RESUMO
Accelerated in vitro release testing methodology has been developed as an indicator of product performance to be used as a discriminatory quality control (QC) technique for the release of clinical and commercial batches of biodegradable microspheres. While product performance of biodegradable microspheres can be verified by in vivo and/or in vitro experiments, such evaluation can be particularly challenging because of slow polymer degradation, resulting in extended study times, labor, and expense. Three batches of Leuprolide poly(lactic-co-glycolic acid) (PLGA) microspheres having varying morphology (process variants having different particle size and specific surface area) were manufactured by the solvent extraction/evaporation technique. Tests involving in vitro release, polymer degradation and hydration of the microspheres were performed on the three batches at 55°C. In vitro peptide release at 55°C was analyzed using a previously derived modification of the Weibull function termed the modified Weibull equation (MWE). Experimental observations and data analysis confirm excellent reproducibility studies within and between batches of the microsphere formulations demonstrating the predictability of the accelerated experiments at 55°C. The accelerated test method was also successfully able to distinguish the in vitro product performance between the three batches having varying morphology (process variants), indicating that it is a suitable QC tool to discriminate product or process variants in clinical or commercial batches of microspheres. Additionally, data analysis utilized the MWE to further quantify the differences obtained from the accelerated in vitro product performance test between process variants, thereby enhancing the discriminatory power of the accelerated methodology at 55°C.
Assuntos
Portadores de Fármacos , Ácido Láctico/química , Leuprolida/química , Ácido Poliglicólico/química , Tecnologia Farmacêutica/métodos , Química Farmacêutica , Cinética , Leuprolida/normas , Microesferas , Modelos Químicos , Modelos Estatísticos , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Porosidade , Controle de Qualidade , Reprodutibilidade dos Testes , Solubilidade , Propriedades de Superfície , Tecnologia Farmacêutica/normas , Água/químicaRESUMO
BACKGROUND: Schistosomiasis is a parasitic disease caused by trematode worms of the genus Schistosoma and belongs to the neglected tropical diseases. The disease has been reported in 78 countries, with around 290.8 million people in need of treatment in 2018. Schistosomiasis is predominantly considered a rural disease with a subsequent focus of research and control activities in rural settings. Over the past decades, occurrence and even expansion of schistosomiasis foci in peri-urban and urban settings have increasingly been observed. Rural-urban migration in low- and middle-income countries and subsequent rapid and unplanned urbanization are thought to explain these observations. Fifty-five percent (55%) of the world population is already estimated to live in urban areas, with a projected increase to 68% by 2050. In light of rapid urbanization and the efforts to control morbidity and ultimately achieve elimination of schistosomiasis, it is important to deepen our understanding of the occurrence, prevalence, and transmission of schistosomiasis in urban and peri-urban settings. A systematic literature review looking at urban and peri-urban schistosomiasis was therefore carried out as a first step to address the research and mapping gap. METHODOLOGY: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic computer-aided literature review was carried out using PubMed, ScienceDirect, and the World Health Organization Database in November 2019, which was updated in March 2020. Only papers for which at least the abstract was available in English were used. Relevant publications were screened, duplicates were removed, guidelines for eligibility were applied, and eligible studies were reviewed. Studies looking at human Schistosoma infections, prevalence, and intensity of infection in urban and peri-urban settings were included as well as those focusing on the intermediate host snails. PRINCIPAL FINDINGS: A total of 248 publications met the inclusion criteria. The selected studies confirm that schistosomiasis is prevalent in peri-urban and urban areas in the countries assessed. Earlier studies report higher prevalence levels in urban settings compared to data extracted from more recent publications, yet the challenge of migration, rapid uncontrolled urbanization, and resulting poor living conditions highlight the potential for continuous or even newly established transmission to take place. CONCLUSIONS: The review indicates that schistosomiasis has long existed in urban and peri-urban areas and remains a public health problem. There is, however, a challenge of comparability of settings due to the lack of a clear definition of what constitutes urban and peri-urban. There is a pressing need for improved monitoring of schistosomiasis in urban communities and consideration of treatment strategies.
