RESUMO
BACKGROUND: Collaborative working between academic institutions and those who provide health and social care has been identified as integral in order to produce acceptable, relevant, and timely research, and for outputs to be useful and practical to implement. The ExCHANGE Collaboration aims to bring together researchers and people working, living in and visiting care homes to build capacity, share and mobilise knowledge, and identify key areas for future research. This paper describes an embedded, formative, realist and theory-driven evaluation which aims to gather information about how successful the ExCHANGE Collaboration is perceived to be in achieving its aims. An existing realist programme theory from the literature - Closer Collaboration - will be supplemented by two substantive theories: Co-production and Knowledge Brokering. This will result in an initial programme theory which will be tested by this formative evaluation to refine understanding of how the ExCHANGE Collaboration works. METHODS: The evaluation will employ mixed qualitative methods, including: analysis of documents such as feedback forms, Knowledge Broker journal/diary, event attendance records, risk and issues logs and other relevant paperwork gathered as part of project delivery; observations of events/activities; and interviews with care home providers and staff, care home residents, residents' family members, and researchers who are involved in the project (both project design/delivery, and also attendance or involvement in project activities/events). Framework Analysis will be used to interpret the data collected; analysis will be strategic, by focusing on particular key areas of importance in the developing theory of how the ExCHANGE Collaboration might achieve change. RESULTS: The results of this study are expected to be published in 2022. DISCUSSION: This evaluation will investigate how successful the ExCHANGE Collaboration is perceived to be in achieving its aims, in what way, in which contexts, and how this may differ for those involved. It will do this by testing an initial programme theory about how the collaboration works, for whom, under which circumstances, and in what way. Findings will be shared through written publication, an end of project learning event for those involved/interested in the project, and a lay summary to be made publically available.
Assuntos
Glicemia/análise , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/economia , Diabetes Mellitus Tipo 1/epidemiologia , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Reembolso de Seguro de Saúde/estatística & dados numéricos , Demandas Administrativas em Assistência à Saúde/estatística & dados numéricos , Glicemia/metabolismo , Automonitorização da Glicemia/economia , Automonitorização da Glicemia/instrumentação , Automonitorização da Glicemia/estatística & dados numéricos , Análise Custo-Benefício , Diabetes Mellitus Tipo 1/tratamento farmacológico , Inglaterra/epidemiologia , Disparidades em Assistência à Saúde/economia , Disparidades em Assistência à Saúde/estatística & dados numéricos , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/economia , Insulina/administração & dosagem , Insulina/economia , Sistemas de Infusão de Insulina/economia , Sistemas de Infusão de Insulina/estatística & dados numéricos , Estudos LongitudinaisRESUMO
PCR ribotyping is currently used in many countries for epidemiological investigation to track transmission and to identify emerging variants of Clostridium difficile. Although PCR ribotyping differentiates over 300 types, it is not always sufficiently discriminatory for epidemiological investigations particularly for common ribotypes, e.g., ribotypes 027, 106, and 017. Multilocus variable-number tandem-repeat analysis (MLVA) is a highly discriminatory molecular subtyping method that has been applied to a number of bacterial species for high-level subtyping. Two MLVA typing schemes for C. difficile have been previously published, each utilizing seven variable-number tandem-repeat (VNTR) loci on the genome with four loci common to both schemes. Although these schemes are good genotyping methods with the ability to discriminate between isolates, they do not identify the ribotype. We show here that increasing the number of VNTR loci to 15, creating the extended MLVA (eMLVA) scheme, we have successfully subtyped all clinically significant ribotypes while still clustering isolates in concordance with PCR ribotyping. The eMLVA scheme developed here provides insight into the genetic diversity of the C. difficile population at both global and cross-infection clusters in patient levels, with the possibility of replacing PCR ribotyping.
