IA 2015 | Posters

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Influence of characteristics of inhaled nanoparticles on their fate after lung deposition
Jieyu Zhou

As a non-invasive route of administration, pulmonary drug delivery is capable of exerting local or systemic effects. Nanotechnology has been widely applied to inhaled drug delivery system with a series of advantages. In this review, diverse inhaled nanosystems designed for local therapy, systemic effects and targeted delivery to lymphatic system will be presented. Since the fate of inhaled nanoparticles mainly depends on their deposition in the central, intermediate or peripheral regions of the lung, avoidance of nanoparticles fast clearance and guarantee of rapid translocation play important roles in increasing lung retention time and improving drug’s absorption. Influence of physico-chemical properties of the nanoparticles such as size, surface properties and hydrophilicity on the interaction with mucus, epithelial cells, macrophages and in vivo organ distribution, especially lung retention will be presented. Biodegradable polymeric nanoparticles such as poly(lactide-co-glycolide) nanoparticles, chitosan nanoparticles, solid lipid nanoparticles and liposomes are commonly designed for the pulmonary delivery of various drugs. Beyond the impact of the carrier itself, the particle size determines the final drug distribution and whether the uptake by macrophages occurs. The nanoparticles with diameter lower than 260nm will stay in situ and seldom be taken up by macrophages after deposition in the deeper lung. Nanoparticles with various surface charges which can be adjusted by surface coating behave inconsistently upon contact with mucus and epithelial cells on the surface of the respiratory tract. Those with negative charge would diffuse unimpeded across the mucus barrier leading to a higher intracellular accumulation. In contrast, those with positive and neutral charges are difficult to penetrate the epithelium and tend to interact with mucin chains. Additionally, inhaled nanoparticles conjugated with functional biomolecules can be delivered to a specific region and accumulate in a targeted way which has been proved in vivo. Increasing surface hydrophobicity of the nanoparticles prolongs drug retention in the surfactant monolayer of the lung, while the nanoparticles with more hydrophilic surface tend to pass through mucus layer more rapidly. In a word, acquisition of the above mentioned properties of nanoparticles would contribute to a safer and effective delivery system design to achieve desired therapeutic effect.


Human factors and handling studies
Stefan Leiner

Chronic obstructive pulmonary disease and asthma are diseases with an increasing prevalence worldwide. Inhalation therapy has long been dominated by pressurized metered dose inhalers (pMDIs), such inhalers are still in frequent use. While all pMDIs, irrespective of the active ingredient, followed the same handling principles (hold the pMDI upside down, shake, actuate while inhaling), the development of alternative inhalation dosage forms, especially of dry powder inhalers (DPIs), offers new challenges and complexity for use. Not only do delivered dose and fine particle dose depend on the patient’s air flow and are varying amongst the patients; even more, the operations to use the inhaler correctly get more complex and vary from product to product.

One way to evaluate whether an inhaler has been designed to assure correct use are Human Factor studies. Human Factor studies are first a theoretical consideration of which hazards may occur, e.g., due to failure to perceive information, due to unintuitive device design or due to not anticipated device use. This is followed by applying strategies to mitigate or control use-related hazards and finally verified by demonstrating safe device use through human factors validation testing where patients are observed using the inhaler.

A second, complementary investigation are handling studies: Inhalers that have been used in phase III clinical studies are returned and checked for correct function. This gives two important information: • Did the inhaler perform correctly during the clinical study?  (If not: how valid are the clinical results?) • Are there any signs that the patient did not use the inhaler correctly? For example, manipulated nozzles or broken joints are signs of mis-use; foils that should stay intact may have been opened as the instructions for use was not clear, or powder residues may indicate that cleaning instructions have not been understood or followed. Such information must trigger corrections of the inhaler design and / or of the handling instructions.

A third investigation are potential mis-use studies where anticipated mis-use, e.g. storage in humid climate, is investigated.

The author encourages all developing companies to conduct and report Human Factor studies, Handling Studies and potential mis-use studies in new drug applications. Authorities need to review these data to get an impression of reliable and easy use.  Further, the author encourages all involved parties in discussing on how close or how different inhaler designs may be before they pose a risk to the public health.  Innovation in design must not leave the patient confused. This will achieve the opposite of what innovation is aiming at: improving medication delivery.


Recent advances in controlled pulmonary drug delivery
Shirui Mao

For alleviation and treatment of respiratory diseases, oral, parenteral and pulmonary delivery methods are the most frequently used administration routes for patients and medical practitioners. Characterized by large surface area, high vascularization and thin blood–alveolar barrier, drug delivery by the pulmonary route has many outstanding features compared with oral or parenteral routes, including local targeting, circumvention of first-pass hepatic metabolism and rapid onset of action. Moreover, high therapeutic ratio, increased selectivity, lower administered dose and reduced side-effects are also advantages. In addition, for locally applied drugs, the systemic side-effects could be reduced because of minimized systemic exposure by targeting to the desired site (particularly for drugs with a narrow therapeutic window). However, to date most of the marketed inhalable products are short-acting formulations that require the patient to inhale several times every day, thus reducing patient compliance. Controlled pulmonary drug delivery is a promising system but the formidable airway clearance mechanisms need to be avoided, which include mucociliary clearance, macrophages clearance, systemic absorption, metabolic degradation and so on. Studies demonstrated that large porous particles, swellable microparticles and porous nanoparticle–aggregate-based particles are the most promising carriers to control drug release in the lung. Properties and mechanisms of different sustained drug delivery systems for pulmonary inhalation will be presented, which can be used as a guidance for inhalation dosage form development.


