Drugs in R & D最新文献

Background: Orodispersible tablets (ODTs) are tablet or wafer forms of medication that disintegrate in the mouth, aided only by saliva. ODTs rely on different fast dissolve/disintegration manufacturing technologies.

Objectives: Disintegration time differences for several olanzapine ODT forms were investigated. Risperdal M-Tab(®) was included as a non-olanzapine ODT comparator.

Research design and methods: Eleven olanzapine ODT examples and orodispersible risperidone strengths were evaluated in vitro for formulation composition, manufacturing method, disintegration and dissolution characteristics, and formulation differences in comparison with freeze dried Zydis(®) ODT. Automated dissolution test equipment captured ODT dissolution rates by measuring real-time release of active ingredient. A high-speed video camera was used to capture tablet disintegration times in warm simulated saliva.

Main outcome measure: The main outcome measure was the disintegration and dissolution characteristics of the ODT formulations.

Results: The ODT manufacturing method was associated with time to disintegrate; the fastest were freeze dried tablets, followed by soft compressed tablets and then hard/dense tablets. Olanzapine Zydis(®) was the only ODT that completely disintegrated in less than 4 s for all strengths (5, 10, 15, and 20 mg), followed by 5-mg Prolanz FAST(®) (12 s) and then risperidone ODT 4 mg (40 s). Reasons for slow dissolution of the olanzapine generics may include low product potency, excipient binding, excipient solubility, active ingredient particle size and incomplete disintegration.

Conclusions: Differences in the formulation and manufacturing process of olanzapine ODTs appear to have a strong influence on the disintegration time of the active compound; differences that may potentially impact their use in clinical practice.

Background and objectives: Busulfan is used as part of a conditioning regimen prior to hematopoietic stem cell transplantation for the treatment of certain cancers and immune deficiency syndromes. Due to its instability in aqueous preparations, busulfan for infusion is prepared from a concentrate and has a relatively short shelf life once prepared. The purpose of this study was to identify the most suitable storage container and temperature to maximize the shelf life of busulfan therapeutic infusions prepared from Busilvex(®).

Methods: Busilvex(®) 6 mg/mL was diluted to 0.55 mg/mL with 0.9 % NaCl and aliquots dispensed into polypropylene syringes, polyvinyl chloride bags, and glass bottles. Three storage temperatures were evaluated: 2-8 °C, 13-15 °C (thermostatically controlled chamber), and room temperature (20 ± 5 °C). At set time points, samples were analysed for busulfan content, using a high-performance liquid chromatography (HPLC) system with ultraviolet detection. The change in pH and osmolarity on storage was also determined, and solutions were inspected visually for formation of a precipitate or colour change. To determine the contribution of precipitation to loss of busulfan content on storage, samples from one time series were treated with the solvent dimethylacetamide prior to HPLC separation and quantitation of busulfan.

Results: The results of the active substance content monitoring study over a 48-h period demonstrate that busulfan solution is stable at a 5 % threshold, at 2-8 °C for 16 h in syringes, 14 h in glass bottles, and 6 h in bags. In addition, the period of stability decreases as the temperature increases (4 h at 20 ± 5 °C). The solution is considered to be stable, subject to precipitation liable to be observed regardless of the temperature.

Conclusion: The best stability was observed for busulfan solutions placed at 2-8 °C in syringes. This study demonstrated that precipitation, in addition to hydrolysis, has a significant influence on the busulfan content.

Background and objectives: Limited data are available regarding the use of golimumab (100 mg) every 4 weeks, with or without methotrexate (MTX). The aim of this retrospective analysis was to evaluate the effectiveness and safety of golimumab following usual clinical practice in Japanese patients with rheumatoid arthritis (RA) according to the recommendations given in the Japanese package insert.

Patients and methods: Japanese RA patients with moderate-to-high disease activity, according to the 28-joint disease activity score based on C-reactive protein (DAS28-CRP) criteria, despite treatment with MTX or another biological agent, were enrolled. Patients were assigned to 50 mg golimumab plus MTX or 100 mg golimumab monotherapy every 4 weeks for 24 weeks. All patients were given MTX if it was not contraindicated. The primary endpoint was the proportion of patients achieving clinical remission (defined as a DAS28-CRP <2.3 or a simplified disease activity index [SDAI] score <3.3) at 24 weeks.

Results: Most patients received combined 50 mg golimumab plus MTX (41/43). In these patients, the primary endpoint, clinical remission, was attained in 83 % of patients according to DAS28-CRP criteria (p < 0.001) and 69 % according to SDAI criteria (p < 0.001) by week 24. Adverse events were reported in 11.6 % of patients receiving golimumab.

Conclusions: Golimumab (50 mg) plus MTX effectively reduced the signs and symptoms of RA and was generally well tolerated in patients with an inadequate response to MTX and other biological agents.

Background and objectives: Aspirin is widely used for short-term treatment of pain, fever or colds, but there are only limited data regarding the safety of this use. To summarize the available data on this topic, we conducted a meta-analysis of the published clinical trial literature regarding the gastrointestinal adverse effects of short-term use of aspirin in comparison with placebo and other medications commonly used for the same purpose.

Data sources and methods: An extensive literature search identified 119,310 articles regarding possible adverse effects of aspirin, among which 23,131 appeared to possibly include relevant data. An automated text-mining procedure was used to score the references for potential relevance for the meta-analysis. The 3,983 highest-scoring articles were reviewed individually to identify those with data that could be included in this analysis. Ultimately, 78 relevant articles were identified that contained gastrointestinal adverse event data from clinical trials of aspirin versus placebo or an active comparator. Odds ratios (ORs) computed using a Mantel-Haenszel estimator were used to summarize the comparative effects on dyspepsia, nausea/vomiting, and abdominal pain, considered separately and also aggregated as 'minor gastrointestinal events'. Gastrointestinal bleeds, ulcers, and perforations were also investigated.

Results: Data were obtained regarding 19,829 subjects (34 % treated with aspirin, 17 % placebo, and 49 % an active comparator). About half of the aspirin subjects took a single dose. Aspirin was associated with a higher risk of minor gastrointestinal events than placebo or active comparators: the summary ORs were 1.46 (95 % confidence interval [CI] 1.15-1.86) and 1.81 (95 % CI 1.61-2.04), respectively. Ulcers, perforation, and serious bleeding were not seen after use of aspirin or any of the other interventions.

Conclusions: During short-term use, aspirin is associated with a higher frequency of gastrointestinal complaints than other medications commonly used for treatment of pain, colds, and fever. Serious adverse events were not observed with aspirin or any of the comparators.