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1.  Effect of Inhaler Design Variables on Paediatric Use of Dry Powder Inhalers 
PLoS ONE  2014;9(6):e99304.
Age appropriateness is a major concern of pulmonary delivery devices, in particular of dry powder inhalers (DPIs), since their performance strongly depends on the inspiratory flow manoeuvre of the patient. Previous research on the use of DPIs by children focused mostly on specific DPIs or single inspiratory parameters. In this study, we investigated the requirements for a paediatric DPI more broadly using an instrumented test inhaler. Our primary aim was to assess the impact of airflow resistance on children’s inspiratory flow profiles. Additionally, we investigated children’s preferences for airflow resistance and mouthpiece design and how these relate to what may be most suitable for them. We tested 98 children (aged 4.7–12.6 years), of whom 91 were able to perform one or more correct inhalations through the test inhaler. We recorded flow profiles at five airflow resistances ranging from 0.025 to 0.055 kPa0.5.min.L−1 and computed various inspiratory flow parameters from these recordings. A sinuscope was used to observe any obstructions in the oral cavity during inhalation. 256 flow profiles were included for analysis. We found that both airflow resistance and the children’s characteristics affect the inspiratory parameters. Our data suggest that a medium-high resistance is both suitable for and well appreciated by children aged 5–12 years. High incidences (up to 90%) of obstructions were found, which may restrict the use of DPIs by children. However, an oblong mouthpiece that was preferred the most appeared to positively affect the passageway through the oral cavity. To accommodate children from the age of 5 years onwards, a DPI should deliver a sufficiently high fine particle dose within an inhaled volume of 0.5 L and at a peak inspiratory flow rate of 25–40 L.min−1. We recommend taking these requirements into account for future paediatric inhaler development.
doi:10.1371/journal.pone.0099304
PMCID: PMC4047113  PMID: 24901338
2.  Stability of Lysozyme in Aqueous Extremolyte Solutions during Heat Shock and Accelerated Thermal Conditions 
PLoS ONE  2014;9(1):e86244.
The purpose of this study was to investigate the stability of lysozyme in aqueous solutions in the presence of various extremolytes (betaine, hydroxyectoine, trehalose, ectoine, and firoin) under different stress conditions. The stability of lysozyme was determined by Nile red Fluorescence Spectroscopy and a bioactivity assay. During heat shock (10 min at 70°C), betaine, trehalose, ectoin and firoin protected lysozyme against inactivation while hydroxyectoine, did not have a significant effect. During accelerated thermal conditions (4 weeks at 55°C), firoin also acted as a stabilizer. In contrast, betaine, hydroxyectoine, trehalose and ectoine destabilized lysozyme under this condition. These findings surprisingly indicate that some extremolytes can stabilize a protein under certain stress conditions but destabilize the same protein under other stress conditions. Therefore it is suggested that for the screening extremolytes to be used for protein stabilization, an appropriate storage conditions should also be taken into account.
doi:10.1371/journal.pone.0086244
PMCID: PMC3900503  PMID: 24465983
3.  Correction: Mixing Time Effects on the Dispersion Performance of Adhesive Mixtures for Inhalation 
PLoS ONE  2013;8(12):10.1371/annotation/7302762a-a6fe-4fcd-8656-36d8b7c259a5.
doi:10.1371/annotation/7302762a-a6fe-4fcd-8656-36d8b7c259a5
PMCID: PMC3878871
4.  Quantitative Characterization of Agglomerate Abrasion in a Tumbling Blender by Using the Stokes Number Approach 
AAPS PharmSciTech  2012;14(1):183-188.
Removal of microcrystalline cellulose agglomerates in a dry-mixing system (lactose, 100 M) predominantly occurs via abrasion. The agglomerate abrasion rate potential is estimated by the Stokes abrasion (StAbr) number of the system. The StAbr number equals the ratio between the kinetic energy density of the moving powder bed and the work of fracture of the agglomerate. Basically, the StAbr number concept describes the blending condition of the dry-mixing system. The concept has been applied to investigate the relevance of process parameters on agglomerate abrasion in tumbling blenders. Here, process parameters such as blender rotational speed and relative fill volumes were investigated. In this study, the StAbr approach revealed a transition point between abrasion rate behaviors. Below this transition point, a blending condition exists where agglomerate abrasion is dominated by the kinetic energy density of the powder blend. Above this transition point, a blending condition exists where agglomerates show (undesirable) slow abrasion rates. In this situation, the blending condition is mainly determined by the high fill volume of the filler.
doi:10.1208/s12249-012-9909-x
PMCID: PMC3581662  PMID: 23250711
agglomerates; dry-mixing; stokes; tumbling blender
5.  A User-Friendly Model for Spray Drying to Aid Pharmaceutical Product Development 
PLoS ONE  2013;8(9):e74403.
