A growing number of therapeutic compounds currently being developed by pharmaceutical companies are poorly water soluble leading to limited and/or erratic bioavailability. The rate limiting step for absorption of these compounds is dependent on the dissolution and apparent solubility. Nanoparticle formation has been exploited as a method to improve the bioavailability of these poorly water soluble active pharmaceutical ingredients (API) by increasing the dissolution rates and apparent solubilities. The influence of hydrophilic stabilizers in powder compositions prepared by the spray freezing into liquid (SFL) process using either an emulsion feed dispersion or organic co-solvent feed solutions on enhancing the wetting and dissolution properties of nanostructured aggregates containing itraconazole (ITZ). Subsequently, an in vivo pharmacokinetic study was conducted comparing the SFL processed powder to commercial Sporanox®. An ultra-rapid freezing (URF) technology has been developed to produce high surface area powders composed of solid solutions of an active pharmaceutical ingredient (API) and a polymer stabilizer. Rapid freezing technologies are known to enhance the physico-chemical properties of APIs and thus increase bioavailability. However, the effect of the different freezing geometries and rates in the URF process are unknown. Therefore, this study investigated how solvent properties and thin film geometry of the droplet affect the freezing rate and thus the physico-chemical properties of micronized danazol powders. Amorphous nanoparticles containing tacrolimus (TAC) in a solid dispersion were prepared using the Ultra-rapid Freezing (URF) process. The objective of this study was to assess the effects of combinations of polymeric stabilizers on the maximum degree and extent of supersaturation of TAC. An attempt to establish if an in vitro-in vivo correlation exists between supersaturation and improved pharmacokinetic parameters for orally dosed TAC was performed. Enteric solid dispersions could overcome limitations of premature precipitation of supersaturated solutions by 1.) delaying dissolution until the compound enters the intestines where absorption is favored and 2.) increasing the apparent solubility at higher pH to increase the driving force for absorption. The objective of the study is to investigate the influence of composition parameters including drug:polymer ratio and polymer type, and particle structure of enteric solid dispersions on the release of ITZ. / text

Orientadores : Thales Rocha de Mattos Filho, Francisco Carlos Groppo / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-08-06T06:37:26Z (GMT). No. of bitstreams: 1 Junqueira_MarcelodeSouza_D.pdf: 648615 bytes, checksum: 3b46ad75b56af2255d981b942d82fa8f (MD5) Previous issue date: 2006 / Resumo: O uso de antimicrobianos e de antiinflamatórios é prática comum na odontologia, embora haja escassez de trabalhos sobre seu uso simultâneo. Portanto, o objetivo deste trabalho foi avaliar, em ratos, os efeitos do diclofenaco sódico na absorção, concentração sérica e excreção da amoxicilina utilizando a técnica de perfusão tecidual e o método microbiológico. Foram utilizados 108 ratos Wistar machos (12 grupos, n= 9), com peso entre 150 e 200 g. Foram administrados aos animais: amoxicilina 25 mg/Kg (grupos: G1, D1, S1 e R1), diclofenaco sódico 2,5 mg/Kg + amoxicilina 25 mg/Kg (grupos: G2, D2, S2 e R2) e 1,0 mL de solução de cloreto de sódio a 0,9% (grupos: G3, D3, S3 e R3). As drogas foram administradas por injeção intraluminal aos animais dos grupos G1, G2, G3, D1, D2 e D3 e por via oral aos animais dos grupos S1, S2, S3, R1, R2 e R3. Foram avaliadas nos tempos de 15, 30, 45, 60, 120, 180, 240, 300 e 360 minutos as concentrações plasmáticas e urinárias de amoxicilina e a absorção gastrintestinal ¿in vitro¿ do antimicrobiano. O diclofenaco sódico causou uma redução significativa na absorção intestinal e um aumento na excreção renal do antimicrobiano em ratos, com conseqüente diminuição da sua concentração sérica. Portanto, em algumas situações clínicas, a eficácia da amoxicilina poderia