Inhalation of estradiol for sustained systemic delivery.

Large porous estradiol particles were formulated by spray drying estradiol in combination with various U.S. Food and Drug Administration (FDA)-approved or endogenous excipients. The powders were characterized in terms of their geometrical size, mass density, and aerosolization properties. Small nonporous particles were also prepared using the same excipients and were physically characterized to insure that they possessed a similar mean aerodynamic size as the large porous particles. The two powders were aerosolized into the lungs of rats via an endotracheal tube or subcutaneously injected as a control to assess relative bioavailability. Two different large porous particle formulations were found to produce elevated systemic estradiol concentrations upon inhalation for approximately 5 days, with relative bioavailabilities of 59.7% and 86.0%. Systemic estradiol concentrations following inhalation of two different small nonporous particle powders remained elevated for only approximately 1 day, with relative bioavailabilities of 18.3% and 38.7%. Bronchoalveolar lavage was performed up to 96 hours after inhalation of porous and nonporous estradiol powders. Small changes in neutrophil and macrophage populations were observed following inhalation of both the porous and nonporous powders.     

Physical characteristics and aerosolization performance of insulin dry powders for inhalation prepared by a spray drying method

The objective of this study was to investigate the influence of formulation excipients on the physical characteristics and aerosolization performance of insulin dry powders for inhalation. Insulin dry powders were prepared by a spray drying technique using excipients such as sugars (trehalose, lactose and dextran), mannitol and amino acids (L-leucine, glycine and threonine). High performance liquid chromatography and the mouse blood glucose method were used for determination of the insulin content. The powder properties were determined and compared by scanning electron microscopy, thermo-gravimetric analysis and size distribution analysis by a time-of-flight technique. The in-vitro aerosolization behaviour of the powders was assessed with an Aerolizer inhaler using a twin-stage impinger. Powder yield and moisture absorption were also determined. Results showed that there was no noticeable change in insulin content in any of the formulations by both assay methods. All powders were highly wrinkled, with median aerodynamic diameters of 2-4 microm, and consequently suitable for pulmonary administration. The tapped density was reduced dramatically when glycine was added. The powders containing mannitol, with or without L-leucine, were less sensitive to moisture. The highest respirable fraction of 67.3 +/- 1.3% was obtained with the formulation containing L-leucine, in contrast to formulations containing glycine and threonine, which had a respirable fraction of 11.2 +/- 3.9% and 23.5 +/- 2.5%, respectively. In addition, powders with good physical properties were achieved by the combination of insulin and trehalose. This study suggests that L-leucine could be used to enhance the aerosolization behaviour of the insulin dry powders for inhalation, and trehalose could potentially be used as an excipient in the formulations.     

Local and systemic delivery of high-molecular weight drugs by powder inhalation

The pulmonary route has recently attracted attention as a noninvasive administration route for peptide and protein drugs, and an insulin powder for inhalation was approved by authorities in Europe and the USA. The present study examined usefulness of insulin and gene powders for systemic and local inhalation therapy. We prepared several dry insulin powders by spray drying to examine the effect of additives on insulin absorption. Citric acid appears to be a safe and potent absorption enhancer for insulin in dry powder. However, in the powder with citric acid (MIC0.2 SD) insulin was unstable compared with the other powders examined. To improve insulin stability, a combination of insulin powder and citric acid powder was prepared (MIC Mix). MIC Mix showed hypoglycemic activity comparable to MIC0.2 SD while the insulin stability was much better than that of MIC SD. Next, dry insulin powders with mannitol were prepared with supercritical carbon dioxide (SCF); the powder thus prepared reduced blood glucose level rapidly and was more effective than that prepared by spray drying. Chitosan-pDNA complex powders as a pulmonary gene delivery system were also prepared with SCF and their in vivo activity was evaluated. The addition of chitosan suppressed the degradation of pCMV-Luc during preparation and increased the storage stability. The luciferase activity in mouse lung was evaluated after pulmonary administration of the powders. The chitosan-pDNA powder with an N/P ratio=5 increased the luciferase activity to 27 times that of the pCMV-Luc solution. These results suggest that gene powder with chitosan is a useful pulmonary gene delivery system.     