The aim of this study was to develop a user-friendly model for spray drying that can aid in the development of a pharmaceutical product, by shifting from a trial-and-error towards a quality-by-design approach. To achieve this, a spray dryer model was developed in commercial and open source spreadsheet software. The output of the model was first fitted to the experimental output of a Büchi B-290 spray dryer and subsequently validated. The predicted outlet temperatures of the spray dryer model matched the experimental values very well over the entire range of spray dryer settings that were tested. Finally, the model was applied to produce glassy sugars by spray drying, an often used excipient in formulations of biopharmaceuticals. For the production of glassy sugars, the model was extended to predict the relative humidity at the outlet, which is not measured in the spray dryer by default. This extended model was then successfully used to predict whether specific settings were suitable for producing glassy trehalose and inulin by spray drying. In conclusion, a spray dryer model was developed that is able to predict the output parameters of the spray drying process. The model can aid the development of spray dried pharmaceutical products by shifting from a trial-and-error towards a quality-by-design approach.
doi:10.1371/journal.pone.0074403
PMCID: PMC3767666  PMID: 24040240
6.  Drug Content Effects on the Dispersion Performance of Adhesive Mixtures for Inhalation 
PLoS ONE  2013;8(8):e71339.
The drug content in adhesive mixtures for inhalation is known to influence their dispersion performance, but the direction and magnitude of this influence depends on other variables. In the past decades several mechanisms have been postulated to explain this finding and a number of possible interacting variables have been identified. Still, the role of drug content in the formulation of adhesive mixtures for inhalation, which includes its significance as an interacting variable to other parameters, is poorly understood. Therefore, the results from a series of drug detachment experiments are presented in which the effect of drug content and its dependence on flow rate, the mixing time and the type of drug is studied. Furthermore, it is investigated whether the effect depends on the range within which the drug content is changed. Quantitative and qualitative multiple order interactions are observed between these variables, which may be explained by a shifting balance between three different mechanisms. The results therefore demonstrate that accounting for (multiple order) interactions between variables has to be part of quality by design activities and the rational design of future experiments.
doi:10.1371/journal.pone.0071339
PMCID: PMC3743805  PMID: 23967195
7.  Mixing Time Effects on the Dispersion Performance of Adhesive Mixtures for Inhalation 
PLoS ONE  2013;8(7):e69263.
This paper deals with the effects of mixing time on the homogeneity and dispersion performance of adhesive mixtures for inhalation. Interactions between these effects and the carrier size fraction, the type of drug and the inhalation flow rate were studied. Furthermore, it was examined whether or not changes in the dispersion performance as a result of prolonged mixing can be explained with a balance of three processes that occur during mixing, knowing drug redistribution over the lactose carrier; (de-) agglomeration of the drug (and fine lactose) particles; and compression of the drug particles onto the carrier surface. For this purpose, mixtures containing salmeterol xinafoate or fluticasone propionate were mixed for different periods of time with a fine or coarse crystalline lactose carrier in a Turbula mixer. Drug detachment experiments were performed using a classifier based inhaler at different flow rates. Scanning electron microscopy and laser diffraction techniques were used to measure drug distribution and agglomeration, whereas changes in the apparent solubility were measured as a means to monitor the degree of mechanical stress imparted on the drug particles. No clear trend between mixing time and content uniformity was observed. Quantitative and qualitative interactions between the effect of mixing time on drug detachment and the type of drug, the carrier size fraction and the flow rate were measured, which could be explained with the three processes mentioned. Generally, prolonged mixing caused drug detachment to decrease, with the strongest decline occurring in the first 120 minutes of mixing. For the most cohesive drug (salmeterol) and the coarse carrier, agglomerate formation seemed to dominate the overall effect of mixing time at a low inhalation flow rate, causing drug detachment to increase with prolonged mixing. The optimal mixing time will thus depend on the formulation purpose and the choice for other, interacting variables.
doi:10.1371/journal.pone.0069263
PMCID: PMC3699552  PMID: 23844256
8.  The Stokes Number Approach to Support Scale-Up and Technology Transfer of a Mixing Process 
AAPS PharmSciTech  2012;13(3):928-933.
