Experimental measurements of particle deposition in three proximal lung bifurcation models with an idealized mouth-throat.

In this paper, particle deposition in three idealized proximal lung bifurcation models with an idealized mouth-throat were investigated experimentally. These bifurcation models included (1) a small symmetric bifurcation, (2) an intermediate asymmetric bifurcation, and (3) a large symmetric bifurcation. An idealized mouth-throat geometry (the "Alberta geometry") was used as the inlet to these bifurcation models. Monodisperse aerosol particles of DEHS (di-2-ethylhexyl-sebecate) oil with mass median diameters in the range of 2.5-7.5 microm were employed at steady flow rates of 30-90 L/min. Particle deposition measurements were conducted by gravimetry. The results show that particle deposition in the mouth-throat and trachea accounts for the major portion of total deposition in the entire models used, and particle deposition fraction in the proximal lung bifurcations is lower compared with that deposited in the regions upstream (the mouth-throat and the trachea). Total particle deposition efficiency increases with increasing either inertial parameter or Stokes number. Total particle deposition varies appreciably from model to model. The laryngeal jet is the key factor dominating particle deposition within the trachea. An effect of Reynolds number on particle deposition efficiency in the trachea is observed. In addition, particle deposition in the bifurcation region is influenced little by the upstream flow condition, and therefore the effect of the laryngeal jet on deposition seemingly does not propagate to the bifurcations downstream.     

In vivo-in vitro correlations: predicting pulmonary drug deposition from pharmaceutical aerosols

In order to answer the question "what research remains to be done?" we review the current state of the art in pharmaceutical aerosol deposition modeling and explore possible in vivo- in vitro correlations (IVIVC) linking drug deposition in the human lung to predictions made using in vitro physical airway models and in silico computer models. The use of physical replicas of portions of the respiratory tract is considered, alongside the advantages and disadvantages of the different imaging methods used to obtain their dimensions. The use of airway replicas to determine drug deposition in vitro is discussed and compared with the predictions from different empirical curve fits to long-standing in vivo deposition data for monodisperse aerosols. The use of improved computational models and three-dimensional computational fluid dynamics (CFD) to predict aerosol deposition within the respiratory tract is examined. CFD's ability to predict both drug deposition from pharmaceutical aerosol sprays and powder behavior in dry powder inhalers is examined; both were highlighted as important areas for future research. Although the authors note the abilities of current in vitro and in silico methods to predict in vivo data, a number of limitations remain. These include our present inability to either image or replicate all but the most proximal airways in sufficient spatial and temporal detail to allow full capture of the fluid and aerosol mechanics in these regions. In addition, the highly complex microscale behavior of aerosols within inhalers and the respiratory tract places extreme computational demands on in silico methods. When the complexity of variations in respiratory tract geometry is associated with additional factors such as breathing pattern, age, disease state, postural position, and patient-device interaction are all considered, it is clear that further research is required before the prediction of all aspects of inhaled pharmaceutical aerosol deposition is possible.     

In vivo-in vitro correlations with various aspirin formulations

In vivo evaluation of gastric irritation as determined by gastric transmural potential difference (GPD) and in vitro characterization of four formulations have been made. The four formulations were: (A) highly buffered, (B) cytoprotective, (C) microencapsulated and (D) a plain tablet. The GPD results showed C to be much less irritating than A or D, and slightly less-irritating than B. The release from all formulations was well represented by dissolution efficiency (DE%) and mean time of dissolution. When correlation coefficients were calculated, significant relationships were found between DE% and the GPD parameters area under the baseline (AUB) and the Reiz Index (RI), and between the mean time of dissolution and the GPD parameters AUB, mean potential drop (MD) and RI.     

A dry powder inhaler with reduced mouth-throat deposition.

A novel, compact, and highly efficient dry powder inhaler (DPI) with low mouth-throat deposition is described. The performance of this DPI was evaluated by measuring both (1) the total aerosol deposition in and distal to an idealized mouth-throat cast and (2) the fine particle fraction (FPF) using a standard Mark II Anderson impactor. Ultraviolet (UV) spectroscopy techniques were used in the aerosol deposition measurements. Two inhalation aerosol powders, namely budesonide (extracted from a Pulmicort/Turbuhaler multi-dose device, 200 microg/dose) and ciprofloxacin + lipid + lactose (in-house), were dispersed by the DPI at a steady inhalation flow rate of 60 L/min. The newly developed DPI had a total aerosol delivery distal to the mouth-throat cast of 50.5% +/- 3.04% and 69.7% +/- 1.5% for the budesonide and ciprofloxacin + lipid + lactose aerosols, respectively. This is a significant improvement over the Turbuhaler original device delivery of 34.5% +/- 5.2%, particularly considering that in vitro mouth-throat deposition dropped from 27.5% +/- 5.4% with the budesonide Turbuhaler to 11.0% +/- 3.5% with the present inhaler. The different lung deliveries from the same inhaler for the two formulations above also confirm that the overall performance of an inhaler is optimizable via powder formulations.     