Assuntos
Schistosoma/isolamento & purificação , Esquistossomose/epidemiologia , Animais , Humanos , Schistosoma/classificação , Esquistossomose/transmissão , Caramujos/parasitologia , População Suburbana , População UrbanaRESUMO
People with disabilities and the neglected tropical diseases (NTDs) are separately receiving increased focus. In light of this positive development, and the similarities and intersections between the negative impacts experienced by both people with disabilities and people with NTDs, we believe now is the right time to focus attention on the overlap between the two. Both people with NTDs and people with disabilities experience a myriad of overlapping negative health, financial and socio-cultural consequences. Despite this, we believe that disability is not yet properly prioritised on the development agenda, and that there are multiple opportunities to make NTD programming more inclusive, to the benefit of those at this neglected intersection and beyond. There are both opportunities and need to scale up, integrate, and invest in inclusive, health system-focused NTD programming. Realisation of the Sustainable Development Goals, Universal Health Coverage, and the control and elimination of NTDs all rely on ensuring people with disabilities are not left behind.
Assuntos
Controle de Doenças Transmissíveis/tendências , Pessoas com Deficiência , Saúde Global , Doenças Negligenciadas/prevenção & controle , Medicina Tropical/tendências , Congressos como Assunto , HumanosRESUMO
PURPOSE: We set out to estimate the prevalence of trachoma and access to water and sanitation in seven suspected-trachoma-endemic districts of northern Congo, surveyed as a single evaluation unit. METHODS: From a complete list of rural villages in the seven districts, we systematically selected 22 with probability proportional to village size. In selected villages, we included all households where there were fewer than 25 in total, or used compact segment sampling to select a group of approximately 20 households by random draw. In each selected household, all consenting residents aged ≥1 year were examined by Global Trachoma Mapping Project-certified trachoma graders, and data collected on household-level access to water and sanitation. RESULTS: In November and December 2015, 466 households were visited in 22 villages, and 2081 (88%) of 2377 residents of those households were examined. No examined individual had trichiasis. The age-adjusted prevalence of the active trachoma sign trachomatous inflammation-follicular (TF) in 1-9-year-olds was 2.5% (95%CI 0.9-4.5%). Only 39% (95%CI 35-44%) of households had access to an improved source of drinking water. Only 10% (95%CI 7-13%) of households had access to an improved sanitation facility. CONCLUSION: Trachoma is not a public health problem in this part of Congo. Access to water and sanitation is inadequate.
Assuntos
Tracoma/epidemiologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Congo/epidemiologia , Estudos Transversais , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Prevalência , Saneamento/normas , Triquíase/epidemiologia , Abastecimento de Água/normas , Adulto JovemRESUMO
PURPOSE: To estimate the prevalence of trachoma in suspected-endemic areas of Chad, and thereby determine whether trachoma is a public health problem requiring intervention. METHODS: We divided the suspected-endemic population living in secure districts into 46 evaluation units (EUs), and used the standardized methodologies of the Global Trachoma Mapping Project. A two-stage cluster-sampling procedure was adopted. In each EU, the goal was to examine at least 1019 children aged 1-9 years by recruiting 649 households; all consenting residents aged ≥ 1 year living in those households were examined. Each participant was examined for trachomatous inflammation-follicular (TF), trachomatous inflammation-intense (TI), and trichiasis. RESULTS: Two EUs had data that could not be validated, and were excluded from the analysis. GPS data for three other pairs of EUs suggested that EU divisions were inaccurate; data for each pair were combined within the pair. In the 41 resulting EUs, 29,924 households in 967 clusters were visited, and 104,584 people were examined. The age-adjusted EU-level prevalence of TF in 1-9-year-olds ranged from 0.0% to 23.3%, and the age- and gender-adjusted EU-level prevalence of trichiasis in ≥ 15-year-olds ranged from 0.02% to 1.3%. TF was above the WHO elimination threshold in 16 EUs (39%) and trichiasis was above the WHO elimination threshold in 29 EUs (71%). Women had a higher prevalence of trichiasis than did men in 31 EUs (76%). A higher ratio of trichiasis prevalence in women to trichiasis prevalence in men was associated (p = 0.03) with a higher prevalence of trichiasis at EU level. CONCLUSION: Public health-level interventions against trachoma are needed in Chad. Over 10,000 people need management of their trichiasis; women account for about two-thirds of this total. The association between a higher ratio of trichiasis prevalence in women to that in men with higher overall trichiasis prevalence needs further investigation.