Transferring processes between different scales and types of mixers is a common operation in industry. Challenges within this operation include the existence of considerable differences in blending conditions between mixer scales and types. Obtaining the correct blending conditions is crucial for the ability to break up agglomerates in order to achieve the desired blend uniformity. Agglomerate break up is often an abrasion process. In this study, the abrasion rate potential of agglomerates is described by the Stokes abrasion (StAbr) number of the system. The StAbr number equals the ratio between the kinetic energy density of the moving powder bed and the work of fracture of the agglomerate. In this study, the StAbr approach demonstrates to be a useful tool to predict the abrasion of agglomerates during blending when technology is transferred between mixer scales/types. Applying the StAbr approach revealed a transition point between parameters that determined agglomerate abrasion. This study gave evidence that (1) below this transition point, agglomerate abrasion is determined by a combination of impeller effects and by the kinetic energy density of the powder blend, whereas (2) above this transition point, agglomerate abrasion is mainly determined by the kinetic energy density of the powder blend.
doi:10.1208/s12249-012-9818-z
PMCID: PMC3429663  PMID: 22733375
dry mixing; scale-up; stokes number
9.  CLSM as Quantitative Method to Determine the Size of Drug Crystals in a Solid Dispersion 
Pharmaceutical Research  2011;28(10):2567-2574.
ABSTRACT
Purpose
To test whether confocal laser scanning microscopy (CLSM) can be used as an analytical tool to determine the drug crystal size in a powder mixture or a crystalline solid dispersion.
Methods
Crystals of the autofluorescent drug dipyridamole were incorporated in a matrix of crystalline mannitol by physical mixing or freeze-drying. Laser diffraction analysis and dissolution testing were used to validate the particle size that was found by CLSM.
Results
The particle size of the pure drug as determined by laser diffraction and CLSM were similar (D50 of approximately 22 μm). CLSM showed that the dipyridamole crystals in the crystalline dispersion obtained by freeze-drying of less concentrated solutions were of sub-micron size (0.7 μm), whereas the crystals obtained by freeze-drying of more concentrated solutions were larger (1.3 μm). This trend in drug crystal size was in agreement with the dissolution behavior of the tablets prepared from these products.
Conclusion
CLSM is a useful technique to determine the particle size in a powder mixture. Furthermore, CLSM can be used to determine the drug crystal size over a broad size distribution. A limitation of the method is that the drug should be autofluorescent.
doi:10.1007/s11095-011-0484-8
PMCID: PMC3170464  PMID: 21607777
confocal laser scanning miscroscopy; controlled crystallization during freeze-drying; dipyridamole; dissolution; freeze-drying
10.  A New Strategy to Stabilize Oxytocin in Aqueous Solutions: I. The Effects of Divalent Metal Ions and Citrate Buffer 
The AAPS Journal  2011;13(2):284-290.
In the current study, the effect of metal ions in combination with buffers (citrate, acetate, pH 4.5) on the stability of aqueous solutions of oxytocin was investigated. Both monovalent metal ions (Na+ and K+) and divalent metal ions (Ca2+, Mg2+, and Zn2+) were tested all as chloride salts. The effect of combinations of buffers and metal ions on the stability of aqueous oxytocin solutions was determined by RP-HPLC and HP-SEC after 4 weeks of storage at either 4°C or 55°C. Addition of sodium or potassium ions to acetate- or citrate-buffered solutions did not increase stability, nor did the addition of divalent metal ions to acetate buffer. However, the stability of aqueous oxytocin in aqueous formulations was improved in the presence of 5 and 10 mM citrate buffer in combination with at least 2 mM CaCl2, MgCl2, or ZnCl2 and depended on the divalent metal ion concentration. Isothermal titration calorimetric measurements were predictive for the stabilization effects observed during the stability study. Formulations in citrate buffer that had an improved stability displayed a strong interaction between oxytocin and Ca2+, Mg2+, or Zn2+, while formulations in acetate buffer did not. In conclusion, our study shows that divalent metal ions in combination with citrate buffer strongly improved the stability of oxytocin in aqueous solutions.
doi:10.1208/s12248-011-9268-7
PMCID: PMC3085697  PMID: 21448747
citrate buffer; divalent metal ions; improved stability; oxytocin
11.  A New Strategy to Stabilize Oxytocin in Aqueous Solutions: I. The Effects of Divalent Metal Ions and Citrate Buffer 
The AAPS Journal  2011;13(2):284-290.
