Este trabalho tem por objetivo desenvolver e caracterizar minicomprimidos de besilato de anlodipino para liberação imediata. Para tanto, foi realizado um estudo de pré-formulação de amostras do fármaco provenientes de diferentes fornecedores. Os resultados indicaram que o ativo é de alta solubilidade, de acordo com o Sistema de Classificação Biofarmacêutica. Além disso, não foram encontradas diferenças nas estruturas cristalinas das matérias-primas estudadas. Em seguida, foi feito um estudo de velocidade de dissolução intrínseca (VDI) do besilato de anlodipino, utilizando planejamento fatorial fracionado (33-1) cujas variáveis foram o meio de dissolução, velocidade de rotação e pressão de compactação. Verificou-se, que a VDI do besilato de anlodipino é afetada principalmente pelo meio de dissolução. Por fim, nove lotes de minicomprimidos (F1 a F9), contendo o fármaco para liberação imediata, foram produzidos de acordo com um planejamento fatorial completo 32, no qual foi avaliado o impacto do diluente e do desintegrante nas características físicas da formulação e na dissolução do ativo. Os resultados indicam que o diluente influencia no peso médio e relação diâmetro / espessura das formulações, o que é evidenciado pelas diferentes propriedades plásticas da celulose microcristalina e do fosfato de cálcio diidratado. Por outro lado, a eficiência de dissolução é uma resposta influenciada pelo uso do desintegrante. Considerando as recomendações da OMS para dissolução de medicamentos contendo fármacos de classe I ou III do Sistema de Classificação Biofarmacêutica, tal resultado indica que, somente com o uso de crospovidona ou croscarmelose, é possível alcançar uma liberação de 85% da dose em não mais do que 15 minutos, mesmo se tratando de um fármaco de alta solubilidade. / The purpose of this study was to develop and characterize immediate release mini-tablets containing amlodipine besylate. Accordingly, a pre-formulation study of samples of the drug from different suppliers was carried out. The results indicate that the active ingredient is highly-soluble, as defined by the Biopharmaceutics Classification System. Furthermore, no differences in the crystalline structures of the raw material in question were encountered. Subsequently, a study of the intrinsic dissolution rate (IDR) of amlodipine besylate was carried out using a fractional factorial design (33-1), whose variables were the dissolution medium, rotation speed and compaction pressure. We ascertained that the IDR of amlodipine besylate is mainly affected by the dissolution medium. Finally, nine batches of mini-tablets (F1 to F9) containing the drug for immediate release were produced in accordance with a complete factorial design (32), in which the impact of the diluent and the excipient on the physical characteristics of the formulation and on the dissolution of the active ingredient was assessed. The results indicate that the diluent influences the average weight and the diameter / thickeness ratio of the formulations, which is evidenced by the different plastic properties of microcrystalline cellulose and calcium phosphate dihydrate. On the other hand, dissolution efficiency is influenced by the use of the disintegrant. Considering WHO recommendations for the dissolution of medications containing class I or III drugs of the Biopharmaceutics Classification System, this result indicates that it is possible to attain 85% of the dosage dissolved in less than 15 minutes only with the use of crospovidone or croscarmellose, even for a highly-soluble drug.

