RESUMO
We present here the development of a photochemical model used to quantify the risk to photodegradation of a solid drug substance. A key feature of the proposed model development is streamlined estimation of the dependence of the absorption spectra and the quantum yield to the wavelength. A mathematical description of the relationship between the quantum yield and the wavelength enables estimation of photodegradation kinetics under any light anticipated to be encountered in the manufacturing environment. The system studied here consisted of a first order irreversible transformation (Aâ¯ââ¯B(1Φ)) and the formalism strongly suggested the quantum yield was constant over the relevant wavelength range. The predictive power of the model enabled the design of a control strategy to limit the formation of the photo-degradant to very low levels. Also presented are insights obtained from quantum mechanical modeling of the electronic transitions associated with the UV absorption spectra.
Assuntos
Modelos Teóricos , Preparações Farmacêuticas/efeitos da radiação , Fotólise , Estabilidade de Medicamentos , Cinética , Luz , Espectrofotometria UltravioletaRESUMO
INTRODUCTION: The incremental shuttle walk test was initially developed to be carried out in a hallway (ISWT-H) but has been modified to be performed on a treadmill (ISWT-T). However, it is still unknown whether performance on ISWT-H and ISWT-T are similar in patients with bronchiectasis. In this study, we compared the performance, physiological responses, and perception of effort between the ISWT-T with a handrail and ISWT-H for subjects with bronchiectasis. We also sought to estimate and compare the prescription for training intensity with both tests. METHODS: This was a cross-sectional study in which 24 subjects with bronchiectasis were evaluated on 2 different days (24 h apart). Distance walked (m) was compared between the ISWT-H and ISWT-T. A training session was held on a treadmill at 75% of the speed obtained from both tests. The walking distance, oxygen uptake (VÌO2 ), carbon dioxide production (VÌCO2 ), heart rate, and ventilation (VÌE) were measured. RESULTS: There was a difference in the walking distance between the ISWT-T and ISWT-H, but physiological responses for VÌO2 , VÌCO2 , heart rate, and VÌE were similar. However, the speed estimated for training was different, as were the VÌO2 , VÌCO2 , and heart rate. CONCLUSIONS: The ISWT-T with handrail and the ISWT-H are not interchangeable in subjects with bronchiectasis. A slower speed of training intensity may occur when the test is performed in a hallway, as originally described, and this may underestimate responses to aerobic training.
Assuntos
Bronquiectasia/fisiopatologia , Teste de Caminhada/métodos , Caminhada/fisiologia , Adulto , Idoso , Bronquiectasia/reabilitação , Dióxido de Carbono/metabolismo , Estudos Transversais , Terapia por Exercício , Tolerância ao Exercício , Feminino , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Consumo de Oxigênio , Prescrições , Ventilação PulmonarRESUMO
Photochemical kinetic models to describe the solution phase degradation of pharmaceutical compounds have been extensively reported, but formalisms applicable to the solid phase under polychromatic light have not received as much attention. The objective of this study was to develop a mathematical model to describe the solid state photodegradation of pharmaceutical powder materials under different area/volumetric scales and light exposure conditions. The model considered the previous formalism presented for photodegradation kinetics in solution phase with important elements applied to static powder material being irradiated with a polychromatic light source. The model also included the influence of optical phenomena (i.e. reflectance, scattering factors, etc.) by applying Beer-Lambert law to light attenuation, including effects of powder density. Drug substance and drug product intermediates (blends and tablet cores) were exposed to different light sources and intensities. The model reasonably predicted the photodegradation levels of powder beds of drug substance and drug product intermediates under white and yellow lights with intensities around 5-11kLux. Importantly, the model estimates demonstrated that the reciprocity law for photoreactions was held. Further model evaluation showed that, due to light attenuation, the powder bed is in virtual darkness at cake depths greater than 500µm. At 100µm, the photodegradation of the investigated compound is expected to be close to 100% in 10days under white fluorescent halophosphate light at 9.5kLux. For tablets, defining the volume over exposed surface area ratio is more challenging. Nevertheless, the model can consider a bracket between worst and best cases to provide a reasonable photodegradation estimate. This tool can be significantly leveraged to simulate different light exposure scenarios while assessing photostability risk in order to define appropriate control strategy in manufacturing.