In the current study, the effect of metal ions in combination with buffers (citrate, acetate, pH 4.5) on the stability of aqueous solutions of oxytocin was investigated. Both monovalent metal ions (Na+ and K+) and divalent metal ions (Ca2+, Mg2+, and Zn2+) were tested all as chloride salts. The effect of combinations of buffers and metal ions on the stability of aqueous oxytocin solutions was determined by RP-HPLC and HP-SEC after 4 weeks of storage at either 4°C or 55°C. Addition of sodium or potassium ions to acetate- or citrate-buffered solutions did not increase stability, nor did the addition of divalent metal ions to acetate buffer. However, the stability of aqueous oxytocin in aqueous formulations was improved in the presence of 5 and 10 mM citrate buffer in combination with at least 2 mM CaCl2, MgCl2, or ZnCl2 and depended on the divalent metal ion concentration. Isothermal titration calorimetric measurements were predictive for the stabilization effects observed during the stability study. Formulations in citrate buffer that had an improved stability displayed a strong interaction between oxytocin and Ca2+, Mg2+, or Zn2+, while formulations in acetate buffer did not. In conclusion, our study shows that divalent metal ions in combination with citrate buffer strongly improved the stability of oxytocin in aqueous solutions.
doi:10.1208/s12248-011-9268-7
PMCID: PMC3085697  PMID: 21448747
citrate buffer; divalent metal ions; improved stability; oxytocin
12.  Prediction of the Ease of Subdivision of Scored Tablets from Their Physical Parameters 
AAPS PharmSciTech  2010;11(1):126-132.
At present, the ease of subdivision of scored tablets is estimated in vivo. In order to replace such in vivo testing and to develop a surrogate test which uses in vitro techniques, the association between physical parameters of scored tablets and their ease of subdivision was studied. The physical properties of 23 brands of scored tablets of which their ease of subdivision in vivo was known were established. Statistical modeling using a logistic regression model was used to fit the data and estimate the contribution of each physical parameter to the goodness of the fit. For scored oblong tablets, the critical parameters for their ease of subdivision are: diameter; diameter/width ratio; depth of score line and resistance to crushing. Criteria for each of these parameters were derived. All criteria need to be complied with to guarantee sufficient ease of subdivision of scored oblong tablets. For scored round tablets the critical parameters, in decreasing order of importance, for their ease of subdivision, are: resistance to crushing, diameter, score mark (one- or two-sided), and shape (flat or biconvex). A five-parameter predictive model was developed, showing excellent discrimination. For development, the proposed surrogate tests are sufficiently reliable. For release testing and stability studies, resistance to crushing of a scored tablet is a reliable predictor of its ease of subdivision.
doi:10.1208/s12249-009-9365-4
PMCID: PMC2850449  PMID: 20077042
break-mark; score line; statistical modeling; subdivision; tablet
13.  Bottom-Up Preparation Techniques for Nanocrystals of Lipophilic Drugs 
Pharmaceutical Research  2010;28(5):1220-1223.
doi:10.1007/s11095-010-0323-3
PMCID: PMC3073053  PMID: 21086152
bottom-up; large-scale production; nanocrystal; solubility
14.  Controlled Crystallization of the Lipophilic Drug Fenofibrate During Freeze-Drying: Elucidation of the Mechanism by In-Line Raman Spectroscopy 
The AAPS Journal  2010;12(4):569-575.
We developed a novel process, “controlled crystallization during freeze-drying” to produce drug nanocrystals of poorly water-soluble drugs. This process involves freeze-drying at a relatively high temperature of a drug and a matrix material from a mixture of tertiary butyl alcohol and water, resulting in drug nanocrystals incorporated in a matrix. The aim of this study was to elucidate the mechanisms that determine the size of the drug crystals. Fenofibrate was used as a model lipophilic drug. To monitor the crystallization during freeze-drying, a Raman probe was placed just above the sample in the freeze-dryer. These in-line Raman spectroscopy measurements clearly revealed when the different components crystallized during freeze-drying. The solvents crystallized only during the freezing step, while the solutes only crystallized after the temperature was increased, but before drying started. Although the solutes crystallized only after the freezing step, both the freezing rate and the shelf temperature were critical parameters that determined the final crystal size. At a higher freezing rate, smaller interstitial spaces containing the freeze-concentrated fraction were formed, resulting in smaller drug crystals (based on dissolution data). On the other hand, when the solutes crystallized at a lower shelf temperature, the degree of supersaturation is higher, resulting in a higher nucleation rate and consequently more and therefore smaller crystals. In conclusion, for the model drug fenofibrate, a high freezing rate and a relatively low crystallization temperature resulted in the smallest crystals and therefore the highest dissolution rate.
doi:10.1208/s12248-010-9215-z
PMCID: PMC2976986  PMID: 20625865
dissolution; fenofibrate; nanocrystal; poorly water-soluble drug; raman spectroscopy
15.  Controlled Crystallization of the Lipophilic Drug Fenofibrate During Freeze-Drying: Elucidation of the Mechanism by In-Line Raman Spectroscopy 
The AAPS Journal  2010;12(4):569-575.
