Alternative propellant aerosol delivery systems

The year 2006 represents the 50th anniversary of the pressurized metered dose inhaler. With most technologies, 50 years represents a significant time span for technology evolution and modification, but with propellant-driven metered dose inhalers, the pace of change has been relatively slow. We are now in the era of alternative propellant aerosol delivery systems, but at this 50-year juncture, what are the characteristics of these systems and what are the prospects for future advances? This review will consider alternative propellant aerosol delivery systems broadly from their inception through future opportunities and challenges.     

The effects of surface morphology on the aerosol performance of spray-dried particles within HFA 134a based metered dose formulations

The aim of this study was to produce fine particles with different corrugated degree of surface by spray-drying and to investigate the effect of surface morphology on in vitro aerosol performance of the particles within HFA 134a based metered dose formulations. Compositions of rizatriptan and scutellarin were spray-dried using different spray-drying parameters, and particles were suspended within HFA 134a. The surface morphology were determined using scanning electron microscopy (SEM), while the aerodynamic performance of MDIs was evaluated using a next generation pharmaceutical impactor. The surface morphology of spray-dried particles could vary from smooth to moderately corrugated, and to raisin-like depending upon spray-drying parameters and preparation compositions. In general, increasing inlet temperature, decreasing feed concentration and/or adding leucine to the feed solution tended to increase the corrugated degree of particle surface. Deposition results indicated that raisin-like particle based MDIs for all compositions of the two drugs produced significantly better aerodynamic performance in terms of fine particle fractions and mass median aerodynamic diameters relative to the formulations of the corresponding smooth or slightly corrugated particles when the particle compositions were the same. The present results demonstrated that wrinkled particles increased fine particle fractions within surfactant-free MDI formulations.     

克伤痛气雾剂抛射剂替代研究

目的：优选抛射剂及用量,制备以四氟乙烷为抛射剂的中药克伤痛气雾剂。方法：以喷射速率、喷出量作为评价指标,对抛射剂及用量进行优化,对成品进行低温、加速稳定性试验。结果：对以四氟乙烷为抛射剂生产的克伤痛气雾剂产品进行加速稳定性试验,结果显示,产品质量稳定,符合气雾剂制剂要求。结论：所选抛射剂性能稳定可靠,适合克伤痛气雾剂的生产。     

Influence of formulation technique for hydroxypropyl-beta-cyclodextrin on the stability of aspirin in HFA 134a.

The objective of this study was to determine the influence of the formulation technique for 2-hydroxypropyl-beta-cyclodextrin (HP beta CD) on the stability of aspirin in a suspension-based pressurized metered-dose inhaler (pMDI) formulation containing a hydrofluoroalkane (HFA) propellant. HP beta CD was formulated in a pMDI as a lyophilized inclusion complex or a physical mixture with aspirin. A pMDI formulation containing aspirin alone was used as the control. The chemical stability of aspirin in each pMDI formulation was determined over 6-months storage at 5, 25 and 40 degrees C. The quantity of water taken up into the pMDI canister was determined by Karl Fisher titration after storage for 6 months. Differential scanning calorimetry (DSC) was used to confirm the formation of a complex between HP beta CD and aspirin. Aspirin in the lyophilized inclusion complex exhibited the most significant degree of degradation during the 6-months storage, while aspirin alone in the pMDI demonstrated a moderate degree of degradation. Aspirin formulated in the physical mixture displayed the least degree of degradation. The water uptake study showed that water ingress occurred to the greatest extent for formulations containing aspirin and HP beta CD physical mixture, and to the least extent for formulations containing aspirin alone. Finally, the DSC study indicated that an inclusion complex was formed in situ in the pMDI formulations containing the HP beta CD and aspirin physical mixture. In conclusion, HP beta CD may be used to enhance the stability of a chemically labile drug, but the drug stability may be affected by the method of preparation of the formulation.     