Assuntos
Tracoma/epidemiologia , Adolescente , Adulto , Idoso , Chade/epidemiologia , Criança , Pré-Escolar , Análise por Conglomerados , Estudos Transversais , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Prevalência , Triquíase/epidemiologia , Adulto JovemRESUMO
BACKGROUND: The Global Programme to Eliminate Lymphatic Filariasis (GPELF), launched in 2000, has the target of eliminating the disease as a public health problem by the year 2020. The strategy adopted is mass drug administration (MDA) to all eligible individuals in endemic communities and the implementation of measures to reduce the morbidity of those suffering from chronic disease. Success has been recorded in many rural endemic communities in which elimination efforts have centered. However, implementation has been challenging in several urban African cities. The large cities of West Africa, exemplified in Nigeria in Kano are challenging for LF elimination program because reaching 65% therapeutic coverage during MDA is difficult. There is therefore a need to define a strategy which could complement MDA. Thus, in Kano State, Nigeria, while LF MDA had reached 33 of the 44 Local Government Areas (LGAs) there remained eleven 'urban' LGAs which had not been covered by MDA. Given the challenges of achieving at least 65% coverage during MDA implementation over several years in order to achieve elimination, it may be challenging to eliminate LF in such settings. In order to plan the LF control activities, this study was undertaken to confirm the LF infection prevalence in the human and mosquito populations in three urban LGAs. METHODS: The prevalence of circulating filarial antigen (CFA) of Wuchereria bancrofti was assessed by an immuno-chromatography test (ICT) in 981 people in three urban LGAs of Kano state, Nigeria. Mosquitoes were collected over a period of 4 months from May to August 2015 using exit traps, gravid traps and pyrethrum knock-down spray sheet collections (PSC) in different households. A proportion of mosquitoes were analyzed for W. bancrofti, using dissection, loop-mediated isothermal amplification (LAMP) assay and conventional polymerase chain reaction (PCR). RESULTS: The results showed that none of the 981 subjects (constituted of <21% of children 5-10 years old) tested had detectable levels of CFA in their blood. Entomological results showed that An. gambiae s.l. had W. bancrofti DNA detectable in pools in Kano; W. bancrofti DNA was detected in between 0.96% and 6.78% and to a lesser extent in Culex mosquitoes where DNA was detected at rates of between 0.19% and 0.64%. DNA analysis showed that An. coluzzii constituted 9.9% of the collected mosquitoes and the remaining 90.1% of the mosquitoes were Culex mosquitoes. CONCLUSION: Despite detection of W. bancrofti DNA within mosquito specimens collected in three Kano urban LGAs, we were not able to find a subject with detectable level of CFA. Together with other evidence suggesting that LF transmission in urban areas in West Africa may not be of significant importance, the Federal Ministry of Health advised that two rounds of MDA be undertaken in the urban areas of Kano. It is recommended that the prevalence of W. bancrofti infection in the human and mosquito populations be re-assessed after a couple of years.
Assuntos
Erradicação de Doenças/métodos , Filariose Linfática/tratamento farmacológico , Filariose Linfática/prevenção & controle , Filaricidas/administração & dosagem , Adolescente , Adulto , Animais , Anopheles/parasitologia , Antígenos de Helmintos/sangue , Antígenos de Helmintos/genética , Criança , Culex/parasitologia , Esquema de Medicação , Filariose Linfática/epidemiologia , Filariose Linfática/transmissão , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nigéria/epidemiologia , Reação em Cadeia da Polimerase , Saúde da População Urbana , Wuchereria bancrofti/genética , Wuchereria bancrofti/isolamento & purificação , Adulto JovemRESUMO
The purpose of this research was to evaluate the effect and nature of hydration on the glass transition temperature (Tg) of poly(D,L-lactide-co-glycolide) and investigate the physical state of water within the polymer during hygrothermal aging. The polymer was incubated in water at 23, 30, 37 and 55 degrees C, while the vapor sorption studies were carried out at 37 degrees C using saturated salt solutions. The water content and the thermal behavior of PLGA-water system were assessed by Karl Fischer titration and modulated differential scanning calorimetry, respectively, the hygrothermal aging was monitored by gel permeation chromatography. Water depressed reversibly the Tg by about 15 degrees C regardless of the incubation conditions. The Tg then remained constant at approximately 30 degrees C for five days, except when degradation occurred. A broad ice melting peak was detected around 0 degrees C. In the sorption studies, a linear correlation (r2 0.9837) between the Tg and the moisture content was observed in the range of 0.3-2.6% w/w, but there was no discernible endothermic event associated with the melting of ice. Data were found to fit reasonably well to the Gordon-Taylor/Kelley-Bueche equation. There were no differences between bulk and vapor water aging. It is proposed that the water responsible for plasticizing the polymer was non-freezable (bound) water and the small fraction of such water which was absorbed at high relative humidity caused polymer degradation in the same manner as bulk water.