Assuntos
Clostridioides difficile/classificação , Clostridioides difficile/genética , Infecções por Clostridium/transmissão , Infecção Hospitalar/transmissão , Repetições Minissatélites , Tipagem Molecular/métodos , Clostridioides difficile/isolamento & purificação , Infecções por Clostridium/epidemiologia , Infecções por Clostridium/microbiologia , Infecção Hospitalar/epidemiologia , Infecção Hospitalar/microbiologia , Hospitais , Humanos , Epidemiologia Molecular/métodos , Ribotipagem/métodos , Estatística como AssuntoRESUMO
BACKGROUND: Recombinant human TSH (rhTSH) can be used to enhance (131)I therapy for shrinkage of multinodular goiter (MG). OBJECTIVE, DESIGN, AND SETTING: The objective of the study was to compare the efficacy and safety of 0.01 and 0.03 mg modified-release (MR) rhTSH as an adjuvant to (131)I therapy, vs. (131)I alone, in a randomized, placebo-controlled, international, multicenter study. PATIENTS AND INTERVENTION: Ninety-five patients (57.2 ± 9.6 yr old, 85% females, 83% Caucasians) with MG (median size 96.0, range 31.9-242.2 ml) were randomized to receive placebo (group A, n = 32), MRrhTSH 0.01 mg (group B, n = 30), or MRrhTSH 0.03 mg (group C, n = 33) 24 h before a calculated activity of (131)I. MAIN OUTCOME MEASURES: The primary end point was a change in thyroid volume (by computerized tomography scan, at 6 months). Secondary end points were the smallest cross-sectional area of the trachea; thyroid function tests; Thyroid Quality of Life Questionnaire; electrocardiogram; and hyperthyroid symptom scale. RESULTS: Thyroid volume decreased significantly in all groups. The reduction was comparable in groups A and B (23.1 ± 8.8 and 23.3 ± 16.5%, respectively; P = 0.95). In group C, the reduction (32.9 ± 20.7%) was more pronounced than in groups A (P = 0.03) and B. The smallest cross-sectional area of the trachea increased in all groups: 3.8 ± 2.9% in A, 4.8 ± 3.3% in B, and 10.2 ± 33.2% in C, with no significant difference among the groups. Goiter-related symptoms were effectively reduced and there were no major safety concerns. CONCLUSION: In this dose-selection study, 0.03 mg MRrhTSH was the most efficacious dose as an adjuvant to (131)I therapy of MG. It was well tolerated and significantly augmented the effect of (131)I therapy in the short term. Larger studies with long-term follow-up are warranted.
Assuntos
Bócio Nodular/terapia , Tireotropina/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anatomia Transversal , Terapia Combinada , Preparações de Ação Retardada , Método Duplo-Cego , Feminino , Bócio Nodular/tratamento farmacológico , Bócio Nodular/radioterapia , Humanos , Radioisótopos do Iodo/farmacocinética , Radioisótopos do Iodo/uso terapêutico , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Proteínas Recombinantes/uso terapêutico , Testes de Função Tireóidea , Hormônios Tireóideos/sangue , Tireoidectomia , Tireotropina/administração & dosagem , Tireotropina/efeitos adversos , Traqueia/anatomia & histologiaRESUMO
Generation of new beta-cells from the adult pancreas or the embryonic stem cells is being pursued by research groups worldwide. Success will be dependent on confirmation of true beta-cell phenotype evidenced by capacity to process and store proinsulin. The aim of these studies was to robustly determine endocrine characteristics of the AR42J rat pancreatic acinar cell line before and after in vitro transdifferentiation. beta-cell phenotypic marker expression was characterised by RT-PCR, immunostaining, western blotting, ELISA and in human preproinsulin transgene over-expression studies in wild-type AR42J cells and after culture on Matrigel basement membrane matrix with and without growth/differentiation factor supplementation. Pancreatic duodenal homeobox 1 (PDX1), forkhead box transcription factor a2 (Foxa2), glucokinase, pancreatic polypeptide and low-level insulin gene transcription in wild-type AR42J cells were confirmed by RT-PCR. Culture on Matrigel-coated plates and supplementation of medium with glucagon-like peptide 1 induced expression of the beta-cell Glut 2 with maintained expression of insulin and PDX1. Increased biosynthesis and secretion of proinsulin were confirmed by immunocytochemical staining and sensitive ELISA. Absence of the regulated secretory pathway was demonstrated by undetectable prohormone convertase expression. In addition, inability to process and store endogenous proinsulin or human proinsulin translated from a constitutively over-expressed preproinsulin transgene was confirmed. The importance of robust phenotypic characterisation at the protein level in attempted beta-cell transdifferentiation studies has been confirmed. Rodent and human sensitive/specific differential proinsulin/insulin ELISA in combination with human preproinsulin over-expression enables detailed elucidatation of core endocrine functions of proinsulin processing and storage in putative new beta-cells.
