Formulation Development and Evaluation Studies of Linezolid Inhaler in the Treatment of Tuberculosis

The primary objective of this study was to prepare and evaluate a linezolid inhaler. Dry powder inhaler liposomes were formulated to investigate the efficacy of pulmonary delivery of Linezolid for tuberculosis. The liposomes were prepared using soya lecithin and cholesterol in different weight ratios, drug in a constant amount, and two different methods: physical dispersion and ethanol injection. The F9 formulation was characterized for physical and chemical properties such as vesicle size, shape, and zeta potential. The results of physical characterization, in vitro testing, and stability studies indicate that liposomes containing Linezolid can be used for the treatment of tuberculosis. The evaluated batch exhibited favorable physicochemical properties, with spherical liposomes having a mean size below 100?nm and high entrapment efficiency (98.8%). The prepared liposomal dry powder inhalers (DPIs) sustained drug release for up to 8 hours. Liposome stability was assessed 90 days after storage at room temperature, revealing its stability. The liposomal formulation had steady zeta potential, good entrapment efficiency, improved stability, and an extended drug release time. In conclusion, linezolid-loaded liposomal inhalers were successfully formulated.

Preparation and in vitro Release Property Study of Curcumin Dry Powder Inhalation Loaded by Nanoporous Flower-shaped Lactose / 中国药房

OBJECTIVE：To preparea novel Curcumin （Cur）dry powder inhalation （DPI）loaded by nanoporous flower-shaped lactose（FL），and to provide a safe and effective intrapulmonary drug delivery method for the therapy of chronic obstructive pulmonary disease with insoluble drugs. METHODS ：FL-loaded Cur （Cur-FL） compound powder was prepared by solution adsorption method. Using drug-loading amount and adsorption rate as indicators ，single-factor experiment was used to optimize Cur concentration，Cur-FL ratio （m/m）and adsorption time so as to determine the optimal preparation technology for Cur-FL compound powder. Fourier transform infrared spectroscopy ，scanning electron microscope and differential scanning calorimetry were used to characterize the physical and chemical properties of Cur-FL compound powder prepared with optimal technology. The water content and aerodynamic properties were determined ；in vitro drug release behavior was investigated by simulating the environment of artificial lung fluid. RESULTS ：The optimal preparation technology of Cur-FL compound powder was Cur concentration of 5 mg/mL，Cur-FL ratio of 1 ∶ 4，adsorption time of 1 h. The drug-loading amount of compound powder was （23.37±0.43）％，the encapsulation rate was （91.64±0.44）％，and the adsorption rate was （30.50±0.72）％. Cur-FL particles were flower shaped ；Cur was physically adsorbed in the pores of FL without chemical changes. The bulk density of Cur-FL compound was （0.21±0.02） g/cm3，tap density was （0.33±0.01）g/cm3，angle of repose was（24.07±0.31）°，average particle size was （3.96±0.80） μm，aerodynamic particle size was （3.33±0.99）μm，water content was （5.63 ±0.24）％，emptying rate was （92.53± 0.87）％，and deposition rate of effective parts in vitro was son- （45.93 ± 1.77）％ . Its 24 h solubility in artificial lung gwen.tan@csu.edu.cn fluid [（358.93±1.67）μg/mL] were 3.28 times of Cur ，48 h cumulative release ratesin in vitro （90.21％）were 1.63 times of Cur ，but Cur+FL physical mixture could not improve the solubility and release of Cur in artificial lung fluid. CONCLUSIONS ：Cur-FL compound powder has good in vitro release property ，and its powder properties ，solubility，water content ，fluidity and aerodynamic properties meet the requirements of DPI in Chinese Pharmacopoeia.

Assessment of Errors during Inhaler Usage among Asthma and COPD Patients.

BACKGROUND The cornerstone therapy for respiratory diseases is drugs for inhalation. Effectiveness of inhalers can be influenced by factors such as gender, age, educational status, and type of inhaler used and correct inhalation technique. The aim of this study is to provide information about common errors in technique that occur during inhalation.METHODSMale and female patients who met the inclusion criteria (age 18 - 80) years, using inhalers particularly MDI and DPI were included in the study. The study patients were asked to perform inhalation technique and the errors in technique that occur during inhalation were recorded. The sample size was 150 and duration of study was 6 months.RESULTSThe common errors during the use of inhalers included, no exhalation before inhalation, no breath hold, and absence of proper washing of mouth after inhalation. Among the 86 MDI users, no exhalation before inhalation (n=50), no breath hold (n=35) and absence of proper washing of mouth after inhalation (n=21). For the 64 patients using DPI, no exhalation before inhalation (n=68), no breath hold (n=51) and absence of proper washing of mouth after inhalation (n=35).

