Formulation of pyrazinamide-loaded large porous particles for the pulmonary route: Avoiding crystal growth using excipients

We have designed a novel formulation of pyrazinamide (PZA), an antitubercular drug within large porous particles intended for deep lung delivery. By simply spray-drying PZA, we have obtained crystalline particles of the δ polymorph of PZA that were unstable and not adapted for lung administration. Several excipients were added to the formulation to obtain stable large porous particles with a median size above 5 μm and a low tap density. Although a combination of leucine and ammonium bicarbonate (AB) allowed to reduce tap density and to increase particle size, these excipients were not sufficient to prevent crystallization and promote stability. The addition of hyaluronic acid (HA) in combination with dipalmitoylphosphatidylcholine (DPPC) allowed to obtain stable partially crystalline spherical particles adapted for deep lung delivery. The optimized formulation obtained by spray-drying 0.9 g/L PZA, 0.6 g/L leucine, 0.2 g/L HA, 0.3 g/L DPPC and 2 g/L AB in a mixture of ethanol–water (70/30, v/v) possesses a median size of 5.8 ± 0.1 μm and a tap density around 0.09 ± 0.01 g/cm³. The estimated aerodynamic diameter is around 1.75 μm and the powder is stable for more than 4 weeks of storage.     

Pulmonary delivery of scutellarin solution and mucoadhesive particles in rats

The objectives of this study were to investigate the effects of mucoadhesive excipients on systemic bioavailability of an inhaled drug and to evaluate the feasibility of using the pulmonary route for non-invasive systemic delivery of scutellarin, a poorly orally absorbed flavonoid glucuronide. Following intratracheal spray of the scutellarin solution, the bioavailability was found to be approximately 77% in rats, which was >30-fold higher than that via the peroral route. In addition, the pulmonary absorption of scutellarin appeared to avoid the intestinal first-pass metabolism accompanied by peroral administration. Spray-dried scutellarin particles with the presence of mucoadhesive excipients were found to affect the corresponding mucociliary transport rate (MTR) as evaluated by a frog palate model. The pharmacokinetic results indicated that the magnitude of AUC_0–480 of intrapulmonary delivered drug particles was not correlated to the fine particle fraction (FPF) but inversely related to the MTR. Incorporating mucoadhesive polymeric mixtures into the scutellarin particles, the MTR decreased by sixfold, and the absolute bioavailability of the drug was found to increase from 70.1% to 97.9% despite a decrease in the FPF. Moreover, in vitro results evaluated using Calu-3 and A549 cell lines showed that scutellarin and spray-dried particles with or without the presence of mucoadhesives exhibited no local cell cytotoxic effects in the tested concentration range. In conclusion, the conducting airway is well permeable to scutellarin, and scutellarin may be effectively delivered systemically through inhalation of respirable droplets or particles.     

Targeted delivery of nanoparticles for the treatment of lung diseases

Targeted delivery of drug molecules to organs or special sites is one of the most challenging research areas in pharmaceutical sciences. By developing colloidal delivery systems such as liposomes, micelles and nanoparticles a new frontier was opened for improving drug delivery. Nanoparticles with their special characteristics such as small particle size, large surface area and the capability of changing their surface properties have numerous advantages compared with other delivery systems. Targeted nanoparticle delivery to the lungs is an emerging area of interest. This article reviews research performed over the last decades on the application of nanoparticles administered via different routes of administration for treatment or diagnostic purposes. Nanotoxicological aspects of pulmonary delivery are also discussed.     