Applying MDRS to dry powder inhaler development
Shuai Zhang

The particle size and particle size distribution of the active pharmaceutical ingredients (APIs) delivered by Dry Powder Inhalers (DPIs) is known to be critical in defining product bioavailability. The compendial methods for DPI particle size analysis are based around the use of cascade impaction. Impaction techniques, such as the Next Generation Impactor (NGI), offer advantages for DPI analysis compared to other particle sizing methods as they enable the aerodynamic diameter of the emitted dose to be assessed specifically for the API. However, analysis of the dose collected during impactor analysis is generally carried out using High Pressure Liquid Chromatography (HPLC) via dissolution of the dose. The requirement for dissolution effectively destroys the dose, removing the ability to assess the specific microstructural properties of the particles within the aerosol. In this paper we present a method for extending the capabilities of cascade impaction through the use of Morphologically Directed Raman Spectroscopy (MDRS). MDRS combines static image analysis, for particle size and shape analysis, with Raman spectroscopy, for particle chemical analysis. The technique can be applied during cascade impactor analysis by collecting the emitted dose on microscope slides placed within each stage of the impactor. These slides can be collected and then analysed to enable component specific particle size distributions to be calculated for the aerosol particles over a size range from 1-40 m. Data obtained for a typical combination product containing fluticasone propionate, salmeterol xinafoate and a lactose excipient show the ability of the technique to determine the state of dispersion of each API in the respirable range (1-10 m), allowing developers to confirm whether each is dispersed to a similar particle size. In addition, the relative concentration of each API can be assessed on a particle number (count) basis. 


Comparison of current quality specifications and in-vitro characterization methods for inhalation powders
Zhang Lan

In this paper, current quality specifications of inhalation powders described in pharmacopeias and relevant literatures were compared, together with the in-vitro characterization methods. Especially, the inhalation powder standards in the pharmacopeias of the United States (USP37),the European (EP8.0), the British (BP2014) and China (ChP2015 draft), were analyzed and discussed. The test methods and limits of several parameters in different pharmacopeias were compared. For the test of uniformity of delivered dose,the same apparatus is applied by the four pharmacopeias, with identical requirements of the pressure drop across the inhaler and gas flow rate, except for that the gas volume stated in USP37 is 2 L while 4 L in the other three pharmacopeias. Moreover, there are some differences between USP37 and other pharmacopeias in the delivered dose uniformity test of metered dose preparations. All the four pharmacopeias provided more than three apparatus to determine the fine particle dose of dry powder inhalers, and both next generation impactor and Anderson cascade impactor are recorded, with the same method and parameters, indicating good agreement of fine particle dose standards in China, United States, United Kingdom and European Union. In addition, factors influencing dry powder inhalation characteristics and aerosolization performance were discussed, including characteristics of active pharmaceutical ingredients (API), excipients (category and specification of carriers), the ratio of carrier and API, the process environment such as relative humidity (RH), and manufacture parameters such as inlet temperature and flow velocity of spray drying. Dry powders can be characterized by different properties, including morphology, particle size, flowability, density, bitterness level, moisture absorption and aerodynamic behavior such as in vitro deposition. This review proposed methods and suggestions for improving inhalation powders quality and provided reference for the choice of essential aerodynamic characterization methods for inhalation powders.


Aerosol therapy for the upper airways
Heribert Mentzel

Upper airway diseases and especially the acute and chronic rhinosinusitis (ARS/CRS) have a strong health-economic impact. About 10-15% of the US and EU population suffers from CRS. In order to avoid systemic side effects, topical therapy is principally desirable. It is considered as an essential element in treating acute and chronic sinusitis, particularly during postoperative care involving the upper airways. But the success of topical drug delivery to the sinuses is limited because the paranasal cavities are virtually non-ventilated areas.

Surgery (FESS, functional endonasal sinus surgery) should be seen as a last therapeutic measure and as such all conservative options should be exhausted before it is considered. Well-known and often chosen are nasal rinses with saline solutions and the treatment with aerosols. Conventional aerosols transporting mostly coarse particles are a perfect approach for the treatment of the upper airways whereas an efficient therapy for the virtually non-ventilated paranasal sinuses needs small aerosol particles as well as a non-conventional vibrating aerosol airflow.

Inhalation systems providing a pulsating aerosol have been shown to improve the particle deposition within the paranasal sinuses compared to an inhalation without vibration. Compared to a nasal spray the deposition in the sinus cavities can be 27 fold higher by using a vibrating aerosol administration. A multicentric non-interventional retrospective survey in 81 patients with acute and chronic rhinosinusitis showed that the  well accepted inhalation procedure also may result in symptom relief and in an improvement of the quality of life (QoL) and indicates a possible lowering of the need for oral antibiotics and nasal steroids as well as the decline in sick leave days. It is shown that patients with lower airway diseases may benefit from the treatment as well as patients with upper airway diseases. 


Vibrating aerosols – an approach for acute/chronic rhinosinusitis?
Heribert Mentzel

About 10-15% of the US and EU population have chronic rhinosinusitis (CRS) which leads to an enormous health economic burden. The paranasal cavities are non-ventilated areas. Hence a desirable topical drug delivery e.g. by usual inhalation is not very successful. With an innovative inhalation technology providing a pulsating aerosol a significantly improved particle deposition in the paranasal sinuses – compared to an inhalation which does not present the vibration – has been shown. The patients’ acceptance and the clinical benefits of the treatment have been evaluated. 

A multicentric, non-interventional, retrospective survey including a 2-page-question-naire completed by community ENT-specialists after the pulsating aerosol therapy (PARI SINUS, PARI GmbH, Germany) with saline solution. Therapeutic effects on the main ARS (acute rhinosinusitis) and CRS symptoms and the acceptance of the device and the treatment option were assessed on a 7-point scale from -3 (very negative) to +3 (very positive). 

Data from 81 rhinosinusitis patients (33 ARS patients, 17 female (f), 16 male (m) average age 39.3±18; 48 CRS patients, 29 f, 22 m, average age 49.8±12 receiving the treatment twice daily (mean 2.05±0.92) have been evaluated. The effect on the symptoms was rated +2.27±0.36 for ARS and +1.76±0.43 for CRS patients. The acceptance of the therapy and the handling of the inhalation technique were valued as +2.46±0.95 and +2.27±0.98. An impact on facial pain (ARS +2.17±0.89; CRS +1.55±1.18) was reported as well as a reduction of the post nasal drip (ARS +2.16±0.73; CRS +1.74±0.93). The effect on quality of life (QoL) was graded +2.39±0.84 for ARS and +2.18±0.76 for CRS. The course of the disease was marked +2.48±0.81 (ARS) and +2.05±1.01 (CRS). For ARS patients the therapy led to a reduced need for oral antibiotics rated +1.63±1.31and nasal steroids rated +1.42±1.26. CRS patients also needed fewer oral antibiotics (+1.49±1.06) and nasal steroids (+1.19±1.19). A decrease in sick leave days was reported (ARS+1.70±1.07, CRS +1.26 ±1.23).