Background: Abdominal solid organ transplantation has evolved from an experimental procedure to a well-established therapy within a few decades. This success is largely due to the introduction of calcineurin inhibitor immunosuppression. Tacrolimus is the most widely used calcineurin inhibitor but has a narrow therapeutic range which requires close drug monitoring to prevent both toxicity and inadequate immunosuppression. Previous studies in renal transplantation have shown that genetic polymorphisms, CYP3A5, CYP3A4*22 and ABCB1 can influence the bioavailability and pharmacokinetics of tacrolimus. These polymorphisms are closely linked to ethnicity and have never been studied in a Scottish population before. Additionally, increasing evidence suggests that high variability of tacrolimus is linked to increased graft loss in kidney transplant patients. Methods: 5889 subjects were genotyped for the genetic polymorphisms CYP3A5 A > G allele transition, CYP3A4*22 C > T and ABCB1 C > T transition. This included 4899 healthy individuals from Generation Scotland bio-resource and 990 patients who underwent renal, liver, or simultaneous pancreas kidney transplants or were organ donors. Tacrolimus dose, trough level and renal function were measured at 11 time points from date of transplant up to and including 12 months post-transplant. Clinical data including episodes of acute rejection, graft and patient survival were compared between the different genotypes. Separate analyses were undertaken for kidney, SPK transplants, as well as liver transplants, the latter looking at recipient and liver donor genotype. A separate cohort of 103 renal transplant patients converted from twice-daily to once-daily tacrolimus had their tacrolimus variability calculated and compared with graft survival. Results: The distribution of the 3 different genotypes of CYP3A5, CYP3A4*22 and ABCB1 were comparable with other Caucasian populations studied previously. In renal transplant recipient expression of the A allele (GA/AA) led to significantly increased dose requirements of tacrolimus and initially lower tacrolimus trough levels. The different genotypes of ABCB1 had no effect. Expression of a CYP3A4*22 T allele trended towards a lower tacrolimus dose requirement but this was not significant. There was no difference in renal function, graft survival or patient survival with any of the polymorphisms. SPK patients had comparable results. In the liver transplant patients, the donor genotype had a greater influence than the recipient one. The donors with CYP3A5 A allele expression had significantly higher tacrolimus dose requirements and lower initial tacrolimus levels. This was apparent to a lesser extent with the recipient expression of CYP3A5 and did not reach statistical significance at all time points. There was no significant difference in tacrolimus dose requirements or level with either donor or recipient expression of ABCB1 or CYP3A4*22. There was a significantly higher incidence of acute rejection in donor CYP3A5 A allele expressers of liver transplant patients in univariate and multivariate analysis. There was no significant different in acute rejection with ABCB1 or CYP3A4*22 genotype. No differences in graft or patient survival with either donor or recipient genotype of any of the 3 polymorphisms were noted. Conversion from twice-daily to once-daily tacrolimus in the first 12 months post-transplant reduced tacrolimus variability. Patients with high tacrolimus variability pre and post conversion had significantly greater graft loss than patients with low tacrolimus variability. Conclusion: CYP3A5 expression results in increased tacrolimus requirements to achieve adequate immunosuppression in renal transplant and SPK patients. Donor rather than recipient CYP3A5 expression is relevant for liver transplantation and dose requirements. There may be an association with donor CYP3A5 expression in liver transplant patients and acute rejection which needs further evaluation. ABCB1 and CYP3A4*22 do not appear to have a significant impact in any of the organ transplants. High tacrolimus variability is associated increased graft loss in renal transplant patients.

The thesis focuses on the yield curve modeling using the dynamic Nelson-Siegel approach. We propose two models of the yield curve and apply them on four currency areas - USD, EUR, GBP and CZK. At first, we distill the entire yield curve into the time-varying level, slope and curvature factors and estimate the parameters for individual currencies. Subsequently, we build a novel model investigating to what extent unobservable factors of the dynamic Nelson-Siegel model are determined by macroeconomic drivers. The main contribution of this thesis resides in the innovative approach to yield curve modeling with the application of advanced technical tools. Our primary objective was to increase the accuracy and the estimation power of the model. Moreover, we applied both models across different currency areas, which enabled us to compare the dynamics of the yield curves as well as the influence of the macroeconomic drivers. Interestingly, the results proved that both models we developed not only demonstrate strong validity, but also produce powerful estimates across all examined currencies. In addition, the incorporated macroeconomic factors contributed to reach higher precision of the modeling. JEL Classification: C51, C53, G17 Keywords: Nelson-Siegel, Kalman filter, Kalman smoother, Stace space formulation...