Assuntos
Pós/química , Comprimidos/química , Estabilidade de Medicamentos , Corantes Fluorescentes/química , Cinética , Luz , Modelos Teóricos , Fotólise/efeitos dos fármacos , Soluções/químicaRESUMO
Coenzyme Q10 (CoQ10) is a poorly-water soluble compound that is being investigated for the treatment of carcinomas. The aim of this study was to investigate the feasibility of preparing phospholipid-stabilized dispersions of the anticancer agent for continuous pulmonary delivery using a vibrating-mesh nebulizer. We determined the physicochemical properties (drug particle size distribution in dispersion, zeta potential, surface tension, and rheology) and compared the aerosolization profiles (nebulization performance, aerodynamic drug deposition and total emitted dose) of dispersions of CoQ10 prepared with different phospholipids. The hydrodynamic sizes of the drug particles in dispersion were primarily in the submicron range, but formulations with drug particle sizes greater than the aperture size of the nebulizer presented superior aerosolization profiles. At high shear rates, certain formulations presented increased shear-thickening behavior, which was connected to a decrease in mass and drug output over time, and with decreased aerodynamic and geometric sizes. Other formulations presented shear-thinning behavior and showed similarly high drug depositions. In this investigation, we found that dispersed formulations of CoQ10 presented different in vitro performance for pulmonary delivery based on their rheological behavior. In conclusion, this characterization methodology provides an innovative approach to screen formulations of poorly-water soluble compounds for continuous (no clogging) active vibrating-mesh nebulization.
Assuntos
Aerossóis/administração & dosagem , Fosfolipídeos/administração & dosagem , Ubiquinona/administração & dosagem , Administração por Inalação , Composição de Medicamentos/métodos , Nebulizadores e Vaporizadores , Tamanho da Partícula , Fosfolipídeos/química , Reologia , Tensão Superficial , Ubiquinona/químicaRESUMO
OBJECTIVES: In this review paper, we explore the interaction between the functioning mechanism of different nebulizers and the physicochemical properties of the formulations for several types of devices, namely jet, ultrasonic and vibrating-mesh nebulizers; colliding and extruded jets; electrohydrodynamic mechanism; surface acoustic wave microfluidic atomization; and capillary aerosol generation. KEY FINDINGS: Nebulization is the transformation of bulk liquids into droplets. For inhalation therapy, nebulizers are widely used to aerosolize aqueous systems, such as solutions and suspensions. The interaction between the functioning mechanism of different nebulizers and the physicochemical properties of the formulations plays a significant role in the performance of aerosol generation appropriate for pulmonary delivery. Certain types of nebulizers have consistently presented temperature increase during the nebulization event. Therefore, careful consideration should be given when evaluating thermo-labile drugs, such as protein therapeutics. We also present the general approaches for characterization of nebulizer formulations. SUMMARY: In conclusion, the interplay between the dosage form (i.e. aqueous systems) and the specific type of device for aerosol generation determines the effectiveness of drug delivery in nebulization therapies, thus requiring extensive understanding and characterization.