Vibrating aerosol inhalation for rhinosinusitis is well accepted by ARS and CRS patients (by reaching 79% of the full marks. Symptom relief, reduction of oral antibiotics and nasal steroids, improvement of QoL and declining sick leave days make this painless and non-invasive treatment an interesting therapy option. For the investigation of the full potential of this treatment option further studies on this topical therapy for ARS and CRS are desirable.


Aztreonam spray-dried powders for inhalation
Hao Ying Li

It is highly attractive to develop inhaled antibiotics for the treatment of lung infections. Among the antibiotics, special attention has been paid to aztreonam (AZT) as it has strong activity against susceptible gram-negative bacteria. AZT-lysine aqueous solution (Cayston®) has been approved by US FDA for inhalation, however, the use of nebulization has drawbacks of low delivery efficiency, risk of cross infections and cumbersome device. In contrast, DPIs offer the advantages of portable device, ease of administration, accurate dose and improved delivery efficiency. In this study, we developed AZT spray-dried (SD) powders for inhalation, and amino acids (AAs) were utilized with the aim to optimize formulations for the improvement of delivery efficiency. AZT spray-drying solution (2 % w/v) was made through fully dissolving AZT (2.0g) in 100 mL of deionised distilled water (ddH2O, with a bit of 1 % of ammonia solution to ensure complete drug dissolution). The AA-AZT spray-drying solutions were prepared through dissolving AZT and a specific AA, including leucine (LEU), arginine (ARG), histine (HIS), lysine (LYS) and glycine (GLY) respectively, at a series of scheduled mass ratios (total mass: 2.0g) in ddH2O. These solutions were subsequently spray-dried (inlet temperature 150 0C, aspiration rate 100 %, airflow rate 550 L/h, pump setting 8 % and the outlet temperature 76 0C) respectively to generate dry powders. The physiochemical properties (e.g. size, morphology, flowability, water content) were subsequently investigated, and the in-vitro aerosolization performance was assessed by a next generation impactor (Aerolizer®, flow rate 60 L/min for 5 s). Clearly, the AZT SD powders showed sphere-like particles with highly wrinkled surface. The inclusion of AAs in the formulations can tremendously change the morphology of SD powders, and these powders can have smooth surface (LYS), ‘golf’ ball shape (ARG and HIS), hollow structure with crumpled façade (LEU), or even large size (GLY). The GLY-modified powders showed a broad size distribution up to 500 μm with a mean size of 144.5 μm in diameter, while all other SD powders showed a unimodal size distribution less then 10 μm with a mean size of ~ 2 μm in diameter, potentially can be inhaled into the lungs. The tapped density (TD) of AZT SD powders was 0.58 g/cm3 and would be generally increased (up to 0.8 g/cm3) for those modified by AAs except LEU that can decrease the TD to only 0.28 g/cm3. In in-vitro aerosolization, all AA-modified SD powders demonstrated a significantly (One-way ANOVA, Duncan’s test, p<0.05) increased emitted dose (ED) over AZT powders and of 98 % (w/w) (LEU) as the highest. More importantly, the SD powders modified by HIS, LEU or LYS showed improved lung deposition with fine particle (< 4.46 μm) fraction up to 65 % w/w, significantly (One-way ANOVA, Duncan’s test, p<0.05) higher than that of AZT powders.


Improvement of pulmonary absorption of poorly absorbable macromolecules by hydroxypropyl-β-cyclodextrin grafted polyethylenimine (HP-β-CD-PEI) in rats
Yang Gao

Effects of hydroxypropyl-β-cyclodextrin grafted polyethylenimine (HP-β-CD-PEI) including HP-β-CD-PEI600, HP-β-CD-PEI1800, HP-β-CD-PEI10000 on the pulmonary absorption of insulin, calcitonin, 5(6)-carboxyfluorescein (CF) and fluorescein isothiocyanate dextrans (FDs) with various molecular weights (FD4, FD10 and FD70) were examined by an pulmonary absorption study in rats. Pulmonary absorptions of these poorly absorbable drugs were significantly enhanced by HP-β-CD-PEI1800 and HP-β-CD-PEI10000, and HP-β-CD-PEI1800 with the concentration of 5% (w/v) provided maximal absorption enhancing effect on pulmonary absorption of these model drugs. The toxicity study demonstrated that HP-β-CD-PEI did not induce any toxic action to rat pulmonary membranes. In addition, zeta potential of insulin solution changed to positive by addition of various HP-β-CD-PEI, meanwhile, the degree of positive charge was linearly correlated with absorption enhancing effect of HP-β-CD-PEI, suggesting that positive charge of HP-β-CD-PEI might be related to their absorption enhancing mechanisms for enhancing pulmonary absorption of insulin in rats. In conclusion, HP-β-CD-PEI is a potential and safe absorption enhancer for improving absorption of hydrophilic macromolecules especially peptide and protein drugs by pulmonary delivery.


Effect of the morphology on aerosol performance and flowability of inhalable particles
Wen Bo Wang

The particle morphology of inhalable dry powders has a significant effect on aerosol performance and flowability. However, exactly how the morphology of dry particles influences aerosol performance has been controversial. In this study, Mannitol was used as a model compound and methylene blue was used as a marker for UV/VIS analysis. Three kinds of inhalable dry powders containing mannitol and methylene blue (19:1 w/w), were prepared using three different spray drying inlet temperatures: 110°C, 130°C and 150°C, respectively. The morphology of the spray-dried mannitol particles was evaluated by using a scanning electron microscope (SEM). The solid state composition of the spray dried powders were characterized using X-ray powder diffraction (XRPD). The aerosol performance and flowability of the three dry powders were investigated by a Next Generation Pharmaceutical Impactor (NGI) and a ring shear tester, respectively. In addition the three spray-dried powders were blended with lactose (Respitose® SV003) as a carrier. The aerosol performance and flowability of the blends were evaluated using the aforementioned techniques.