Este trabalho tem por objetivo desenvolver e caracterizar minicomprimidos de besilato de anlodipino para liberação imediata. Para tanto, foi realizado um estudo de pré-formulação de amostras do fármaco provenientes de diferentes fornecedores. Os resultados indicaram que o ativo é de alta solubilidade, de acordo com o Sistema de Classificação Biofarmacêutica. Além disso, não foram encontradas diferenças nas estruturas cristalinas das matérias-primas estudadas. Em seguida, foi feito um estudo de velocidade de dissolução intrínseca (VDI) do besilato de anlodipino, utilizando planejamento fatorial fracionado (33-1) cujas variáveis foram o meio de dissolução, velocidade de rotação e pressão de compactação. Verificou-se, que a VDI do besilato de anlodipino é afetada principalmente pelo meio de dissolução. Por fim, nove lotes de minicomprimidos (F1 a F9), contendo o fármaco para liberação imediata, foram produzidos de acordo com um planejamento fatorial completo 32, no qual foi avaliado o impacto do diluente e do desintegrante nas características físicas da formulação e na dissolução do ativo. Os resultados indicam que o diluente influencia no peso médio e relação diâmetro / espessura das formulações, o que é evidenciado pelas diferentes propriedades plásticas da celulose microcristalina e do fosfato de cálcio diidratado. Por outro lado, a eficiência de dissolução é uma resposta influenciada pelo uso do desintegrante. Considerando as recomendações da OMS para dissolução de medicamentos contendo fármacos de classe I ou III do Sistema de Classificação Biofarmacêutica, tal resultado indica que, somente com o uso de crospovidona ou croscarmelose, é possível alcançar uma liberação de 85% da dose em não mais do que 15 minutos, mesmo se tratando de um fármaco de alta solubilidade. / The purpose of this study was to develop and characterize immediate release mini-tablets containing amlodipine besylate. Accordingly, a pre-formulation study of samples of the drug from different suppliers was carried out. The results indicate that the active ingredient is highly-soluble, as defined by the Biopharmaceutics Classification System. Furthermore, no differences in the crystalline structures of the raw material in question were encountered. Subsequently, a study of the intrinsic dissolution rate (IDR) of amlodipine besylate was carried out using a fractional factorial design (33-1), whose variables were the dissolution medium, rotation speed and compaction pressure. We ascertained that the IDR of amlodipine besylate is mainly affected by the dissolution medium. Finally, nine batches of mini-tablets (F1 to F9) containing the drug for immediate release were produced in accordance with a complete factorial design (32), in which the impact of the diluent and the excipient on the physical characteristics of the formulation and on the dissolution of the active ingredient was assessed. The results indicate that the diluent influences the average weight and the diameter / thickeness ratio of the formulations, which is evidenced by the different plastic properties of microcrystalline cellulose and calcium phosphate dihydrate. On the other hand, dissolution efficiency is influenced by the use of the disintegrant. Considering WHO recommendations for the dissolution of medications containing class I or III drugs of the Biopharmaceutics Classification System, this result indicates that it is possible to attain 85% of the dosage dissolved in less than 15 minutes only with the use of crospovidone or croscarmellose, even for a highly-soluble drug.

Para o estudo de formulações da suspensão de benzoilmetronidazol recorreu-se a utilização de um planejamento estatístico dos ensaios. Este permitiu avaliar a pesquisa de maneira mais eficiente comparada ao método tradicional, onde o planejamento das experiências é conduzido estudando-se uma variável por vez, mantendo-se as outras constantes. A utilização do planejamento fatorial permitiu elucidar o efeito de diferentes fatores, individualmente ou sobre o ponto de vista das interações dos componentes da formulação da suspensão de benzoilmetronidazol. No trabalho foram utilizados o projeto fatorial fracionado quadrado greco-latino, onde se combinou 4 tipos de cada adjuvantes como, agentes tensoativos, agentes suspensores, poliois e conservantes obtendo-se 16 formulas. Por meio da análise de variância e a comparação das medias empregando o teste \"t\" de student selecionaram-se as melhores fórmulas. Por outro lado, para melhor compreensão das influências dos insumos na formulação procederam-se ensaios conforme o delineamento de meia fração de um projeto fatorial completo 24. A análise dos resultados foi realizada com as variáveis independentes codificadas avaliando-se seus efeitos estimados. Para a verificar se a região experimental já continha as melhores condições foi empregado o planejamento fatorial de primeira ordem. Por meio da equação para o modelo linear representativo desta região explorada, conclui-se que seria necessário realizar mais ensaios para obtenção de um modelo quadrático, ou seja, encontrar a região ótima por meio do arranjo fatorial de segunda ordem. Com o ponto ótimo estabelecido, pode-se determinar quais são os valores de cada variável independente. Por meio do modelo que representa a região, pode-se prever as respostas quando se varia os fatores dentro de limite estabelecido. O modelo foi representado em forma de equação e gráfico. A aplicação de técnicas de otimização no planejamento de fórmulas ampliaram, portanto, as perspectivas de racionalizar processos de formulação. / For the study of formulations of benzoyl metronidazole suspension went over the experimental design. This method permitted to evaluate the reserchs in a more efficient way when compared to the classical one variable-at-a time strategy. The use of fatorial design permitted to explain the effect of different factors, either individually or regarding the interactions of the components of formulation of the benzoyl metronidazole suspension. In this work it was used the fractional desings graeco-latin square, in which four types of adjuvants were combined as surfactant agents, suspending agents, polyols and preservatives to obtain sixteen formulations. Through the analysis of variance and comparison of average throug the \"t\" test of Student the more addequate formulation were selected. For a better comprehention of the influences of the adjuvants in the formulation experiments were conducted according to the delinegment of half-fraction of a complete factorial design 24. The analysis of the results were done with independent variables coded evaluating their estimated effects. To certify wether the experimental region had already the best condictions, the first order factorial design was used. By means of the equation for the representative linear model of the explored region, it was conclued that it would be necessary to do more experiments for the obtaintion of quadratic model, i.e. to locate the best re gion through thre factorial design of second order. With the optimum point could determine the best region for each dependent variable. Through the represented model, it is possible to foresee the answers to the factors when within the fixed limits. The model was represented in the form of equation and grafic. Therefore, the use of optimization techniques in the planning of formulations increase the perspectives in rationalizing formulations processes.