Large Porous Particles for Sustained Protection from Carbachol-Induced Bronchoconstriction in Guinea Pigs

Purpose. To determine whether a new formulated albuterol aerosol could sustain inhibition to bronchoconstriction for approximately one day in guinea pigs challenged with carbachol. Methods. Large and porous particles, comprising a combination of endogenous or PDA-approved excipients and albuterol sulfate, were prepared by spray drying using a NIRO portable spray drier. The anesthetized animals inhaled 5 mg of large porous or small nonporous particles by forced ventilation via cannulae inserted in the lumen of their exposed tracheae. At regular intervals over a period of 36 hours after drug delivery, airway resistance was determined in response to carbachol challenge dose. Results. Whereas inhalation of small nonporous albuterol particles protected from the carbachol-induced bronchoconstriction for up to 5 hours, inhalation of large porous albuterol particles produced a significant inhibition of carbachol-induced bronchoconstriction for at least 16 hours. Conclusions. The absence of substantial side effects, verified over a period of 24 hours by evaluating cardio-respiratory parameters as well as pulmonary inflammation, supports the utility of large porous albuterol particles for sustained therapies in asthma and other types of lung disease.Dr. Ben-Jebria is also affiliated with     

Spray freeze drying to produce a stable Delta(9)-tetrahydrocannabinol containing inulin-based solid dispersion powder suitable for inhalation.

The purpose of this study is to investigate whether spray freeze drying produces an inhalable solid dispersion powder in which Delta(9)-tetrahydrocannabinol (THC) is stabilised. Solutions of THC and inulin in a mixture of tertiary butanol (TBA) and water were spray freeze dried. Drug loads varied from 4 to 30 wt.%. Various powder characteristics of the materials were determined. Stability of THC was determined and compared with freeze dried material. The powders, dispersed with an inhaler based on air classifier technology, were subjected to laser diffraction analysis and cascade impactor analysis. Highly porous particles having large specific surface areas (about 90 m(2)/g) were produced. At high drug loads, THC was more effectively stabilised by spray freeze drying than by freeze drying. Higher cooling rates during spray freeze drying result in improved incorporation. Fine particle fractions of up to 50% were generated indicating suitability for inhalation. It was concluded that spray freeze drying from a water-TBA mixture is a suitable process to include lipophilic drugs (THC) in inulin glass matrices. High cooling rates during the freezing process result in effective stabilisation of THC. The powders can be dispersed into aerosols with a particle size appropriate for inhalation.     

Formulation and process development of (recombinant human) deoxyribonuclease I as a powder for inhalation

A formulation and process development study was performed to formulate recombinant human deoxyribonuclease I as a powder for inhalation. First, excipient compatibility (with bovine DNase as a model substance) was examined with a stability study at stressed conditions (60 and 85°C) while monitoring for occurrence of the Maillard reaction. Next, powders for inhalation were prepared by spray drying and spray freeze drying. We found that spray drying with inulin as stabilizer resulted in the best powder for inhalation. Finally, an ex-vivo test with the spray dried rhDNase I/inulin powder significantly decreased elastic and viscous moduli of sputum from five cystic fibrosis patients.     

Aerosol Delivery of Nanoparticles in Uniform Mannitol Carriers Formulated by Ultrasonic Spray Freeze Drying

Purpose

While most examples of nanoparticle therapeutics have involved parenteral or IV administration, pulmonary delivery is an attractive alternative, especially to target and treat local infections and diseases of the lungs. We describe a successful dry powder formulation which is capable of delivering nanoparticles to the lungs with good aerosolization properties, high loadings of nanoparticles, and limited irreversible aggregation.

Methods

Aerosolizable mannitol carrier particles that encapsulate nanoparticles with dense PEG coatings were prepared by a combination of ultrasonic atomization and spray freeze drying. This process was contrasted to particle formation by conventional spray drying.