SEM and XRPD results showed that the surface of the three spray-dried mannitol/methylene blue particles changed from a relatively smooth into more wrinkle with an increase in the inlet temperature from 110 to 150°C, while the three spray-dried powders have similar polymorphic forms, i.e. a mixture of alpha and beta-mannitol. NGI measurements showed that the FPFs of the spherical smooth particles were significantly higher (p < 0.01) than those of the spherical rough particles, while there was no significant difference in ED (P>0.05) among the samples. The similar trend was observed when the spray-dried powders were blended with lactose as a carrier. It suggests reducing surface roughness of spray-dried mannitol/methylene blue particles can significantly improve their respirable fraction. However, the difference in surface roughness of spray-dried particles did not result in a significant difference in the flowability of the spray-dried fine particles as well as when the spray-dried fine particles were composited on the surface of lactose. These results suggested that an increase in the surface roughness of the spray-dried mannitol/methylene blue particles might increase not only the interaction between the fine particles but also the interaction between the fine particles and the carrier. Rugose particles are known to reduce interparticulate forces by small effective diameters of the asperities but can promote mechanical interlocking as the surface irregularities increase, particularly for small particles in interactive mixtures. A higher mechanical interlocking of the rugose spray-dried mannitol/methylene blue particles as compared to their smooth counterparts may explain the NGI results.

In this study, we observed an increase in surface rugosity led to a decrease in the fine particle fraction of spray dried mannitol/methylene powder, while this finding needs to be further justified by other characterizations e.g. surface charge.  All the spray-dried samples were cohesive under the preshear stress of 2000 pa. Different pre-shear stresses will warrant further investigations to see the difference of flowability among three spray-dried samples under other pressures.


Combination of curcumin and silver nanoparticles as hydrogels for treatment of endotracheal tube-associated infections
Ching Yee Loo

Endotracheal intubation is associated with hospital-acquired infections as it is a reservoir for bacterial colonization in lungs, which develops into life-threatening biofilms. In addition, the emergence of bacterial biofilm resistance to multiple antibiotics is becoming a serious clinical concern. Therefore there is a need to develop alternative combination drug therapies that are effective via attacking different mechanisms. Furthermore, to reduce the incidence of bacterial colonisation on the tubes, hydrogel coatings loaded with antimicrobial agents are gaining popularity. Silver nanoparticles (AgNPs) are effective as anti-biofilm agent against both Gram-positive and Gram-negative bacteria. Silver acts simultaneously on various sites within bacterial cells that are important to physiological function. Meanwhile, curcumin, a phenolic plant extract, has displayed natural anti-biofilm properties through the inhibition of bacterial-bacterial communication (quorum sensing) systems. Nano-sized particles of both curcumin and silver could be prevalent owing to longer residence time at the site of infection. In this study, poly(vinyl alcohol)/poly(N-vinyl pyrrolidone) (PVA–PVP) hydrogels containing AgNPs and curcumin nanoparticles (Cur-NPs) were prepared via physical cross-linking techniques (freeze-thaw) to form stable hydrogels with mechanical properties comparable to commercial endotracheal tubes. The morphologies of nanoparticles in PVA-PVP hydrogels were examined using transmission electron microscopy (TEM) whereby no significant aggregation was observed during the freeze and thawing procedures. The average diameter of nanoparticles was maintained as 30 nm. Fourier transform infrared (FTIR) analysis demonstrated that both AgNPs and CurNPs interacted with the –OH groups of PVA-PVP probably due to the formation of intermolecular hydrogen bonds. The hydrogels containing combination of AgNPs and CurNPs displayed excellent bactericidal activities and simultaneously inhibited totally the attachment of Pseudomonas aeruginosa PAO1 and Staphlococcus aureus. In contrast, hydrogels containing either AgNPs or Cur-NPs alone were only effective against P. aeruginosa or S. aureus, respectively. In addition, the cytotoxicity assay of the hydrogels against human normal bronchial epithelial (BEAS2B) cells demonstrated that these materials were non-toxic.



How critical quality attributes and process variables drive the in-vitro performance of pMDIs: new technologies and methods
Ben Okorodudu

Few published sources exist to help guide pressurized metered dose inhaler (“pMDI”) formulation and device development, which incorporate an understanding of the complex relationships that drive product performance. Current analytical methods are complicated and labor intensive, and provide little insight into commonly occurring defects in pMDIs or their performance during development and release testing. The measurement technologies and analysis techniques described in this paper rapidly promote a knowledge-driven understanding of the complex relationships between the critical quality attributes and process variables that drive pMDI in vitro performance. This paper will examine the importance of shaking, the connection between dose content uniformity (“DCU”) and spray pattern using predictive models, and rapid screening for actuator mold defects to aid in aerodynamic particle size distribution (“APSD”) testing.

Using commercially available albuterol sulfate pMDI samples, a Design of Experiments (“DoE”) approach was employed to determine the effects of device shaking (duration, angle, and frequency) on spray pattern and DCU performance.  These experiments were conducted with the SprayVIEW® Measurement System SFpMDI (Proveris Scientific, Marlborough, MA U.S.A.) and the data was collected in a systematic manner to simplify the determination of statistical correlations between the output results. Additionally, through precise alignment of the device, the center of gravity (“COG”) coordinates of each collected spray pattern were used to rapidly screen various actuator molds for defects.

Using predictive modeling, the data indicates that shake duration was the driving parameter for product performance.  An optimal shaking regime was readily determined and was used to show significant correlation between DCU and spray pattern through-life testing for the product samples. The data also indicates that defective actuator molds produce skewed spray angle positions (as indicated by the spray pattern COG), which is manifested by drug deposition build up on the interior surfaces of the actuator mouthpiece.

Shaking effects pMDI performance in through-life testing. Optimal shaking parameters provide a strong connection between DCU and spray pattern. The new COG rapid screening method can eliminate defective actuator molds from being used during APSD testing, which can lead to more consistent results.


Effect of relative humidity conditions on the flowability and dispersion behavior of different lactose blends
Lan Chen

It has been an active research area of investigating the effect of moisture uptake on the flowability of dry powders and the relationship between powder flowability and their dispersion behavior. The model powders of Dry powder inhaler (DPI) used in the present study were the blends of carrier lactose Inhalac®120 (D50=128μm) and fine lactose Inhalac®400 (D50=8μm) (Meggle Pharma, Wasserburg, Germany) with different fine lactose ratios of 0, 5, 10 and 20%, respectively. The flow and dispersion properties were investigated after storage at relative humidity (RH) conditions of 0±5, 30±5, 58±5, 85±5%, respectively, at 25±2℃ for 48 hours. 

