Formulation of High-Performance Dry Powder Aerosols for Pulmonary Protein Delivery

Purpose

Pulmonary delivery of biologics is of great interest, as it can be used for the local treatment of respiratory diseases or as a route to systemic drug delivery. To reach the full potential of inhaled biologics, a formulation platform capable of producing high performance aerosols without altering protein native structure is required.

Methods

A formulation strategy using Particle Replication in Non-wetting Templates (PRINT) was developed to produce protein dry powders with precisely engineered particle morphology. Stability of the incorporated proteins was characterized and the aerosol properties of the protein dry powders was evaluated in vitro with an Andersen Cascade Impactor (ACI).

Results

Model proteins bovine serum albumin (BSA) and lysozyme were micromolded into 1 μm cylinders composed of more than 80% protein, by mass. Extensive characterization of the incorporated proteins found no evidence of alteration of native structures. The BSA formulation produced a mass median aerodynamic diameter (MMAD) of 1.77 μm ± 0.06 and a geometric standard deviation (GSD) of 1.51 ± 0.06 while the lysozyme formulation had an MMAD of 1.83 μm ± 0.12 and a GSD of 1.44 ± 0.03.

Conclusion

Protein dry powders manufactured with PRINT could enable high-performance delivery of protein therapeutics to the lungs.

     

Development of a Spray-Dried Formulation of Peptide-DNA Nanoparticles into a Dry Powder for Pulmonary Delivery Using Factorial Design

Pharmaceutical Research - Gene therapy via pulmonary delivery holds the potential to treat various lung pathologies. To date, spray drying has been the most promising method to produce inhalable...     

Fundamental Effects of Particle Morphology on Lung Delivery: Predictions of Stokes' Law and the Particular Relevance to Dry Powder Inhaler Formulation and Development

Key factors that contribute to the aerodynamic properties of aerosol particles are found in Stokes' law. These factors may be monitored or controlled to optimize drug delivery to the lungs. Predictions of the aerodynamic behavior of therapeutic aerosols can be derived in terms of the physical implications of particle slip, shape and density. The manner in which each of these properties have been used or studied by pharmaceutical scientists to improve lung delivery of drugs is readily understood in the context of aerosol physics. Additional improvement upon current aerosol delivery of particulates may be predicted by further theoretical scrutiny.     

Development of an Inhaled Sustained Release Dry Powder Formulation of Salbutamol Sulphate,an Antiasthmatic Drug

The present research was aimed to develop and characterize a sustained release dry powder inhalable formulation of salbutamol sulphate. The salbutamol sulphate microparticles were prepared by solvent evaporation method using biodegradable polymer poly (D,L-lactic-co-glycolic acid) to produce salbutamol sulphate microparticle mixed with carrier respirable grade lactose for oral inhalation of dry powder. The drug content were estimated to produce 1 mg sustained release salbutamol sulphate per dose. Total four formulations K1, K2, K3 and K4 were prepared with 1:1, 1:2, 1:3, 1:4 ratio of salbutamol sulphate:poly (D,L-lactic-co-glycolic acid). The developed formulations were studied for physicochemical properties, in vitro drug relase and Anderson cascade impaction studies. The prepared formulations effectively releases drug for 12 h in diffusion bag studies. Based on dissolution performance the 1:1 ratio of salbutamol sulphate:poly (D,L-lactic-co-glycolic acid) produces in vitro release 92.57% at 12 h and having particle size of microparticles (D_0.5μm) 5.02±0.6 and the pulmonary deposition of dry powder 34.5±3.21 (respiratory fraction in percentage).     

Identification of a Multi-Component Formulation for Intestinal Delivery of a GLP-1/Glucagon Co-agonist Peptide

Pharmaceutical Research - Oral delivery of therapeutic peptides has been challenging due to multiple physiological factors and physicochemical properties of peptides. We report a systematic...     

The Impact of Inspiratory Flow Rate on Drug Delivery to the Lungs with Dry Powder Inhalers

Current marketed dry powder inhalers utilize the energy from patient inspiration to fluidize and disperse bulk powder agglomerates into respirable particles. Variations in patient inspiratory flow profiles can lead to marked differences in total lung dose (TLD), and ultimately patient outcomes for an inhaled therapeutic. The present review aims to quantitate the flow rate dependence in TLD observed for a number of drug/device combinations using a new metric termed the Q index. With this data in hand, the review explores key attributes in the design of the formulation and device that impact flow rate dependence. The review also proposes alternative in vitro methods to assess flow rate dependence that more closely align with in vivo observations. Finally, the impact of variations in flow rate on lung function for inhaled bronchodilators is summarized.     