Drug Release in vitro and Acute Toxicity in vivo of Curcumin Solid Lipid Nanoparticles Dry Powder Inhaler and Its Effects on Inflammatory Response in Asthmatic Model Mice / 中国药房

OBJECTIVE： To study in vitro drug release and acute toxicity in vivo of Curcumin （Cur） solid lipid nanoparticles （SLN） dry powder inhaler （DPI） and its effects of inflammatory response in asthmatic model mice. METHODS： Cur-SLN-DPI was obtained with spray-drying method by micronizing the Cur-SLN suspension prepared by the microemulsion method and thoroughly mixing with lactose （200 mesh） etc. The drug release in vitro was investigated by dynamic membrane dialysis. Accumulative release rates （Q） of Cur raw material， Cur-SLN and Cur-SLN-DPI in 3 kinds of release mediums [phosphate buffer solution （PBS， pH 7.4） containing 1.0％ sodium dodecyl sulfate （SDS）， PBS （pH 7.4） containing 0.2％ tween 80， normal saline-20％ ethanol solution] were compared 5， 15， 30 min and 1， 1.5， 3， 6， 8， 12， 18， 24， 36， 48 h after releasing. Drug release model was fitted. The effects of intravenous injection of maximal dose 2 000 mg/kg Cur-SLN-DPI via tail vein on KM mice were investigated by acute toxicity test. KM mice were randomly divided into normal control group， model group， positive drug group （budesonide 3 mg）， Cur-SLN-DPI high-dose and low-dose groups （100， 50 mg/kg）， with 7 mice in each group. The ovalbumin （OVA） was used as sensitizer to induce asthma model； the model mice were given relevant medicine with aerosol administration 30 min before aerosol administration of OVA inducing asthma on Monday， Wednesday and Friday per week， for consecutive 3 weeks. Within 24 h after last induction， total number of leukocyte， the number of lymphocyte， neutrophil and eosinophil were counted in broncho alveolar lavage fluid （BALF）； the pathological changes of bronchus and lung tissue were observed. RESULTS： Compared with Cur raw material， Cur-SLN and Cur-SLN-DPI showed good sustained-release effect， and Cur-SLN-DPI had more stable sustained release in 3 kinds of release mediums. The characteristics of drug release conformed to the Weibull model. Intravenous injection of 2 000 mg/kg Cur-SLN-DPI via tail vein had no significant acute toxicity in mice. Compared with normal control group， total number of leukocyte， the number of lymphocyte， neutrophil and eosinophil were increased significantly （P＜0.01）； bronchial mucosal epithelium was covered with pseudostratified ciliated columnar cells， with severe infiltration of inflammatory cells， pulmonary congestion and moderate interstitial pneumonia. Compared with model group， the number of above cells in BALF of mice were decreased significantly in administration group （P＜0.01）； tracheal lesions of mice were improved in Cur-SLN-DPI low-dose and high-dose groups； pulmonary congestion of them were alleviated， and that of high-dose group was alleviated more significantly. CONCLUSIONS： Cur-SLN-DPI shows sustained-release effect in vitro and has no obvious acute toxicity to mice. Cur-SLN-DPI can improve the inflammatory response of the airway and the degree of pulmonary congestion in asthmatic model mice.

Prescription pattern among patients having mild to moderate bronchial asthma using metered dose inhaler and dry powder inhaler in tertiary hospital in western india

