 0.05 vs. tetracycline hydrochloride with water). Multiple linear regression analysis of the spectral absorbance data demonstrated a calculated recovery of tetracycline of 100.9% and, therefore, a lack of in vitro complexation with bismuth. At pH 1.2, the amount of tetracycline adsorbed to Veegum ranged from 91.5% to 97.2% over the concentration range of 0.25 to 2 mg/mL. At pH 7.0, the values ranged from 82.9% to 83.9% over the concentration range of 0.25 to 1 mg/mL. CONCLUSIONS: In vitro and in vivo data from this study indicate that Veegum, a suspending agent, and not the active agent bismuth subsalicylate, is the primary ingredient in liquid formulations of bismuth subsalicylate responsible for a decrease in tetracycline bioavailability. In addition, the mechanism of interaction is not likely due to complexation between tetracycline and bismuth subsalicylate, as previously postulated, but rather is caused by adsorption of tetracycline to the excipient Veegum, which is present only in the liquid formulation of bismuth subsalicylate. The clinical relevance of this interaction has not been determined.

Impaired oesophageal transit of capsule versus tablet formulations in the elderly.

Drug induced oesophageal injury is an important and preventable cause of iatrogenic injury. In most cases the injury is considered to be due to mucosal contact from formulations lodged in the oesophagus. A scintigraphic study was performed comparing the oesophageal transit of enteric coated tablets with similar sized and shaped gelatin capsules, using a population of elderly healthy volunteers similar in age (50-79 years) to the population most likely to be receiving regular treatment. Twenty three volunteers injected the radiolabelled tablet or capsule with 50 ml of water while sitting on two separate occasions according to a randomisation schedule. Oesophageal transit was assessed by gamma scintigraphy. Gastric residence was also assessed in 11 of 23 subjects. While the tablet was readily cleared from the oesophagus, mean transit time 4.3 seconds (range 1.0-14.0), the capsule often showed a comparatively prolonged holdup, mean transit time 20.9 seconds (range 1.5-174.5). Ten of 11 tablets emptied from the stomach intact, while all 11 capsules broke up in the stomach. Gelatin capsules showed a clear tendency to remain within the oesophagus of healthy elderly volunteers, while similar sized enteric coated tablets did not. These studies show the importance of assessing oesophageal transit when designing the formulation of drugs with a potential for oesophageal injury.

Use of in vitro and in vivo data in the design, development, and quality control of sustained-release decongestant dosage forms.

STUDY OBJECTIVES: To investigate the use of in vitro and in vivo data in the development of a sustained-release, carbomer-based dosage form (Entex LA tablets); and to compare the in vitro dissolution of pseudoephedrine from a sustained-release, hydroxypropylcellulose-based dosage form (Entex PSE tablets) and four branded competitors with different sustained-release matrixes. DESIGN: Entex LA: In vitro testing by rotating bottle method and in vivo testing as double-blind, randomized, crossover, 24-hour study. Entex PSE and four competitors: in vitro testing by paddle method. SETTING: A pharmaceutical research and development facility. PATIENTS: Fifteen health, adult, volunteer Caucasian men between ages 18 and 40 years. MAIN RESULTS: Three formulations of Entex LA, varying in carbomer content by 3-5%, were studied. As carbomer content increased, in vitro dissolution rate directionally decreased. Plasma concentrations of active ingredients guaifenesin and phenylpropanolamine were also slightly although directionally decreased. The in vitro method was sensitive to small changes in carbomer content. Larger changes in carbomer content would be required to establish an in vitro-in vivo correlation. The in vitro comparison of Entex PSE and four similar branded products showed important differences in dissolution profiles. The mean cumulative release of pseudoephedrine from Entex PSE was 39% at 1.5 hours, 62% at 4.0 hours, and 80% at 8.0 hours. The other products released pseudoephedrine more rapidly, with the two fastest-dissolving products releasing 61-62% in the first 1.5 hours. CONCLUSIONS: Sustained-release, polymer-based dosage forms such as Entex LA and Entex PSE can be complex and pose special challenges in design, development, and reformulation. For Entex LA, changes in polymer concentration and dye system influenced the in vitro (dissolution) performance. In vivo (plasma) data helped establish a defined range in which carbomer concentration could be varied to achieve the best manufacturing performance without affecting product performance. For Entex PSE and four branded competitor products, the cumulative in vitro release (dissolution) of pseudoephedrine varied widely. Release from Entex PSE was more consistent and more gradual than that from some of the comparison products. Because the absorption rate of the active ingredients pseudoephedrine and gauifenesin is governed by the dissolution rate, the observed differences suggest that the products tested may differ in biologic performance. Although in vitro dissolution data may not necessarily correlate with in vivo differences in clinical safety or efficacy, the potential for unexpected product performance may be signaled by inconsistent in vitro dissolution characteristics, especially for sustained-release dosage forms.

Hospital nuclear pharmacy--a comparison of physician and pharmacist practice.

OBJECTIVE: Nuclear pharmacy is practiced in every hospital with a nuclear medicine clinic. Pharmacists control this practice in fewer than four percent of these institutions. The authors wish to bring to the attention of hospital pharmacists an area of practice in which they can make a significant contribution to the state of pharmacy practice. METHOD: The current state of the physician practice of nuclear pharmacy is described and compared with the accepted standards of pharmacy practice. CONCLUSIONS: Hospital pharmacists can improve pharmaceutical care administered in nuclear medicine by their participation in nuclear pharmacy practice and by the application of hospital pharmacy practice standards. It is also suggested that nuclear pharmacy should be integrated into the pharmacy curriculum at schools of pharmacy.