Assuntos
Diferenciação Celular , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/fisiologia , Proinsulina/metabolismo , Animais , Western Blotting , Linhagem Celular , Ensaio de Imunoadsorção Enzimática , Expressão Gênica , Perfilação da Expressão Gênica , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Glucoquinase/genética , Fator 3-beta Nuclear de Hepatócito/genética , Proteínas de Homeodomínio/genética , Humanos , Imuno-Histoquímica , Insulina , Células Secretoras de Insulina/química , Masculino , Polipeptídeo Pancreático/genética , Fenótipo , Proinsulina/biossíntese , Proinsulina/genética , Precursores de Proteínas/genética , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transativadores/genética , Transfecção , Transgenes/genéticaRESUMO
It was hypothesised that formulating a dry-powder inhaler (DPI) using a refined, smooth grade of lactose, without fines and a polymer coated drug microparticle should produce an homogeneous formulation in which aerosolization behaviour could be modified. Hence, the aim of this study was to develop a simple two component polymer coated-budesonide/lactose blend in which the drug microparticle adhesive forces could be optimised by modifying the drug coating in order to improve aerosolization from a DPI. Budesonide microparticles (1.83 +/- 0.03 microm) were coated with the vinyl polymers by adsorption and then spray-dried. The drug was blended with three different types of lactose, checked for uniformity of mixing and loaded into Pulvinal devices. The median volume particle size of all but one of the polymer coated microparticles remained below 4 microm after spray-drying and the content uniformity for all the blends >96%. Coating the budesonide with 0.01% poly(vinyl alcohol) increased the fine particle fraction (FPF) in the next generation impactor (NGI) from 29.1 +/- 0.7% to 52.8 +/- 1.0% and reduced the force of adhesion from 410 +/- 182 to 241 +/- 82 nN with smooth lactose. This illustrates that vinyl polymers could effectively modify adhesive interactions without the need for ternary components such as fines.
Assuntos
Budesonida/administração & dosagem , Polímeros/química , Microscopia de Força Atômica , Microscopia Eletrônica de Varredura , PósRESUMO
Despite the availability of numerous crystal engineering techniques, generating drug-rich microparticles with a predetermined size, morphology and crystallinity still represents a significant challenge. A microparticle manufacturing method has recently been developed that attempts to 'shield' the physicochemical properties of micronised drugs by the application of a microfine polymer coating. The aims of this study were to investigate the nature of the drug-polymer interactions and determine the effects of this manufacturing strategy upon release of the drug from the microparticles. The adsorption of poly(vinyl alcohol) (PVA) on the micronised hydrophobic drug surface was found to reach equilibrium between 23 and 27 h. The Freundlich isotherm model was shown to give the most accurate fit to the experimental data and thus multilayer adsorption was assumed. The adsorptive capacity (1/n) was specific to the substrate and PVA grade. An increase in the PVA (%) hydrolysis value caused 1/n to increase from 0.76 to 1.05 using budesonide and from 0.31 to 0.79 when betamethasone valerate (BMV) was used. Increasing the molecular weight of the adsorbing polymer caused a reduction in the strength of PVA-adsorbate interaction when budesonide was used as the substrate (from 0.76 to 0.59), whereas a three-fold increase (from 0.31 to 0.86) was achieved when the BMV substrate was employed. A proportion of the adsorbed polymer was shown to remain associated with the substrate during the spray-drying process and the polymer coating resulted in a significantly higher (p<0.05, ANOVA) amount of drug release in 60 min (ca. 100%) compared to budesonide alone.