Formulation and characterization of spray-dried powders containing nanoparticles for aerosol delivery to the lung

Spray-drying is a common practice of powder preparation for a wide range of drugs. Spray-dried powders can be used to deliver particles to the lungs via a dry powder inhaler (DPI). The present study investigated the feasibility of developing a platform for aerosol delivery of nanoparticles. Lactose was used as the excipient and spray-dried with two different types of nanoparticles: gelatin and polybutylcyanoacrylate nanoparticles. Results showed that some carrier particles were hollow while others had a continuous matrix. Gelatin nanoparticles were incorporated throughout the matrix and sometimes accumulated at one end of the lactose. Polycyanoacrylate nanoparticles mostly clustered in different spots within the lactose carriers. The mean sizes of both nanoparticle types were characterized at two different times: before they were spray-dried and after they were redissolved from the spray-dried powders. Both nanoparticle types remained in the nano-range size after spray-drying. The mean nanoparticle sizes were increased by approximately 30% after spray-drying, though this increase was statistically significant only for the gelatin nanoparticles. Dispersion of the powder with an in-house passive dry powder inhaler and subsequent cascade impaction measurements showed that incorporation of the nanoparticles did not affect the fine particle fraction (FPF) or mass median aerodynamic diameter (MMAD) of the powders. FPF was approximately 40% while MMAD was 3.0+/-0.2 microm, indicating the present formulations yield aerosols of a suitable particle size for efficient lung delivery of nanoparticles.The present work demonstrates that nanoparticles can be delivered to the lungs via carrier particles that dissolve after coming in contact with the aqueous environment of the lung epithelium. This opens the way for new drug-targeting strategies using nanoparticles for pulmonary delivery of drugs and diagnostics.     

The effects of polyvinyl alcohol on the in vitro stability and delivery of spray-dried protein particles from surfactant-free HFA 134a-based pressurised metered dose inhalers

The objective of the present study was to investigate the physical stability of spray-dried proteins within surfactant-free hydrofluoroalkane (HFA) pressurised metered dose inhalers (pMDIs) during prolonged storage. Two model proteins (lysozyme and catalase) were spray-dried and stabilised in the presence of excipients, and subsequently suspended within HFA 134a. The pMDIs were stored valve-up for 6 months at room temperature (ca. 25 degrees C). Activities of the proteins were determined using biological assays and the fine particle fraction of the pMDIs was measured using a twin-stage impinger. The biological activities of catalase and lysozyme were found to be preserved in the presence of sugars and/or 80% hydrolysed polyvinyl alcohol (PVA) during spray drying. In addition, suspending the stabilised proteins within HFA for up to 6 months had little effect on their activity. The aerosolisation performance of lysozyme or catalase formulations containing either sucrose or trehalose as stabilisers appeared to deteriorate as a function of storage time. However, those formulations containing PVA were found to generate the greatest fine particle fraction, which in some cases was up to 50%, and to possess excellent physical stability during storage. The results indicated that the presence of PVA in the spray-dried stabilised protein particles could enhance the physical stability of particles, when suspended in the surfactant-free HFA MDI formulations, without affecting the protein stability upon prolonged storage.     

Prospective observational cohort safety study to monitor the introduction of a non-CFC formulation of salbutamol with HFA134a in England

OBJECTIVE: To monitor the safety of a salbutamol MDI with a hydrofluoroalkane propellant (Ventolin Evohaler) during its introduction into primary care use in England. METHODS: Prospective observational cohort study. 1,365 GPs in England submitted data on 10,472 regular users of Ventolin MDI, over five 3-month periods of observation between October 1, 1998 and December 31, 1999. The primary aim was to compare event rates occurring before and after the introduction of Ventolin Evohaler. The secondary aim was a comparison of event rates between users of Ventolin Evohaler and Ventolin MDI. The main outcome measures were: indication for use of Ventolin MDI, assessment of disease severity, event rates during each period of observation; deaths, pregnancies, reported adverse drug reactions and reasons for discontinuation of MDI. Event rates were adjusted using a ratio for under-reporting derived from a validation study on 4.6% of the study population and stratified by severity of indication. RESULTS: The primary indication was asthma in 94%, distributed by severity as 47% mild, 44% moderate and 9% severe; 13% were children. By October 1999, 52.7% of the 8,973 remaining patients had transitioned to Ventolin Evohaler. There was no increase in major or minor events observed following the introduction of Ventolin Evohaler. No serious adverse events, abnormal pregnancy outcomes or deaths have been related to Ventolin MDI or Ventolin Evohaler. The validation study showed a degree of under-reporting. CONCLUSION: These results on a large cohort of community patients in England indicate that Ventolin Evohaler is well tolerated among asthmatics.     