Submitted by Jaqueline Silva (jtas29@gmail.com) on 2014-09-22T17:08:11Z No. of bitstreams: 2 Santos Filho, Edvande-2014-dissertação.pdf: 3465269 bytes, checksum: fd50a85f70b6b596e0c5c4fb5fd18cb9 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Approved for entry into archive by Jaqueline Silva (jtas29@gmail.com) on 2014-09-22T18:45:16Z (GMT) No. of bitstreams: 2 Santos Filho, Edvande-2014-dissertação.pdf: 3465269 bytes, checksum: fd50a85f70b6b596e0c5c4fb5fd18cb9 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Made available in DSpace on 2014-09-22T18:45:16Z (GMT). No. of bitstreams: 2 Santos Filho, Edvande-2014-dissertação.pdf: 3465269 bytes, checksum: fd50a85f70b6b596e0c5c4fb5fd18cb9 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2014-03-20 / Introduction: Intestinal mucositis is a frequent limiting factor in antineoplastic therapy. There is no truly effective treatment targeted to cure this side effect. Curcuma longa L. has been reported to have antioxidant, antitumor and anti-inflammatory properties. Objective: This study aimed to evaluate the effects of a mucoadhesive formulation with Curcuma longa L. extract (MCL) in mice bearing intestinal mucositis induced by 5-FU. Methods: Swiss male adult mice (35-40g) were randomly allocated into three experimental groups of 5 animals each: control (mucoadhesive formulation 0.6mL/animal, via gavage, from day 1-6); exposed to 5-fluorouracil (5-FU 200mg/kg, i.p., in days 4-6); treated prophylactically and throughout mucositis with FMCL and exposed to 5-FU (MCL 15mg/kg, via gavage, from day 1-6, plus 5-FU 200mg/kg, i.p., in days 4-6). In the 7th day, animals were anesthetized by xylazine-ketamine followed by cervical dislocation. Duodenal samples, 10 cm after pyloric sphincter were removed to perform the essays. The parameters evaluated were: body weight assessment, morphometrics and histo-pathological analysis, apoptosis (p53/Bax, Bcl-2), cell proliferation (Ki-67), myelo-peroxidase (MPO) and malondialdehyde (MDA). Results: 5-FU induced intestinal mucositis characterized by villus shortening, crypt deepening, intense inflammatory infiltration, vacuolization and mucosal edema. Besides, 5-FU induced severe mice body mass reduction, apoptosis in cells of villus and crypts (p<0.001), increase in MPO activity and MDA formation (p<0.05), when compared to the control group. Treatment with MCL attenuated body mass loss, protected intestinal mucosa from villus shortening and crypt deepening, decrease MPO activity and MDA formation (p<0.05). In this group of animals was also observed high expression of the cell proliferation marker Ki-67 in epithelial cells lining of villus and crypts. Conclusion: Our data confirm the therapeutic potential of MCL for the treatment of intestinal mucositis in mice. Further studies are needed to assess this formulation potential for human use. / Introdução: A mucosite intestinal é um dos efeitos adversos limitantes das terapias antineoplásicas. Não existe tratamento realmente efetivo direcionado a cura deste efeito colateral grave. A Curcuma longa L. tem sido proposta como candidata ao tratamento de várias doenças por possuir propriedades antioxidante, antitumoral e anti-inflamatória. Objetivo: Este estudo objetivou avaliar os efeitos da formulação mucoadesiva com extrato de Curcuma longa L. (FMCL) em animais portadores de mucosite intestinal induzida por 5-FU. Métodos: Camundongos Swiss adultos, machos (35-40g) foram aleatoriamente alocados em três grupos experimentais de 5 animais cada: [1] controle (formulação mucoadesiva 0.6mL/animal, via gavagem, do dia 1-6); [2] exposto ao 5-fluorouracil (5-FU 200mg/kg, i.p., dos dias 4-6), [3] tratado profilaticamente e ao curso da mucosite com FMCL e exposto ao 5-FU (FMCL 15mg/kg, via gavagem dos dias 1-6, mais 5-FU 200mg/kg, i.p., dos dias 4-6). No sétimo dia, os animais foram anestesiados por xilazina-ketamina seguido por deslocamento cervical. Amostras de duodeno, 10 cm após o esfíncter pilórico, foram coletadas para realização dos ensaios. Os parâmetros avaliados foram: avaliação de massa corporal, análise morfométrica e histopatológica, apoptose (p53/Bax; Bcl-2), proliferação celular (Ki-67), mieloperoxidase (MPO) e malondialdeído (MDA) Resultados: A administração de 5-FU induziu mucosite intestinal caracterizada por encurtamento das vilosidades, aprofundamento das criptas, intenso infiltrado infla-matório, vacuolização e edema na mucosa. Além disso, o 5-FU induziu grave redução de massa corporal nos camundongos e apoptose nas células das vilosida-des e criptas, quando comparado ao grupo controle (p<0,001). Foi observado ainda aumento na atividade