肺结核合并肺癌的临床分析

目的探讨肺结核并存肺癌的关系及临床特点。方法回顾性分析454例肺结核患者（部分合并肺癌）的临床资料。结果大于50岁肺结核患者为68.5%;32例合并肺癌,且男性占78.1%;非活动性肺结核并肺癌者占87.5%。结论肺结核病多发于中老年,男性肺结核患者发生肺癌的危险性高于女性,肺结核合并肺癌患者临床表现不典型,易延误治疗,故应高度警惕,应及时复查。     

45例肺结核合并肺部感染的病原学探讨与研究

目的分析肺结核合并肺部感染的患者的致病病原菌分类并探讨临床抗生素的合理应用。方法抽对我院近期内收治的45例肺结核合并肺部感染患者的痰液标本进行病原菌的培养,并进行病原学分析。结果我院此次共计培养病原菌67株,其中革兰阴性杆菌39株、革兰阳性球菌4株、真菌24株;存在合并基础疾病的患者与未合并基础疾病的患者在感染病原菌数量方面比较差异明显(P<0.05);继发性肺结核患者感染多种病原菌的概率明显高于其他类型患者,差异明显(P<0.05)。结论临床面对肺结核合并肺部感染的患者时应及时进行病原学检测,根据痰真菌检测结果合理用药,才能抑制多种病原菌的反复感染,是患者病情得以控制。     

肺靶向制剂—硫酸链霉素明胶微球的药理学研究

以１２５Ｉ标记硫酸链霉素明胶微球，小鼠静脉注射后测定其体内分布，结果表明硫酸链霉素明胶微球在小鼠肺部浓度最高，由靶向性参数判定硫酸链霉素明胶微球靶向作用明显，靶向效率较高。用微生物分析法测定并比较了肺组织中硫酸链霉素及其明胶微球的浓度，结果显示，在硫酸链霉素明胶微球给药量约为硫酸链霉素一半的情况下，肺部的药物浓度仍可达到或超过非微球剂。用苏通氏培养基二倍稀释法测得硫酸链霉素及其明胶微球ＭＩＣ值均为０．２ｍｇ／Ｌ。小鼠实验性肺结核治疗结果表明，以实际硫酸链霉素量计，微球剂约为非微球剂的１／３时，即可达到相同的治疗作用，当用药量约为非微球剂的２／３时，微球剂治疗作用明显优于非微球剂     

In vitro and in vivo dose delivery characteristics of large porous particles for inhalation

The purpose of this study was to evaluate the in vitro and in vivo dose delivery characteristics of two large porous particle placebo formulations with different mass median aerodynamic diameters (MMAD approximately equal to 3 and 5 microm). In vitro dose delivery characteristics were measured using the multistage liquid impinger (MSLI). In vitro lung deposition was predicted by calculating the extrathoracic deposition using the ICRP model, with the remaining fraction assumed to deposit in the lungs. Healthy subjects were trained to inhale through the AIR delivery system at a target peak inspiratory flow rate (PIFR) of 60 l/min, The in vivo dose delivery of large porous particles were obtained by gamma-scintigraphy and was characterized by high ( approximately 90%), reproducible emitted doses for both the small and large MMAD powders. The mean in vivo lung deposition relative to the total metered dose were 59.0 and 37.3% for 3 and 5 microm MMAD powders, respectively. The AIR delivery system produced high in vivo lung deposition and low intersubject CVs (approximately 14%) across the range of PIFRs obtained in the study (50-80 l/min), This is relative to a variety of dry powder inhalers (DPI) that have been published in the literature, with in vivo lung deposition ranging from 13 to 35% with intersubject CVs ranging from 17 to 50%. The ICRP model provided a good estimate of the mean in vivo lung deposition for both powders. Intersubject variability was not captured by the ICRP model due to intersubject differences in the morphology and physiology of the oropharyngeal region. The ICRP model was used to predict the regional lung deposition, although these predictions were only considered speculative in the absence of experimental validation.     

Pharmacokinetics of cefazolin administered as a new drug delivery system in healthy volunteers