含有新型抛射剂的硫酸沙丁胺醇气雾剂的制备

目的制备不含氟利昂的硫酸沙丁胺醇气雾剂,并进行处方优化.方法以性状、雾滴(粒)分布、含量等作为评价指标进行处方筛选,并进行加速稳定性考察.结果经处方优化确定的硫酸沙丁胺醇气雾剂其性状、雾滴(粒)分布、含量等指标均符合规定,加速稳定性试验结果显示,本品质量稳定.结论所选处方工艺稳定可靠,适合生产.     

Acute safety of the CFC-free propellant HFA-134a from a pressurized metered dose inhaler

The acute safety of the alternative chlorofluorocarbon-free (CFC-free) propellant HFA-134a from a pressurized metered-dose inhaler (MDI) was assessed in 12 healthy male subjects according to a double-blind, randomized, crossover design. On each of three consecutive days, cumulative doses of 1, 2, 4, 8 and 16 inhalations were administered 30 min apart from one of three MDIs. The three MDIs contained either the HFA-134a CFC-free system without drug (HFA-Placebo), the CFC-free system with salbutamol sulphate (HFA-Salbutamol), or a conventional CFC propellant mixture without drug (CFC-Placebo). Pulmonary function (FEV₁, FEF_25–75%), cardiovascular performance (heart rate and blood pressure), objective tremor measurements and serum potassium were measured after each incremental dose.Similar responses for pulmonary function, cardiovascular performance, tremor and serum potassium were observed between the HFA-Placebo and CFC-Placebo groups. No statistically significant difference was seen in change from baseline of any parameter between the two propellant systems. The administration of HFA-Salbutamol produced statistically significant dose-related increases in heart rate, systolic blood pressure and tremor and a significant dose-related decrease in serum potassium; these responses were expected based on cumulative doses of active drug. Blood samples for HFA-134a analysis were collected to measure systemic absorption of this propellant. Levels of HFA-134a between 200 and 700 ng · ml^–1 were detected in all subjects given the CFC-free system. This study shows that acute inhalation of HFA-134a in a CFC-free system is as safe as a CFC propellant system. Salbutamol sulphate in the CFC-free system can be delivered in a dose-linear fashion, without any noticeable change in the safety profile of active drug.     

Self-nanoemulsifying drug delivery systems (SNEDDS) for oral delivery of protein drugs: I. Formulation development

The global aim of this research project was to develop a self-nanoemulsifying drug delivery system (SNEDDS) for non-invasive delivery of protein drugs. The specific aim of this study was to develop SNEDDS formulations. An experimental design was adopted to develop SNEDDS. Fluorescent labeled beta-lactamase (FITC-BLM), a model protein, was loaded into SNEDDS through solid dispersion technique. The experimental design provided 720 compositions of different oil, surfactant, and co-surfactant at various ratios, of which 33 SNEDDS prototypes were obtained. Solid dispersion of FITC-BLM in SoyPC prepared was able to dissolve in 16 SNEDDS prototypes (approximately 2200mU BLM in 1g SNEDDS). SNEDDS NE-12-7 (composition: Lauroglycol FCC, Cremophor EL and Transcutol; ratio: 5:4:3) formed O/W nanoemulsion with mean droplet size in the range of 22-50nm when diluted with various pH media and different dilution factor with PBS (pH 7.4). The phase diagram of NE-12-7 indicated a broad region of nanoemulsion. BLM-loaded SNEDDS (NE-12-7) stored at 4 degrees C for 12 weeks indicated 10% loss of BLM activity. A SNEDDS was developed to load FITC-BLM into the oil phase which can spontaneously form O/W nanoemulsion upon the addition of water.     

