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Identification of Stability Constraints in the Particle Engineering of an Inhaled Monoclonal Antibody Dried Powder

Identification of Stability Constraints in the Particle Engineering of an Inhaled Monoclonal Antibody Dried Powder

Ashlee D Brunaugh, Li Ding, Tian Wu, Michael Schneider, Ryan Khalaf, Hugh D C Smyth

Abstract

Monoclonal antibody (mAb) based therapies may provide a valuable new treatment modality for acute and chronic lung diseases, including asthma, respiratory infections, and lung cancer. Currently mAbs are delivered via systemic administration routes, but direct delivery to the lungs via the inhaled route could provide higher concentrations at the site of disease and reduced off-target effects. Though lyophilized mAbs may be reconstituted and delivered to the lungs using nebulizers, dry powder inhalers provide a more patient-friendly delivery method based upon their fast administration time and portability. However, particle engineering processes required to prepare respirable dried powders for DPI delivery involve multiple potential stressors for mAbs, which have not been fully explored. In this study, a systematic examination of various aspects of the particle engineering process (atomization, freezing, drying, and storage) was performed to further understand their impact on mAb structure and aggregation. Using anti-streptavidin IgG1 as a model mAb, atomization settings were optimized using a design of experiments approach to elucidate the relationship between feed flow rate, formulation solid content, and atomization airflow rate and protein structural changes and aggregation. The optimized atomization conditions were then applied to spray drying and spray freezing drying particle engineering processes to determine the effects of freezing and drying on IgG1 stability and aerosol performance of the powders. IgG1 was found to be particularly susceptible to degradation induced by the expansive air-ice interface generated by spray freeze drying and this process also produced powders that exhibited decreased storage stability. This study further delineates the design space for manufacturing of respirable biologic therapies and is intended to serve as a roadmap for future development work.

Keywords

Monoclonal antibody; Particle engineering; Pulmonary drug delivery; Spray drying; Spray freeze drying; Stability

Spray-freeze-dried inhalable composite microparticles containing nanoparticles of combinational drugs for potential treatment of lung infections caused by Pseudomonas aeruginosa

Spray-freeze-dried inhalable composite microparticles containing nanoparticles of combinational drugs for potential treatment of lung infections caused by Pseudomonas aeruginosa

Shihui Yu, XiaohuiPu, Maizbha Uddin Ahmed, Heidi H.Yu, Tarun Tejasvi Mutukuri, Jian Li, Qi Tony Zhou

Abstract

The multi-drug resistance of Pseudomonas aeruginosa is an overwhelming cause of terminal and persistent lung infections in cystic fibrosis (CF) patients. Antimicrobial synergy has been shown for colistin and ivacaftor, and our study designed a relatively high drug-loading dry powder inhaler formulation containing nanoparticles of ivacaftor and colistin. The ivacaftor-colistin nanosuspensions (Iva-Col-NPs) were prepared by the anti-solvent method with different stabilizers. Based on the aggregation data, the formulation 7 (F7) with DSPG-PEG-OMe as the stabilizer was selected for further studies. The F7 consisted of ivacaftor, colistin and DSPG-PEG-OMe with a mass ratio of 1:1:1. The F7 powder formulation was developed using the ultrasonic spray-freeze-drying method and exhibited a rough surface with relatively high fine particle fraction values of 61.4 ± 3.4% for ivacaftor and 63.3 ± 3.3% for colistin, as well as superior emitted dose of 97.8 ± 0.3% for ivacaftor and 97.6 ± 0.5% for colistin. The F7 showed very significant dissolution improvement for poorly water soluble ivacaftor than the physical mixture. Incorporating two drugs in a single microparticle with synchronized dissolution and superior aerosol performance will maximize the synergy and bioactivity of those two drugs. Minimal cytotoxicity in Calu-3 human lung epithelial cells and enhanced antimicrobial activity against colistin-resistant P. aeruginosa suggested that our formulation has potential to improve the treatment of CF patients with lung infections.