Results

Spray freeze drying a solution of nanoparticles and mannitol (2 wt% solids) resulted in particles with an average diameter of 21?±?1.7 μm, regardless of the fraction of nanoparticles loaded (0–50% of total solids). Spray freeze dried (SFD) powders with a 50% nanoparticle loading had a fine particle fraction (FPF) of 60%. After formulation in a mannitol matrix, nanoparticles redispersed in water to < 1 μm with hand agitation and to < 250 nm with the aid of sonication. Powder production by spray drying was less successful, with low powder yields and extensive, irreversible aggregation of nanoparticles evident upon rehydration.

Conclusions

This study reveals the unique advantages of processing by ultrasonic spray freeze drying to produce aerosol dry powders with controlled properties for the delivery of therapeutic nanoparticles to the lungs.     

Formulation of pH responsive peptides as inhalable dry powders for pulmonary delivery of nucleic acids

Nucleic acids have the potential to be used as therapies or vaccines for many different types of disease, but delivery remains the most significant challenge to their clinical adoption. pH responsive peptides containing either histidine or derivatives of 2,3-diaminopropionic acid (Dap) can mediate effective DNA transfection in lung epithelial cells with the latter remaining effective even in the presence of lung surfactant containing bronchoalveolar lavage fluid (BALF), making this class of peptides attractive candidates for delivering nucleic acids to lung tissues. To further assess the suitability of pH responsive peptides for pulmonary delivery by inhalation, dry powder formulations of pH responsive peptides and plasmid DNA, with mannitol as carrier, were produced by either spray drying (SD) or spray freeze drying (SFD). The properties of the two types of powders were characterised and compared using scanning electron microscopy (SEM), next generation impactor (NGI), gel retardation and in vitro transfection via a twin stage impinger (TSI) following aerosolisation by a dry powder inhaler (Osmohaler™). Although the aerodynamic performance and transfection efficacy of both powders were good, the overall performance revealed SD powders to have a number of advantages over SFD powders and are the more effective formulation with potential for efficient nucleic acid delivery through inhalation.     

The effect of process variables on the degradation and physical properties of spray dried insulin intended for inhalation

The aim of this study was to investigate the effect of process variables on the degradation and physical properties of spray dried insulin intended for inhalation. A 2(4) full factorial experimentally designed study was performed to investigate the influence of the following independent spray drying variables: feed flow rate, nozzle gas flow rate, inlet air temperature and aspirator capacity (drying gas flow rate). Human insulin (biosynthetic and Ph.Eur. quality) was dissolved in distilled water to concentrations of 5 mg/ml. The solutions were spray dried in a Mini Spray Dryer Büchi and the dry powders produced were characterized by high performance liquid chromatography, size exclusion chromatography, laser diffraction, thermo gravimetric analysis, scanning electron microscopy and weighing. The degradation of insulin was found to be affected mainly by the process variables that determine the outlet air temperature, i.e.: inlet air temperature, aspirator capacity and feed flow rate. The outlet air temperature should be kept below 120 degrees C to avoid degradation. A statistical optimization of the spray drying variables was performed, and found to recommend an experiment with an outlet air temperature of 61+/-4 degrees C. This experiment ought to generate a yield of 54+/-7% by weight of particles with a mass median diameter 2.9+/-0.4 microm, moisture content 3.9+/-0.5% by weight, content of high molecular weight proteins 0.3+/-0.1% by area, A-21 desamido insulin 0.3+/-0.05% by area and other insulin related compounds 0.3+/-0.1% by area.     

Feasibility of spray drying bacteriophages into respirable powders to combat pulmonary bacterial infections

The use of bacterial viruses for antibacterial treatment (bacteriophage therapy) is currently being reevaluated. In this study, we analyze the potential of processing bacteriophages in a dry powder formulation, using a laboratory spray dryer. The phages were dried in the presence of lactose, trehalose or dextran 35, serving as an excipient to give the resulting powder the necessary bulk mass and offer protection to the delicate phage structure. Out of the three excipients tested, trehalose was found to be the most efficient in protecting the phages from temperature and shear stress throughout the spray drying process. A low inlet air temperature and atomizing force appeared to be the best parameter conditions for phage survival. Pseudomonas podovirus LUZ19 was remarkably stable, suffering less than 1 logarithmic unit reduction in phage titer. The phage titer of Staphyloccus phage Romulus-containing powders, a member of the Myoviridae family, showed more than 2.5 logarithmic units reduction. On the other hand, Romulus-containing powders showed more favorable characteristics for pulmonary delivery, with a high percentage of dry powder particles in the pulmonary deposition fraction (1–5 μm particle diameter). Even though the parameters were not optimized for spray drying all phages, it was demonstrated that spray drying phages with this industrial relevant and scalable set up was possible. The resulting powders had desirable size ranges for pulmonary delivery of phages with dry powder inhalers (DPIs).     

