京都大学 / 0048 / 新制・課程博士 / 博士(農学) / 甲第19020号 / 農博第2098号 / 新制||農||1030(附属図書館) / 学位論文||H27||N4902(農学部図書室) / 31971 / 京都大学大学院農学研究科応用生命科学専攻 / (主査)教授 加納 健司, 教授 宮川 恒, 教授 三上 文三 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DFAM

Enabling formulations are growing in popularity due to the large number of drugs within the pharmaceutical development pipeline that possess poor water solubility. These sophisticated formulation techniques can increase the solubility of the drug in aqueous media and/or aid in their dissolution. Amorphous solid dispersions (ASDs) are of particular interest due to their ability to generate highly supersaturated solutions upon dissolution. Typically, an ASD consists of amorphous drug homogenously blended with an amphiphilic polymer. The polymer has several roles including to facilitate drug release, as well as to inhibit crystallization of the drug from the solid matrix and from the supersaturated solution generated following dissolution. A phenomenon termed liquid-liquid phase separation (LLPS) or glass-liquid phase separation (GLPS) can occur during ASD dissolution when the amorphous solubility is exceeded. Here the drug attains its maximum thermodynamic activity in solution with the excess drug forming a second phase consisting of colloidal amorphous aggregates. It has been hypothesized that the presence of the colloidal amorphous aggregates could be advantageous in vivo since they can act as a drug reservoir and subsequently maintain the drug at its maximum thermodynamic activity in the gastro-intestinal fluid following solution depletion arising from permeation across the gastrointestinal membrane. However, there are few in vivo studies which test this hypothesis. If colloids form, the polymer must also inhibit crystallization from the drug-rich phase. Hence, the polymer has many roles during ASD dissolution making rational polymer selection for ASD formulation a complex process. While many studies, both past and present, probe drug release during dissolution, a limited number of studies address a mechanistic understanding of the polymer role during dissolution. The purpose of this study was to 1) investigate the interplay of the polymer’s ability to inhibit crystallization (thought to be primarily through hydrophobic interactions) and to facilitate drug release (via hydrophilic interaction with the aqueous media) on ASD performance and 2) determine the in vivo relevance of colloidal amorphous aggregates. Herein, a preliminary correlation was established between in vitro diffusion cell experiments and the amount of drug absorbed in rats. Further, it was found that rapid drug release through use of a relatively hydrophilic polymer is essential, and that the best crystallization inhibitors may be too hydrophobic to achieve adequate release. Therefore, a polymer needs to be an adequate crystallization inhibitor, but be able to release the drug upon oral administration. The implications from this study provides the necessary foundation for assessing ASD phase behavior and performance in vitro in order to make improved in vivo predictions. Ultimately, this research is expected to improve the speed of life-saving drugs progressing through the development pipeline and reduce drug development costs by reducing the need for animal testing.

Humic substances, such as the closely related humic and fulvic acids are ubiquitous, naturally occurring organic macromolecules of complex but undefined structure. These compounds are known complexing agents due to their supramolecular like structures and are capable of binding a wide variety of compounds. Numerous studies have confirmed that humic and fulvic acids exhibit diverse medicinal and therapeutic properties. For this reason, alternative or “natural” medicinal preparations rich in these substances are being self-administered, often concomitantly with conventional drugs. The possibility exists that these humic substances, found in the alternative medicinal products, may result in drug-drug interactions and bind to simultaneously ingested drugs. Complex formation may affect absorption and alter overall bioavailability. Changes in these parameters may lead to reduced therapeutic effect or toxic side effects of prescribed drugs in patients. Similarly, these humic substances may bind to and alter the uptake of ingested nutrients, such as vitamins and minerals, obtained from food sources as well as dietary supplements. Changes in absorption may result in a loss of proper physiological functioning in the body or in unwanted effects of overdose. This study investigated the effect of fulvic and humic acids on the absorption of commonly administered classes of drugs, vitamins and minerals using the everted mouse gut model that was successfully used to assess the membrane transport of the test compounds. This model made use of everted segments of excised intestinal tissue placed in Krebs Ringer Buffer (pH7.4), where physiological functioning of the tissue is maintained for up to two hours after excision. The amount of test compound which crossed through the intestinal membrane without and in the presence of each humic substance was quantified using LC-MS/MS methods developed for each of the drugs and vitamins, and ICP-MS, in the case of the minerals. The amount of test compound absorbed alone was compared to the amount absorbed when in the presence of each humic substance. Changes in the uptake, for each test compound was noted, the extent of the absorption increase or decrease was compound specific. The changes in absorption observed could be attributed to changes in compound solubility and mechanism of transport across the intestinal membrane once in complex. Drugs and vitamins were seen to be more prone to decreases in absorption in the presence of the humic substances, whereas the majority of the minerals showed significantly increased absorption. Binding of the minerals to the humic substances through chelation, and not complex formation, could have a greater effect on compound solubility. Health care professionals, as well as individuals ingesting these and other substances concurrently, should be aware of the potential effects on absorption that may occur due to drug-drug interactions in order to avoid a loss of therapeutic/physiological activity or negative toxic symptoms. / Dissertation (MSc)--University of Pretoria, 2015. / tm2015 / Pharmacology / MSc / Unrestricted