ser prejudicada pela sua co-administração com o diclofenaco sódico / Abstract: The prescription of antibiotics associated to anti-inflammatory drugs is common in dentistry; however its effects have not been studied enough. Thus, the aim of this work was to evaluate the influence of sodium diclofenac on absorption, serum concentration and excretion of amoxicillin, in rats, by the microbiologic and tissue perfusion methods. The sample consisted of 108 male Wistar rats (12 groups, 9 rats each), weighing 150¿200 g. The animals were given: amoxicillin 25 mg/Kg (groups G1, D1, S1 and R1), sodium diclofenac 2.5 mg/Kg plus amoxicillin 25 mg/Kg (groups G2, D2, S2 and R2) and 1.0 mL of solution of sodium chloride 0.9% (groups G3, D3, S3 and R3). The animals in the groups G1, G2, G3, D1, D2 and D3 were administered drugs by intra-luminal injection and the animals in the groups S1, S2, S3, R1, R2 and R3 were administered drugs p.o. After 15, 30, 45, 60, 120, 180, 240, 300 and 360 minutes, were evaluated the blood and urine concentrations of amoxicillin and the ¿in vitro¿ absorption of the antibiotic. Sodium diclofenac had decreased the intestinal absorption, increased renal excretion and, consequently, decreased the serum concentration of the amoxicillin. Thus, sodium diclofenac could decrease the efficacy of amoxicillin under some clinical situations / Doutorado / Farmacologia, Anestesiologia e Terapeutica / Doutor em Odontologia

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / NÃveis subterapÃuticos de drogas antimicobacterianas tÃm sido observados no curso do tratamento de pacientes com tuberculose e nos co-infectados TB/HIV e podem facilitar o surgimento de cepas de M. tuberculosis resistentes Ãs drogas. A mal-absorÃÃo intestinal inclue-se entre as provÃveis causas e tem sido descrita em tuberculosos desnutridos, alcoÃlatras, diabÃticos, aidÃticos ou com patologias gastrointestinais associadas. Estudos da permeabilidade intestinal permitem a avaliaÃÃo da funÃÃo intestinal em vÃrias doenÃas, mas tÃm sido escassos na tuberculose. O teste da lactulose / manitol tem sido utilizado como critÃrio de lesÃo com dÃficit absortivo da mucosa intestinal e pode ser de utilidade no prognÃstico da absorÃÃo intestinal de drogas em pacientes com tuberculose. Foram estudados 41 pacientes (30H e 11M). A coleta dos dados foi realizada no Hospital de MaracanaÃ, Fortaleza-CE, em 2001. Procedeu-se descriÃÃo clÃnica, social e laboratorial do grupo de pacientes e estudo piloto de observaÃÃo utilizando o teste da lactulose / manitol em 40 pacientes com tuberculose pulmonar ativa, comparando com grupo controle de 28 voluntÃrios sadios objetivando estudar a permeabilidade intestinal. Testes de sensibilidade Ãs drogas antituberculose, pelo mÃtodo das proporÃÃes indireto, foram realizados em 20 pacientes com cultura de escarro positivas. O grau de nutriÃÃo avaliado atravÃs do Ãndice de Massa CorpÃrea (IMC) e o nÃvel sÃrico das drogas foram correlacionados com os valores da permeabilidade intestinal. CinqÃenta e nove por cento (24 pacientes) foram considerados desnutridos pelo IMC<18,5 kg/m2, sendo vinte e dois por cento (9 pacientes) considerados severamente desnutridos (IMC<16 kg/m2). Em 18 pacientes, apÃs 2 h da tomada de 600mg de rifampicina (R) e 400 mg de isoniazida (H) os nÃveis sÃricos de R (CRM 2h) e H (CINH 2h) foram analisados por HPLC. A taxa de excreÃÃo urinÃria de manitol (mÃdia  desvio padrÃo) foi significativamente menor p<0,001 (9,52  5,70) nos pacientes que dos controles (20,14  10,84). A taxa de excreÃÃo de lactulose foi significativamente maior p<0,05 nos pacientes (0,59  1,79) que nos controles (0,52  0,47) e a razÃo L/M foi aumentada de forma consistente, embora nÃo significativa p>0,05 (0,05  0,10 pacientes contra 0,02  0,02 controles). Considerando a faixa terapÃutica da R (8-24 mcg/mL ) e da H (3-6 mcg/mL) observamos que as CRM2h e CINH2h em 16/18 (88,8%) pacientes nÃo atingiram nÃveis sÃricos adequados para as duas drogas. 