Assuntos
Sistemas de Liberação de Medicamentos/instrumentação , Nebulizadores e Vaporizadores , Preparações Farmacêuticas/administração & dosagem , Administração por Inalação , Aerossóis , Animais , Difusão de Inovações , Composição de Medicamentos , Desenho de Equipamento , Humanos , Tamanho da Partícula , Preparações Farmacêuticas/química , Propriedades de SuperfícieRESUMO
Determining liability of photosensitive compounds during manufacturing, packaging, and storage remains a challenge for formulation scientists prior to the confirmatory photostability studies as per International Conference on Harmonisation (ICH) Q1B guideline. The purpose of this study was to determine the effect of light exposure to bulk process intermediates and drug product in the manufacturing environment as well as to evaluate package configurations for tablets containing Compound A. Samples were analyzed for both photodegradant levels and tablet appearance. Final blend, uncoated tablets, and coated tablets were exposed to fluorescent light relevant to the manufacturing environment. Final blend presented linear photodegradant growth from 6 to 72 h of equivalent light exposure in the manufacturing environment. Change in color of uncoated tablets occurred before quantifiable levels of photodegradant were reached. The film-coated tablets did not show photodegradation above quantifiable levels or a color shift for up to 48 h. Tablets in open conditions and packaged in HPDE bottles and PVC/Aclar (clear and opaque) were exposed to light at 1 × and 3 × the cumulative light exposure as defined in the ICH Q1B using Option 2 as the light source. The results showed that photodegradation is not a concern for all package configurations investigated and that extreme light exposure may cause a slight color shift for tablets in packages made of transparent materials. Most importantly, the study design presented herein provided a framework for an end-to-end evaluation of risks of manufacturing and packaging of tablets containing photolabile compounds prior to performing confirmatory photostability studies.
Assuntos
Embalagem de Medicamentos , Preparações Farmacêuticas/química , Fotólise , Química Farmacêutica/métodos , Cor , Estabilidade de Medicamentos , Excipientes/química , Luz , Fotoquímica/métodos , Comprimidos/químicaRESUMO
Coenzyme Q10 (CoQ10) is a poorly-water soluble compound that is being investigated for the treatment of carcinomas. The aim of this research was to develop a suitable formulation for pulmonary delivery of this anticancer agent. An appropriate selection of excipients (phospholipids) and a suitable device (Aeroneb Pro® vibrating-mesh nebulizer) were selected initially after reviewing the literature. After characterization of the bulk drug, a feasible manufacturing process was selected to obtain small particle size dispersions of CoQ10. Following selection of an appropriate process, the parameters affecting drug particle size were studied. Using LD and gravimetrical analysis, nebulization was evaluated to assess the performance of the inhalation system triad: drug-excipients-device. CoQ10 powder studied was crystalline with a melting point approximately at 51 °C and with a particle size of 30 µm. Microfluidization was found to be a suitable method to prepare submicron drug particles in aqueous dispersions. Increasing microfluidization processing to more than 50 passes did not provide further particle downsizing for both soya phosphatidylcholine (lecithin) and dipalmitoyl phosphatidylcholine (DPPC) dispersions of CoQ10, presenting Z-average values of approximately 130 and 70 nm, respectively. Nebulization performance of lecithin-stabilized CoQ10 dispersions varied according to number of passes in the microfluidizer. Formulations processed with 10 passes presented steadier nebulization over time and different rheological behavior compared to those processed with 30 or 50 passes. In conclusion, aqueous dispersions of CoQ10 were adequately produced using a microfluidizer with characteristics that were suitable for pulmonary delivery with an Aeroneb Pro® nebulizer. Furthermore, the rheology of these dispersions appeared to play a significant role in the aerosol generation from the active vibrating-mesh nebulizer used.
Assuntos
Nebulizadores e Vaporizadores , Fosfolipídeos/química , Ubiquinona/análogos & derivados , Microscopia Eletrônica de Varredura , Tamanho da Partícula , Tensão Superficial , Ubiquinona/química , Vibração , Água/química , Difração de Raios XRESUMO
A 2,4-dinitrophenylhydrazine (DNPH) precolumn derivatization high-performance liquid chromatography-ultraviolet detection (HPLC-UV) method was developed to quantify levels of formaldehyde and acetaldehyde in polyethylene glycol (PEG) solutions. Formic acid and acetic acid were quantified by HPLC-UV. Samples of neat and aqueous PEG 400 solutions were monitored at 40°C and 50°C to determine effects of excipient source, water content, pH, and trace levels of hydrogen peroxide or iron metal on the formation of reactive impurities. The effects of antioxidants were also evaluated. Formic acid was the major degradation product in nearly all cases. The presence of water increased the rate of formation of all impurities, especially formic acid as did the presence of hydrogen peroxide and trace metals. Acidic pH increased the formation of acetaldehyde and acetic acid. A distribution of unidentified degradation products formed in neat PEG 400 disappeared upon addition of HCl with corresponding increase of formic acid, indicating they were likely to be PEG-formyl esters. Other unidentified degradation products reacted with DNPH to form a distribution of derivatized products likely to be PEG aldehydes. Antioxidants butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate d-alpha tocopheryl polyethylene glycol-1000 succinate, and sodium metabisulfite were effective in limiting reactive impurity formation, whereas ascorbic acid and acetic acid were not.