含碳酸氢铵羟基喜树碱粉雾剂的研制

目的:提高10-羟基喜树碱(HPCT)粉雾剂的沉积性能。方法:利用喷雾干燥法制备HPCT粉雾剂,考察处方中加入碳酸氢铵后粉末的密度、比表面积、表面形态、粒度及体外沉积性能。结果:制备出了敲击密度为0.015g·mL-1、比表面积为19.81m2·g-1、体积平均直径为15.64μm的粉末,该低密度、大粒径的多孔性粉粒大大提高了药物的体外沉积性能,粉雾剂的体外沉积率由18.0%提高至51.6%。结论:加入碳酸氢铵能够显著提高HPCT粉雾剂的沉积性能。     

Improvement of insulin absorption from intratracheally administrated dry powder prepared by supercritical carbon dioxide process

The purpose of this study was to improve insulin absorption from dry powder after administration in lung without an absorption enhancer. The dry powders, with mannitol as a carrier, were prepared with or without an absorption enhancer (citric acid) by supercritical carbon dioxide (SCF) and spray drying (SD) processes. Insulin powder was precipitated from dimethyl sulfoxide and aqueous solutions by dispersing the insulin solutions from parallel and V-type nozzles, respectively, into supercritical carbon dioxide, which is an antisolvent for insulin. In vitro aerosol performance was evaluated with a cascade impactor. Insulin powder containing citric acid prepared by the SCF method (MIC SCF) showed improved inhalation performance compared with insulin powder prepared by the SD process, although the particle size of the former powder was larger than that in powders prepared by SD. Insulin absorption was estimated from the change in plasma glucose level. The blood glucose level after administration of the insulin powder without citric acid prepared by the SCF process (MI SCF) decreased rapidly, and a significant difference was observed for areas under the curve of change in plasma glucose concentration versus time (AUCs) between MI SCF and the insulin powder without citric acid prepared by the SD process (MI SD). These results suggest that the SCF technique would be useful to prepare dry powders suitable for inhalation.     

Cyclodextrins in the production of large porous particles: Development of dry powders for the sustained release of insulin to the lungs

The aim of this work was to develop dry powders intended for insulin pulmonary delivery. To this purpose, large porous particles (LPP) made of poly(lactide-co-glycolide) (PLGA) were produced by the double emulsion-solvent evaporation technique. Hydroxypropyl-beta-cyclodextrin (HPbetaCD), also known as absorption enhancer for pulmonary protein delivery, was tested as aid excipient to optimize the aerodynamic behaviour of the microparticles. Several microsphere formulations, differing in HPbetaCD and insulin loadings, were produced and their properties compared. A contemporary release of insulin and HPbetaCD from the system can be achieved by selecting appropriate formulation conditions. HPbetaCD-containing LPP with flow properties and dimensions suitable for aerosolization and deposition in deep regions of the lung following inhalation were produced. In conclusion, the developed system turns to be of great potential for the combined delivery of the protein and the adsorption promoter in the respiratory tract.     