Poorly water soluble drugs have been manipulated to make them more soluble, increasing the bioavailability of these drugs. Several cryogenic processes allow for production of drug nanoparticles, without mechanical stress that could cause degradation. The Ultra Rapid Freezing (URF) process is a technique which improves water solubility of drugs by reducing primary drug particle size by producing amorphous solid dispersions. Heat conduction is improved, using a cryogenic material with a high thermal conductivity relative to the solution being frozen to maintain the surface temperature and heat transfer rate while the solution is being frozen. With URF technology, the freezing rate is fixed, which drives the particle formation and determines its characteristics. Supersaturation of drug in aqueous solution can allow for better absorption of the drug via the oral and pulmonary routes. Drug formulations that supersaturate the dissolution media show the possibility for increased bioavailability from an amorphous drug form. If the concentration of drug in solution is significantly increased, higher chemical potential will lead to an increase in flux across an exposed membrane, leading to higher blood levels for an amorphous drug, compared to an identical crystalline formulation. During oral delivery, supersaturated drug concentrations would also saturate PGP efflux sites in the gut lumen, increasing the drug's bioavailability. Saturated PGP sites show zero order efflux kinetics, so increasing the drug concentration in supersaturated biological fluid will increase serum drug levels. High supersaturation levels maintained for prolonged periods would have a beneficial effect on a drug's absolute bioavailability. Pulmonary administration offers therapeutic advantages over more invasive routes of administration. Limited amount of metabolizing enzymes like CYP 3A4 in lung tissue along with avoidance of first pass metabolism are advantages to pulmonary delivery. The objective of the research presented in this dissertation is to show the versatility of nanoparticulate poorly water soluble drug formulations. Due to the reduced particle size and the URF manufacturing process, a wide range of applications can be used with these nanoparticles. Oral and pulmonary administration routes can be explored using nanoparticles, but in vitro cell culture testing can show clinical benefits from this type of processing technology. / text

Introdução: O metilfenidato de liberação imediata (MFD-LI) é um psicofármaco receitado mundialmente para o tratamento do Transtorno de Déficit de Atenção/hiperatividade (TDAH). Embora eficaz, o MFD-LI está associado a problemas de adesão ao tratamento, uma vez que os pacientes necessitam ingerir os comprimidos várias vezes ao dia. O Spheroidal Oral Drug Absorption System (SODAS™) é uma formulação de metilfenidato de liberação prolongada (MFD-LP) que mimetiza a administração de MFD-LI duas vezes ao dia, e que apresenta menor flutuação nos níveis séricos. Nesta formulação, cinqüenta por cento dos grânulos com revestimento para liberação entérica são liberados aproximadamente 4 horas após a administração, proporcionando um perfil de ação semelhante a duas tomadas ao dia do MFD-LI. O MFD SODAS™ libera de imediato 50% do medicamento, proporcionando um rápido início de ação quando comparado ao sistema de liberação OROS®. Poucos estudos avaliaram a troca do MFD-LI para o MFD-LP, sendo que desses, apenas crianças e adolescentes foram avaliados, e nenhum verificou os preditores de insatisfação da troca do MFD-LI para o MFD-LP. Objetivos: Este estudo tem como objetivo avaliar os sintomas de TDAH, ou preditores de insatisfação e/ou desistência do tratamento naqueles pacientes clinicamente estáveis que fizeram a troca do MDF-LI para o MFD SODAS™. Método: Os critérios de inclusão foram: diagnóstico de TDAH de acordo com os critérios do DSM-IV, e estabilidade de sintomas com o uso do MFD-LI. Os critérios de exclusão foram: condição clínica coexistente que pudesse impedir a prescrição de MFD SODAS™; diagnóstico de abuso ou dependência de álcool e/ou drogas de abuso; diagnóstico prévio de retardo mental moderado; tratamento psicoterápico concomitante. Este é um ensaio clínico aberto realizado em oito semanas. Os pacientes foram designados a receber doses de MFD SODAS™ de acordo com a dose de MFD-LI previamente estabelecida. A eficácia foi avaliada através das escalas SNAP-IV e CGI-S, e eventos adversos através da Barkley's Side Effect Rating Scale (SERS). Foi solicitado aos participantes que classificassem sua satisfação com o tratamento através de uma escala Likert de 5 pontos. Também foram avaliados os seguintes potenciais preditores de resposta: sexo, idade, etnia, nível socioeconômico, comorbidades, subtipos de TDAH, resultados das escalas SNAP-IV e SERS no baseline, tempo de tratamento, tratamento farmacológico concomitante, dose de MFD-LI prévia ao início do estudo e a existência de pausa do tratamento nos finais de semana. Resultados: A partir de uma amostra total de 207 crianças, adolescentes e adultos (provenientes do ambulatório adulto e infantil de transtorno de déficit de atenção/hiperatividade do Hospital de Clínicas de Porto Alegre) foi possível contatar 133 pacientes, os quais sessenta e dois pacientes foram elegíveis a participar do estudo, e 47 completaram as oito semanas de tratamento. Não se encontrou diferença significativa no escore total do SNAP-IV durante o protocolo - baseline, semana 4 e 8 [F(1, 51,26) =0,012; p=0,913]. Ao todo, 46 (74,2%) dos pacientes