RESUMO
The compatibility of thermodynamically unstable polymorph of two active pharmaceutical compounds (xylazine hydrochloride form X and zopiclone form C) with different excipients was investigated. The effects of the excipient and its amount in the sample on the thermal properties and possible chemical interactions were studied. The most commonly used excipients in the pharmaceutical industry - calcium carbonate, lactose hydrate, cellulose, magnesium stearate hydrate and calcium stearate hydrate were selected for this study. The dependence of the phase transition rate from an unstable to a more stable polymorph on the excipients and their amounts in the initial sample was analysed at 80°C, and the corresponding phase transition rate constants were calculated.
Assuntos
Compostos Azabicíclicos/química , Excipientes/química , Piperazinas/química , Xilazina/química , Indústria Farmacêutica/métodos , Estabilidade de Medicamentos , Cinética , Transição de Fase , Temperatura , TermodinâmicaRESUMO
OBJECTIVES: A "chiral switch" occurs in the pharmaceutical market when a drug made up of 2 enantiomer forms is replaced with a purified single-enantiomer version, often in the context of a patent expiration. We studied the prevalence of chiral switching in the United States over the past decade, including trends in use of, and expenditures on, these products in Medicaid. STUDY DESIGN: Retrospective analysis. METHODS: We used US Adopted Names prefixes (lev/levo/ar/es/dex/dextro) to identify all single-enantiomer drugs approved from 2001 to 2011. From publicly available US Food and Drug Administration (FDA) approval documents, we extracted the characteristics of the pivotal premarket trials for the single enantiomers. Specifically, we evaluated whether the single enantiomer was directly compared with the precursor racemic drug and whether there was evidence of superior efficacy. We used quarterly drug expenditure data from each state Medicaid program to chart trends in use of, and spending on, the single-enantiomer products and their racemic precursors during the study period. RESULTS: From 2001 to 2011, the FDA approved 9 single-enantiomer products: dexlansoprazole, levoleucovorin, levocetirizine, armodafinil, arformoterol, eszopiclone, escitalopram, dexmethylphenidate, and esomeprazole. Of those 9 drugs, 3 had at least 1 pre-approval randomized trial that included the racemic precursor as a direct comparator, but there was no evidence of superiority of the single enantiomer over the racemic at comparable doses. Between 2001 and 2011, US Medicaid programs spent approximately $6.3 billion on these 9 single-enantiomer drugs. CONCLUSIONS: Recently approved single-enantiomer drugs showed no evidence of superior efficacy over the older racemic precursors in the pivotal trials leading to their approval, and in a majority of cases, they were not directly compared.
Assuntos
Aprovação de Drogas , Prescrições de Medicamentos/estatística & dados numéricos , Medicaid/economia , Antídotos/química , Antídotos/economia , Compostos Azabicíclicos/química , Compostos Azabicíclicos/economia , Compostos Benzidrílicos/química , Compostos Benzidrílicos/economia , Broncodilatadores/química , Broncodilatadores/economia , Estimulantes do Sistema Nervoso Central/química , Estimulantes do Sistema Nervoso Central/economia , Cetirizina/química , Cetirizina/economia , Dexlansoprazol/química , Dexlansoprazol/economia , Cloridrato de Dexmetilfenidato/química , Cloridrato de Dexmetilfenidato/economia , Medicamentos Genéricos/economia , Esomeprazol/química , Esomeprazol/economia , Zopiclona , Etanolaminas/química , Etanolaminas/economia , Fumarato de Formoterol , Antagonistas não Sedativos dos Receptores H1 da Histamina/química , Antagonistas não Sedativos dos Receptores H1 da Histamina/economia , Humanos , Hipnóticos e Sedativos/química , Hipnóticos e Sedativos/economia , Levoleucovorina/química , Levoleucovorina/economia , Modafinila , Patentes como Assunto , Piperazinas/química , Piperazinas/economia , Inibidores da Bomba de Prótons/química , Inibidores da Bomba de Prótons/economia , Estudos Retrospectivos , Estereoisomerismo , Estados Unidos , United States Food and Drug Administration , Promotores da Vigília/química , Promotores da Vigília/economiaRESUMO
Compound 1, a potent and irreversible inhibitor of ß-lactamases, is in clinical trials with ß-lactam antibiotics for the treatment of serious and antibiotic-resistant bacterial infections. A short, scalable, and cost-effective route for the production of this densely functionalized polycyclic molecule is described.
Assuntos
Antibacterianos/farmacologia , Compostos Azabicíclicos/farmacologia , Inibidores Enzimáticos/farmacologia , Compostos Policíclicos/farmacologia , Inibidores de beta-Lactamases , Antibacterianos/síntese química , Antibacterianos/química , Compostos Azabicíclicos/síntese química , Compostos Azabicíclicos/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Estrutura Molecular , Compostos Policíclicos/síntese química , Compostos Policíclicos/química , Relação Estrutura-Atividade , beta-Lactamases/metabolismoAssuntos
Compostos Azabicíclicos , Medicamentos Genéricos , Patentes como Assunto/legislação & jurisprudência , Piperazinas , Compostos Azabicíclicos/química , Medicamentos Genéricos/química , Zopiclona , Humanos , Piperazinas/química , Estereoisomerismo , Estados Unidos , United States Food and Drug AdministrationRESUMO
Eszopiclone is the single (S)-enantiomer of the cyclopyrrolone hypnotic zopiclone. It was marketed in the U.S. in December 2004. Its kinetics and possible mode of action, pivotal regulatory trials and its use in insomnia comorbid with other conditions are reviewed, together with trials in patients with obstructive sleep apnea syndromes. Safety and tolerability aspects are discussed, including its dysgeusic profile and effects on memory, cognitive and psychomotor function. U.S.-based pharmacoeconomic data are included together with the design features of key regulatory studies submitted for regulatory approval in Japan.