The powder flowability was characterized in dynamic, bulk and shear modes by FT4 powder rheometer (Freeman Technology, Tewkesbury, UK). Information of permeability, basic flow energy (BFE), cohesion and unconfined yield stress (UYS) were obtained. The dispersion measurements of different powder blends aerosolized from a home-made inhaler were carried out in Spraytec laser diffraction system (Malvern Instruments Ltd., UK) at the airflow rate of 60 L/min.

According to FT4 measurement results, the permeability of pure carrier lactose (0%) was similar at the four RH storage conditions. With the increasing fine lactose ratio, the permeability of powders was getting worse even under the same RH storage condition. The permeability of 20% fine lactose powder mixture became better after 85% RH or 0% RH storage treatment. After the high humid (85% RH) storage treatment, all the dry powder models showed significant differences (p<0.05) in BFE, UYS and cohesion. The highest humid treated samples exhibited the lowest BFE and UYS, highest cohesion and worst flow property.

The dispersion results showed that under the same RH condition, 20% fine content powders had the highest fine particle proportion and smallest D50 .With the same ratio of fine lactose, 58% RH treated lactose powders had the best dispersion performance.

The dispersion behavior of 20% fine lactose blends at 58% RH condition was relatively better, but the permeability, BFE, UYS and cohesion of the powders showed no significant differences.  No obvious correlation between flowability and dispersion property was found in the experimental range of this study.


Mucoadhesive microspheres for inhalation and sustained release of salbutamol sulphate
Dong Mei Cun

Pulmonary administration by inhalation is a preferred way of delivering the medication to treat lung restricted diseases such as asthma and COPD, since it could potentially provide direct access to the targeted tissue, high local concentration and relatively low systemic exposure. While the existence of many highly efficient clearance mechanisms in lung give a very short time for drug action of inhaled substances in the target site. Mucoadhesive particulate drug delivery is gaining increasing attention for their capacity of prolonging residence time in mucosal tissue via interaction with mucus and providing the possibility of manipulating the release rate of the payload. Hyaluronic acid is a component of synovial fluid and extracellular matrices and possesses excellent bioadhesive feature by anchoring the associated protein and enzymes of mucus, which could delay the mucociliary escalaton in lung. Salbutamol sulphate, an effective bronchodilator, has a short biological half-life (4.5h) and multiple daily doses are always needed to achieve clinical effects. Therefore, by encapsulating SAS into inhalable HA microspheres with excellent aerodynamic properties, the considerable portion of SAS might deposit in lung and high local SAS concentration might be maintained for a prolonged period by virtue of the mucoadhesive property of HA. The purpose of this study was to manufacture SAS loaded HA microspheres suitable for pulmonary drug delivery by using spray drying (SD) technique. The resulted dry powder was comprehensively evaluated in terms of physicochemical properties and aerodynamic performance. The capability of HA microsphere to cling to lung mucosa and slow down the release of SAS was also evaluated with the modified falling liquid film method and in-vitro release study respectively. The optimized microspheres were shown to have MMAD around 4.2μm diameter, which is suitable for pulmonary drug delivery , and spherical morphology of microspheres with the surfaces covered with wrinkles. The content of SAS in HA microspheres were about 22%. The in-vitro drug deposition study showed that the powder displayed excellent aerodynamic characteristics with smaller MMAD (~4.2μm) and higher FPF value (~33%). In addition, the powder showed an obvious a sustained release effect within 20 h and possessed good mucoadhesive ability.


A novel in-vitro dissolution devices for orally inhaled drug products
William Wu

In-vitro dissolution testing of inhaled products is a relatively new area of pharmaceutical science which has received increasing attention in recent years. However, until now, there is no standardized dissolution test method has been approved by any regulatory authorities for orally inhaled products (OIPs). The objectives of this study were to develop a novel in-vitro dissolution testing device to determine the dissolution kinetics for different inhaled corticosteroids (ICS). Different sizes of filter holders are designed to analyze glass fiber filter samples from the following apparatus: 1. MDI DUSA, 2. DPI DUSA, 3. Next Generation Impactor (NGI) dissolution cup, 4. Fast Screening Impactor (FSI). Factors affecting dissolution test results were investigated to develop an optimal test procedure for the use of these holders. For the most hydrophilic drugs among the ICS we tested, Ciclesonide, the kinetics was first-order, reaching ≥90 % dissolution in 5 h. On the other hand, for the least hydrophilic fluticasone propionate (FP), reaching only 50 % dissolution in 5 h. The dissolution rate of several FP HFA MDI commercial products has also been tested. Differences in initial rate was observed between these FP products. Same observations were also seen between different sample collection method, such as FSI and MDI DUSA. We believe it is due to different source of active, particle size distribution (PSD) and formulation or any combination thereof. The dissolution kinetics overall conformed to the rank order of the aqueous solubility, while also being affected by ICS aerosol’s mass, size, formulation and dosage forms. The three kinds of filter holders have been developed that enables the dissolution testing of inhaled actives and that can differentiate different solubility characteristics of OIPs sensitively. The dissolution profiles of difference source FP were successfully estimated by analyzing the amount of drug released from the membrane holder. Advantages of the devices are easy-operated, low variability and can be used for a variety of commercial inhalation analysis apparatus. It is foreseen that dissolution method may be applied to evaluate the pharmacokinetics between test and reference product or even quality control studies for various inhalation products in the future.