A study was made of the pharmacokinetic behaviour in plasma and urine of cefazolin in seven healthy volunteers following parenteral administration of sodium cefazolin (1250 mg) and a sustained release formulation containing sodium cefazolin: cefazolin-dibenzylamine (1:4) at a total dose of 1250 mg, both formulations being administered over 1 week by the i.m. route. Cefazolin concentrations in plasma and urine were determined by a HPLC technique. Kinetic analysis of the experimental results was performed using an open single-compartment kinetic model and a sustained release model for the drug administered as standard formulation and the sustained release formulation, respectively. The results obtained point to significant variations in the pharmacokinetic profile of the drug when administered in the DDS. The time of cefazolin at levels greater than 1 microgram ml-1 was 16.03 +/- 2.51 and 47.76 +/- 14.18 h-1 after administration of the standard formulation and the DDS, respectively. The urinary excretion rate curves also show the existence of sustained drug levels in the urine following administration of the DDS. The renal clearance of the drug did not show statistically significant differences between the two formulations administered. The process of release of cefazolin from the cefazolin-dibenzylamine complex proved to be a first order kinetic process. The release constant of the antibiotic was calculated according to three different methods: the Wagner-Nelson method; the statistical moments method; and the fitting of the plasma levels curves to a compartmental model considering release and absorption. The values obtained for this constant ranges from 0.026 +/- 0.02 h-1 calculated with the method of statistical moments to 0.094 +/- 0.03 h-1 as calculated by the equation derived for the plasma fitting of cefazolin administered as DDS.     

56例肺癌合并肺结核患者的临床特点观察

目的观察肺癌合并肺结核的临床特点,以便为患者早日确诊,找到最佳的治疗时机。方法对近10年来我院的56例肺癌合并肺结核患者的临床特点及临床表现进行探究与分析。结果肺癌合并肺结核主要临床表现为胸闷、发热、咳嗽、咳痰、气短、气促;中心型和周围型肺癌分别占42.1%(32例)和43.4%(33例),28例(36.8%)伴有胸腔积液;肺结核以浸润型为主而肺癌主要以鳞癌和腺癌为主;并且男性患者明显多于女性患者且比例为5∶2,平均年龄为57岁。结论肺癌合并肺结核以中年男性为好发人群,肺癌的临床表现、影像学表现、病理类型、临床分期和肺结核的类型无特异性。     

Pulmonary delivery of anti-inflammatory agents

Introduction: Respiratory infections and diseases are accompanied by or exhibit inflammation. Recent advances in nanoparticle engineering technology, together with the increased knowledge of inflammatory pathophysiology, have ignited interest in the pulmonary delivery of anti-inflammatory agents (AIAs) to achieve local treatment of pulmonary inflammatory disorders.

Areas covered: This review summarizes and discusses the investigated formulation approaches for the pulmonary delivery of AIAs, including: inhalation of actives as suspensions or dry powder formulations, with polymeric micro- and nano-delivery carriers, or within liposomes and lipid nanoparticles. Some recent approaches for targeting AIAs to the pulmonary endothelium have also been reviewed. The discussion focuses on finding out whether the investigated approaches were really able to achieve lung targeting and reduce the side effects associated with the systemic administration of AIAs.

Expert opinion: The use of the inhalation route for the pulmonary delivery of AIAs is facing several challenges. Some of the investigated formulation approaches appear to be promising in overcoming these challenges. However, in order to create products that reach patients, more therapeutically oriented studies are still needed to ensure formulation stability, in-vivo sustained release behavior, pulmonary retention, and bypassing lung clearance mechanisms.     

Pulmonary delivery of nucleic acids

The lung is an appropriate present and future target for gene therapy approaches designed to treat inherited monogenic diseases, eradicate bronchial tumours, transfer pharmacologically active products to the general circulation, express enzymes to catabolise toxins, manage pulmonary hypertension and lung injury and vaccinate against infection. Despite 35 years of gene therapy research and some significant milestones in molecular biology, the clinical potential of gene therapy has yet to be realised. In pulmonary gene therapy the nucleic acid cargo needs to be delivered to cells in the ?target region of the lung, and even in cases when these targets are well defined this is severely limited by the pulmonary architecture, clearance mechanisms, immune activation, the presence of respiratory mucus and the availability of a truly representative biological model. The challenge from a drug delivery perspective is to consider the suitability of conventional nebulisers and inhalers for delivering DNA to the lung and design and apply integrated formulation and device solutions specific to nucleic acid delivery.     

Nanostructured porous silicon-mediated drug delivery

Introduction: The particular properties of nanostructured porous silicon (nanoPS) make it an attractive material for controlled and localized release of therapeutics within the body, aiming at increased efficacy and reduced risks of potential side effects. Since this is a rapidly evolving field as a consequence of the number of research groups involved, a critical review of the state of the art is necessary.