Assuntos
Poliglactina 910/química , Água/química , Elasticidade , Vidro , Modelos Químicos , Peso Molecular , TermodinâmicaRESUMO
The purpose of this research was to develop a simple and convenient in vitro release method for biodegradable microspheres using a commercially available dialyzer. A 25 KD MWCO Float-a-Lyzer was used to evaluate peptide diffusion at 37 degrees C and 55 degrees C in different buffers and assess the effect of peptide concentration. In vitro release of Leuprolide from PLGA microspheres, having a 1-month duration of action, was assessed using the dialyzer and compared with the commonly used sample and separate method with and without agitation. Peptide diffusion through the dialysis membrane was rapid at 37 degrees C and 55 degrees C in all buffers and was independent of peptide concentration. There was no detectable binding to the membrane under the conditions of the study. In vitro release of Leuprolide from PLGA microspheres was tri-phasic and was complete in 28 days with the dialysis technique. With the sample and separate technique, linear release profiles were obtained with complete release occurring under conditions of agitation. Diffusion through the dialysis membrane was sufficiently rapid to qualify the Float-a-Lyzer for an in vitro release system for microparticulate dosage forms. Membrane characteristics render it useful to study drug release under real-time and accelerated conditions.
Assuntos
Microesferas , Preparações Farmacêuticas/metabolismo , Tecnologia Farmacêutica/métodos , Diálise , Preparações Farmacêuticas/químicaRESUMO
The purpose of this study was to determine the feasibility of applying accelerated in vitro release testing to correlate or predict long-term in vitro release of leuprolide poly(lactide-co-glycolide) microspheres. Peptide release was studied using a dialysis technique at 37 degrees C and at elevated temperatures (50 degrees C-60 degrees C) in 0.1M phosphate buffered saline (PBS) pH 7.4 and 0.1M acetate buffer pH 4.0. The data were analyzed using a modification of the Weibull equation. Peptide release was temperature dependent and complete within 30 days at 37 degrees C and 3 to 5 days at the elevated temperatures. In vitro release profiles at the elevated temperatures correlated well with release at 37 degrees C. The shapes of the release profiles at all temperatures were similar. Using the modified Weibull equation, an increase in temperature was characterized by an increase in the model parameter, alpha, a scaling factor for the apparent rate constant. Complete release at 37 degrees C was shortened from approximately 30 days to 5 days at 50 degrees C, 3.5 days at 55 degrees C, 2.25 days at 60 degrees C in PBS pH 7.4, and 3 days at 50 degrees C in acetate buffer pH 4.0. Values for the model parameter beta indicated that the shape of the release profiles at 55 degrees C in PBS pH 7.4 (2.740) and 50 degrees C in 0.1M acetate buffer pH 4.0 (2.711) were similar to that at 37 degrees C (2.677). The E(a) for hydration and erosion were determined to be 42.3 and 19.4 kcal/mol, respectively. Polymer degradation was also temperature dependent and had an E(a) of 31.6 kcal/mol. Short-term in vitro release studies offer the possibility of correlation with long-term release, thereby reducing the time and expense associated with long-term studies. Accelerated release methodology could be useful in the prediction of long-term release from extended release microsphere dosage forms and may serve as a quality control tool for the release of clinical or commercial batches.