Critical factors in the design of valved holding chambers for use with pMDIs
John N. Pritchard

Propellant based metered-dose inhalers (pMDIs) are a relatively cheap and convenient way of delivering most classes of medication to treat respiratory diseases. However, some patients (notably the very young and old) struggle to coordinate the actuation of the pMDI with the start of inhalation. Furthermore, inhaled corticosteroids can give rise to candidiasis in the throat due to local drug deposition. Both issues can be overcome by the use of a valved holding chamber (VHC) to capture the pMDI spray and allow for the drug to be inhaled over a couple of breaths. However, VHCs are not widely used in China due to concerns over cost and performance. In order to be successful, a VHC must deliver a respirable dose equivalent to that of a pMDI being used correctly by a patient. There are a number of key design considerations to achieve this outcome: A) Size and shape: There may be a delay between actuation and inhalation, so the overall design should minimize the impact of this. Modern VHCs, such as the OptiChamber Diamond (OCD), lose <20% of emitted dose for delays up to 10 s. B) Volume: A large volume (750 mL) VHC will require multiple breaths to access all of the available drug, whereas small volume (<250 mL) VHCs will require fewer breaths, such that a 5-year-old may get a complete dose from the OCD in a single breath. C) Static: Early designs used plastic construction materials that were prone to build up of electrostatic charge on the walls, which enhances wall losses. Modern designs use materials that eliminate this problem; e.g. at 15 L/min inhalation, the AeroChamber Plus delivers 28% fewer salbutamol particles below 5 m compared with the non-static OCD. D) Valve: In order not to lose drug from within the chamber, exhaled air should not pass back into it. A low resistance one-way valve, with minimal drug deposition thereon, is required. E) Flow indication: It may not be obvious that a young child is actively breathing through the device, so a flow indicator can provide reassurance. High inspiratory flow enhances deposition in the throat, which can be avoided by use of an audible warning. F) Mask: Where required, a mask should provide an excellent fit, with an effective seal, using the smallest amount of applied force; the OCD facemask system delivers in excess of 50% of the delivered dose with only 1.9 kg of applied force to the seal. G) Ease of use: Other ergonomic considerations are also important, such as insertion of the pMDI, and ease of assembly and disassembly for cleaning.


Advances in nebuliser design
John N. Pritchard

Respiratory diseases are on the increase in China, notably COPD, which is estimated to affect over 8% of the over-60-year-old Chinese population, whilst asthma affects nearly 4% of Chinese children. Nebulisers are frequently used with very young, old or sick patients and represent a common form of hospital out-patient treatment in China. Nebulised drug sales have the largest market share of asthma and COPD treatment in China. This is because patients in China perceive nebulisers as more effective than inhalers, even though the monthly cost of treatment is higher. Budesonide accounts for 75% of nebulised drug sales. However, inhaled corticosteroids are intended for preventative use, which is not practical to administer on a daily basis in an out-patient setting, so having a nebuliser suited to home use is important. Traditionally, this is provided by jet nebulisers powered by a compressor. However, there is now a new generation of battery operated mesh-type nebulisers that, in contrast, are portable and silent, and impose a lower overall treatment burden (preparation and treatment time) than conventional jet nebulisers, thereby encouraging better adherence to the medication regime. Control of respirable dose and robustness of the mesh is achieved through careful monitoring of the mesh production process. Crucially, mesh nebulisers operate differently to traditional ultrasonic nebulisers and, in contrast, are able to deliver suspension formulations such as budesonide efficiently. For example, under a CEN breathing pattern, an Aeroneb Go (mesh) delivers over 40 g fine particle dose (<5 m) from 2 mL of budesonide (0.5 mg/mL) in <3 minutes, compared to 7 g from a Schill ultrasonic nebuliser. Because such devices are electronic in nature, it is easy to add features such as breath-activation. This avoids the drug wastage that occurs from a continuous nebuliser during exhalation. Providing feedback to the patient also enables breathing patterns to be optimised, so lung deposition of over 70% is achieved. In consequence, greater efficiency means that only 0.5 mL or less formulation needs to be nebulised, thereby significantly shortening treatment times. Efficiency may be particularly important in the development of new drugs for nebulisation, which may be costly to produce, especially in the early stages of development. Thus, an innovative breath-actuated small volume aerosol device (<300 µL) will also be described, which is now available for drug development studies. It gives precise delivery of a high fine particle fraction mist in only a few breaths, with retained drug less than 10% of the filled volume. Lung deposition also exceeds 70% of the nominal dose. Using a state-of-the-art nebuliser will become increasingly important as regulatory authorities expect the new drug only to be promoted with nebulisers for which the developer has clinical experience. 


Pulmonary retention of Yuxingcao essential oil after intratracheal administration to rats
Yun Zhao

Yuxingcao (Houttuynia cordata) injection was one of the top selling TCM injections for the treatment of pulmonary infections in clinics before its withdrawal in 2006 due to the occurrence of fatal adverse reactions. Many clinicians still believe that the unique therapeutic benefits of Yuxingcao injections cannot be fully replaced by currently available medicine and hence, an alternative to the injection is highly desirable. Interestingly, the extensive off-label uses of the injection have demonstrated that nebulized Yuxingcao achieves comparable efficacy without eliciting side effects. The objective of the present study was to investigate the pulmonary retention of the Yuxingcao essential oil after intratracheal administration to rats with also a view to increasing the lung retention by encapsulating the oil into solid lipid nanoparticles (SLN). 

The Yuxingcao essential oil loaded SLN were prepared with glyceryl behenate as the lipid material. TIn vitro drug release was performed using the dialysis bag method with 0.05% SDS as the medium. To test the in vivo lung retention, rats were divided into 5 groups, each of which was given an intratracheal (IT) dose of SLN-200, SLN-400, SLN-800 aqueous suspensions or the essential oil solution solubilized by Tween 80, or an intravenous (IV) dose of the essential oil solution. IT administration was given at a dose of 1 mg/kg essential oil at a concentration of 1 mg/ml whereas IV at a dose of 10 mg/kg. Three rats were sacrificed at each predetermined time point and the lung tissues were collected for analysis. The content of essential oil in the lung tissues were determined by detection of 2-Undecanone, the main ingredient of the essential oil, using a gas chromatography (GC) method. 