Areas covered: In this work, the most promising and successful applications of nanoPS in the field of drug delivery are reviewed and discussed. Two key issues such as drug loading and release are also analyzed in detail. The development of multifunctional (hybrid) systems, aiming at imparting additional functionalities to the nanoPS particles such as luminescence, magnetic response and/or plasmonic effects (allowing simultaneous tracking and guiding), is also examined.

Expert opinion: Nanostructured materials based on silicon are promising platforms for pharmaceutical applications given their ability to degrade and low toxicity. However, a very limited number of clinical applications have been demonstrated so far.     

脂质体肺部给药的研究

由于脂质体肺部给药具有刺激性小、吸收迅速、生物利用度高、安全性好、可实现持续缓慢释药等独特优势而成为近年来制剂领域的研究热点之一。本文论述脂质体肺部给药的特点、稳定性以及在药代动力学、药效学和安全性等方面的最新研究进展。     

吡嗪酰胺抗结核化疗致高尿酸血症流行病学调查

目的：对抗结核治疗方案中吡嗪酰胺致高尿酸血症发生率进行流行病学调查,为临床用药和尿酸检测提供参考。方法：回顾性调查我院2003～2010年诊断为原发或继发性肺结核和结核性胸膜炎的住院患者,根据是否使用吡嗪酰胺,将病例分为暴露组（HRZE）134例和非暴露组（HRE）40例,比较两组间高尿酸血症发生率。结果：我院结核病患者使用吡嗪酰胺比例为86.2%,暴露组和非暴露组高尿酸血症发生率分别为79.1%和10.0%。平均用药11 d后,暴露组血尿酸均值从（275.3±77.2）μmol·L~-1升高到（562.9±160.0）μmol·L~-1。与非暴露组比较,暴露组发生高尿酸血症的相对危险度（RR）为7.91（95%CI=4.74～13.19）,两组高尿酸血症发生率差异有统计学意义（P〈0.01）。结论：使用吡嗪酰胺致高尿酸血症发生率较高,临床应定期监测血尿酸浓度。     

联合检测癌性与结核性标志群对肺结核、肺炎、肺癌患者的临床意义评价

目的 寻求适用于肺结核、肺癌、肺炎的早期诊断最佳标志群组。方法 酶联免疫吸附法联合检测294例肺病患者血清中癌胚抗原(CEA)、神经元烯醇化酶(NSE)、转铁蛋白(Tf)的含量及结核抗体(TB-CHECK-1)的定性。结果 肺癌组血清CEA、NSE、Tf的含量分别为16.7±18.7μg/L、158±42.7μg/L、52.6±68.1μg/L,均高于结核组及肺炎组,P<0.001;肺结核组血TB-CHECK-1的阳性率为79.4％,高于肺癌组及肺炎组,P<0.001。CEA对肺腺癌、NSE对肺小细胞癌、Tf对肺鳞癌有较高的敏感性及特异性。以CEA+NSE+Tf为组合(任一单项阳性即为组合阳性、三项均阴性即组合阴性),结合TB-CHECK-1检测结果,对肺癌、肺结核及肺炎进行判断,其敏感性分别为90.5％、70.2％、81.0％,特异性分别为90.0％、97.5％、93.0％。结论 联合检测肺病组血清中CEA、NSE、Tf,并结合TB-CHECK-1定性对肺部疾病的鉴别和早期诊断有重要价值。     

Nanostructured liquid-crystalline particles for drug delivery

Introduction: Nanostructured lyotropic liquid crystal particles (LLC NPs) have proven to be extremely useful tools for applications in drug delivery. These structured nanoparticles are formed by amphiphilic molecules and contain internal water channels, which are not in contact with external water, and where polar drugs can situate; on the other hand, apolar drugs can be loaded in the lipophilic part of the structure and the amphiphilic drugs can locate at the polar/apolar interfaces.

Areas covered: A revision of the most relevant results published in the field of LLC NPs has been made. The first section discusses the most common compounds used in these nanoparticles and their preparation and characterization. A summary of recent and relevant results including the composition and type of nanoparticles used, the illness treated, the administration via and some special features in each case have been summarized in a table.