Assuntos
Interações Hidrofóbicas e Hidrofílicas , Microesferas , Preparações Farmacêuticas/química , Álcool de Polivinil/química , Corticosteroides/química , Corticosteroides/farmacocinética , Adsorção , Algoritmos , Valerato de Betametasona/química , Valerato de Betametasona/farmacocinética , Budesonida/química , Budesonida/farmacocinética , Calibragem , Colorimetria/métodos , Liofilização/métodos , Hidrólise , Cinética , Peso Molecular , Tamanho da Partícula , Preparações Farmacêuticas/metabolismo , Polímeros/química , Solubilidade , Tecnologia Farmacêutica/métodos , TermodinâmicaRESUMO
The analysis of weakly basic drugs such as salmeterol xinafoate (SX) by reverse-phase liquid chromatography remains a problem, particularly when present in combination with other drugs such as steroids and weak acids. This study describes the validation of an assay for a weakly basic drug, salmeterol (SB), its weakly acidic counter-ion, 1-hydroxy-2-naphthoic acid (XA), and the neutral glucocorticoid, fluticasone propionate (FP) using a second-generation silica stationary phase (Inertsil ODS-2). The assay utilized an Inertsil ODS-2 base-deactivated 250 mm x 4.6mm, 5 microm HPLC column, with 75:25 methanol:0.6% aqueous ammonium acetate as the mobile phase. Under these near neutral conditions, SB demonstrated a good peak shape (tailing factor=1.21+/-0.02, n=85). The method provided a short analysis time: XA, t(R)=2.96 min; SB, t(R)=5.23 min and FP, t(R)=7.01 min. The assay displayed good sensitivity for both XA (LOD for SX=0.22 microgmL(-1)) and SB (LOD for SX=0.26 microgmL(-1)). The limit of detection for FP was 0.19 microgmL(-1). Neither of the drugs was found to interfere in the determination of the other and the assay accuracy (% recovery) was high (the recoveries were: 99.58+/-1.85% for XA, 99.49+/-1.88% for SB and 100.24+/-1.28% for FP). The assay reproducibility was determined with a mean coefficient of variance for the five calibration concentrations of XA=0.71+/-0.18%; SB=1.11+/-0.64% and FP=0.92+/-0.14%. Analysis of a pressurized metered dose inhaler formulation demonstrated recovery of the analytes that are within pharmacopoeial limits. It was shown that RP-HPLC was suitable for the high throughput analysis of the combination of SX and FP.
Assuntos
Albuterol/análogos & derivados , Androstadienos/análise , Albuterol/análise , Calibragem , Cromatografia Líquida de Alta Pressão , Fluticasona , Concentração de Íons de Hidrogênio , Indicadores e Reagentes , Padrões de Referência , Reprodutibilidade dos Testes , Xinafoato de SalmeterolRESUMO
Recently, a dimeticone formulation has been shown to be effective at preventing Schistosoma cercariae infecting skin, while DEET (N,N-diethyl-m-toluamide), a highly effective insecticide, has been shown to have activity against cercariae. Seven formulations, 3 containing DEET, were prepared and applied to excised human skin in Franz cells for 1 h. Schistosoma cercariae were applied for 30 min at 1 and 24 h, and the number that penetrated the skin calculated (n = 9). DEET could not be incorporated into the dimeticone formulation, yet it remained the most effective at preventing cercarial penetration, both 1 and 24 h after application. The ointments that contained DEET did prevent penetration but their mode of action was due to the toxicity of DEET against the cercariae. The persistence of the protection afforded by the dimeticone formulation after washing suggests that the formulation may be interacting with the stratum corneum to prevent cercarial recognition of skin.