Spray-dried respirable powders containing bacteriophages for the treatment of pulmonary infections

Myoviridae bacteriophages were processed into a dry powder inhalable dosage form using a low‐temperature spray‐drying process. The phages were incorporated into microparticles consisting of trehalose, leucine, and optionally a third excipient (either a surfactant or casein sodium salt). The particles were designed to have high dispersibility and a respirable particle size, and to preserve the phages during processing. Bacteriophages KS4‐ M, KS14, and cocktails of phages ΦKZ/D3 and ΦKZ/D3/KS4‐M were spray‐dried with a processing loss ranging from 0.4 to 0.8 log pfu. The aerosol performance of the resulting dry powders as delivered from an Aerolizer® dry powder inhaler (DPI) exceeded the performance of commercially available DPIs; the emitted mass and the in vitro total lung mass of the lead formulation were 82.7% and 69.7% of filled capsule mass, respectively. The total lung mass had a mass median aerodynamic diameter of 2.5–2.8 µm. The total in vitro lung doses of the phages, delivered from a single actuation of the inhaler, ranged from 10⁷ to 10⁸ pfu, levels that are expected to be efficacious in vivo. Spray drying of bacteriophages into a respirable dry powder was found to be feasible.     

The role of particle engineering in relation to formulation and de-agglomeration principle in the development of a dry powder formulation for inhalation of cetrorelix.

We formulated cetrorelix acetate, as an adhesive mixture for use in dry powder inhalation. To achieve the highest possible deposition efficiency we investigated both the influence of different micronization techniques and different inhalers. The Novolizer with an air classifier as the powder de-agglomeration principle and the ISF inhaler were used for in vitro deposition experiments (cascade impaction). Micronization by milling as the classical approach and micronization by spray drying and spray freeze drying as advanced particle engineering techniques were investigated to determine whether advanced techniques are necessary to obtain high fine particle fractions (FPF) for this specific drug. It was found that the effects obtained with a certain micronization technique depended on the complex interaction of the physical characteristics of the drug substance with the type of formulation chosen, as well as with the de-agglomeration principle used. The combination of particle engineering by spray drying and the use of the air classifier technology resulted in a fine particle fraction of 66%, while spray freeze drying yielded extremely fragile particles resulting in a FPF of only 25%. The behaviour of the milled material showed similar trends as the spray dried material but FPF values were lower. It was concluded that when a drug is to be formulated as a powder for inhalation with high fine particle fractions, it is profitable to use advanced particle engineering techniques, however the applied technique should be tuned with the characteristics of the formulation type and process as well as with device development.     

Spray Drying Technique: II. Current Applications in Pharmaceutical Technology

This review presents current applications of spray drying in pharmaceutical technology. The topics discussed include the obtention of excipients and cospray dried composites, methods for increasing the aqueous solubility and bioavailability of active substances, and modified release profiles from spray-dried particles. This review also describes the use of the spray drying technique in the context of biological therapies, such as the spray drying of proteins, inhalable powders, and viable organisms, and the modification of the physical properties of dry plant extracts. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:587–597, 2010     

Low-Voltage Electrohydrodynamic (EHD) Spray Drying of Respirable Particles

Spray drying is a widely used process to produce pharmaceutical powders. In traditional spray drying, the particle size distribution is wide and not well controlled. Using EHD atomization for spray drying offers a possibility to tailor the particle size and morphology. In conventional EHD spray drying, the generated particles are charged and need to be discharged to avoid Rayleigh breakup. Discharging adds complexity to the process and eliminates the possibility to collect the powder using an electric field. The present work describes a novel EHD spray drying setup based on a low-voltage nozzle. The low-voltage nozzle imparts moderate charge to the droplets, which makes discharging unnecessary. The charged particles can be controlled and collected by using an auxiliary electric field. The EHD spray dryer has been characterized in terms of particle size, particle morphology, process output, and yield. The size distribution of the generated particles is very narrow. Both porous and completely spherical particles can be produced. The yield of small-scale bench-top equipment was 20%, which is similar to the yield of a small-scale conventional spray dryer. The effective output with five nozzles was 75 mg/hr of dry powder. Because of the repelling forces associated with the unipolarly charged droplets, the number of nozzles can be increased without risking coalescence.     