Formulation issues associated with transdermal fentanyl delivery

Supersaturation has previously been studied as a mechanism to enhance membrane transport of fentanyl from propylene glycol:water formulations (PG:H₂O) across silicone. In this study these supersaturated fentanyl formulations were evaluated in human skin. A number of polymers were also screened for their ability to stabilise the supersaturated formulations and permeation was evaluated for both infinite and finite doses. For infinite dose studies, permeation in skin increased linearly with increasing degree of drug saturation (DS) for formulations containing 0.5, 1, 2 DS of fentanyl and a 3 DS formulation stabilised with 1% (w/v) hydroxypropylcellulose (HPC). An excellent correlation was obtained for flux values in silicone compared with flux values in skin, for infinite dose studies for formulations containing 0.5, 1, 2 DS of fentanyl and the 3 DS formulation stabilised HPC. The concentration of the fentanyl in the stratum corneum also increased in proportion to the DS. However the same trend was not observed for finite dose studies. This is because the depletion of the solvent carrier promotes drug crystallisation with consequent implications for membrane transport. Tape-stripping experiments indicated that supersaturation of the drug is maintained in the outer layers of the stratum corneum. The ideal vehicle must, therefore, maintain the drug in solution on and in the skin in a sustained manner for effective transdermal delivery.     

Development of Room Temperature Stable Formulation of Formoterol Fumarate/Beclomethasone HFA pMDI

The primary aim of present investigation was to develop and formulate room temperature stable formulation of formoterol fumarate and beclomethasone dipropionate with extra fine part size of hydrofluoroalkane pressurized metered dose inhalers. Particle size distribution of hydrofluoroalkane pressurized metered dose inhalers was evaluated using Twin Stage Glass Impinger and Anderson Cascade Impactor. A tetrafluoroethane and/or heptafluoropropane were evaluated for preparation of hydrofluoroalkane pressurized metered dose inhalers. The fine particle fractions delivered from hydrofluoroalkane propellant suspension pressurized metered dose inhalers can be predicted on the basis of formulation parameters and is dependent of metering chamber of valve and orifice size of actuators. The results presented in investigation showed the importance of formulation excipients with formulation of pressurized metered dose inhalers viz, canister, valve and actuators used in formulations.     

Fractal morphology of drug aggregates in aerosol propellant suspensions

The study and formulation of drug suspensions in aerosol propellants is frequently hampered by lack of information concerning the structure and properties of the aggregated drug particles in suspension. We describe apparatus for the photomicrographic study of aggregates in suspension of volatile liquids, and apply this technique to measure the fractal properties of the drug aggregates. The boundary fractal dimensions of such flocs indicate that the model drugs studied (lactose and salbutamol sulphate) aggregate by a diffusion limited cluster-cluster mechanism in the absence of surfactants. However in the presence of Span 80, a typical surfactant used in aerosol systems, the morphology of the aggregates is significantly altered. The tenuous convoluted flocs become more compact and spherical. This is characterized by a reduction in the boundary fractal dimension, suggesting that considerable floc rearrangement occurs during aggregation. This implies that the surfactant reduces bonding forces between drug particles, allowing dynamic changes in floc structure.     

Formulation of Liposome for topical delivery of arbutin

The aims of this study were to encapsulate arbutin (AR) in liposome to enhance the skin-whitening activity, and to investigate the effect of liposome formulation on the entrapment efficiency (EE%), skin permeation rate and skin deposition. The liposomes were prepared by a film dispersion method with several different formulations and were separated from the solution by using the gel-filtration method. The physical (size distribution, morphology) and chemical (drug entrapment efficiency, hairless mouse skin permeation and deposition) properties of liposomes were characterized. The entrapment efficiency in all liposome formulations varied between 4.35% and 17.63%, and was dependent on the lipid content. The particle sizes of liposomes were in the range of 179.9-212.8 nm in all liposome formulations. Although the permeation rate of AR in the liposome formulations decreased compared with AR solution, the deposition amount of AR in the epidermis/dermis layers increased in AR liposomal formulation. These results suggest that liposomal formulation could enhance the skin deposition of hydrophilic skin-whitening agents, thereby enhancing their activities.     