We developed a novel process, “controlled crystallization during freeze-drying” to produce drug nanocrystals of poorly water-soluble drugs. This process involves freeze-drying at a relatively high temperature of a drug and a matrix material from a mixture of tertiary butyl alcohol and water, resulting in drug nanocrystals incorporated in a matrix. The aim of this study was to elucidate the mechanisms that determine the size of the drug crystals. Fenofibrate was used as a model lipophilic drug. To monitor the crystallization during freeze-drying, a Raman probe was placed just above the sample in the freeze-dryer. These in-line Raman spectroscopy measurements clearly revealed when the different components crystallized during freeze-drying. The solvents crystallized only during the freezing step, while the solutes only crystallized after the temperature was increased, but before drying started. Although the solutes crystallized only after the freezing step, both the freezing rate and the shelf temperature were critical parameters that determined the final crystal size. At a higher freezing rate, smaller interstitial spaces containing the freeze-concentrated fraction were formed, resulting in smaller drug crystals (based on dissolution data). On the other hand, when the solutes crystallized at a lower shelf temperature, the degree of supersaturation is higher, resulting in a higher nucleation rate and consequently more and therefore smaller crystals. In conclusion, for the model drug fenofibrate, a high freezing rate and a relatively low crystallization temperature resulted in the smallest crystals and therefore the highest dissolution rate.
doi:10.1208/s12248-010-9215-z
PMCID: PMC2976986  PMID: 20625865
dissolution; fenofibrate; nanocrystal; poorly water-soluble drug; raman spectroscopy
16.  Preservation of the Immunogenicity of Dry-powder Influenza H5N1 Whole Inactivated Virus Vaccine at Elevated Storage Temperatures 
The AAPS Journal  2010;12(2):215-222.
Stockpiling of pre-pandemic influenza vaccines guarantees immediate vaccine availability to counteract an emerging pandemic. Generally, influenza vaccines need to be stored and handled refrigerated to prevent thermal degradation of the antigenic component. Requirement of a cold-chain, however, complicates stockpiling and the logistics of vaccine distribution. We, therefore, investigated the effect of elevated storage temperatures on the immunogenicity of a pre-pandemic influenza A H5N1 whole inactivated virus vaccine. Either suspended in liquid or kept as a freeze-dried powder, vaccines could be stored for 1 year at ambient temperature (20°C) with minimal loss of immunogenicity in mice. Elevation of the storage temperature to 40°C, however, resulted in a significant loss of immunogenic potency within 3 months if vaccines were stored in liquid suspension. In sharp contrast, freeze-dried powder formulations were stable at 40°C for at least 3 months. The presence of inulin or trehalose sugar excipients during freeze-drying of the vaccine proved to be critical to maintain its immunogenic potency during storage, and to preserve the characteristic Th1-type response to whole inactivated virus vaccine. These results indicate that whole inactivated virus vaccines may be stored and handled at room temperature in moderate climate zones for over a year with minimal decline and, if converted to dry-powder, even in hot climate zones for at least 3 months. The increased stability of dry-powder vaccine at 40°C may also point to an extended shelf-life when stored at 4°C. Use of the more stable dry-powder formulation could simplify stockpiling and thereby facilitating successful pandemic intervention.
doi:10.1208/s12248-010-9179-z
PMCID: PMC2844510  PMID: 20195930
freeze-drying; inulin; pandemic influenza; vaccine stockpiling; whole inactivated influenza vaccine (H5N1)
17.  Preservation of the Immunogenicity of Dry-powder Influenza H5N1 Whole Inactivated Virus Vaccine at Elevated Storage Temperatures 
The AAPS Journal  2010;12(2):215-222.