Assuntos
Implantes Absorvíveis , Sistemas Computacionais , Microesferas , Modelos Biológicos , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinéticaRESUMO
In humans, the incidence and severity of abdominal aortic aneurysms (AAA) are greater in males than in females. Chronic infusion of angiotensin II (AngII) into apolipoprotein E-deficient (apoE(-/-)) mice promotes atherosclerosis and causes the formation of AAAs. Just as human males are more susceptible to developing AAAs, male mice are more susceptible to AngII-induced AAAs. We hypothesized that sex steroid hormones mediate gender differences in AngII-induced AAA through regulation of the renin-angiotensin system. To define the role of ovarian hormones, female apoE(-/-) mice were subjected to ovariectomy or sham operation and infused with AngII (1000 ng/kg x min) for 28 d. Ovariectomy had no effect on AngII-induced atherosclerosis, nor did it influence the incidence or severity of AAA. To define the role of testicular hormones, male apoE(-/-) mice were subjected to orchidectomy (orx) or sham operation and infused with AngII (1000 ng/kg x min) for 28 d. Orx resulted in a profound reduction in AAA incidence (85% vs. 18%, sham vs. orx; P = 0.003) to the level observed in females (25%). However, orx had no effect on AngII-induced reductions in plasma renin concentration or spleen AngII receptor density. In contrast, orx resulted in an increase in atherosclerosis (0.46 +/- 0.07 vs. 1.20 +/- 0.21 mm(2), sham vs. orx; P = 0.002). These results suggest that estrogen does not mediate gender differences in AngII-induced AAA. In contrast, androgens mediate a higher incidence of AngII- induced AAA, through mechanisms that do not appear to involve circulating renin or angiotensin receptor density.
Assuntos
Angiotensina II/farmacologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Apolipoproteínas E/fisiologia , Arteriosclerose/induzido quimicamente , Hormônios Esteroides Gonadais/fisiologia , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Orquiectomia , Ovariectomia , Caracteres SexuaisRESUMO
The purpose of this study was to assess whether male rats whose testosterone levels were suppressed to castration levels (<0.5 ng/mL) for a 1-year period by the sustained delivery of orntide acetate, a GnRH antagonist, would return to fertility (ie, produce offspring) after serum testosterone returned to control levels. Male rats comprising a treatment group (orntide microspheres, dose = 27 mg/kg/y), a vehicle control group, and a control group of proven male breeders were used. For the treatment and vehicle control groups, serum orntide and testosterone levels were monitored at periodic intervals for 14 months from the initiation of treatment. After serum testosterone levels returned to vehicle control levels and orntide serum levels were no longer discernible for the treated group, each of the animals was housed with 2 drug-naive, female, proven breeders. All the breeder females produced offspring with the exception of 1 female housed with a male rat from the treatment group and the 2 females housed with a single male rat from the vehicle control group. The mean size and weight of the litters from each group were not statistically different. Further, fertility of the offspring from each group was assessed. The male and female offspring studied were all shown to be fertile. The results suggest that lack of fertility due to testosterone suppression in male rats is reversible after cessation of treatment with the GnRH analog, orntide.
Assuntos
Fertilidade/efeitos dos fármacos , Hormônio Liberador de Gonadotropina/análogos & derivados , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Hormônio Liberador de Gonadotropina/farmacologia , Testosterona/metabolismo , Animais , Castração , Anticoncepcionais Masculinos/farmacologia , Masculino , Ratos , Ratos Sprague-DawleyAssuntos
Dengue/complicações , Necrose/complicações , Esplenopatias/complicações , Humanos , Masculino , Adulto JovemRESUMO
Arthritis is one of the less common, yet challenging problems that may confront a pediatrician. The potential pathology is diverse ranging from the benign with a good prognosis to the serious and ultimately fatal. From a spot diagnosis to conditions that evolve over time, few other conditions challenge and stimulate the clinical acumen. Several diagnoses can be made clinically with the laboratory investigations providing additional support. An approach through which the clinician seeks answers through a logical sequence of questions is presented to help shortlist the possible diagnosis.
Assuntos
Artrite/diagnóstico , Tomada de Decisões , Algoritmos , Criança , HumanosRESUMO
The combination of Congenital Central Hypoventilation with Hirschsprung's disease belongs to the family of diseases now designated as Neurocristopathies. The authors report a polysomnographically documented case and review literature on this disorder.