Ventolin Diskus and Inspyril Turbuhaler: an in vitro comparison.

Dose delivery (total emitted dose, or TED) from dry powder inhalers (DPIs), pulmonary deposition, and the biological effects depend on drug formulation and device and patient characteristics. The aim of this study was to measure, in vitro, the relationship between parameters of inhalation profiles recorded from patients, the TED and fine particle mass (FPM) of Diskus and Turbuhaler inhalers. Inhalation profiles (IPs) of 25 patients, a representative sample of a wide range of 1500 IPs generated by 10 stable asthmatics, 3 x 16 (mild/moderate/severe) COPD patients and 15 hospitalized patients with an exacerbation asthma or COPD, were selected for each device. These 25 IPs were input IPs for the Electronic Lung (a computerdriven inhalation simulator) to determine particle size distribution from Ventolin Diskus and Inspyril Turbuhaler. The TED and FPM of Diskus and FPM of Turbuhaler were affected by the peak inspiratory flow (PIF) and not by slope of the pressure-time curve, inhaled volume and inhalation time. This flow-dependency was more marked at lower flows (PIF < 40 L/min). Both the TED and FPM of Diskus were significantly higher as compared to those of the Turbuhaler [mean (SD) TED(_diskus) (%label claim) 83.5 (13.9) vs. TED(_turbuhaler) (72.5 (11.1) (p = 0.004), FPM(_diskus) (%label claim) 36.8 (9.8) vs FPM(_turbuhaler) (28.7 (7.7) (p < 0.05)]. The TED and FPM of Diskus and FPM of Turbuhaler were affected by PIF, the flow-dependency being greater at PIF values below 40 L/min. Lower PIFs occurred more often when using Turbuhaler than Diskus, since Turbuhaler have a higher resistivity, requires substantially higher pressure in order to generate the same flow as Diskus. TED, dose consistency and the FPM were higher for Diskus as compared to Turbuhaler. The flow dependency of TED and FPM was substantially influenced by inhalation profiles when not only profiles of the usual outpatient population were included but also the real outliers from exacerbated patients.     

In vitro effect of a holding chamber on the mouth-throat deposition of QVAR (hydrofluoroalkane-beclomethasone dipropionate).

Experimental work has been conducted on the effect of an add-on holding chamber (Aerochamber) on the characteristics of deposition in a mouth-throat model using 100-microg hydrofluoroalkane-beclomethazone dipropionate (QVAR) metered dose inhalers at inhalation flow rates of 28.3, 60, and 90 L/min. A filter or cascade impactor downstream of the mouth-throat collected aerosol not depositing. The results emphasize the important well documented effect of a valved holding chamber (VHC), in reducing drug deposition in the mouth-throat. This reduction is largest (24% of nominal dose) at the lowest flow rate tested, becoming insignificant at 60 L/min. Total amount of drug delivered distal to the mouth-throat increases with flow rate both with and without a holding chamber, increasing from 42% to 69% of the nominal dose without a VHC as the inspiratory flow rate increases from 28.3 to 90 L/min. The effect of the holding chamber on post mouth-throat delivery was small, reaching significance only at the highest flow rate (90 L/min), where an increase by 8% of the nominal dose was observed. No significant effect on MMAD of beclomethasone-dipropionate occurred when the holding chamber was used. An argument based on the interaction between induced turbulence and particle inertia is used to shed light on the above observations.     

Patient perception and acceptability of multidose dry powder inhalers: a randomized crossover comparison of Diskus/Accuhaler with Turbuhaler.

This study was designed to provide information on correct use and preference to features and device handling of two multidose dry powder inhalers, the Diskus/Accuhaler and the Turbuhaler. A total of 169 powder-naive patients (mean age 40 years) with asthma or chronic obstructive pulmonary disease (COPD) were enrolled in a randomized crossover comparison of both inhalers. An effective use of either inhaler was assessed before (leaflet only) and after inhaler education. Ease of use especially during an attack and the presence of a dose counter were regarded as the most important features for an ideal inhaler. The percentage of correct handling maneuvers and the percentage of patients achieving 100% of correct maneuvers increased significantly (p < 0.001) after inhaler education in both devices, but percentage of correct use after the intervention was significantly higher for the Diskus/Accuhaler (92.6%) than for the Turbuhaler (89.8%; p = 0.036). Overall 60% of patients thought the Diskus/Accuhaler was preferable to the Turbuhaler (p < 0.001). The main reasons given were presence of a dose counter, perceived ease of use including ease of learning to use, design, and attached cover. Among those who preferred the Turbuhaler device, the main reason cited was small size, discreetness, and ease of holding. In the multivariate analysis, inhaler education (p = 0.005) and education level (p = 0.009) were significantly associated with the percentage of correct maneuvers. Age, sex, or tested inhaler showed no effect on appropriateness of the inhalation technique.     