8/18 (44,4%) pacientes nÃo alcanÃaram nÃveis sÃricos para ambas as drogas simultaneamente. Na anÃlise das drogas isoladas verificamos que em 12/18 (66,7%) pacientes a CRM2h o nÃvel sÃrico mÃnimo nÃo foi alcanÃado (mÃdia R =6,47 mcg/mL) e 13/18 (72,2%) a CINH2h tambÃm foi reduzida (mÃdia H =2,17 mcg/mL). Quanto ao perfil de resistÃncia do M. tuberculosis em cultura de escarro, observamos 4/20 (20%) multirresistentes (3 à R+H e 1 à todas as drogas) e 2/20 (10%) monorresistentes à H sendo 14/20 (70%) amostras consideradas sensÃveis Ãs drogas testadas. Os resultados observados sugerem uma intensa reduÃÃo na Ãrea de absorÃÃo e lesÃo da mucosa intestinal nos indivÃduos estudados. Os dados sÃo consistentes com a reduÃÃo na biodisponibilidade de rifampicina e isoniazida e com o estado nutricional destes pacientes. Os dados preliminares recomendam estudos adicionais na avaliaÃÃo completa da biodisponibilidade das drogas antimicobacterianas em pacientes com tuberculose / Subtherapeutic antimycobacterial drugs levels have been observed during treatment of patients with tuberculosis and in HIV coinfected. It may facilitate the development of M. tuberculosis resistant strains. Malabsorption may be one of the underlyne cause. It has been documented in tuberculosis patients associated to malnutrition, alchoolics, diabetes, AIDS and gastrointestinal symptoms. Intestinal permeability studies have been conducted in order to evaluate the intestinal function in some diseases but are scant in tuberculosis. Lactulose / manitol ratio in urine a widely used measure of malabsorption and intestinal permeability may be useful to assesss the drug absorption area in tuberculosis. In order to study the intestinal permeability in tuberculosis, we conducted in a pilot study 40 patients and 28 healthy volunteers, using the urinary excretion of ingested lactulose and manitol as respective markers of barrier disruption and overall villous surface area. The Maracanaà Hospital in Fortaleza-CE, was choosen and the data were collected in 2001. Eigthteen patients receiving 600 mg rifampicin (R) and 400 mg isoniazid (H) were evaluated through venous blood analysis obtained at 2 hours after directly observed ingestion. The serum samples were analysed by HPLC at the Infectious Disease Pharmacokinetics Laboratory / National Jewish Center / Denver, USA. Nutritional status by body mass index (BMI) and serum drug levels were correlated with intestinal permeability data. M. tuberculosis isolates from 20 clinical specimens were tested to drug susceptibility by standard proportion method (APM ) using Lowestein-Jensen medium. Forty-one patients (30 M, 11 F) were studied. Fifty nine per cent (24) patients were malnourish (BMI<18,5 kg/m2); 22% (9) were severely malnourish (BMI<16 kg/m2). The urinary excretion of mannitol (mean  standard deviation) showed a significant decrease p < 0,001 in patients (9,52  5,70) compared to controls (20,14  10,84). The excretion of lactulose was significant increased p < 0,05 in patients (0,59  1,79), than controls (0,52  0,47) and the L/M ratio shown consistent increased (0,05  0,10) in patients compared to controls (0,029  0,0,02) p > 0,05. Considering the reported target range for R (8-24 mcg/mL ) and H (3-6 mcg/mL) we observed that 2-h serum levels were below the lower limit for R and H in 88,8% (16/18) patients. Forty four per cent ( 8/18) of patients had reduced levels for the two drugs. Analysing single drugs we documented that 66,7% (12/18) patients had levels below the target limit for R (mean R =6,47 mcg/mL) and 72,2% (13/18) for H (mean H =2,17mcg/mL). Concerning to M. tuberculosis susceptibility profile in sputum culture, we observed 20% (4/20) multidrug resistants strains (3 for R + H and 1 for all drugs). Ten per cent (2/20) were resistant only for H and 70% (14/20) strains were sensitive. These results suggests an important decrease in the funcional absorptive surface of the intestine and damage of the intestine in patients studied. The data are consistent with reduced antituberculosis drugs bioavailability and compromissed nutritional status of these patients. The preliminary results indicate the necessity of new approaches to accurate portrait of drugs bioavailability in tuberculosis patients