Stockpiling of pre-pandemic influenza vaccines guarantees immediate vaccine availability to counteract an emerging pandemic. Generally, influenza vaccines need to be stored and handled refrigerated to prevent thermal degradation of the antigenic component. Requirement of a cold-chain, however, complicates stockpiling and the logistics of vaccine distribution. We, therefore, investigated the effect of elevated storage temperatures on the immunogenicity of a pre-pandemic influenza A H5N1 whole inactivated virus vaccine. Either suspended in liquid or kept as a freeze-dried powder, vaccines could be stored for 1 year at ambient temperature (20°C) with minimal loss of immunogenicity in mice. Elevation of the storage temperature to 40°C, however, resulted in a significant loss of immunogenic potency within 3 months if vaccines were stored in liquid suspension. In sharp contrast, freeze-dried powder formulations were stable at 40°C for at least 3 months. The presence of inulin or trehalose sugar excipients during freeze-drying of the vaccine proved to be critical to maintain its immunogenic potency during storage, and to preserve the characteristic Th1-type response to whole inactivated virus vaccine. These results indicate that whole inactivated virus vaccines may be stored and handled at room temperature in moderate climate zones for over a year with minimal decline and, if converted to dry-powder, even in hot climate zones for at least 3 months. The increased stability of dry-powder vaccine at 40°C may also point to an extended shelf-life when stored at 4°C. Use of the more stable dry-powder formulation could simplify stockpiling and thereby facilitating successful pandemic intervention.
doi:10.1208/s12248-010-9179-z
PMCID: PMC2844510  PMID: 20195930
freeze-drying; inulin; pandemic influenza; vaccine stockpiling; whole inactivated influenza vaccine (H5N1)
18.  Intranasal Delivery of Influenza Subunit Vaccine Formulated with GEM Particles as an Adjuvant 
The AAPS Journal  2010;12(2):109-116.
Nasal administration of influenza vaccine has the potential to facilitate influenza control and prevention. However, when administered intranasally (i.n.), commercially available inactivated vaccines only generate systemic and mucosal immune responses if strong adjuvants are used, which are often associated with safety problems. We describe the successful use of a safe adjuvant Gram-positive enhancer matrix (GEM) particles derived from the food-grade bacterium Lactococcus lactis for i.n. vaccination with subunit influenza vaccine in mice. It is shown that simple admixing of the vaccine with the GEM particles results in a strongly enhanced immune response. Already after one booster, the i.n. delivered GEM subunit vaccine resulted in hemagglutination inhibition titers in serum at a level equal to the conventional intramuscular (i.m.) route. Moreover, i.n. immunization with GEM subunit vaccine elicited superior mucosal and Th1 skewed immune responses compared to those induced by i.m. and i.n. administered subunit vaccine alone. In conclusion, GEM particles act as a potent adjuvant for i.n. influenza immunization.
doi:10.1208/s12248-009-9168-2
PMCID: PMC2844513  PMID: 20058113
influenza vaccine; intranasal vaccine; Lactococcus lactis GEM particles
19.  Intranasal Delivery of Influenza Subunit Vaccine Formulated with GEM Particles as an Adjuvant 
The AAPS Journal  2010;12(2):109-116.
Nasal administration of influenza vaccine has the potential to facilitate influenza control and prevention. However, when administered intranasally (i.n.), commercially available inactivated vaccines only generate systemic and mucosal immune responses if strong adjuvants are used, which are often associated with safety problems. We describe the successful use of a safe adjuvant Gram-positive enhancer matrix (GEM) particles derived from the food-grade bacterium Lactococcus lactis for i.n. vaccination with subunit influenza vaccine in mice. It is shown that simple admixing of the vaccine with the GEM particles results in a strongly enhanced immune response. Already after one booster, the i.n. delivered GEM subunit vaccine resulted in hemagglutination inhibition titers in serum at a level equal to the conventional intramuscular (i.m.) route. Moreover, i.n. immunization with GEM subunit vaccine elicited superior mucosal and Th1 skewed immune responses compared to those induced by i.m. and i.n. administered subunit vaccine alone. In conclusion, GEM particles act as a potent adjuvant for i.n. influenza immunization.
doi:10.1208/s12248-009-9168-2
PMCID: PMC2844513  PMID: 20058113
influenza vaccine; intranasal vaccine; Lactococcus lactis GEM particles
20.  Concepts for increasing gentamicin release from handmade bone cement beads 
Acta Orthopaedica  2009;80(5):508-513.
Background and purpose Commercial gentamicin-loaded bone cement beads (Septopal) constitute an effective delivery system for local antibiotic therapy. These beads are not available in all parts of the world, and are too expensive for frequent use in others. Thus, orthopedic surgeons worldwide make antibiotic-loaded beads themselves. However, these beads are usually not as effective as the commercial beads because of inadequate release kinetics. Our purpose was to develop a simple, cheap, and effective formulation to prepare gentamicin-loaded beads with release properties and antibacterial efficacy similar to the commercially ones.