relataram estar satisfeitos com o novo tratamento, 16 (25,8%) estavam insatisfeitos ou saíram do protocolo. Nas análises univariadas, foi detectada uma tendência para a associação entre etnia e insatisfação (p=0.05). Não se encontrou uma diferença significativa nos escores da SERS durante o ensaio clínico [F(1, 111,49) =0,748; p=0,389]. Em onze eventos adversos ocorreram ao menos 5% em alguma das avaliações (baseline, 4ª ou 8ª semana). Um adulto, que apresentava uma doença cardiovascular previamente ao estudo, apresentou um acidente vascular cerebral hemorrágico (AVCH) após a quarta semana de tratamento, evoluindo ao óbito após três semanas. Conclusão: Poucos estudos abordaram os sintomas de TDAH após a troca do MFD-LI para qualquer formulação de MFD-LP, e nenhum estudo prévio foi conduzido em populações de países em desenvolvimento ou em amostras com adultos. A taxa de satisfação encontrada (74,2%) na troca do MFD-LI para MFD SODAS™ possivelmente reflete a conveniência da dose única diária deste MFD-LP, como já especulado em estudos prévios. Não foram identificados fatores preditores de insatisfação. O número médio de efeitos colaterais pode ser considerado alto, mas isso pode ser o resultado do uso de uma escala de avaliação adequada, diferentemente do relato espontâneo do evento adverso. Não foi possível encontrar uma relação direta entre os efeitos do MFD SODAS™ e a morte por AVCH ocorrida em um dos sujeitos da amostra. Entretanto, o evento cardiovascular ocorrido sugere extrema cautela ao medicar pacientes com doenças cardiovasculares, conforme proposto pelo FDA. Os achados desse estudo sugerem que o MFD SODAS™ possui eficácia e perfil de eventos adversos similares ao MFD-LI. / Introduction: Immediate-release methylphenidate (MPH-IR) is a pharmacological treatment prescribed worldwide for patients with attention-deficit/hyperactivity disorder (ADHD). The MPH-IR, although highly efficacious, need to be used more than once a day, and consequently might be associated with poor adherence. The Spheroidal Oral Drug Absorption System (SODAS™) is one type of MPH-ER (Extended-release methylphenidate) that mimics the twice-daily administration of MPH-immediate release, but presents less peak and trough fluctuations. This formulation allows the immediate release of 50% of the drug, providing a rapid onset if compared with OROS® formulation. Few studies have evaluated specifically the switching from MPH-IR to MPH-ER. All previous studies accessed only children and adolescents; none evaluated switching to MPH SODAS™ and no predictors of treatment dissatisfaction were mentioned. Objectives: The present study aims to assess ADHD symptoms for 08 weeks after switching from MPH-IR to MPH SODAS™ in clinically stable patients, and to identify predictors of dissatisfaction with MPH SODAS™, and/ or withdrawal from the protocol. Method: The inclusion criteria were: ADHD diagnosis according to the DSM-IV criteria and clinical stability with MPH-IR. The exclusion criteria were: a clinically coexisting medical condition interfering with the administration of MPH SODAS™; previous diagnosis of alcohol and/or drug abuse or dependence; previous diagnosis of moderate mental retardation; concomitant psychotherapy. This is an 8-week open clinical trial. Patients were assigned to doses of MPH SODAS™ according to their pre-study dose of MPH-IR. Assessment of efficacy and side effects was performed by means of the SNAP-IV, CGI-S, Barkley's Side Effect Rating Scale (SERS). Subjects were also asked to report their satisfaction with the treatment in a 5-point Likert scale. We also evaluated the following potential predictors of treatment response: sex, age, ethnicity, socioeconomic status, comorbidities, baseline scores on the SNAP-IV, and SERS, length of treatment, concomitant treatment, previous prescribed dose of MPH-IR, and pause of treatment on weekends. Results: From a total sample of 207 children, adolescents and adults (enrolled from the ADHD outpatient clinic at both Adult and Child and Adolescent Psychiatric Division of Hospital de Clínicas de Porto Alegre) we were able to re-contact 133 patients, where sixty-two patients were eligible to the clinical trial, and 47 completed the 08 weeks of treatment. There was no significant change in the total score of the SNAP-IV during the protocol – baseline, week 4 and 8 [F(1, 51.26)=0.012; p=0.913]. Overall, 46 (74.2%) patients had reported to be satisfied with the new treatment, and 16 (25.8%) were dissatisfied or withdrew from the protocol. In univariate analyses, only ethnicity (p=0.05) were associated with dissatisfaction. No significant change in the SERS score was found during the protocol [F(1, 111.49)=0.748; p=0.389]. Eleven adverse events occurring in at least 5% of the group in any assessment (baseline, 04 or 08 weeks) were observed according to SERS. One adult, with previous cardiovascular disease, presented a hemorrhagic cerebral vascular accident (CVA) after the forth week assessment, resulting in her obit. Conclusion: There is a scarcity of research assessing the switch from MPH-IR to different forms of MPH-ER, and none across the life cycle or in populations from developing countries. The 74.2% of satisfaction with the new treatment may reflect the convenience of the once-a-day dosing of the MPH SODAS™. No predictor of dissatisfaction/withdrawal from the trial was found. The number of adverse events reported during the protocol could be considered high, but this can be the result of the use of an appropriate assessment scale, rather than monitoring only by spontaneous report. It was not possible to find a direc relationship between the MPH SODAS™ and death from a CVA occurred in one of the subjects. However, the cardiovascular event found during the trial, suggest extreme caution when medicating patients with cardiovascular diseases as recently proposed by the FDA. Findings from this study suggest that MPH SODAS™ has similar efficacy and adverse event profile than MPH-IR.