Expert opinion: LLC NPs are highly versatile drug delivery systems, which can be applied by topical, oral and intravenous treatments. Especially relevant is their use for the release of anticancer drugs, biomolecules and vaccines. Nevertheless a number of critical points need to be solved in order to attain practical applications.     

Oligoarginine-PEG-lipid particles for gene delivery

Cell-penetrating peptides (CPPs) are small peptides that can facilitate the uptake of macromolecular drugs, such as proteins or nucleic acids, into mammalian cells. Cytosolic delivery of CPPs could be beneficial to bypass conventional endocytosis in order to avoid degradation in the lysosomes. Oligoarginine conjugates have characteristics similar to CPPs in terms of cell translocation and are used in the intracellular delivery of plasmid DNA. In these cases, oligoarginine length and/or charge are important factors in the cellular uptake of oligoarginine alone. The arginine moiety of oligoarginine-modified particles may also be a decisive factor for vectors to deliver plasmid DNA. Oligoarginine-PEG-lipids can form self-assembled particles and modify the surface of lipid- and polymer-based particles. This review focuses on the influence of: i) oligoarginine-modified particles such as micelles, liposomes and polymer-based particles; ii) the morphology of oligoarginine-PEG-lipid complexed with plasmid DNA by decreasing the charge ratio; and iii) the oligoarginine length in the complex on its cellular uptake, transfection efficiency and uptake mechanism. The oligoarginine length of oligoarginine-modified particle complexed with plasmid DNA governs the cellular uptake pathway that determines the destiny of intracellular trafficking and finally transfection efficiency. The new aspects of surface-functionalized particle vectors with oligoarginine are discussed.     

Variability in the population pharmacokinetics of pyrazinamide in South African tuberculosis patients

Objective This study was designed to characterize the population pharmacokinetics of pyrazinamide in South African pulmonary tuberculosis patients, with special reference to interindividual and interoccasional variability (IIV and IOV, respectively).Methods Concentration-time measurements obtained from 227 patients receiving oral doses of pyrazinamide were pooled to create a dataset containing 3,092 data points spanning multiple dosing occasions. The software program NONMEM was used to analyze the data.Results A one-compartment model with first-order absorption, including a zero-order component describing release from formulation, and first-order elimination best described the data. The absorption rate constant was estimated to be bimodally distributed between two distinct subgroups, fast and slow, in approximately even proportion. Absorption rate was threefold greater in fast absorbers (3.56 h⁻¹) in comparison to slow absorbers (1.25 h⁻¹). Typical values of oral clearance and apparent volume of distribution were estimated as 3.42 L h⁻¹ and 29.2 l, respectively. IOV was supported in oral clearance (0.0238, variance) and absorption rate (0.623, variance). The duration of zero-order absorption was estimated as 0.290 h, and was quite variable between patients (0.957, variance).Conclusion The absorption of pyrazinamide in the studied population was highly variable and two separate subpopulations were identified. IOV accounted for a proportion of the variability in clearance and the absorption rate constant.An erratum to this article can be found at     

Use of commercial porous ceramic particles for sustained drug delivery

Three commercially available microparticulate porous ceramics, N-light N3, Starlight SLK1000 and Carbolite 16/20, were characterised using a range of techniques. Starlight SLK1000 and Carbolite 16/20 were principally composed of mullite, while N-light N3 was principally composed of quartz. Each porous ceramic was partly open-cell with varying porosities and pore size distributions. Using a novel vacuum loading technique, N-light N3 was loaded with benzoic acid, sodium benzoate and diltiazem HCl, while Starlight SLK1000 and Carbolite 16/20 were loaded with diltiazem HCl. The drug loading was influenced by the solution concentration and by the porosity and bulk density of the ceramic. In vitro dissolution testing of the loaded porous microparticles showed an initial burst release of each drug followed by sustained release. The release was influenced by the surface pore size distribution of the ceramic and by electrostatic interactions between the interior and exterior microparticle surfaces and the drug.