Background: Bronchial asthma is a syndrome characterized by airflow obstruction that manifests as shortness of breath, wheezing and cough. The treatment is tailored according to the severity of the disease. The drugs used for treatment of bronchial asthma include inhaled corticosteroids, beta-2 agonists, methylxanthines, leukotriene antagonists and mast cell stabilizers. Despite the availability of all these drugs, which are recommended for the treatment, not every patient achieves complete control of the disease. The reason behind this could be irrational prescribing of drugs for the treatment and errors in the technique of using inhaler devices. Though rational prescribing of drugs and correct technique for the use of inhaler can be improved by proper training of target population, but there is paucity of such data in our country.Methods: This study was planned to monitor prescription pattern and errors in use of inhalation devices, in patients diagnosed as cases of mild to moderate bronchial asthma, attending Out Patient Department (OPD) of respiratory medicine of a tertiary hospital. A total of 207 patients were recruited and their prescription pattern and inhalation technique were assessed.Results: The study showed that inhaled short acting ?2-agonists and inhaled corticosteroids were the most commonly used drug groups, which were prescribed to all the patients in the study, followed by long acting ?2-agonists, leukotriene antagonists and methylxanthines in decreasing order.Conclusions: As a conclusion, the treating physicians were prescribing according to the laid down guidelines. It is concluded that such studies should be periodically done to ensure the adherence to the treatment guidelines.

Inhalation treatment of primary lung cancer using liposomal curcumin dry powder inhalers

Lung cancer is the leading cause of cancer-related deaths. Traditional chemotherapy causes serious toxicity due to the wide bodily distribution of these drugs. Curcumin is a potential anticancer agent but its low water solubility, poor bioavailability and rapid metabolism significantly limits clinical applications. Here we developed a liposomal curcumin dry powder inhaler (LCD) for inhalation treatment of primary lung cancer. LCDs were obtained from curcumin liposomes after freeze-drying. The LCDs had a mass mean aerodynamic diameter of 5.81 μm and a fine particle fraction of 46.71%, suitable for pulmonary delivery. The uptake of curcumin liposomes by human lung cancer A549 cells was markedly greater and faster than that of free curcumin. The high cytotoxicity on A549 cells and the low cytotoxicity of curcumin liposomes on normal human bronchial BEAS-2B epithelial cells yielded a high selection index partly due to increased cell apoptosis. Curcumin powders, LCDs and gemcitabine were directly sprayed into the lungs of rats with lung cancer through the trachea. LCDs showed higher anticancer effects than the other two medications with regard to pathology and the expression of many cancer-related markers including VEGF, malondialdehyde, TNF-, caspase-3 and BCL-2. LCDs are a promising medication for inhalation treatment of lung cancer with high therapeutic efficiency.

Preparation and Evaluation of Levosalbutamol Sulfate-Ambroxol Hydrochloride Dry Powder Inhalation / 中国药学杂志

OBJECTIVE: To select excipients and optimize preparation for the ambroxol hydrochloride/levosalbutamol sulfate dry powder inhalation. METHODS: Drug and different excipients in the same ratio were prepared by spray drying to obtain a certain particle size as drug particles or carriers for dry powder inhalation, respectively. Study and compare the parameters of powders of the dry powder inhaler, such as the angle of repose, moisture content, and emptying rate, etc, to screen the excipient of the vectors. Afterward, Box-Behnken design method was adopted to optimize of preparation parameters. RESULTS: When lactose-high branched cyclodextrin compounds were used as composite carriers, their powder properties meet the requirements of dry powder inhaler, such as the repose angle was 39.69 degrees, the bulk density was 0.37 g·mL-1, the tap density was 0.66 g·mL-1, the evacuation rate of drug-carrier powders in capsules was 93.12%, and the water content was 0.10% and the simulated lung deposition rate was 14.63%. The preparation parameters, such as sample concentration, inlet air temperature, nozzle diameter parameters, theirs values were 50 mg·mL-1, 110℃, 1 mm, respectively, were opmized by Box-Behnken design method, which could obtain the carrier particle size of 30.33 μm. CONCLUSION: Lactose-high branched cyclodextrin complexes can be used as carrier for levosalbutamol sulfate-ambroxol hydrochloride compound dry powder inhaler, which could meet the requirements of dry powder inhaler by spray-drying preparation method.

Influence of physical properties of carrier on the performance of dry powder inhalers

Dry powder inhalers (DPIs) offer distinct advantages as a means of pulmonary drug delivery and have attracted much attention in the field of pharmaceutical science. DPIs commonly contain micronized drug particles which, because of their cohesiveness and strong propensity to aggregate, have poor aerosolization performance. Thus carriers with a larger particle size are added to address this problem. However, the performance of DPIs is profoundly influenced by the physical properties of the carrier, particularly their particle size, morphology/shape and surface roughness. Because these factors are interdependent, it is difficult to completely understand how they individually influence DPI performance. The purpose of this review is to summarize and illuminate how these factors affect drug-carrier interaction and influence the performance of DPIs.