Assuntos
Química Farmacêutica , DEET/uso terapêutico , Repelentes de Insetos/uso terapêutico , Schistosoma mansoni/efeitos dos fármacos , Esquistossomose/prevenção & controle , Animais , DEET/administração & dosagem , Feminino , Humanos , Repelentes de Insetos/administração & dosagem , Pele/efeitos dos fármacosRESUMO
This paper describes the use of finite element (FE) analysis as a tool in the design process for laboratory based ultrasonic test cells. The system was designed to incorporate an array of ultrasonic transducers to provide a pressure focus in the centre of the cell and importantly, operate both above and below the cavitation threshold of the load medium. Furthermore, the cell incorporates a coolant jacket to accommodate temperature control of the load material associated with the process. A 2D FE model corresponding to a slice through the operational plane of the cell was developed and used to investigate the influence of cell wall material and thickness, transducer configuration, rotation of a metallic stirrer blade and heat transfer fluid on the cell acoustic response. Importantly, experimentally measured pressure field maps demonstrate good correlation with the FE predicted fields. A final manufactured test cell is shown to produce a highly focussed region of cavitation. Finally, the importance in accurately representing the acoustic properties of the constituent materials used in such FE models is demonstrated through an illustrated example.
RESUMO
Schistosomiasis is initiated when cercarial larvae invade human skin. Contrary to long-held assumptions, most cercariae of Schistosoma mansoni do not shed their propulsive tails as they penetrate. Scanning electron microscopy studies and infection experiments with entire human skin and differentiated, stratum corneum-like, human keratinocyte cultures, have shown that most cercarial tails enter the skin along with their bodies. We propose that this behaviour is an adaptive trait linked with concomitant immunity.
Assuntos
Schistosoma mansoni/patogenicidade , Pele/parasitologia , Animais , Células Cultivadas , Humanos , Queratinócitos/parasitologia , Estágios do Ciclo de Vida , Camundongos , Microscopia Eletrônica de Varredura , Schistosoma mansoni/citologia , Schistosoma mansoni/crescimento & desenvolvimento , Schistosoma mansoni/ultraestrutura , Esquistossomose mansoni/transmissão , Pele/ultraestrutura , Cauda/ultraestruturaRESUMO
It has previously been postulated that L-arginine emitted by penetrating Schistosoma mansoni cercariae serves as an intraspecific signal guiding other cercariae to the penetration site. It was suggested that penetrating in groups offers a selective advantage. If this hypothesis is correct and group penetration at one site on the host offers an advantage, it would follow that at such a site, successive groups of cercariae would be able to penetrate skin in either greater numbers or at a faster rate. This prediction was tested by the use of an in vitro model of cercarial penetration based on the Franz cell and using human skin. It was demonstrated that there was no increase in the percentage of cercariae able to penetrate the skin with subsequent exposures. Consequently, it seems unlikely that the release of L-arginine by cercariae during penetration could have evolved as a specific orientation system based on a selective advantage offered by group penetration.
Assuntos
Schistosoma mansoni/fisiologia , Pele/parasitologia , Animais , Arginina/metabolismo , Humanos , Larva , Parasitologia/métodos , Schistosoma mansoni/metabolismoRESUMO
One approach to the prevention of schistosomiasis is the use of topical formulations to inhibit cercarial penetration of skin. A number of formulations containing either cercaricidal ingredients or components designed to inhibit penetration have been studied, but with variable results. Such studies have rarely considered the persistence of inhibitory effects through time, and to date, there have been no systematic investigations of barrier formulations. The aim of this study was to use Franz cells to investigate the effect of such barrier creams on the penetration of S. mansoni cercariae into human skin. The results show that a single application of a barrier cream based on dimethicone offers a high level of protection against penetration that is sustained for at least 48 hr.