Introdução: O metilfenidato de liberação imediata (MFD-LI) é um psicofármaco receitado mundialmente para o tratamento do Transtorno de Déficit de Atenção/hiperatividade (TDAH). Embora eficaz, o MFD-LI está associado a problemas de adesão ao tratamento, uma vez que os pacientes necessitam ingerir os comprimidos várias vezes ao dia. O Spheroidal Oral Drug Absorption System (SODAS™) é uma formulação de metilfenidato de liberação prolongada (MFD-LP) que mimetiza a administração de MFD-LI duas vezes ao dia, e que apresenta menor flutuação nos níveis séricos. Nesta formulação, cinqüenta por cento dos grânulos com revestimento para liberação entérica são liberados aproximadamente 4 horas após a administração, proporcionando um perfil de ação semelhante a duas tomadas ao dia do MFD-LI. O MFD SODAS™ libera de imediato 50% do medicamento, proporcionando um rápido início de ação quando comparado ao sistema de liberação OROS®. Poucos estudos avaliaram a troca do MFD-LI para o MFD-LP, sendo que desses, apenas crianças e adolescentes foram avaliados, e nenhum verificou os preditores de insatisfação da troca do MFD-LI para o MFD-LP. Objetivos: Este estudo tem como objetivo avaliar os sintomas de TDAH, ou preditores de insatisfação e/ou desistência do tratamento naqueles pacientes clinicamente estáveis que fizeram a troca do MDF-LI para o MFD SODAS™. Método: Os critérios de inclusão foram: diagnóstico de TDAH de acordo com os critérios do DSM-IV, e estabilidade de sintomas com o uso do MFD-LI. Os critérios de exclusão foram: condição clínica coexistente que pudesse impedir a prescrição de MFD SODAS™; diagnóstico de abuso ou dependência de álcool e/ou drogas de abuso; diagnóstico prévio de retardo mental moderado; tratamento psicoterápico concomitante. Este é um ensaio clínico aberto realizado em oito semanas. Os pacientes foram designados a receber doses de MFD SODAS™ de acordo com a dose de MFD-LI previamente estabelecida. A eficácia foi avaliada através das escalas SNAP-IV e CGI-S, e eventos adversos através da Barkley's Side Effect Rating Scale (SERS). Foi solicitado aos participantes que classificassem sua satisfação com o tratamento através de uma escala Likert de 5 pontos. Também foram avaliados os seguintes potenciais preditores de resposta: sexo, idade, etnia, nível socioeconômico, comorbidades, subtipos de TDAH, resultados das escalas SNAP-IV e SERS no baseline, tempo de tratamento, tratamento farmacológico concomitante, dose de MFD-LI prévia ao início do estudo e a existência de pausa do tratamento nos finais de semana. Resultados: A partir de uma amostra total de 207 crianças, adolescentes e adultos (provenientes do ambulatório adulto e infantil de transtorno de déficit de atenção/hiperatividade do Hospital de Clínicas de Porto Alegre) foi possível contatar 133 pacientes, os quais sessenta e dois pacientes foram elegíveis a participar do estudo, e 47 completaram as oito semanas de tratamento. Não se encontrou diferença significativa no escore total do SNAP-IV durante o protocolo - baseline, semana 4 e 8 [F(1, 51,26) =0,012; p=0,913]. Ao todo, 46 (74,2%) dos pacientes relataram estar satisfeitos com o novo tratamento, 16 (25,8%) estavam insatisfeitos ou saíram do protocolo. Nas análises univariadas, foi detectada uma tendência para a associação entre etnia e insatisfação (p=0.05). Não se encontrou uma diferença significativa nos escores da SERS durante o ensaio clínico [F(1, 111,49) =0,748; p=0,389]. Em onze eventos adversos ocorreram ao menos 5% em alguma das avaliações (baseline, 4ª ou 8ª semana). Um adulto, que apresentava uma doença cardiovascular previamente ao estudo, apresentou um acidente vascular cerebral hemorrágico (AVCH) após a quarta semana de tratamento, evoluindo ao óbito após três semanas. Conclusão: Poucos estudos abordaram os sintomas de TDAH após a troca do MFD-LI para qualquer formulação de MFD-LP, e nenhum estudo prévio foi conduzido em populações de países em desenvolvimento ou em amostras com adultos. A taxa de satisfação encontrada (74,2%) na troca do MFD-LI para MFD SODAS™ possivelmente reflete a conveniência da dose única diária deste MFD-LP, como já especulado em estudos prévios. Não foram identificados fatores preditores de insatisfação. O número médio de efeitos colaterais pode ser considerado alto, mas isso pode ser o resultado do uso de uma escala de avaliação adequada, diferentemente do relato espontâneo do evento adverso. Não foi possível encontrar uma relação direta entre os efeitos do MFD SODAS™ e a morte por AVCH ocorrida em um dos sujeitos da