Three SLN with particle size of 171.2±12.9 nm (SLN-200), 412.2±19.0 nm (SLN-400) and 811.9±18.6 nm (SLN-800) were prepared. The Zeta potentials of SLN were about -18eV, EE greater than 75% and drug-loading capacity between 2.5% and 3.4%. The in vitro release profile showed that the three SLN had good sustained release characteristics independent of particle size, compared with Tween 80 solution. Compared to IV dosed Tween 80 solution, IT administration increased the AUC by 6-fold whereas upon encapsulation into SLN, the AUC were increased by 26-fold, 36-fold and 44-fold for SLN-200, SLN-400 and SLN-800, respectively. In addition, SLN with different particle size all showed superior sustained release properties to Tween 80 solution, achieving a therapeutic level of 2-Undecanone up to 24 h. Inhalation delivery of Yuxingcao essential oil markedly improved the local bioavailability as compared to IV administration and SLN loaded essential oil could further prolong the residence time and increase the local bioavailability.


Key indicators to predict dosing performance of lactose-based powders for inhalation
Xiao Long Chen

Precise dosing of powders for inhalation remains a challenging task for pharmaceutical formulators in development and production. In commonly used adhesive mixtures of lactose monohydrate and API, the coarse lactose carrier content usually improves the powder flow and hence facilitates dosing. However many formulations additionally contain micronized carrier particles to improve the fine particle fraction delivered by the device. This may deteriorate powder flow and thus dosing accuracy. Several dosing methods are used for industrial filling of dry powder inhalers (DPIs): Reservoir-based inhalers containing 200 mg to > 1 g of powder are filled using screw augers, whereas pre-metered DPIs containing 1 mg to approx. 25 mg of powder per dose unit can be filled using vacuum drum systems, dosator or specially dedicated equipment. In the course of product development it is desirable to know at an early state which dosing system and what settings will be most appropriate to dose the given formulation and to find key powder parameters which are suitable to predict the dosing performance of DPI formulations. In order to address this question model blends of lactose monohydrate carriers with 3 different median particle sizes (InhaLac® 70, 120, 250) were prepared. Each carrier type was blended with 0%, 5% and 20% of micronized lactose (InhaLac® 400), respectively. Pharmacopoeial and dynamic powder testing methods were used to characterize the pure lactose grades and their blends. Subsequently the pure lactose grades as well as their mixtures were dosed on two different systems (screw auger and vacuum drum system). Key powder parameters correlating with their dosing performance could be found by using FT4 powder rheometer (Freeman Technology Ltd., UK). For the screw auger system reproducible dosing with fill weights between 230 and 285 mg could be achieved with BFE values ≥ 15.5 mJ/g and AE values≥ 5.5 mJ/g whereas the vacuum drum dosing system with fill weights in the range of 2.7 to 4.0 mg (the variance even below 1.5 % RSD) required powders with BFE values < 15.5 mJ/g and AE values < 5.5 mJ/g.


Effects of leucine on the in vitro stability and aerosol performance of polymeric micelles
Fei Fei Yang

The application of polymeric micelles to pulmonary drug delivery is limited due to the poor physical stability of polymeric micelles in aqueous dispersion in vitro and in biomatrices in vivo. The aim of the present study is to improve the stability of polymeric micelles by adding leucine to the carrier. The stabilizing effect of leucine was evaluated by determining the enzymatical stability of encapsulated curcumin acetate (CA). A further aim of this study was to investigate the effect of leucine on the aerosol performance of nebulized solution or spray-dried particles of polymeric micelle in presence of leucine.

CA was loaded into mPEG2000-PLGA5000 micelles in the presence of leucine (1% of the polymer) by solvent evaporation. CA acetonitrile solution and the micelles with or without the presence of leucine were added to water and PBS buffer (pH 7.4) and incubated at 40°C with continuous magnetic stirring protected from light. At predetermined time intervals, aliquots of 200 μl incubated media were withdrawn, and 200 μl acetonitrile with aloe-emodin were added to the plasma sample to quench the esterase activity. The samples were vortexed and centrifuged, and the supernatant was subjected to HPLC analysis. Finally, the leucine containing micelles were prepared as a DPI after spray-drying or a formulation for nebulization after freeze-drying, followed by aerodynamic characterization using an NGI or a Spraytec.

The micelles with or without the addition of leucine exhibited hydrodynamic particle size of ~28nm and excellent encapsulation efficiency. The presence of leucine in the micelles provided not only better stabilization of CA but also more sustained release as compared to the leucine free controls in vitro.  The presence of leucine resulted in a significantly high yields during spray-drying and the use of spray-dried particles in a Cyclohaler DPI provided a fine particle fraction of 55%, whereas the reconstituted solutions of lyophilized micelles were readily nebulized to give an average median droplet diameter of 3.2 μm. The particle size, encapsulation efficiency and in vitro release profiles of the polymeric micelles in the presence of leucine was not affected after spray-drying, freeze-drying and aerosolization from either DPI or nebulization

This study demonstrates that the presence of leucine in mPEG-PLGA micelles can not only facilitate pulmonary delivery of the carrier, but also increase the stability during preparation and aerosolization. 

Acknowledgments: This work was supported by the PUMC Youth Fund (No.: 33320140077) from the Fundamental Research Funds for the Central Universities grants of the People’s Republic of China.


Inhalable non-steroidal anti-inflammatory drug for quick pain relief
Dong Hao Chen

Analgesia represents a large medical market for which further improvements in treatment are necessary. It is well established that acute and breakthrough pain can be better managed with pharmaceuticals when drug levels are achieved as rapidly as possible after the symptoms begin to emerge. However most, if not all, current available drug delivery methods can not offer such fast onsite pain relief. The aim of this study is to investigate the application of a light particle based inhalable drug delivery system on quick pain relief in established animal model. One FDA approved Non-Steroidal Anti-Inflammatory Drug (NSAID), ketoprofen, was chosen and formulated into light and micron-sized particles with demonstrated novel air dynamic properties by using novel two-solvent spray dry process, and then applied to rat model of acute pain (hot-plate). It is found that pulmonary delivery produced a rapid elevation in plasma levels of ketoprofen.  Peak levels were seen at the earliest time point examined (5 minutes).  Then decreased markedly over the next 120 minutes and remained stable thereafter.  Relative to oral administration of the same dose of ketoprofen, pulmonary delivery produced significantly higher plasma concentrations at all time points from 5 to 60 minutes post drug administration (p < 0.01).  With the exception of the 6 hour time point (where pulmonary delivery also produced modestly higher, but statistically significant, plasma levels of ketoprofen; p < 0.05), no differences between the two routes of administration existed beyond 1 hour.  Bioavailability was estimated with AUC calculations.  The AUC over the entire time course for oral ketoprofen was 11.1 and for pulmonary ketoprofen was 19.9. This line of study suggested that pulmonary delivery of proper formulated ketoprofen can be an effective way of providing ‘on demand’ pharmaceutical therapy for pain.