Assuntos
Schistosoma mansoni/crescimento & desenvolvimento , Esquistossomose mansoni/prevenção & controle , Simeticone/farmacologia , Pele/parasitologia , Administração Tópica , Animais , Emolientes/administração & dosagem , Emolientes/farmacologia , Feminino , Humanos , Técnicas In Vitro , Schistosoma mansoni/metabolismo , Simeticone/administração & dosagemRESUMO
The aim of the study was to investigate the interdependence of carrier particle size, surface treatment of the carrier, and inclusion of fines on the drug delivery from dry power inhaler formulations. Two size fractions (< 63 and 63-90 microm) of alpha-lactose monohydrate were subjected to treatment with 95% (v/v) ethanol to introduce small asperities or cavities onto the otherwise smooth surface without substantially changing the particle shape. After blending with albuterol sulfate [ALB; volume median diameter (VMD), 1.9 microm; geometric standard deviation (GSD), 1.5], the solvent-treated lactose produced a fine particle fraction (FPF; < 6.18 microm) and dispersibility of the drug that was significantly (ANOVA p < 0.01) lower than that which resulted from formulations containing untreated lactose of a similar size fraction, after aerosolization at 60 L min(-1) via a Rotahaler. The two size fractions of the treated lactose resulted in similar deposition profiles of ALB. The effects of such surface asperities or cavities of lactose were offset by introducing a small amount (5% w/w) of smaller-sized lactose (5-10 microm) to the powder formulations. The fine lactose increased the FPF and dispersibility of ALB to such a level that all lactose batches, regardless of particle size or whether solvent treated, produced a similar fraction of aerosolized ALB. The inclusion of recrystallized needle lactose (5-15 microm) was superior to micronized lactose in improving the aerosolization of ALB. The findings of this study indicate that the presence and characteristics of the finer fraction of lactose carrier particles dominate over the particle size and surface smoothness of the carrier particles in determining dispersion and deaggregation of drugs from dry powder formulations for inhalation.
Assuntos
Sistemas de Liberação de Medicamentos/métodos , Lactose/administração & dosagem , Lactose/química , Pós/administração & dosagem , Pós/química , Química Farmacêutica , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Nebulizadores e Vaporizadores , Tamanho da Partícula , Propriedades de SuperfícieRESUMO
Nonviral vectors have been shown to be a safe and valid alternative to recombinant viruses for gene therapy of cystic fibrosis (CF). Nevertheless, gene transfer efficiency needs to be increased before clinical efficacy is likely in man. One barrier to increased efficacy is normal airway mucus. Using an ex vivo model of sheep tracheal epithelium, we show that this barrier can, in part, be overcome by treatment with the mucolytic agents, Nacystelyn or N-acetylcysteine using either a cationic lipid or a cationic polymer as the gene transfer agent. Further, in vivo application of either Nacystelyn or the anticholinergic glycopyrrolate, both clinically used agents, resulted in increased reporter gene expression in the mouse lung, but no significant correction of the bioelectric defect in CF null mice. These results, whilst unlikely to be sufficient in themselves to achieve clinically relevant gene therapy, may be a further useful step in the attainment of this goal.
Assuntos
Acetilcisteína/farmacologia , Cloranfenicol O-Acetiltransferase/genética , Fibrose Cística/terapia , Expectorantes/farmacologia , Terapia Genética/métodos , Lisina/farmacologia , Traqueia/metabolismo , Acetilcisteína/análogos & derivados , Animais , Antagonistas Colinérgicos/farmacologia , Relação Dose-Resposta a Droga , Expressão Gênica/efeitos dos fármacos , Vetores Genéticos/farmacologia , Glicopirrolato/administração & dosagem , Injeções Intramusculares , Lisina/análogos & derivados , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos CFTR , Modelos Animais , Mucosa Nasal/metabolismo , Ovinos , Traqueia/efeitos dos fármacosRESUMO