amostra. Entretanto, o evento cardiovascular ocorrido sugere extrema cautela ao medicar pacientes com doenças cardiovasculares, conforme proposto pelo FDA. Os achados desse estudo sugerem que o MFD SODAS™ possui eficácia e perfil de eventos adversos similares ao MFD-LI. / Introduction: Immediate-release methylphenidate (MPH-IR) is a pharmacological treatment prescribed worldwide for patients with attention-deficit/hyperactivity disorder (ADHD). The MPH-IR, although highly efficacious, need to be used more than once a day, and consequently might be associated with poor adherence. The Spheroidal Oral Drug Absorption System (SODAS™) is one type of MPH-ER (Extended-release methylphenidate) that mimics the twice-daily administration of MPH-immediate release, but presents less peak and trough fluctuations. This formulation allows the immediate release of 50% of the drug, providing a rapid onset if compared with OROS® formulation. Few studies have evaluated specifically the switching from MPH-IR to MPH-ER. All previous studies accessed only children and adolescents; none evaluated switching to MPH SODAS™ and no predictors of treatment dissatisfaction were mentioned. Objectives: The present study aims to assess ADHD symptoms for 08 weeks after switching from MPH-IR to MPH SODAS™ in clinically stable patients, and to identify predictors of dissatisfaction with MPH SODAS™, and/ or withdrawal from the protocol. Method: The inclusion criteria were: ADHD diagnosis according to the DSM-IV criteria and clinical stability with MPH-IR. The exclusion criteria were: a clinically coexisting medical condition interfering with the administration of MPH SODAS™; previous diagnosis of alcohol and/or drug abuse or dependence; previous diagnosis of moderate mental retardation; concomitant psychotherapy. This is an 8-week open clinical trial. Patients were assigned to doses of MPH SODAS™ according to their pre-study dose of MPH-IR. Assessment of efficacy and side effects was performed by means of the SNAP-IV, CGI-S, Barkley's Side Effect Rating Scale (SERS). Subjects were also asked to report their satisfaction with the treatment in a 5-point Likert scale. We also evaluated the following potential predictors of treatment response: sex, age, ethnicity, socioeconomic status, comorbidities, baseline scores on the SNAP-IV, and SERS, length of treatment, concomitant treatment, previous prescribed dose of MPH-IR, and pause of treatment on weekends. Results: From a total sample of 207 children, adolescents and adults (enrolled from the ADHD outpatient clinic at both Adult and Child and Adolescent Psychiatric Division of Hospital de Clínicas de Porto Alegre) we were able to re-contact 133 patients, where sixty-two patients were eligible to the clinical trial, and 47 completed the 08 weeks of treatment. There was no significant change in the total score of the SNAP-IV during the protocol – baseline, week 4 and 8 [F(1, 51.26)=0.012; p=0.913]. Overall, 46 (74.2%) patients had reported to be satisfied with the new treatment, and 16 (25.8%) were dissatisfied or withdrew from the protocol. In univariate analyses, only ethnicity (p=0.05) were associated with dissatisfaction. No significant change in the SERS score was found during the protocol [F(1, 111.49)=0.748; p=0.389]. Eleven adverse events occurring in at least 5% of the group in any assessment (baseline, 04 or 08 weeks) were observed according to SERS. One adult, with previous cardiovascular disease, presented a hemorrhagic cerebral vascular accident (CVA) after the forth week assessment, resulting in her obit. Conclusion: There is a scarcity of research assessing the switch from MPH-IR to different forms of MPH-ER, and none across the life cycle or in populations from developing countries. The 74.2% of satisfaction with the new treatment may reflect the convenience of the once-a-day dosing of the MPH SODAS™. No predictor of dissatisfaction/withdrawal from the trial was found. The number of adverse events reported during the protocol could be considered high, but this can be the result of the use of an appropriate assessment scale, rather than monitoring only by spontaneous report. It was not possible to find a direc relationship between the MPH SODAS™ and death from a CVA occurred in one of the subjects. However, the cardiovascular event found during the trial, suggest extreme caution when medicating patients with cardiovascular diseases as recently proposed by the FDA. Findings from this study suggest that MPH SODAS™ has similar efficacy and adverse event profile than MPH-IR.