Formulation of carbenoxolone for delivery to the skin

Carbenoxolone (CEX), a semi-synthetic derivative of glycyrrhetinic acid, has previously been used as a disodium salt for the management of dyspepsia and peptic ulcer because of its anti-inflammatory properties. Although glycyrrhetinic acid is available in pharmaceutical and personal care products for skin care, the topical use of the free acid form of CEX, has not previously been reported. In this work we investigated the percutaneous penetration of CEX. Solubility and permeability studies were conducted using a range of solvents or skin permeation enhancers (SPEs) commonly used for skin delivery. Binary combinations of dimethyl isosorbide (DMI) and Transcutol™ (TC) with isopropyl myristate (IPM) were effective in promoting skin permeation of CEX although individual solvents were not. Alternative fatty acid esters to IPM were subsequently investigated with the most promising formulation consisting of TC and propylene glycol laurate (PGL). Interestingly, propylene glycol monolaurate (PGML) did not demonstrate comparable efficacy when combined with TC. A ternary formulation consisting of TC, PGL and IPM demonstrated the best permeation enhancement of CEX compared with all other vehicles. The findings confirm (i) the feasibility of promoting CEX penetration across the skin (ii) the synergistic effect of combinations of solvents and SPEs on dermal and transdermal delivery (iii) the necessity for more fundamental studies to explain the differential effects of fatty acid esters on the skin barrier.     

Rationale for the selection of an aerosol delivery system for gene delivery.

Genetic therapeutics show great promise toward the treatment of illnesses associated with the lungs; however, current methods of delivery such as jet and ultrasonic nebulization decrease the activity and effectiveness of these treatments. Extremely low transfection rates exhibited by non-complexed plasmid DNA in these nebulizers have been primarily attributed to poor translocation and loss of molecular integrity as a consequence of shear-induced degradation. Current research focusing on methods to increase transfection rates via the pulmonary delivery route has largely concentrated on the incorporation of carbon dioxide in the air stream to increase breath depth as well as the addition of cationic agents that condense DNA into compact, ordered complexes. The purpose of this study was to examine the impact of several classic as well as the latest atomization devices on the structure of non-complexed DNA. Various sizes of plasmid and cosmid DNA were processed through an electrostatic spray, ultrasonic nebulizer, vibrating mesh nebulizer, and jet nebulizer. Results varied dramatically based upon atomization device as well as DNA size. This may explain the inefficiency experienced by genetic therapeutics during pulmonary delivery. More importantly, this suggests that the selection of an atomization device should consider DNA size in order to achieve optimal gene delivery to the lungs.     

Formulation and evaluation of a bioadhesive patch for buccal delivery of tizanidine

Tizanidine hydrochloride (THCl) is an antispasmodic agent which undergoes extensive first pass metabolism making it a possible candidate for buccal delivery. The aim of this study was to prepare a monolayered buccal patch containing THCl using the emulsification solvent evaporation method. Fourteen formulations were prepared using the polymers Eudragit^® RS 100 or Eudragit^® RL 100 and chitosan. Polymer solutions in acetone were combined with a THCl aqueous solution (in some cases containing chitosan) by homogenization at 9000 rpm for 2 min in the presence of triethyl citrate as plasticizer and cast in novel Teflon molds. Physicochemical properties such as film thickness, in vitro drug release and in vitro mucoadhesion were evaluated after which permeation across sheep buccal mucosa was examined in terms of flux and lag time. Formulations prepared using a Eudragit^® polymer alone exhibited satisfactory physicomechanical properties but lacked a gradual in vitro drug release pattern. Incorporation of chitosan into formulations resulted in the formation of a porous structure which did exhibit gradual release of drug. In conclusion, THCl can be delivered by a buccal patch formulated as a blend of Eudragit^® and chitosan, the latter being necessary to achieve gradual drug release.     

Formulation and delivery issues for monoclonal antibody therapeutics

Antibodies can have exquisite specificity of target recognition and thus generate highly selective outcomes following their systemic administration. While antibodies can have high specificity, the doses required to treat patients, particularly for a chronic condition, are typically large. Fortunately, advances in production and purification capacities have allowed for the exceptionally large amounts of highly purified monoclonal antibodies to be produced. Additionally, genetic engineering of antibodies has provided a stable of antibody-like proteins that can be easier to prepare. Together, these advances have made antibody-based therapies one of the most commonly pursued pharmaceuticals in biotechnology pipelines. With this success, however, has come a series of technical challenges in the formulation of antibody-based materials to maintain sufficient stability in a variety of configurations and sometimes at particularly high concentrations. This review focuses on issues related to identifying and verifying stable antibody-based formulations.