水飞蓟素自乳化给药系统处方设计及溶出度评价

目的: 设计水飞蓟素自乳化系统处方并评价其溶出度.方法: 采用正交设计进行水飞蓟素自乳化系统处方设计,以溶解状况、乳化速度及透光率为指标进行综合评价,确定最佳处方.结果: 水飞蓟素自乳化系统除主药外,主要由吐温85、橄榄油、甘油组成.结论: 按最佳处方制备的水飞蓟素自乳化系统在人工胃液及人工肠液的溶出度均与德国的对照胶囊基本相同.     

Design and Characterization of Atorvastatin Dry Powder Formulation as a potential Lung Cancer Treatment

Lung cancer is the leading cause of cancer death. Many studies have shown the beneficial effects of Atorvastatin in decreasing the mortality risk and improving survival among patients with lung cancer. This research paper focuses on improving AVT cytotoxic activity and cellular uptake by developing mannitol microcarriers as a promising drug delivery system for lung cancer treatment and, studying the impact of improving inhalation deposition on the delivery and Dry Powder formulations efficiency. The AVT loaded mannitol (AM) microparticles (AVT-AM) formulation was prepared by spray drying and characterized for its physicochemical properties and aerodynamic deposition. The results revealed that the AVT-AM formulation has good flow properties and aerosol deposition with a particle size of 3418 nm ± 26.86. The formulation was also assessed in vitro for cytotoxicity effects (proliferation, apoptosis, and cell cycle progression) on A549 human lung adenocarcinoma. Compared with free AVT, the AVT-AM formulation has significantly higher cellular uptake and anti-cancer properties by disrupting cell cycle progression via either apoptosis or cell cycle arrest in the G2/M phase. This study shows that AVT loaded mannitol microcarriers may provide a potentially effective and sustained pulmonary drug delivery for lung cancer treatment.     

Design and Development of Multiparticulate System for Targeted Drug Delivery to Colon

A multiparticulate system combining pH-sensitive property and specific biodegradability for colon-targeted delivery of metronidazole has been investigated. Cross-linked chitosan microspheres were prepared from an emulsion system using liquid paraffin as the external phase and solution of chitosan in acetic acid as the disperse phase. The multiparticulate system was prepared by coating cross-linked chitosan microspheres exploiting Eudragit® L-100 and S-100 as pH-sensitive polymers. Morphology and surface characteristics of the formulations were determined by scanning electron microscopy. Particle size of the chitosan microspheres was determined by optical microscopy while that of coated microspheres was determined by particle size analyzer. In vitro drug-release studies were performed in conditions simulating stomach-to-colon transit in presence and absence of rat caecal contents. The size of the microspheres was small and they were efficiently microencapsulated within Eudragit® microspheres, forming a multireservoir system. By coating the microspheres with Eudragit® pH-dependant release profiles were obtained. No release was observed at acidic pH; however, when it reached the pH where Eudragit® starts solublizing there was continuous release of drug from the formulation. Further, the release of drug was found to be higher in the presence of rat caecal contents, indicating the susceptibility of chitosan matrix to colonic enzymes released from rat caecal contents.     

Potential of a Cyclone Prototype Spacer to Improve In Vitro Dry Powder Delivery

Purpose

Low inspiratory force in patients with lung disease is associated with poor deagglomeration and high throat deposition when using dry powder inhalers (DPIs). The potential of two reverse flow cyclone prototypes as spacers for commercial carrier-based DPIs was investigated.

Methods

Cyclohaler®, Accuhaler® and Easyhaler® were tested with and without the spacers between 30 and 60 Lmin^?1. Deposition of particles in the next generation impactor and within the devices was determined by high performance liquid chromatography.

Results

Reduced induction port deposition of the emitted particles from the cyclones was observed due to the high retention of the drug within the spacers (e.g. salbutamol sulphate (SS): 67.89?±?6.51% at 30 Lmin^?1 in Cheng 1). Fine particle fractions of aerosol as emitted from the cyclones were substantially higher than the DPIs alone. Moreover, the aerodynamic diameters of particles emitted from the cyclones were halved compared to the DPIs alone (e.g. SS from the Cyclohaler® at 4 kPa: 1.08?±?0.05 μm vs. 3.00?±?0.12 μm, with and without Cheng 2, respectively) and unaltered with increased flow rates.

Conclusion

This work has shown the potential of employing a cyclone spacer for commercial carrier-based DPIs to improve inhaled drug delivery.     