Introdução: O metilfenidato de liberação imediata (MFD-LI) é um psicofármaco receitado mundialmente para o tratamento do Transtorno de Déficit de Atenção/hiperatividade (TDAH). Embora eficaz, o MFD-LI está associado a problemas de adesão ao tratamento, uma vez que os pacientes necessitam ingerir os comprimidos várias vezes ao dia. O Spheroidal Oral Drug Absorption System (SODAS™) é uma formulação de metilfenidato de liberação prolongada (MFD-LP) que mimetiza a administração de MFD-LI duas vezes ao dia, e que apresenta menor flutuação nos níveis séricos. Nesta formulação, cinqüenta por cento dos grânulos com revestimento para liberação entérica são liberados aproximadamente 4 horas após a administração, proporcionando um perfil de ação semelhante a duas tomadas ao dia do MFD-LI. O MFD SODAS™ libera de imediato 50% do medicamento, proporcionando um rápido início de ação quando comparado ao sistema de liberação OROS®. Poucos estudos avaliaram a troca do MFD-LI para o MFD-LP, sendo que desses, apenas crianças e adolescentes foram avaliados, e nenhum verificou os preditores de insatisfação da troca do MFD-LI para o MFD-LP. Objetivos: Este estudo tem como objetivo avaliar os sintomas de TDAH, ou preditores de insatisfação e/ou desistência do tratamento naqueles pacientes clinicamente estáveis que fizeram a troca do MDF-LI para o MFD SODAS™. Método: Os critérios de inclusão foram: diagnóstico de TDAH de acordo com os critérios do DSM-IV, e estabilidade de sintomas com o uso do MFD-LI. Os critérios de exclusão foram: condição clínica coexistente que pudesse impedir a prescrição de MFD SODAS™; diagnóstico de abuso ou dependência de álcool e/ou drogas de abuso; diagnóstico prévio de retardo mental moderado; tratamento psicoterápico concomitante. Este é um ensaio clínico aberto realizado em oito semanas. Os pacientes foram designados a receber doses de MFD SODAS™ de acordo com a dose de MFD-LI previamente estabelecida. A eficácia foi avaliada através das escalas SNAP-IV e CGI-S, e eventos adversos através da Barkley's Side Effect Rating Scale (SERS). Foi solicitado aos participantes que classificassem sua satisfação com o tratamento através de uma escala Likert de 5 pontos. Também foram avaliados os seguintes potenciais preditores de resposta: sexo, idade, etnia, nível socioeconômico, comorbidades, subtipos de TDAH, resultados das escalas SNAP-IV e SERS no baseline, tempo de tratamento, tratamento farmacológico concomitante, dose de MFD-LI prévia ao início do estudo e a existência de pausa do tratamento nos finais de semana. Resultados: A partir de uma amostra total de 207 crianças, adolescentes e adultos (provenientes do ambulatório adulto e infantil de transtorno de déficit de atenção/hiperatividade do Hospital de Clínicas de Porto Alegre) foi possível contatar 133 pacientes, os quais sessenta e dois pacientes foram elegíveis a participar do estudo, e 47 completaram as oito semanas de tratamento. Não se encontrou diferença significativa no escore total do SNAP-IV durante o protocolo - baseline, semana 4 e 8 [F(1, 51,26) =0,012; p=0,913]. Ao todo, 46 (74,2%) dos pacientes relataram estar satisfeitos com o novo tratamento, 16 (25,8%) estavam insatisfeitos ou saíram do protocolo. Nas análises univariadas, foi detectada uma tendência para a associação entre etnia e insatisfação (p=0.05). Não se encontrou uma diferença significativa nos escores da SERS durante o ensaio clínico [F(1, 111,49) =0,748; p=0,389]. Em onze eventos adversos ocorreram ao menos 5% em alguma das avaliações (baseline, 4ª ou 8ª semana). Um adulto, que apresentava uma doença cardiovascular previamente ao estudo, apresentou um acidente vascular cerebral hemorrágico (AVCH) após a quarta semana de tratamento, evoluindo ao óbito após três semanas. Conclusão: Poucos estudos abordaram os sintomas de TDAH após a troca do MFD-LI para qualquer formulação de MFD-LP, e nenhum estudo prévio foi conduzido em populações de países em desenvolvimento ou em amostras com adultos. A taxa de satisfação encontrada (74,2%) na troca do MFD-LI para MFD SODAS™ possivelmente reflete a conveniência da dose única diária deste MFD-LP, como já especulado em estudos prévios. Não foram identificados fatores preditores de insatisfação. O número médio de efeitos colaterais pode ser considerado alto, mas isso pode ser o resultado do uso de uma escala de avaliação adequada, diferentemente do relato espontâneo do evento adverso. Não foi possível encontrar uma relação direta entre os efeitos do MFD SODAS™ e a morte por AVCH ocorrida em um dos sujeitos da