Optimization of Particle Properties of Nanocrystalline Solid Dispersion Based Dry Powder for Inhalation of Voriconazole

A one-step spray drying based process was employed to generate ready-to-use nanocrystalline solid dispersion (NCSD) dry powder for inhalation (DPI) of voriconazole (VRC). The solid dispersion was prepared by spray drying VRC, MAN (mannitol) and soya lecithin (LEC) from mixture of methanol-water. Various formulation and process related parameters were screened, including LEC, inlet temperature, total solid content and feed flow rate to generate particles of geometric size ≤5 µm. Aerosil® 200 was explored as the quaternary excipient either during spray drying or by physically mixing with the optimized ternary NCSD. The powders were extensively characterized for solid form, primary particle size, assay, embedded nanocrystal size, morphology, porosity, density and moisture content. Aerodynamic properties were studied using next generation impactor (NGI), while surface elemental composition and topography were investigated using SEM-EDS (scanning electron microscopy- energy dispersive spectroscopy) and AFM (atomic force microscopy), respectively. At selected inlet temperature of 120 ?C, total solid content and feed flow rate significantly impacted the size of primary NCSD particles. Size of primary particles increased with increase in total solid content and feed flow rate of the solution. VRC nanocrystals were obtained in polymorphic Form B whereas the matrix of MAN consisted of mixture of polymorphic Forms α, β and δ. SEM-EDS analysis confirmed deposition of Aerosil® 200 on surface of spray dried particles. In addition to increased porosity and reduced density, increase in surface roughness of particles (evident from AFM topographic analysis) contributed to enhanced powder deposition at stages 3 and 4 in NGI. In comparison, physical blending of NCSD with Aerosil® 200 showed improvement in aerosolization due to flow enhancement property.     

Low-voltage electrohydrodynamic (EHD) spray drying of respirable particles

Spray drying is a widely used process to produce pharmaceutical powders. In traditional spray drying, the particle size distribution is wide and not well controlled. Using EHD atomization for spray drying offers a possibility to tailor the particle size and morphology. In conventional EHD spray drying, the generated particles are charged and need to be discharged to avoid Rayleigh breakup. Discharging adds complexity to the process and eliminates the possibility to collect the powder using an electric field. The present work describes a novel EHD spray drying setup based on a low-voltage nozzle. The low-voltage nozzle imparts moderate charge to the droplets, which makes discharging unnecessary. The charged particles can be controlled and collected by using an auxiliary electric field. The EHD spray dryer has been characterized in terms of particle size, particle morphology, process output, and yield. The size distribution of the generated particles is very narrow. Both porous and completely spherical particles can be produced. The yield of small-scale bench-top equipment was 20%, which is similar to the yield of a small-scale conventional spray dryer. The effective output with five nozzles was 75 mg/hr of dry powder. Because of the repelling forces associated with the unipolarly charged droplets, the number of nozzles can be increased without risking coalescence.     

Formulation and Physical Characterization of Large Porous Particles for Inhalation

Purpose. Relatively large (>5 µm) and porous (mass density < 0.4 g/cm³) particles present advantages for the delivery of drugs to the lungs, e.g., excellent aerosolization properties. The aim of this study was, first, to formulate such particles with excipients that are either FDA-approved for inhalation or endogenous to the lungs; and second, to compare the aerodynamic size and performance of the particles with theoretical estimates based on bulk powder measurements. Methods. Dry powders were made of water-soluble excipients (e.g., lactose, albumin) combined with water-insoluble material (e.g., lung surfactant), using a standard single-step spray-drying process. Aerosolization properties were assessed with a Spinhaler ^TM device in vitro in both an Andersen cascade impactor and an Aerosizer^TM.. Results. By properly choosing excipient concentration and varying the spray drying parameters, a high degree of control was achieved over the physical properties of the dry powders. Mean geometric diameters ranged between 3 and 15 µm, and tap densities between 0.04 and 0.6 g/cm³. Theoretical estimates of mass mean aerodynamic diameter (MMAD) were rationalized and calculated in terms of geometric particle diameters and bulk tap densities. Experimental values of MMAD obtained from the Aerosizer^TM most closely approximated the theoretical estimates, as compared to those obtained from the Andersen cascade impactor. Particles possessing high porosity and large size, with theoretical estimates of MMAD between 1–3 µm, exhibited emitted doses as high as 96% and respirable fractions ranging up to 49% or 92%, depending on measurement technique. Conclusions. Dry powders engineered as large and light particles, and prepared with combinations of GRAS (generally recognized as safe) excipients, may be broadly applicable to inhalation therapy.