The purpose of the present study was to investigate the effects of molecular weight (MW) of polyvinylpyrrolidone (PVP) on glass transition and crystallization of sucrose. Thus, sucrose was co-lyophilized with 2.5 and 5.0% w/w PVP of different molecular weights, which were characterized using gel permeation chromatography. Freeze drying was carried out for 48 h at a shelf temperature of -40 degrees C and a pressure of about 36 Pa. The samples were then dried in a vacuum oven at 24 degrees C for 12 h before drying for a further 12 h at 40 degrees C. Differential scanning calorimetry (DSC) was employed to measure the glass transition temperature (Tg), dynamic crystallization temperature (Tc) and isothermal crystallization induction time (tc) at 85 degrees C of sucrose. Isothermal water vapour sorption of each sample was also measured at different relative humidities. Tg values of sucrose varied from 48.3+/-0.8 degrees C for freeze-dried (FD) sucrose alone to 58.8+/-0.8 degrees C for the mixture containing 5.0% PVP of nominal MW 300 K. PVP increased sucrose T(g) significantly (ANOVA P<0.05). Although there was no significant difference (P>0.05) in Tg of the mixtures containing 2.5% w/w PVP of different MW, samples with 5.0% PVP of MW 300 K produced a significantly higher (P<0.05) Tg than the other mixtures. All mixtures were shown to possess higher (P<0.01) Tc than FD sucrose alone, which exhibited a T(c) of approximately 85 degrees C. PVP of MW 300 K consistently induced a significantly (P<0.05) higher Tc of sucrose than PVP of smaller MW. Increasing PVP concentration from 2.5 to 5.0% also resulted in a substantial increase in sucrose Tc. Using isothermal water vapour absorption, sucrose tc was found to increase up to over 10 times when it was co-lyophilized with 2.5% PVP, the actual value of tc being dependent upon the MW of the PVP. For example, PVP of MW 300 K resulted in a sucrose tc at 85 degrees C (89.1-95.6 min), which was approximately seven times higher than that of 2.5% PVP of MW 24 or 40 K. A longer tc of sucrose was also observed for mixtures containing PVP of MW 300 K than when sucrose was mixed with PVP of smaller MW. Thus the effect of PVP on sucrose Tg, Tc and tc was found to be dependent upon MW. PVP of higher MW was more efficient in inhibiting sucrose crystallization and by stabilizing glassy structures of the sugar, these polymers may improve the stability of co-lyophilized proteins and peptides.
Assuntos
Povidona/química , Sacarose/química , Varredura Diferencial de Calorimetria , Cromatografia em Gel , Cristalização , Peso Molecular , Temperatura , Fatores de Tempo , Água/químicaRESUMO
Lactose was crystallised either from Carbopol gel without stirring or from a constantly-stirred aqueous solution, to obtain lactose crystals designated as Carbo and control lactose, respectively. The Carbo lactose was shown to have a more regular shape with smoother surface as compared with the control lactose. These lactoses were fractionated by sieving to produce batches with different sizes before blending separately with salbutamol sulphate (SS, VMD 5.8 microm) in a ratio of 67.5:1 w/w using the same mixing procedure. SS dispersion and deaggregation were investigated using a 4-stage liquid impinger after aerosolisation at 28.3, 60.0 and 96.0 l/min via a Rotahaler. At all flow rates, the Carbo lactose produced significantly higher (ANOVA, P<0.01) emission of SS from the Rotahaler as compared with the control lactose of a similar size. The Carbo lactose also resulted in a significantly (P<0.05) higher fine particle fraction of SS than the control lactose. Moreover, drug emission from formulations containing the Carbo lactose was consistently more reproducible than those of the control lactose blends. In conclusion, the efficiency and reproducibility of drug delivery by dry powder inhalers can be improved using carrier particles of precisely defined morphological features.