In vivo-in vitro study of biodegradable and osteointegrable gentamicin bone implants.

Three implants composed of phosphate (25% hydroxyapatite, 75% tricalcium phosphate), 20% poly(DL-lactide) (DL-PLA; weight-average molecular weight (Mw), 30 kD) and 3% gentamicin sulphate (GS) were assayed in vitro and in vivo to study their release profiles as potential drug delivery systems to prevent or treat osteomyelitis. To prolong GS release, some implants were coated with poly(lactide-co-glycolide) (PLGA; Mw, 100 kD; I-PLGA) or DL-PLA (Mw, 200 kD; I-PLA). GS levels were measured in bone, kidney and blood after implantation into the femur of rats. The release profiles show a burst in the first few days, followed by a slower release rate. After I-PLA implantation, bone antibiotic concentrations higher than the minimum bactericidal concentration were maintained for 4 weeks. A linear correlation between in vitro and in vivo GS release was found to continue until complete drug release. Histological and radiological analysis showed that the implants were well tolerated and gradual new bone formation was observed.     

In vitro evaluation of dry powder inhalers I: drug deposition of commonly used devices

Inhalation of aerosolized drugs has become the therapy of choice for the treatment of lung diseases. The most commonly used device, the pressurized metered-dose inhaler (pMDI), however, relied on propellants that were found to deplete the ozone layer. To overcome this drawback dry powder inhalers (DPI) have been developed and MDIs with alternative propellants have been introduced recently. Several products are available by now. This study was carried out to evaluate the accuracy of the dose and the theoretically respirable fraction emitted from commonly used DPIs. In vitro measurements were performed using the Twin Impinger (Appendix A, British Pharmacopoiea, 1993) and a self constructed Four Stage Impinger at the standard flow rate of 60 l min⁻¹. Eleven dry powder formulations that are commercially available on the german market were tested with eight dry powder devices: Pulmicort™ and Aerodur™ Turbuhaler™, Intal™ Spinhaler™, Flui™ SCG and Cromolyn™ Orion Inhaler, Sultanol™ Diskhaler™, Flutide™ Diskus™, Atrovent™ with Inhalator M™, Ventilat™ with Inhalator Ingelheim and Buventol™ and Beclomet™ Easyhaler™. As every dry powder inhaler has a specific air flow resistance that limits flow under in vivo conditions, inhaler devices should be tested at corresponding flow conditions in vitro. Though this is not yet reflected in the pharmacopeias, a general consensus can be seen in the scientific literature. Therefore DPIs having a high resistance were tested at 30 l min⁻¹ and those showing a low resistance at 90 l min⁻¹ with the Twin Impinger additionally. Most products were found to emit a fine particle dose of 20–30% of total emitted dose at 60 l min⁻¹. The results of the Twin Impinger and the Four Stage Impinger were in good agreement. Measurements at increasing flow rates generally resulted in increasing fine particle fractions.     

In vitro evaluation of dry powder inhalers II: influence of carrier particle size and concentration on in vitro deposition

Dry powders and their delivery devices are an alternative to pressurized metered-dose inhalers (pMDI) for the administration of aerosols to the lungs. Generally dry powder aerosols are formulated by mixing a cohesive micronized drug with larger carrier particles resulting in an interactive powder mixture. Redispersion of the drug from agglomerates or the carrier surface during inhalation is a critical factor which greatly influences the fine particle fraction (particles<6.4 μm) to be achieved. Two devices, the single-unit-dose Spinhaler™ (Fisons) and the multiple-unit-dose Easyhaler™ (Orion Pharma) were used to investigate the influence of dry powder formulation on the deposition of interactive mixtures. Following the scheme of a 3²-factorial design budesonide was mixed with lactose-α-monohydrate varying the lactose sieve fractions and the drug to carrier proportion. The in vitro deposition of these mixtures was determined using a Twin Stage Impinger (Apparatus A, BP 93) and compared to control experiments performed with unsieved drug carrier. Deposition was found to be highly dependent on the dry powder formulation. Fine particle fractions from 10 up to 50% were observed. The Easyhaler™ shows little differences compared to the Spinhaler™ device.     