Assuntos
Doença de Hirschsprung/complicações , Apneia do Sono Tipo Central/complicações , Evolução Fatal , Humanos , Recém-Nascido , Masculino , Polissonografia , Apneia do Sono Tipo Central/congênito , SíndromeRESUMO
The objective of this study was to compare the in vitro behavior of four long-acting subcutaneous risperidone formulations with in vivo performance, with the intent of establishing an IVIVC. Two copolymers of PLGA (50:50 and 75:25) were used to prepare four microsphere formulations of risperidone, an atypical antipsychotic. In vitro behavior was assessed at the physiological temperature (37 °C) using the 'modified dialysis' technique. The in vitro release profile demonstrated rank order behavior with Formulations A and B, prepared using the 50:50 copolymer, exhibiting rapid drug release, while Formulations C and D, prepared using 75:25 PLGA, released drug in a slower manner. In vivo profiles were obtained by two approaches, i.e., deconvolution using the Nelson-Wagner equation (the FDA recommended approach) and using fractional AUC. With both in vivo approaches, the 50:50 PLGA preparations released drug faster than the 75:25 PLGA microspheres, exhibiting the same rank order observed in vitro. Additionally, profiles for the four formulations obtained using the deconvolution approach were nearly superimposable with fractional AUC, implying that the latter procedure could be used as a substitute for the Nelson-Wagner method. A comparison of drug release profiles for the four formulations revealed that in three of the four formulations, in vivo release was slightly faster than that in vitro, but the results were not statistically significant (P > 0.0001). An excellent linear correlation (R2 values between 0.97 and 0.99) was obtained when % in vitro release for each formulation was compared with its corresponding in vivo release profile, obtained by using fraction absorbed (Nelson-Wagner method) or fractional AUC. In summary, using the four formulations that exhibited different release rates, a Level A IVIVC was established using the FDA-recommended deconvolution method and fractional AUC approach. The excellent relationship between in vitro drug release and the amount of drug absorbed in vivo in this study was corroborated by the nearly 1:1 correlation (R2 greater than 0.97) between in vitro release and in vivo performance. Thus, the results of the current study suggest that proper selection of an in vitro method to assess drug release from long-acting injectables will aid in obtaining a Level A IVIVC.
RESUMO
The aim of this study was to design and evaluate biodegradable PLGA microspheres for sustained delivery of Risperidone, with an eventual goal of avoiding combination therapy for the treatment of schizophrenia. Two PLGA copolymers (50 : 50 and 75 : 25) were used to prepare four microsphere formulations of Risperidone. The microspheres were characterized by several in vitro techniques. In vivo studies in male Sprague-Dawley rats at 20 and 40 mg/kg doses revealed that all formulations exhibited an initial burst followed by sustained release of the active moiety. Additionally, formulations prepared with 50 : 50 PLGA had a shorter duration of action and lower cumulative AUC levels than the 75 : 25 PLGA microspheres. A simulation of multiple dosing at weekly or 15-day regimen revealed pulsatile behavior for all formulations with steady state being achieved by the second dose. Overall, the clinical use of Formulations A, B, C, or D will eliminate the need for combination oral therapy and reduce time to achieve steady state, with a smaller washout period upon cessation of therapy. Results of this study prove the suitability of using PLGA copolymers of varying composition and molecular weight to develop sustained release formulations that can tailor in vivo behavior and enhance pharmacological effectiveness of the drug.
RESUMO
In this study, four PLGA microsphere formulations of Olanzapine were characterized on the basis of their in vitro behavior at 37°C, using a dialysis based method, with the goal of obtaining an IVIVC. In vivo profiles were determined by deconvolution (Nelson-Wagner method) and using fractional AUC. The in vitro and in vivo release profiles exhibited the same rank order of drug release. Further, in vivo profiles obtained with both approaches were nearly superimposable, suggesting that fractional AUC could be used as an alternative to the Nelson-Wagner method. A comparison of drug release profiles for the four formulations revealed that the in vitro profile lagged slightly behind in vivo release, but the results were not statistically significant (P < 0.0001). Using the four formulations that exhibited different release rates, a Level A IVIVC was established using the deconvolution and fractional AUC approaches. A nearly 1 : 1 correlation (R (2) > 0.96) between in vitro release and in vivo measurements confirmed the excellent relationship between in vitro drug release and the amount of drug absorbed in vivo. The results of this study suggest that proper selection of an in vitro method will greatly aid in establishing a Level A IVIVC for long acting injectables.