Methods Acrylic beads were prepared with variable monomer content: 100% (500 μL/g polymer), 75%, and 50% to increase gentamicin release through creation of a less dense polymer matrix. Using the optimal monomer content, different gel-forming polymeric fillers were added to enhance the permeation of fluids into the beads. Polyvinylpyrrolidone (PVP) 17 was selected as a suitable filler; its concentration was varied and the antibiotic release and antibacterial efficacy of these beads were compared with the corresponding properties of the commercial ones.
Results Gentamicin release rate and the extent of release from beads prepared with 50% monomer increased when the PVP17 content was increased. Beads with 15 w/w% PVP17 released 87% of their antibiotic content. This is substantially more than the gentamicin release from Septopal beads (59%). Acrylic beads with 15 w/w% PVP17 reduced bacterial growth by up to 93%, which is similar to the antibacterial properties of the commercial ones.
Interpretation A simple, cheap, and effective formulation and preparation process has been described for hand-made gentamicin-releasing acrylic beads, with better release kinetics and with antibacterial efficacy similar to that of the commercial ones.
doi:10.3109/17453670903389782
PMCID: PMC2823325  PMID: 19916680
21.  Using the Internal Stress Concept to Assess the Importance of Moisture Sorption-induced Swelling on the Moisture Transport through the Glassy HPMC Films 
AAPS PharmSciTech  2008;9(3):891-898.
The purpose of this research was to elucidate the significance of the changes in the mechanical and the volumetric properties on the moisture diffusivity through the polymer films. The internal stress concept was adapted and applied to estimate the relative impact of these property changes on the total stress experienced by a polymer film during storage. Hydroxypropyl Methylcellulose free films were used as a model material prepared at various conditions and stored at different relative humidities. The changes in the internal stress of these films due to the moisture sorption were studied. It was demonstrated that the stress-relaxation of the films increases at increasing moisture content. At the point when there is a definite loss of stress in the film, which is at moisture content higher than 6%, was shown to correlate with the significant increase of the moisture diffusivity. Further investigations revealed that the loss of stress is especially due to the swelling of the polymer rather than the changes in the inherent strain (the quotient between the tensile strength and the modulus of elasticity) of the HPMC films. This implies that the impact of the moisture sorption on the diffusivity is predominantly via volume addition rather than via altering the mechanical properties. Additionally, the approach presented here also brings up a new application of the internal stress concept, which in essence suggests the possibility to estimate the diffusion coefficient from the sorption isotherm and the mechanical analysis data.
doi:10.1208/s12249-008-9128-7
PMCID: PMC2977037  PMID: 18668371
HPMC; internal stress; mechanical properties; moisture diffusion; swelling
22.  Pore Direction in Relation to Anisotropy of Mechanical Strength in a Cubic Starch Compact 
AAPS PharmSciTech  2008;9(2):528-535.
The purpose of this research was to evaluate the relation between preferential direction of pores and mechanical strength of cubic starch compacts. The preferential pore direction was quantified in SEM images of cross sections of starch compacts using a previously described algorithm for determination of the quotient of transitions (Q). This parameter and the mechanical strength were evaluated in compacts of different porosities. Starch was chosen as a model compound for materials with ductile behaviour of which tablets with low porosities can be made and which shows some elastic recovery after compaction. At medium and high porosity Q was significantly higher in the images providing a side view of the compact than in the images providing a top view (0.973 vs. 0.927 and 0.958 vs. 0.874 at 0 mm from the side of the compact and 0.956 vs. 0.854 and 0.951 vs. 0.862 at 3.5 mm), indicating that the pores were mainly oriented in the direction perpendicular to the direction of compression. This was accompanied by a lower crushing force in this direction. This could be explained by considering the pores as cracks which propagate through the sample during crushing. For both directions the crushing force decreased with increasing porosity. The yield strength of the compacts also decreased with increasing porosity, but this parameter was not dependent on the direction of crushing when the porosity was below 10%. The results show that pore direction significantly influences the crushing force but does not influence the yield strength, at porosities below 10%.
doi:10.1208/s12249-008-9074-4
PMCID: PMC2976927  PMID: 18431650
anisotropy; compact; fracture; mechanical strength; pore direction
23.  Characterization of a cyclosporine solid dispersion for inhalation 
The AAPS Journal  2007;9(2):E190-E199.