口服缓释制剂体内外相关性评价方法研究进展

对近年国内外文献中有关口服缓释制剂体外溶出度测定的试验方法和条件、体内评价的相关方法、体内外相关性研究进行了综述。根据药物的不同性质选择尽可能接近体内环境的试验方法,建立较好的体内外相关性,对口服缓释制剂的研究具有重要意义。     

体内外射频热凝毁损灶体积的相关性分析

目的 用MRI及病理榆测方法,观察体内外射频毁损灶体积的差异性,建立射频毁损灶体积与毁损时间、温度的回归方程和三维模型.方法 利用正常大鼠和新鲜蛋清分别建立体内外不同毁损时间、温度下的毁损灶体积模型,体外模型用游标卡尺测量毁损灶的最大直径、高,体内模型通过病理检测及MRI确定毁损灶最大直径、高,经公式转换成体积.结果 相同毁损条件下,体内外获得的毁损灶体积存在显著性差异(P<0.05),体内外射频毁损灶体积均随时间温度变化出现规律性变化.结论 体内外环境因素对毁损体积有不可忽略的影响;利用回归方程可对预定毁损体积选择合适的温度和时间,对临床有一定的指导意义.     

Differential effect of biliary and micronodular cirrhosis on oxidative drug metabolism. In vivo-in vitro correlations of dextromethorphan metabolism in rat models

Oxidative drug metabolism is impaired in liver cirrhosis; it is unclear, however, whether this depends on the etiology of cirrhosis. Therefore, we studied the metabolism of dextromethorphan in two rat models: biliary cirrhosis induced by bile duct ligation and micronodular cirrhosis induced by chronic exposure to CCl4/phenobarbital. Results were compared with aminopyrine N-demethylation assessed by a breath test in vivo; the latter was reduced to a similar extent in biliary (-41%) and micronodular (-37%) cirrhosis compared to controls. In contrast, clearance of dextromethorphan was significantly (P less than 0.001) reduced in biliary (25.4 +/- 5.3 mL/min/kg) but not in micronodular cirrhosis (48.6 +/- 15.6) as compared to controls (62.2 +/- 16.2). Intrinsic clearance of dextromethorphan in vitro was reduced by 95% and 63% in biliary and micronodular cirrhosis, respectively (P less than 0.001 vs controls). It correlated with dextromethorphan clearance in vivo (r = 0.68, P less than 0.001) whereas correlation with aminopyrine N-demethylation was weak (r = 0.42, P less than 0.05). Our results demonstrate a differential effect of biliary and micronodular cirrhosis on isoenzymes responsible for aminopyrine and dextromethorphan demethylation.     

气流速度对粉雾剂在呼吸道沉降的影响

目的 :研究吸入速度对不同粒径粉雾剂在呼吸道沉降的影响。方法 :以硫酸沙丁胺醇为模型药物 ,用双冲程试验仪评价不同的气流速度对吸入型粉雾剂在模拟肺部的沉降量。结果 :粒径为 5 4～ 10 0μm的重结晶乳糖为载体的硫酸沙丁胺醇混合型粉雾剂 ,增加吸入速度 ,提高药物在肺部的沉积量 ;而乳糖、甘露醇为载体 ,喷雾干燥法制备的粒径为 0 .5～ 6.5 μm粉雾剂 ,增加吸入速度 ,药物在肺部沉积量基本不变直至下降。结论 :物理混合型吸入剂随气流速度的增加 ,药物在肺部的沉降量增加。含载体喷干型吸入剂 (0 .5～ 6.5 μm)中的药物在肺部的沉降量取决于载体 (如甘露醇 )和吸入速度 (如 3 0 L· min-1 )。     

The oxidative metabolism of aldicarb in pigs: in vivo-in vitro comparison

Aldicarb was administered (1 mg/kg b.w.) to four female pigs and the kinetics of its major oxidized metabolites (sulfoxide and sulfone) was followed for 6 hours. The in vitro transformations of the carbamate pesticide into these two still active metabolites were also investigated in hepatocytes and in microsomes from pig livers. In all cases, aldicarb was quickly oxidized to the sulfoxide (major metabolite) and only a minor quantity of sulfone was produced. The in vivo toxic symptomatology was related to the peak serum concentration of sulfoxide, suggesting that this metabolite is principally responsible for the aldicarb toxicity. Selective in vitro inhibition of flavin-containing and cytochrome P-450 monooxygenases confirmed that the former enzymes catalyze mainly sulfoxide production whereas the latter that of sulfone.     

In vivo-in vitro correlations with a commercial dissolution simulator. I: Methenamine, nitrofurantoin, and chlorothiazide

Dissolution profiles were determined for nine methenamine, 14 nitrofurantoin, and six chlorothiazide dosage forms using a dissolution simulator. Various in vivo-in vitro correlations were examined. The best correlation for methenamine was between the maximum urinary excretion rate and the time for 15% dissolution. A good correlation for the 50-mg nitrofurantoin tablets was also found between cumulative percent of drug excreted in 12 hr and the percent dissolved in 1 hr. There were no significant correlations for the 100-mg nitrofurantoin dosage forms. Good correlations were also observed for the 250- and 500-mg chlorothiazide tablets between the percent of drug dissolved in 1 min or the time for 15% dissolution and the maximum excretion rate.