A New Powder Design Method to Improve Inhalation Efficiency of Pranlukast Hydrate Dry Powder Aerosols by Surface Modification with Hydroxypropylmethylcellulose Phthalate Nanospheres

Purpose. A new particle design method to improve the aerosolization properties of a dry powder inhalation system was developed using surface modification of hydrophobic drug powders (pranlukast hydrate) with ultrafine hydrophilic particles, hydroxypropylmethylcellulose phthalate (HPMCP) nanospheres. The mechanism of the improved inhalation properties of the surface-modified particles and their deposits on carrier particles (lactose) was clarified in vitro. Methods. Drug particles were introduced to aqueous colloidal HPMCP dispersions prepared by emulsion-solvent diffusion techniques followed by freeze- or spray-drying of the resultant aqueous dispersions. The surface-modified powders obtained with HPMCP nanospheres and their mixture with lactose powders were aerosolized by Spinhaler and their mode of deposition in lung was evaluated in vitro using a twin impinger. To elucidate the inhalation mechanism of these surface modified particles, we measured their modified micromeritic properties, such as surface topography, specific surface area, dissolution rate, and dispersibility in air. Results. Dramatically improved inhalation properties of the surface modified powder, i.e. a two-fold increase in emission and a three-fold increase in delivery to deep lung, were found in vitro compared with the original unmodified powder. Improved inhalation was also found with the surf ace-modified drug deposited on lactose particles. Those improvements were attributed to the increased surface roughness and hydrophilicity of the surface-modified particles, and the resultant increased dispersibility in air. Conclusions. Surface modification of hydrophobic drug particles with HPMCP nanospheres to improve hydrophilicity was extremely useful in increasing the inhalation efficiency of the drug itself and the drug deposited on carrier; this was attributed to increased dispersibility in air and emission from the device, for spray- and freeze-dried particles, respectively.     

Formulation Development and In Vivo Evaluation of a New Dry Powder Formulation of Albuterol Sulphate in Beagle Dogs

Purpose  

Study objectives were to develop, characterize, and evaluate a novel excipient for dry powder inhalation formulations in a canine model with a model compound.     

Optimization of the Fine Particle Fraction of a Lyophilized Lysozyme Formulation for Dry Powder Inhalation

Purpose

A new dry powder inhalation technology creates inhalable particles from a coherent lyophilized bulk at the time of inhalation. The aim of this study was to evaluate several approaches to improve the fine particle fraction (FPF) and to understand underlying mechanisms.

Methods

Lysozyme was chosen as model drug. Phenylalanine and valine were added, and the freezing process was varied. Lyophilisate characteristics as well as aerosolization behavior was analyzed.

Results

The addition of the crystalline amino acids rendered a dose independent three-fold increase of the FPF. This is possibly due to enhanced fracture properties of the lyophilisates upon impact of the air stream and reduced particle agglomeration/cohesion caused by a rougher surface. This positive effect was well preserved over 3 months of storage. The structure of the lyophilisate was influenced by the freezing process which in turn affected the aerosolization behavior. Liquid nitrogen and vacuum-induced freezing performed best, doubling the FPF. The special cake morphology with elongated channels enabled easy disintegration. The resulting large porous particles comprise a low density being advantageous for a high FPF.

Conclusion

The variation of the lyophilization process and formulation utilizing excipients enabled an optimization of the FPF of the novel lyophilisate based DPI system.     

Effect of Device Design and Formulation on the In Vitro Comparability for Multi-Unit Dose Dry Powder Inhalers

The focus of this investigation was to understand the design space to achieve comparable in vitro performance of two multi-unit dose dry powder inhalers (DPIs)—Flixotide® Accuhaler® (reference product) and MultiHaler® (test product). Flow field, pressure drop and particle trajectories within the test and reference DPI devices were modelled via computational fluid dynamics (CFD). Micronized fluticasone propionate (FP) was characterized to determine particle size distribution (PSD), specific surface area (SSA) and surface interfacial properties using cohesive-adhesive balance (CAB). CFD simulations suggested that the pressure drop and airflow velocity in the MultiHaler® were greater than Accuhaler®. Two modified test devices (MOD MH 1 and MOD MH 2) were manufactured with the introduction of by-pass channels in the airflow path, which achieved comparable specific resistance and airflow path between the test and reference devices. Assessment of reference product formulation in modified test devices suggested that MOD MH 2 achieved comparable in vitro performance to the reference product. CAB analysis suggested that adhesion of all FP batches to lactose was different, with batch D showing greatest and batch A least adhesion to lactose. Test DPI formulations were manufactured using four different batches of FP with milled or sieved lactose, and showed that batch A FP formulated with sieved lactose in MOD MH 2 device demonstrated the highest degree of similarity to the Accuhaler® in vitro deposition. Application of CFD modelling and material characterization of formulation raw materials enabled the modification of device and formulation critical material attributes to create an in vitro comparable device/formulation system to the reference product.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-015-9775-z) contains supplementary material, which is available to authorized users.Key words: aerosolization, computational fluid dynamics, device design, dry powder inhaler, in vitro comparability, in vitro performance     