Assuntos
Albuterol/administração & dosagem , Broncodilatadores/administração & dosagem , Lactose/química , Resinas Acrílicas , Aerossóis/administração & dosagem , Cristalização , Portadores de Fármacos , Géis , Nebulizadores e Vaporizadores , Polivinil/químicaRESUMO
We have investigated the interdependence of various factors (particle size, surface smoothness, carrier particle shape, inhalation flow rate) on the deposition of a model drug (salbutamol sulphate) after aerosolization from a model inhaler device (Rotahaler). Different batches of alpha-lactose monohydrate were prepared to have different particle size, particle shape and surface smoothness. Each batch of lactose was then mixed separately with salbutamol sulphate in a ratio of 67.5 : 1 (w/w), under similar conditions. Drug deposition from each formulation was investigated using a 4-stage liquid impinger after aerosolization at 28.3, 60.0 and 96.0 L min(-1) via a Rotahaler. At a flow rate of 28.3 L min(-1), a large portion of drug particles was not emitted from the inhaler, the % emission varying from 29.6% to 66.6% for all formulations investigated. Drug emission tended to increase with particle size of the carrier whilst fine particle fraction, fine particle dose and dispersibility appeared to increase with decreasing particle size but increasing elongation ratio of the carrier particles. Increasing the flow rate to 60.0 L min(-1) was shown to increase drug emission since > 75% total dose was found to be emitted from the inhaler. Again, smaller or more elongated lactose particles resulted in a higher fine particle dose or fine particle fraction of salbutamol sulphate than the coarser carrier, although they produced a similar (analysis of variance P > 0.05) drug emission. Increasing the flow rate to 96.0 L min(-1) did not increase drug emission. Increasing the flow rate resulted in an increase in the fine particle fraction and fine particle dose of salbutamol sulphate from all formulations. The flow rate of the airstream appeared to play the most important role, followed by particle size and elongation ratio of the carrier particles, with the surface smoothness relatively less significant in determining the deposition of salbutamol sulphate from the Rotahaler.
Assuntos
Propelentes de Aerossol/química , Albuterol/química , Broncodilatadores/química , Lactose/química , Nebulizadores e Vaporizadores , Portadores de Fármacos , Tamanho da PartículaRESUMO
The aim of this study was to investigate the dispersion and deaggregation of a model drug, salbutamol sulphate (SS), using lactose, mannitol or sorbitol as coarse and fine carriers. Binary and tertiary formulations containing micronised salbutamol sulphate (SS) and sieved (63-90 microm) coarse sugar crystals or salbutamol sulphate (SS) with a mixture of coarse and fine sugar particles were prepared. Factorial design was employed to investigate the effects of three variables, i.e. the chemical entity of the coarse sugar carrier, the chemical entity of the fine sugar and the concentration of fine sugar, on the dispersion and deaggregation of salbutamol sulphate after aerosolisation at 60 l/min via a Rotahaler(R) into a twin stage liquid impinger (TSI). The binary formulations containing the different sugar entities produced differences in the fine (<6.4 microm) particle fraction (FPF) of SS in a decreasing order of mannitol >sorbitol >lactose, but failed to produce efficient dispersion of SS since the FPF was <10%. Adding fine sugar particles and increasing their concentration to the binary mixtures generally resulted in an increase in the FPF of salbutamol sulphate. The chemical nature of the fine carriers was found to play a less important role in determining respirable fraction of the drug than the coarse carriers. In conclusion, other sugars such as mannitol or sorbitol, besides lactose, may be employed as coarse and/or fine carriers for incorporation into dry powder aerosol formulations to increase FPF.
Assuntos
Albuterol/química , Broncodilatadores/química , Carboidratos/química , Portadores de Fármacos/química , Aerossóis , Química Farmacêutica , Lactose/química , Manitol/química , Tamanho da Partícula , Excipientes Farmacêuticos/química , Pós , Sorbitol/químicaRESUMO
Franz cells (2-chambered, air/fluid phase static diffusion devices, previously used for the study of drugs across viable human skin) are utilized for the first time to investigate the process of infection of human skin by Schistosoma mansoni cercariae. Skin obtained from cosmetic surgery sources was used in the Franz cells to describe the temporal dynamics of the early interaction of cercariae with skin. At 38 degrees C, about 50% of cercariae applied in water to the epidermal surface of the skin were irreversibly attached within 1 min and after 5 min about 85%, were similarly irrecoverable. The technique also provides the means of following the early penetration path of cercariae by histological methods. Franz cell results on the dynamics of attachment/early penetration have been compared with those obtained using artificial skin equivalents and non-human mammalian skin models in the context of the physical and chemical differences between these systems and viable human skin. It is concluded that Franz cells provide a convenient system for directly investigating the early phases of S. mansoni cercariae interaction with human skin.