Preparation of liposomal artesunate dry powder inhalers and the effect on the acute lung injury of rats / 药学学报

Artesunate is one of artemisinin derivatives with anti-malarial and anti-inflammatory activities though its water solubility and bioavailability are low. Acute lung injury (ALI) is a seriously dispersive lung disease with a high mortality. In this study, artesunate liposomes were prepared with the film dispersion method, and then lyophilized to obtain the liposomal artesunate dry powder inhalers (LADPIs). The LADPIs were pulmonary-delivered into the lung to treat ALI in rats. The artesunate liposomes had the capsulation efficiency of 71.4%, the particle size of 47.3 nm, and the zeta potential of -13.7 mV. The LADPIs had the aerodynamic particle size of 4.2 μm and the fine particle fraction (FPF) of 34.5%. ALI was established in rats by instilling lipopolysaccharide (LPS) into the lungs. The rats quickly showed a reduction in movement and acceleration in breath followed by diarrhea and so on. The LADPIs were directly administrated into the lungs of ALI rats through airways after 1 h of LPS challenge. The treatment induced a reduction in ALI syndromes. Two inflammatory factors, including TNF-α and IL-6, were significantly reduced by the artesunate powder in the LADPI group similarly to the reduction in the positive drug dexamethasone group (P<0.05). Therefore, the anti-inflammatory effect of LADPIs contributed to the anti-ALI activity. Furthermore, the liposomal formulation improved drug bioavailability in the lung and increased therapeutic efficiency. The LADPIs are promising medicines for therapy of ALI through local drug administration.

Three-dimensional DEM-CFD analysis of air-flow-induced detachment of API particles from carrier particles in dry powder inhalers

Air flow and particle-particle/wall impacts are considered as two primary dispersion mechanisms for dry powder inhalers (DPIs). Hence, an understanding of these mechanisms is critical for the development of DPIs. In this study, a coupled DEM-CFD (discrete element method-computational fluid dynamics) is employed to investigate the influence of air flow on the dispersion performance of the carrier-based DPI formulations. A carrier-based agglomerate is initially formed and then dispersed in a uniformed air flow. It is found that air flow can drag API particles away from the carrier and those in the downstream air flow regions are prone to be dispersed. Furthermore, the influence of the air velocity and work of adhesion are also examined. It is shown that the dispersion number (i.e., the number of API particles detached from the carrier) increases with increasing air velocity, and decreases with increasing the work of adhesion, indicating that the DPI performance is controlled by the balance of the removal and adhesive forces. It is also shown that the cumulative Weibull distribution function can be used to describe the DPI performance, which is governed by the ratio of the fluid drag force to the pull-off force.

Research progress of in vivo evaluation methods for dry powder inhaler / 中国药学杂志

OBJECTIVE: To summary the common methods that used to assay dry powder inhaler in vivo, and provide a theoretical basis and some research ideas for relative research.

Evaluation methods in vitro and in vivo for dry powder inhalers: Research advances / 国际药学研究杂志

Drug delivery to lungs is becoming an important means of administration of some drugs for lung disease and some protein drugs with systemic effects. This article introduces the inhalation devices and particle characteristics,the two main features of dry powder inhalers (DPI), then reviews the advances on evaluation methods in vitro and in vivo for DPI, such as next generation pharmaceutical impactor (NGI), the imitation between particles and cells using electrodynamic levitation, hydraulic lung and dry powder endotracheal insufflator device, providing references for research and development of DPI evaluation methods.

Evaluation methods in vitro and in vivo for dry powder inhalers:research advances / 国际药学研究杂志

Drug delivery to lungs is becoming an important means of administration of some drugs for lung disease and some protein drugs with systemic effects. This article introduces the inhalation devices and particle characteristics,the two main features of dry powder inhalers (DPI), then reviews the advances on evaluation methods in vitro and in vivo for DPI, such as next generation pharmaceutical impactor (NGI), the imitation between particles and cells using electrodynamic levitation, hydraulic lung and dry powder endotracheal insufflator device, providing references for research and development of DPI evaluation methods.

Pharmacodynamics of dry powder formulations of salbutamol for delivery by inhalation.