de MPO e formação de MDA, quando comparado ao grupo controle (p<0,05). Por outro lado, o tratamento com a FMCL atenuou a perda de massa corporal dos animais com mucosite. Ademais, protegeu a mucosa intestinal da redução no tamanho das vilosidades e criptas induzidas pelo 5-FU. Neste grupo de animais foi observado ainda aumento na expressão do marcador de proliferação celular Ki-67 nas células epiteliais de revestimento das vilosidades e criptas intestinais. O tratamento também diminuiu significantemente a atividade de MPO e formação de MDA (p<0,05). Conclusão: Os dados confirmam o potencial terapêutico da FMCL no tratamento da mucosite intestinal em camundongos. Estudos adicionais são necessários para que esta formulação possa se tornar uma alternativa segura para uso em seres humanos.

In the present thesis we provide compact extended formulations for a wide range of polytopes associated with the constraint satisfaction problem (CSP), monadic second order logic (MSO) on graphs, and extensions of MSO, when the given instances have bounded treewidth. We show that our extended formulations have additional useful properties, and we uncover connections between MSO and CSP. We conclude that a combination of the MSO logic, CSP and geometry provides an extensible framework for the design of compact extended formulations and parameterized algorithms for graphs of bounded treewidth. Putting our framework to use, we settle the parameterized complexity landscape for various extensions of MSO when parameterized by two important graph width parameters, namely treewidth and neighborhood diversity. We discover that the (non)linearity of the MSO extension determines the difference between fixedparameter tractability and intractability when parameterized by neighborhood diversity. Finally, we study shifted combinatorial optimization, a new nonlinear optimization framework generalizing standard combinatorial optimization, and provide initial findings from the perspective of parameterized complexity

A presente dissertação consiste em um estudo sobre políticas públicas de cultura. A atuação do Estado sobre esse campo deve envolver desde a concepção e formulação da política até a avaliação dos impactos. Contudo, não se identifica no campo da gestão pública uma cultura de avaliação para as políticas culturais. Os Estudos Culturais contribuíram para a definição da cultura como objeto de pesquisa e investigação no universo acadêmico, bem como para a análise de suas dimensões e das relações sociais envolvidas nas experiências em cultura. A partir desse enfoque é possível tratar da ação do Poder Público na concretização de políticas especificamente voltadas à Cultura, sob a perspectiva de sua relevância nos processos de desenvolvimento humano e de protagonismo social e democrático. A criação do primeiro órgão público voltado exclusivamente à concepção, formulação e definição de políticas públicas para cultura foi o Departamento de Cultura da cidade de São Paulo, fato que marca historicamente a organização das ações do Estado em torno desse campo. A implementação de uma política pública requer esforços próprios ao seu objeto, tais como a produção de dados, diagnósticos, acompanhamento e avaliação. A Teoria dos Indicadores permite tratar desse processo e sustentar a relevância de sistemas de monitoramento e avaliação também para o campo da cultura. A investigação de iniciativas já em curso e de alguns casos concretos se faz relevante à medida que se discute a propriedade e pertinência de se criarem indicadores culturais. Para a avaliação das políticas públicas são necessários indicadores de eficiência, eficácia e efetividade. Em conclusão, a matriz de avaliação proposta serve como exercício prático para avaliação de uma política pública para Cultura / This dissertation is a study of public policies of culture. The Government action in this field must involve areas from the design and formulation of policy, to an assessment of its implementation impacts. Yet for, it is not identifiable in the field of public management any kind of \"culture of evaluation\" directed to cultural policies. Cultural studies have contributed to the definition of culture as an object of research and investigation in the academic environment, as well as to the analysis of its dimensions and of the social relations involved in the experiences in the culture fields. From this approach, it is possible to analyze the Government action in the implementation of culture policies, under the perspective of its relevance on human development and social and democratic leadership. The creation of the first public agency focused