Using a Model-based Material Sparing Approach for Formulation and Process Development of a Roller Compacted Drug Product

Pharmaceutical Research - The present work details a material sparing approach that combines material profiling with Instron uniaxial die-punch tester and use of a roller compaction mathematical...     

Optimization and Formulation Design of Gels of Diclofenac and Curcumin for Transdermal Drug Delivery by Box-Behnken Statistical Design

The aim of this study was to develop and optimize a transdermal gel formulation for Diclofenac diethylamine (DDEA) and Curcumin (CRM). A 3-factor, 3-level Box-Behnken design was used to derive a second-order polynomial equation to construct contour plots for prediction of responses. Independent variables studied were the polymer concentration (X₁), ethanol (X₂) and propylene glycol (X₃) and the levels of each factor were low, medium, and high. The dependent variables studied were the skin permeation rate of DDEA (Y₁), skin permeation rate of CRM (Y₂), and viscosity of the gels (Y₃). Response surface plots were drawn, statistical validity of the polynomials was established to find the compositions of optimized formulation which was evaluated using the Franz-type diffusion cell. The permeation rate of DDEA increased proportionally with ethanol concentration but decreased with polymer concentration, whereas the permeation rate of CRM increased proportionally with polymer concentration. Gels showed a non-Fickian super case II (typical zero order) and non-Fickian diffusion release mechanism for DDEA and CRM, respectively. The design demonstrated the role of the derived polynomial equation and contour plots in predicting the values of dependent variables for the preparation and optimization of gel formulation for transdermal drug release.     

Influence of Mouthpiece Geometry on the Aerosol Delivery Performance of a Dry Powder Inhaler

Purpose

To investigate the influence of mouthpiece geometry on the amount of throat deposition and device retention produced using a dry powder inhaler (Aerolizer^®), along with the subsequent effect on the overall inhaler performance.

Materials and Methods

Computational Fluid Dynamics analysis of the flowfield generated in the Aerolizer^® with various modified mouthpiece geometries (including cylindrical, conical and oval designs) was used in conjunction with experimental dispersions of mannitol powder using a multi-stage liquid impinger to determine how the overall inhaler performance varied as the mouthpiece geometry was modified.

Results

Geometry of the inhaler mouthpiece had no effect on device retention or the inhaler dispersion performance. In contrast, the mouthpiece geometry strongly affected the amount of throat deposition by controlling the axial component of the exit air flow velocity. The radial motion of the emitted aerosol jet was found to have little effect on throat deposition in representative mouth–throat models. Despite the reduced throat deposition, there was no difference in the overall inhaler performance.

Conclusions

For cases where low throat deposition is a key design parameter, this study demonstrates that the amount of throat deposition can be reduced by making minor modifications to the inhaler mouthpiece design.

     

Development and Validation of a Pig Model for Colon-specific Drug Delivery

The purpose of this investigation was to develop a pig model for colonic drug delivery and to validate the model by determining whether the physiology of the pig colon had been significantly altered after the surgical implantation of a gut cannula into the terminal ileum of the pig. A fistula was created in the terminal ileum of the pig, and a cannula fitted for the purpose of directly administering drug formulations to a point just anterior to the ileocaeco-colonic valve of the gastrointestinal tract. The cephalic vein of the pig was also cannulated to enable continued blood sampling. Sulphasalazine was used as the model drug for the validation study. In the intact colon, sulphasalazine is metabolized by the gut microflora to sulphapyridine which is then absorbed. Sulphasalazine was administered orally to non-fistulated and fistulated pigs and then ileally, via the gut cannula, to fistulated pigs. Absorption of sulphapyridine was monitored by HPLC analysis of plasma samples. There was no significant difference in the absorption obtained for the three groups. Thus it is demonstrated that the colon physiology had not been altered. The colonic pig model is ideal for studying factors affecting the colonic absorption of drugs and as a means for developing drug delivery systems with improved absorption properties.