Background: Salbutamol is a β2-selective adrenoceptor agonist used as a bronchodilator. Delivery by inhalation has many advantages over oral dosage for the treatment of asthma. It offers rapid onset of action with low systemic side effects. Objective: Evaluate the relationship of in vitro particle size characteristics and pharmacodynamics of formulations of inhaled salbutamol dry powder. Methods: Three formulations contained micronized salbutamol and a lactose carrier with different size ranges (40-80, 20-40, and 10-20 μm for formulations 1, 2, and 3, respectively). Following formulation of the drug, resultant powders were characterized using scanning electron microscopy and the aerosolization performance determined using an Andersen Cascade Impactor analysis. A high-performance liquid chromatography method was used for measuring the salbutamol drug content. The in vivo pharmacodynamics of the formulations was monitored in 12 healthy and 12 asthmatic volunteers. Results: The percentage of the fine particle fractions (FPF) for formulations 1, 2, and 3 were 24.87±0.52%, 33.82±3.80%, and 41.50±2.86%, respectively. The mass median aerodynamic diameters (MMAD) were around 3 μm for all formulations. The pharmacodynamic parameters, forced vital capacity (FVC), forced expiratory volume in one second (FEV1) and mid expiratory flow (FEF25-75), were indices for evaluation of the bioavailability of the bronchodilatory drug. All formulations improved the FEF25-75 value in asthmatics, while FVC and FEV1 were not altered. Conclusion: The formulations of salbutamol dry powder aerosols with a fine lactose carrier produced a high deposition in the lower regions of the respiratory tract. Although the FEF25-75 value in asthmatics was improved, the value did not correlate well with the FPF of the salbutamol dry powder.

Tipos y características de los inhaladores para el manejo de asma / Types and characteristics of devices for the treatment of asthma

El tratamiento del asma requiere del uso de medicamentos durante períodos largos para lograr el control de la enfermedad y la vía inhalada es la forma más adecuada para administrarlos. En las últimas 2 décadas se han desarrollado nuevos y mejores dispositivos para la entrega del medicamento, con marcadas diferencias respecto a su diseño, construcción, características de salida y tamaño de las partículas. El médico debe conocer los puntos tecnológicos más destacados de cada aparato para que pueda aprovechar sus ventajas y haga recomendaciones muy precisas. Existen varios dispositivos para administrar medicamentos inhalados: los más viejos y de uso cotidiano en hospitales son los nebulizadores y de manera más reciente se introdujeron los inhaladores de dosis medida presurizados o los inhaladores de polvo seco, que son más usados para el paciente ambulatorio. La condición particular de cada uno de estos dispositivos debe conocerse y aplicarse para ofrecer el máximo beneficio al paciente asmático.

Asthma management requires the use of many drugs for long time with the purpose of achieving control. Inhalator delivery of asthma medications is the best way. In the previous 2 decades, technology has improved delivery devices, changes in design, materials and outsize particles. Physicians should know all the technical points in order to take advantage of these new devises to be able to make appropriate recommendations for their use. There is a large quantity of options for the delivery of asthma medications: nebulizers, metered dose inhaler and dry powder inhalers. Particular characteristics of delivery devices should be known and applied in particular patients.The aim of this review article is assist physicians to choose the best device option.

Comparison of the single dose inhaled salbutamol via a pressurised aerosol and a dry powder inhaler.

Metered dose aerosol bronchodilators are presently widely used in the treatment of asthmatic patients. However, this route of administration has often been ineffective in children and the elderly who find greater difficulty in synchronizing the inspiration with the release of the high velocity aerosol spray. Lately, there have been several developments in inhaled therapy to overcome this problem such as the spacer and the Rotahalerฎ. The objective of this trial was to compare the effectiveness of treatment in asthmatics using either the salbutamol aerosol 200 mcg via the MDI or salbutamol powder 200 and 400 mcg administered via the Rotahalerฎ in a double-blind cross-over study. 27 asthmatic patients were recruited into the study at the Department of Medicine, Siriraj Hospital. Results of the study indicated that the average PF and FEV1 values obtained after using either MDI or Rotahalerฎ were significantly higher than the basal values from 5 minutes to 3 hours after drugs administration. No significant difference in bronchodilating effect was observed for the three regimens. No adverse effect was found with the dosages studied. A majority of patients (66.7%) preferred administration of drug via the Rotahalerฎ to the metered dose inhaler.