exclusively on the inception, formulation and definition of culture public policy was the Department of Culture of the City of São Paulo, fact that historically branded the organization of Government action around the field. The Implementation of public policy requires efforts inherent to its object of action, such as data production, diagnostics, monitoring and evaluation. The Theory of Indicators allows an approach to this process, and sustains the relevance of monitoring and evaluation systems designed for the cultural field. The research of initiatives already in progress, and also of some concrete cases, is relevant amid the discussion of the importance of creation of cultural indicators. For the evaluation of public policies, efficiency, efficacy and effectiveness indicators are needed. In conclusion, the proposed evaluation matrix serves as a practical exercise for the evaluation of a public policy of Culture

Drug based nanoparticle (NP) formulations have gained considerable attention over the past decade for their use in various drug delivery systems. NPs have been shown to increase bioavailability, decrease side effects of highly toxic drugs, and prolong drug release. Furthermore, polymer based, biodegradable nanodelivery has become increasing popular in the field of NP formulation because of their high degree of compatibility and low rate of toxicity. Due to their popularity, commercially available polymers such as poly lactic acid (PLA), poly glycolic acid (PGA) and polylactic-co-glycolic acid (PLGA) are commonly used in the development and design of new nano based delivery systems. Nonsteriodal anti-inflammatory drugs (NSAIDs) are commonly used for the treatment of pain and inflammation. NSAIDs such as diclofenac and celecoxib function by blocking cyclooxygenase expression and reducing prostaglandin synthesis. Unfortunately, the pharmacological actions of NSAIDs can lead to the development of several adverse side effects such as gastrointestinal ulceration and bleeding. The aim of this study was to formulate and optimize diclofenac or celecoxib entrapped polymer NPs using an emulsion-diffusion-evaporation technique. NP formulations were evaluated based on specific formula parameters such as particle size, zeta potential, morphology, and entrapment efficiency. Effects of stabilizer type, stabilizer concentration, centrifugal force, drug amount, and/or emulsifier (lecithin) on nanoparticle characterization were examined for formula optimization. Results of the formulation studies showed that NPs developed using polylactide-co-glycolide (PLGA) polymers and the stabilizer didodecyldimethylammonium bromide (DMAB) demonstrated enhanced stability, drug entrapment, and reduced particle size. These findings demonstrate an effective method for polymer NP formulation of diclofenac or celecoxib. Furthermore, the results reported herein support a novel method of drug delivery that may function to reduce known adverse effects of these pharmacotherapeutic agents.

The US Food and Drug Administration (FDA) is encouraging the innovation of long-acting opioid formulations that are manipulation-resistant. The purpose of this commentary is to assess the benefits and limitations of abuse-deterrent opioid formulations (ADFs) and discuss their role in mitigating the current opioid epidemic. ADFs have been created with chemical properties that make it difficult for people who non-medically use prescription drugs to crush and dissolve opioid tablets, as well as by combining opioids with antagonists such as naloxone or naltrexone, which are released only when the dosage form has been manipulated or the drug is taken by a non-intended route. Despite these and other technologies, consensus regarding the effectiveness of these formulations in preventing non-medical use is lacking given the difficulty in obtaining post-marketing data. Researchers also question if the creation of abuse-deterrent drugs will have a positive effect on those struggling with a severe opioid-use disorder, fearing that current opioid users will simply find a new – perhaps more dangerous – drug of choice. Abuse-deterrent opioids are still opioids, and although they may make manipulation more difficult than non-ADF formulations, they are not “abuse proof.” The introduction of ADFs could provide a false sense of security among prescribers and dispensers, and we fear that ADFs may have a minimal impact on non-medical use of prescription opioids. Further epidemiological studies will be required to determine the large-scale impact of abuse-deterrent opioids in preventing opioid use disorder and its downstream consequences.