amostra. Entretanto, o evento cardiovascular ocorrido sugere extrema cautela ao medicar pacientes com doenças cardiovasculares, conforme proposto pelo FDA. Os achados desse estudo sugerem que o MFD SODAS™ possui eficácia e perfil de eventos adversos similares ao MFD-LI. / Introduction: Immediate-release methylphenidate (MPH-IR) is a pharmacological treatment prescribed worldwide for patients with attention-deficit/hyperactivity disorder (ADHD). The MPH-IR, although highly efficacious, need to be used more than once a day, and consequently might be associated with poor adherence. The Spheroidal Oral Drug Absorption System (SODAS™) is one type of MPH-ER (Extended-release methylphenidate) that mimics the twice-daily administration of MPH-immediate release, but presents less peak and trough fluctuations. This formulation allows the immediate release of 50% of the drug, providing a rapid onset if compared with OROS® formulation. Few studies have evaluated specifically the switching from MPH-IR to MPH-ER. All previous studies accessed only children and adolescents; none evaluated switching to MPH SODAS™ and no predictors of treatment dissatisfaction were mentioned. Objectives: The present study aims to assess ADHD symptoms for 08 weeks after switching from MPH-IR to MPH SODAS™ in clinically stable patients, and to identify predictors of dissatisfaction with MPH SODAS™, and/ or withdrawal from the protocol. Method: The inclusion criteria were: ADHD diagnosis according to the DSM-IV criteria and clinical stability with MPH-IR. The exclusion criteria were: a clinically coexisting medical condition interfering with the administration of MPH SODAS™; previous diagnosis of alcohol and/or drug abuse or dependence; previous diagnosis of moderate mental retardation; concomitant psychotherapy. This is an 8-week open clinical trial. Patients were assigned to doses of MPH SODAS™ according to their pre-study dose of MPH-IR. Assessment of efficacy and side effects was performed by means of the SNAP-IV, CGI-S, Barkley's Side Effect Rating Scale (SERS). Subjects were also asked to report their satisfaction with the treatment in a 5-point Likert scale. We also evaluated the following potential predictors of treatment response: sex, age, ethnicity, socioeconomic status, comorbidities, baseline scores on the SNAP-IV, and SERS, length of treatment, concomitant treatment, previous prescribed dose of MPH-IR, and pause of treatment on weekends. Results: From a total sample of 207 children, adolescents and adults (enrolled from the ADHD outpatient clinic at both Adult and Child and Adolescent Psychiatric Division of Hospital de Clínicas de Porto Alegre) we were able to re-contact 133 patients, where sixty-two patients were eligible to the clinical trial, and 47 completed the 08 weeks of treatment. There was no significant change in the total score of the SNAP-IV during the protocol – baseline, week 4 and 8 [F(1, 51.26)=0.012; p=0.913]. Overall, 46 (74.2%) patients had reported to be satisfied with the new treatment, and 16 (25.8%) were dissatisfied or withdrew from the protocol. In univariate analyses, only ethnicity (p=0.05) were associated with dissatisfaction. No significant change in the SERS score was found during the protocol [F(1, 111.49)=0.748; p=0.389]. Eleven adverse events occurring in at least 5% of the group in any assessment (baseline, 04 or 08 weeks) were observed according to SERS. One adult, with previous cardiovascular disease, presented a hemorrhagic cerebral vascular accident (CVA) after the forth week assessment, resulting in her obit. Conclusion: There is a scarcity of research assessing the switch from MPH-IR to different forms of MPH-ER, and none across the life cycle or in populations from developing countries. The 74.2% of satisfaction with the new treatment may reflect the convenience of the once-a-day dosing of the MPH SODAS™. No predictor of dissatisfaction/withdrawal from the trial was found. The number of adverse events reported during the protocol could be considered high, but this can be the result of the use of an appropriate assessment scale, rather than monitoring only by spontaneous report. It was not possible to find a direc relationship between the MPH SODAS™ and death from a CVA occurred in one of the subjects. However, the cardiovascular event found during the trial, suggest extreme caution when medicating patients with cardiovascular diseases as recently proposed by the FDA. Findings from this study suggest that MPH SODAS™ has similar efficacy and adverse event profile than MPH-IR.