RESUMO
The purpose of this study was to develop a parenteral delivery system of Risperidone that would provide initial and extended drug release and thereby avoid the need for co-administration of oral tablets. Key formulation parameters utilized to achieve desired therapeutic levels in vivo were particle size and drug loading. Three poly (D,L-lactide-co-glycolide) (PLGA) microsphere formulations (Formulations A, B, and C) that encapsulated Risperidone were prepared by varying particle size (19-49 µm) and drug loading parameters (31-37%) but with a uniform bulk density (0.66-0.69)g/cc and internal porosity, utilizing the solvent extraction/evaporation method. The microspheres were characterized for drug content by HPLC, particle size by laser diffractometry, surface morphology by scanning electron microscopy (SEM), and in vivo drug release. In vivo studies were performed in male Sprague-Dawley rats, and levels of the active moiety (Risperidone and its metabolite, 9-hydroxyrisperidone) were assessed. In vivo release profiles from the three microsphere formulations were dependent on particle size and drug loading. The smaller sized microspheres (Formulation A) exhibited a large initial burst and a shorter duration of action, while the larger particles exhibited a smaller initial burst (Formulations B and C) but released drug for a much longer period in vivo. Extended duration of drug release was ascribed to higher drug content in the microspheres. A biweekly simulation of multiple dosing revealed that Formulation C, the selected formulation, with a high load and large particle size would provide adequate initial and maintenance levels of the active moiety (Risperidone and its metabolite, 9-hydroxyrisperidone). A comparison of biweekly dosing in vivo of Formulation C with the marketed product showed that at steady state, though average concentrations for both preparations were similar, the time taken to achieve steady state was much faster for Formulation C. The delay in attaining steady state with Risperdal Consta® was attributed to the 3 week latency in drug release from the microspheres and was in accordance with previous studies indicating a good corroboration with clinical findings. Calculated cumulative AUC (area under the curve) levels for Formulation C were similar to the Risperdal Consta®, though there were marked differences in AUC levels at the early time points. Comparison of Risperidal Consta® and Formulation C by multiple dosing in vivo experiments revealed that the marketed preparation demonstrated a substantial delay in providing an initial loading dose, continuous circulating levels, and attainment of steady state; all of which were observed rapidly with Formulation C. Findings from the current study strongly suggest that a microsphere dosage form of Risperidone can be formulated with an optimum particle size and drug loading to provide an initial bolus followed by maintenance levels, thereby eliminating combination therapy and improving patient compliance.
Assuntos
Sistemas de Liberação de Medicamentos , Isoxazóis/farmacocinética , Microesferas , Pirimidinas/farmacocinética , Risperidona/administração & dosagem , Animais , Antipsicóticos/administração & dosagem , Antipsicóticos/farmacocinética , Área Sob a Curva , Química Farmacêutica , Preparações de Ação Retardada , Portadores de Fármacos/química , Composição de Medicamentos , Ácido Láctico/química , Masculino , Palmitato de Paliperidona , Tamanho da Partícula , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Porosidade , Ratos , Ratos Sprague-Dawley , Risperidona/farmacocinética , Fatores de TempoRESUMO
The aim of this study was to prepare injectable depot formulations of Olanzapine using four poly(D,L-lactide-co-glycolide) (PLGA) polymers of varying molecular weight and copolymer composition, and evaluate in vivo performance in rats. In vivo release profiles from the formulations were governed chiefly by polymer molecular weight and to a lesser extent, copolymer composition. Formulations A and B, manufactured using low molecular weight PLGA and administered at 10 mg/kg dose, released drug within 15 days. Formulation C, prepared from intermediate molecular weight PLGA and administered at 20 mg/kg dose, released drug in 30 days, while Formulation D, manufactured using a high molecular weight polymer and administered at 20 mg/kg dose, released drug in 45 days. A simulation of multiple dosing at 7- and 10-day intervals for Formulations A and B revealed that steady state was achieved within 7-21 days and 10-30 days, respectively. Similarly, simulations at 15-day intervals for Formulations C and D indicated that steady state levels were reached during days 15-45. Overall, steady state levels for 7-, 10-, or 15-day dosing ranged between 45 and 65 ng/mL for all the formulations, implying that Olanzapine PLGA microspheres can be tailored to treat patients with varying clinical needs.