Assuntos
Antioxidantes/química , Contaminação de Medicamentos/prevenção & controle , Excipientes/química , Oxidantes/química , Polietilenoglicóis/química , Acetaldeído/química , Ácido Acético/química , Cromatografia Líquida de Alta Pressão , Formaldeído/química , Formiatos/química , Peróxido de Hidrogênio/química , Concentração de Íons de Hidrogênio , Cinética , Espectrofotometria Ultravioleta , Sulfitos/química , Tecnologia Farmacêutica/métodos , Temperatura , Água/químicaRESUMO
The intrinsic property of liquids is a vital indicator of formulation performance and stability. Therefore, investigation of the interfacial phenomenon of surface tension is a routine procedure in the development of products in a wide variety of areas including foods, pharmaceuticals, cosmetics, and painting technologies. We hypothesize that studies related to the maximum pull on a rod can be extrapolated to disk geometry and applied to measure surface tension using a texture analyzer. A glass disk probe was attached to the arm of a texture analyzer and pulled from the liquid surface. The maximum force of detachment was used to calculate surface tension extrapolating from the theory of maximum pull on a rod. The surface tension of water, ethanol, and a hydroalcoholic solution was measured and compared with literature values to validate this hypothesis. The calculated values of surface tension for the liquids studied were within 5% of the reported values. Probe diameter appears to have an important role on surface tension accuracy compared with literature values. Slight discrepancies can be attributed to temperature control and leveling of liquid surface, although still in accordance with the reported values of surface tension measured using different methods. This study presents a simple, precise, and quick method to determine the surface tension of liquids from the maximum pull on a disk. Further studies are warranted to determine the optimum glass disk probe diameter for better accuracy.
Assuntos
Química Farmacêutica/métodos , Soluções Farmacêuticas/química , Água/química , Tensão SuperficialRESUMO
Chemotherapy plays a significant role both as primary and as supportive care for lung cancer treatment. The majority of currently available anticancer agents are administrated intravenously, causing side effects due to the systemic drug distribution. Alternatively, the bioavailability of orally administrated anticancer agents is usually compromised by the first-pass metabolism. Pulmonary administration may be a potential route for anticancer drug delivery to treat lung tumors, due to its site specific delivery, avoidance of first-pass metabolism, possibility of fewer side effects, and improved comfort for cancer patients using a needle-free delivery device. However, to attain an effective inhalational delivery, there is a requirement to design a formulation with appropriate aerodynamic properties with well-suited excipients. This review article explores work to date related to the formulations developed for pulmonary delivery of small molecule antineoplastic agents to treat primary and metastatic lung carcinomas. Ultimately, it highlights the importance of formulation design to define the role of inhalational chemotherapy.
Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Administração por Inalação , Antineoplásicos/química , Antineoplásicos/farmacocinética , Disponibilidade Biológica , Química Farmacêutica , Composição de Medicamentos , Humanos , Resultado do TratamentoRESUMO
The understanding of deposition of particles in the respiratory tract is of great value to risk assessment of inhalation toxicology and to improve efficiency in drug delivery of inhalation therapies. There are three main basic mechanisms of particle deposition based primarily on particle size: inertial impaction, sedimentation and diffusion. The regional deposition in the lungs can be evaluated in regards to the aerodynamic particle size, in which particle density plays a significant role. In this review paper, we first introduce the available imaging techniques to confirm regional deposition of particles in the human respiratory tract, such as planar scintigraphy, single photon emission computed tomography (SPECT) and positron emission tomography (PET). These technologies have widely advanced and consequently benefited the understanding of deposition pattern, although there is a lack of lung dosimetry techniques to evaluate the deposition of nanoparticles. Subsequently, we present a comprehensive review summarizing the evidence available in the literature that confirms the deposition of smaller particles in the smaller airways as opposed to the larger airways.
Assuntos
Pulmão/metabolismo , Preparações Farmacêuticas , Administração por Inalação , Sistemas de Liberação de Medicamentos , Humanos , Pulmão/diagnóstico por imagem , Tamanho da Partícula , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/química , Tomografia por Emissão de Pósitrons , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
The aim of research was to design a small, restraint free, low stress animal dosing chamber for inhalation studies, and to investigate distribution of a model drug within the chamber. A small animal dosing chamber was designed that consisted of a polymethylmethacrylate (PMMA) airtight box (40.6 x 11.4 x 21.6 cm) with a hinged top, having a nominal wall thickness of 1.25 cm. The chamber was designed to hold up to 14 mice, each having a floor area of approximately 63 cm2, in accordance with Institutional Animal Care and Use Committee (IACUC) guidelines. A "rodent proof" distribution fan was attached to the center of the hinged closure lid. The chamber was divided into 1 inch2 zones (120 in total) to enable a profile of drug distribution within the chamber to be obtained. Small holes were drilled into the side of the chamber and sealed using Parafilm to allow access to the sampling zones. Syringes (5 mL) with appropriate length polytetrafluoroethylene (PTFE) tubing were inserted into the holes to reach the sampling zones (eight on either side of the chamber giving a total of 16 zones). An aqueous caffeine solution (2% w/v) in glycerol (25% w/v) was prepared and nebulized into the chamber using an Aeroneb Pro nebulizer. Caffeine containing droplets were circulated into the chamber at a flow rate of 1.5 L/min(-1), and the air was recirculated in a closed system for a total of 20 minutes to ensure a high concentration of caffeine droplets throughout. Following nebulization, air samples (5 mL) were withdrawn from the 16 sampling zones of the sealed chamber. The process was repeated in quadruplet until a total of 64 sampling zones had been sampled. The entire experiment was also repeated with the absence of the "rodent-proof" distribution fan. Drug concentrations were calculated from a calibration curve of caffeine using UV absorbance at 272 nm. An average mass of caffeine (Standard Deviation; S.D.) of 5.0 (4.2) mg was detected throughout the chamber when the distribution fan was fitted, and caffeine 12.6 (9.7) mg was detected without the fan. This indicated that presence of the fan caused impingement of the drug on both the chamber walls and fan components; effectively removing nebulized drug from circulation within the chamber. The distribution of drug was plotted using a 3D graph; this revealed a lower concentration at the periphery and a higher concentration in the center of the chamber both with and without the distribution fan in place. In conclusion, a humane, nonrestraint rodent dosing chamber was designed for the efficient delivery of nebulized drugs for up to 14 mice simultaneously. The highest levels of the model drug caffeine were detectable throughout the small animal dosing chamber without the distribution fan. A circulation flow rate of 1.5 L/min(-1) was found to be adequate to distribute drug in the chamber. Surprisingly, the results demonstrate that avoiding the use of a distribution fan altogether maximizes the drug concentration within the chamber by reducing impingement of the nebulized drug. The small animal, restraint-free dosing chamber represents an advancement in reproducible dosing via the pulmonary route in the small animal model. The dosing chamber may be adapted to present the lung with an almost unlimited array of compounds, encompassing drugs, toxic compounds, and even pathogens, while still maintaining a relatively stress-free microenvironment for the test subject and furthermore, total safety for the operator.