Bioavailability comparison of intranasally administered dexmedetomidine via atomization and dripping in healthy adults
Philip Kwok

Dexmedetomidine is an alpha agonist indicated for sedation. Intranasal administration of dexmedetomidine has been shown to be effective on adults and children. In our study, a three-period crossover double-blinded clinical study with eight healthy adult subjects was conducted. The subjects received Precedex®, which consisted of dexmedetomidine hydrochloride in 0.9% w/v sodium chloride with 100 μg/mL dexmedetomidine, by intravenous infusion, intranasal dripping, or intranasal atomization in three separate sessions. A Mucosal Atomization Device (MAD®; LMA, San Diego, California, USA) was used for the two types of intranasal administrations. In each session, blood samples were taken at predetermined time points up to eight hours after dosing, and a bioanalytical method utilizing HPLC-MS/MS was developed to determine the plasma concentration of dexmedetomidine. The results showed that the maximum plasma concentrations of 271±147 and 237±82 pg/mL were reached after 1.25±0.69 and 1.34±0.48 hours after intranasal atomization and intranasal dripping, respectively. The bioavailabilities after intranasal atomization and intranasal dripping were 52±22.6% and 58.6±35.9%, respectively (p>0.05). Therefore, intranasal atomization and dripping were comparable administration methods.


Comparison of solid state properties of co-spray dried budesonide and formoterol using 2- and 3-fluid nozzle
Wen Bo Wang

A spray drying process equipped with a 2-fluid nozzle has been used for the co-spray drying of combination preparations. Compared to the commonly used 2-fluid nozzle (2-N, i.e. with one liquid and one gas channel), a 3-fluid nozzle (3-N) is relatively new. The 3-N has a unique, three-layered concentric structure consisting of inner and outer liquid passages and an outermost gas passage. The two liquid passages could be used to feed two different liquid formulations into the drying chamber to mix with the drying gas induced by the outermost passage. Two/three drug solutions could be co-spray-dried in a one-step, continuous manufacturing manner.  The objective of this project is to explore the potential of the spray drying process equipped with a 3-fluid nozzle for designing inhalable combinational medicines. The focus of the current study is to compare solid state properties of inhalable combinational medicines produced via a 2-N and 3-N spray drying.

In the present study, budesonide (BUD) and formoterol (FOR) are used as model drug combination of corticosteroid and long-acting b2 agonist, respectively, and processed using a spray-dryer equipped with a 2-N or a 3-N to obtain dry inhalable combinational formulation. The morphology and solid state of the spray-dried powder were characterized.

Using the same spray drying process parameters (e.g. inlet temperature, feed rate, drying gas flow rate, spray flow rate and feed concentration), the yield of the dry powder from either 2-N or 3-N spray drying are comparable. The X-ray powder diffraction results indicated that the raw material of BUD and FOR were crystalline. Using a 2-N spray dryer BUD, FOR and the mixture of BUD and FOR were spray-dried into amorphous particles. Whereas using a 3-N spray dryer BUD, FOR, and the mixtures of BUD and FOR were spray-dried into crystalline particles. A preliminary stability study showed that the samples produced by using 2-N spray drying remained amorphous for three months under 25 ºC and 10% RH. Using a scanning electron microscopy, similar shapes of the dry particles were observed with 2-N or 3-N spray dried particles, whereas, the 3-N spray-dried particles exhibited rougher surfaces. HPLC quantification showed that after 3-N spray drying, the ratio of BUD / FOR in the dry powder were in consistent with that in the starting feed solution.

In summary, 3-N spray drying can be used to produce inhalable combination formulations. 3-N spray drying produced crystalline materials for BUD and FOR, unlike 2-N spray drying that yielded amorphous particles. The 3-N spray drying may be superior to 2-N spray drying to design inhalable combinational formulations in terms of solid state stability of dry powder.


The orbital DPI device: a dial-up ultra-high dose inhaler
Evangelia Daviskas

Dry powder inhalers (DPI) have been developed over the past 30 years for the treatment of various respiratory diseases. The majority of DPIs have been optimised to deliver very small quantities of drug (<400 ug), for the treatment of a variety of lung disease. While these devices are suited to deliver low dose molecules, such as β2-agonists and corticosteroids, they lack the capacity to deliver higher dose medicaments such as antibiotics or mucolytics. One of the rate limiting steps for high dose inhalation therapy is the device itself. In the passive DPI devices field, there is still nothing commercially available to meet these dose requirements; although devices such as the Twincer® may be capable of reaching the low end (ca. 50 mg) of these dose regimes. Here, the authors present a new approach to delivering high dose inhalation medicines via a passive (breath-actuated), pre-metered multi-inhalation dry powder device (Orbital®). This new device allows the administration of high drug doses, up to 400 mg, with multiple inhalation maneuvers using a single use, disposable unit containing a ‘puck’ that holds the drug powder. To assess the Orbital performance, different drug particulate systems have been engineered and studied. These include spray dried mannitol and ciprofloxacin representing treatments for CF and infection, respectively. Dose ranging from 100-400 mg have been tested in the device using a combination of multi stage liquid Impinger (MSLI) and inline laser diffraction methodologies. Multiple breaths were simulated by applying multiple 4s 60 L/min flow steps. After testing of each inhalation powder with the device, the Orbital was disassembled and the puck and orbital components washed separately for HPLC analysis; along with the MSLI stages and induction port. In general it was found that the orbital could produce high FPFs (>40%) for a number of drugs over multiple breaths. This allows for the delivery of ultra-high doses to the lungs for treatment of diseases such as CF, COPD and infection. Furthermore the aerosol performance of powders emitted from the Orbital during each ‘breath’ remained constant until the puck was empty. Ultimately, this approach will lead to improved ease of use, better patient compliance and open up the possibilities of delivering a wide range of ultra-high dose medicaments that are currently not available for inhalation.