For lung transplant patients, a respirable, inulin-based solid dispersion containing cyclosporine A (CsA) has been developed. The solid dispersions were prepared by spray freezedrying. The solid dispersion was characterized by water vapor uptake, specific surface area analysis, and particle size analysis. Furthermore, the mode of inclusion of CsA in the dispersion was investigated with Fourier transform infrared spectroscopy. Finally, the dissolution behavior was determined and the aerosol that was formed by the powder was characterized. The powder had large specific surface areas (∼160 m2). The water vapor uptake was dependent linearly on the drug load. The type of solid dispersion was a combination of a solid solution and solid suspension. At a 10% drug load, 55% of the CsA in the powder was in the form of a solid solution and 45% as solid suspension. At 50% drug load, the powder contained 90% of CsA as solid suspension. The powder showed excellent dispersion characteristics as shown by the high emitted fraction (95%), respirable fraction (75%), and fine-particle fraction (50%). The solid dispersions consisted of relatively large (x50≈7 μm), but low-density particles (ρ≈0.2 g/cm3). The solid dispersions dissolved faster than the physical mixture, and inulin dissolved faster than CsA. The spray freeze-drying with inulin increased the specific surface area and wettability of CsA. In conclusion, the developed powder seems suitable for inhalation in the local treatment of lung transplant patients.
doi:10.1208/aapsj0902021
PMCID: PMC2751408  PMID: 17614361
DPI; Cyclosporine A; solid dispersion; FTIR; aerosol; large porous particles
24.  In Vitro Performance Testing of the Novel Medspray® Wet Aerosol Inhaler Based on the Principle of Rayleigh Break-up 
Pharmaceutical Research  2007;25(5):1186-1192.
Purpose
A new inhaler (Medspray®) for pulmonary drug delivery based on the principle of Rayleigh break-up has been tested with three different spray nozzles (1.5; 2.0 and 2.5 μm) using aqueous 0.1% (w/w) salbutamol and 0.9% (w/w) sodium chloride solutions.
Materials and methods
Particle size distributions in the aerosol were measured with the principles of time of flight (APS) and laser diffraction (LDA).
Results
The Medspray® inhaler exhibits a highly constant droplet size distribution in the aerosol during dose emission. Droplets on the basis of Rayleigh break-up theory are monodisperse, but due to some coalescence the aerosols from the Medspray® inhaler are slightly polydisperse. Mass median aerodynamic diameters at 60 l.min−1 from APS are 1.42; 1.32 and 1.27 times the theoretical droplet diameters (TD’s) and median laser diffraction diameters are 1.29; 1.14 and 1.05 times TD for 1.5; 2.0 and 2.5 μm nozzles (TD: 2.84; 3.78 and 4.73 μm respectively).
Conclusions
The narrow particle size distribution in the aerosol from the Medspray® is highly reproducible for the range of flow rates from 30 to 60 l.min−1. The mass median aerodynamic droplet diameter can be well controlled within the size range from 4 to 6 μm at 60 l.min−1.
doi:10.1007/s11095-007-9503-1
PMCID: PMC2292500  PMID: 18066714
aerodynamic particle sizer; laser diffraction technique; monodisperse aerosol; pulmonary drug delivery; Rayleigh break-up; wet nebulisation
25.  New Mechanisms to Explain the Effects of Added Lactose Fines on the Dispersion Performance of Adhesive Mixtures for Inhalation 
PLoS ONE  2014;9(1):e87825.
Fine excipient particles or ‘fines’ have been shown to improve the dispersion performance of carrier-based formulations for dry powder inhalation. Mechanistic formulation studies have focussed mainly on explaining this positive effect. Previous studies have shown that higher drug contents may cause a decrease in dispersion performance, and there is no reason why this should not be true for fines with a similar shape, size and cohesiveness as drug particles. Therefore, the effects on drug detachment of ‘fine lactose fines’ (FLF, X50 = 1.95 µm) with a similar size and shape as micronised budesonide were studied and compared to those of ‘coarse lactose fines’ (CLF, X50 = 3.94 µm). Furthermore, interactions with the inhalation flow rate, the drug content and the mixing order were taken into account. The observed effects of FLF are comparable to drug content effects in that the detached drug fraction was decreased at low drug content and low flow rates but increased at higher flow rates. At high drug content the effects of added FLF were negligible. In contrast, CLF resulted in higher detached drug fractions at all flow rates and drug contents. The results from this study suggest that the effects of fines may be explained by two new mechanisms in addition to those previously proposed. Firstly, fines below a certain size may increase the effectiveness of press-on forces or cause the formation of strongly coherent fine particle networks on the carrier surface containing the drug particles. Secondly, when coarse enough, fines may prevent the formation of, or disrupt such fine particle networks, possibly through a lowering of their tensile strength. It is recommended that future mechanistic studies are based on the recognition that added fines may have any effect on dispersion performance, which is determined by the formulation and dispersion conditions.
doi:10.1371/journal.pone.0087825
PMCID: PMC3905031  PMID: 24489969

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