Understanding the processes that govern pre-systemic drug absorption and elimination is of high importance in pharmaceutical research and development, and clinical pharmacotherapy, as the oral route remains the most frequently used route of drug administration. The emergence of systems pharmacology has enabled the utilisation of in silico physiologically-based pharmacokinetic (PBPK) modelling and simulation (M&S) coupled to in vitro-in vivo extrapolation in order to perform extrapolation and exploratory M&S in special populations and scenarios were concerns regarding alterations in oral drug exposure may arise, such as following gastrointestinal (GI) surgery or metabolic drug-drug interactions (DDIs).Due to the multi-factorial physiological implications of bariatric surgery, resulting in the partial resection of the GI tract, the inability to rationalise and predict trends in oral drug bioavailability (Foral) following surgery present considerable pharmacotherapeutical challenges. PBPK M&S is a highly implemented approach for the prediction of DDIs. Reoccurring issues have emerged with regards to predictions of the magnitude of mechanism-based inhibition (MBI) where overestimations of DDIs have repeatedly been reported for drugs exhibiting high intestinal extraction. The aim of this thesis was to explore the interplay between oral drug absorption and metabolism occurring in the GI tract through the exploration of the impact of bariatric surgery on oral drug exposure and by theoretically examining the nesting and hierarchy of enterocyte and enzyme turnover and its impact on MBIs in the small intestine. This would be carried out by utilising a systems pharmacology PBPK M&S approach under a general model development framework of identification and characterisation of critical intrinsic factors and parameters, model implementation and validation. Developed post bariatric surgery PBPK models allow a framework to theoretically explore physiological mechanisms associated with altered oral drug exposure pre to post surgery, which could be assigned to the interplay between dissolution, absorption and gut-wall metabolism, where dissolution and formulation properties emerged as the perhaps most important parameters in predicting the drug disposition following surgery. Model validation identified missing critical factors that are essential for additional model refinement. Developed post bariatric surgery PBPK models have the potential of aiding clinical pharmacotherapy and decision-making following surgery. A mechanistic PBPK model was developed to describe the hierarchical dependency of enzyme and enterocyte turnover in the small intestine. Predicted enzyme recovery using the nested enzyme-within-enterocyte turnover model may potentially account for reported overpredictions of mechanism-based inhibition. Developed models in this thesis showcase the advantage of PBPK M&S in the extrapolation of oral drug exposure to special population and the potential of a PBPK approach in understanding underlying the underlying mechanism governing Foral and additionally highlight the need for generation of interdisciplinary data to support model development.

<p>New effective experimental techniques in medicinal chemistry and pharmacology have resulted in a vast increase in the number of pharmacologically interesting compounds. However, the number of new drugs undergoing clinical trial has not augmented at the same pace, which in part has been attributed to poor absorption of the compounds.</p><p>The main objective of this thesis was to investigate whether computer-based models devised from calculated molecular descriptors can be used to predict aqueous drug solubility, an important property influencing the absorption process. For this purpose, both experimental and computational studies were performed. A new small-scale shake flask method for experimental solubility determination of crystalline compounds was devised. This method was used to experimentally determine solubility values used for the computational model development and to investigate the pH-dependent solubility of drugs. In the computer-based studies, rapidly calculated molecular descriptors were used to predict aqueous solubility and the melting point, a solid state characteristic of importance for the solubility. To predict the absorption process, drug permeability across the intestinal epithelium was also modeled.</p><p>The results show that high quality solubility data of crystalline compounds can be obtained by the small-scale shake flask method in a microtiter plate format. The experimentally determined pH-dependent solubility profiles deviated largely from the profiles predicted by a traditionally used relationship, highlighting the risk of data extrapolation. The <i>in silico</i> solubility models identified the non-polar surface area and partitioned total surface areas as potential new molecular descriptors for solubility. General solubility models of high accuracy were obtained when combining the surface area descriptors with descriptors for electron distribution, connectivity, flexibility and polarity. The used descriptors proved to be related to the solvation of the molecule rather than to solid state properties. The surface area descriptors were also valid for permeability predictions, and the use of the solubility and permeability models in concert resulted in an excellent theoretical absorption classification. To summarize, the experimental and computational models devised in this thesis are improved absorption screening tools applicable to the lead optimization in the drug discovery process. </p>

<p>The general aim of the present project was to increase the understanding of the in vivo dissolution of poorly soluble drugs and thereby improve possibility to predict in vivo solubility from substance properties. Increased understanding of the in vivo limitations of drug solubility could potentially also generate ideas for improved formulation principles for poorly soluble compounds and more relevant in vitro dissolution test methods used in formulation development.</p><p>The dynamic gastrointestinal secretory and enzymatic responses to a liquid meal were studied in human intestinal fluid (HIF) by in vivo perfusion of a nutritional drink. The main diversity found compared to simulated intestinal fluids was the presence of dietary lipids in fed human intestinal fluid. This difference was showed to be of importance in the solubility of low soluble drugs, since this parameter was underestimated in the simulated fluid. Thus suggesting that simulated intestinal fluids should be prepared with the addition of dietary lipids for better in vitro in vivo predictions. </p><p>Solubility and dissolution determinations in fasted and fed HIF showed that the solubility was higher in fed state fluid, probably owing to the higher concentration of lipids in this media. The higher solubility was correlated to both the lipophilicity and aqueous solubility of the drug. The dissolution rate also increased, but not to the same extent as the solubility. These findings need to be considered in the design of in vitro models and in the prediction of food effects on oral bioavailability of poorly soluble drugs.</p><p>In addition, an in vivo porcine perfusion study was performed to investigate importance of different mechanisms in food-drug interactions. The results showed that solubilisation might be a more important factor than P-gp inhibition for food-related effects on the intestinal absorption kinetics of Class II drugs. </p>