Keywords

Colistin, Ivacaftor, Cystic fibrosis, Pseudomonas aeruginosa, Dry powder inhaler, In vitro dissolution

Freeze granulation and spray drying of mixed granules of Al2O3

Freeze granulation and spray drying of mixed granules of Al2O3

M. Singlard, A. Paillassa, L. Ferres, C. Pagnoux, A. Aimable

Abstract

This paper proposes a comparative study of two techniques of granulation of a submicronic alumina powder with high binder content slurries, by spray drying and freeze granulation for the preparation of mixed granules. First, the viscosity and flow index of the suspensions are given as a function of dispersant, solid and binder contents versus alumina content, and the data are analysed in order to give a predictive model in a wide range. Suspensions with varying viscosities (7–208 mPa.s), densities (1.31–1.76) and surface tensions (23–40 mN/m) were then granulated. The first observations reveal the importance of the content and the molar mass of the binder: when they are too high, the freeze granulation fails and filaments are produced instead of granules due to extensive stretching of the molecular chains of the binder during spraying. Then through a theoretical analysis of the phenomena leading to granulation, an original dimensionless number is proposed to describe the evolution of the granule size as a function of suspension formulation. This number is related to the Reynolds and Weber number and is able to predict the granule size over a wide range (20–500 μm for freeze granulation, and 5–30 μm for spray drying). Spray drying leads to smaller granules with various shapes, from full shape to hollow or donut-like, whereas freeze granulation leads to bigger but spherical granules with a microporosity, and a size easier to predict as no drying shrinkage is observed.

Keywords

Spray drying, Freeze granulation, Alumina, Size distribution, Binder, Granules

Full paper

Freeze Granulation of Nanoporous UiO-66 Nanoparticles for Capture of Volatile Organic Compounds

Freeze Granulation of Nanoporous UiO-66 Nanoparticles for Capture of Volatile Organic Compounds

Van Nhieu Le, Daekeun Kim, Jinsoo Kim, Mohd Roslee Othman

Abstract

Nanoporous UiO-66 spherical beads prepared by using PVA binder successfully connected UiO-66 nanoparticles together into granular beads with improved mechanical strength for toluene capture. This was achieved without affecting the crystalline nature and micropore structures of the material. The regular octahedron of the UiO-66 individual nanoparticle remained intact, and the micropore size did not change with increasing PVA addition without which the nanoporous UiO-66 could not granulate into beads. However, PVA bound the nanoparticles together to form compact and cohesive network clusters that reduced the BET surface area and total pore volume. This consequently lowered the toluene adsorption efficacy slightly due to the premature breakthrough that limited the toluene molecular exposure into the micropores of the individual UiO-66 nanoparticles.

Keywords

UiO-66 nanoparticles, freeze granulation, VOC biomarker, microporous media, organic inorganic materials

Maximizing the enzyme immobilization of enzymatic glucose biofuel cells through hierarchically structured reduced graphene oxide

Maximizing the enzyme immobilization of enzymatic glucose biofuel cells through hierarchically structured reduced graphene oxide

Joonyoung Lee, Kyuhwan Hyun, Jae Min Park, Ho Seok Park, Yongchai Kwon

Summary

The number of immobilized glucose oxidase (GOx) molecules is considerably increased by the structural modification of reduced graphene oxide (rGO), and the performance of enzymatic biofuel cells (EBFCs) is positively affected by the modification process. To do this, new rGO with three-dimensional open porous structure is formed by spray freeze drying method (sprGO), while tetrathiafulvalene (TTF) as mediator, and GOx are sequentially immobilized onto sprGO. To improve the loading amount of catalyst, rGO structure is modified to open porous sprGO structure possessing numerous anchoring sites, after which gelatin film crosslinked by glutaraldehyde is fabricated onto sprGO to prevent any losses of other components (sprGO/[TTF-GOx]/crosslinked-gelatin). Specific surface area and charge transfer resistance of sprGO are quantitatively measured, and the actual amount of immobilized GOx and the performance of EBFC using this catalyst are electrochemically examined. With this, it is found that the amount of GOx immobilized in sprGO/[TTF-GOx]/crosslinked-gelatin is twice better that in rGO/[TTF-GOx]/crosslinked-gelatin. More specifically, EBFC using this catalyst shows open circuit voltage of 0.85 V and maximum power density of 380 μW/cm2, and this is 1.4 times better than that using rGO/[TTF-GOx]/crosslinked-gelatin. These results indicate that the amount of immobilized GOx strongly affects the performance capabilities of EBFCs.

Keywords

biofuel cell, freeze-drying method, glucose oxidase, open porous structure, spray frozen reduced graphene oxide

Improvement of Drug Delivery Properties of Risperidone via Preparation of Oral Disintegration Tablet Containing Nanostructured Microparticles

Improvement of Drug Delivery Properties of Risperidone via Preparation of Oral Disintegration Tablet Containing Nanostructured Microparticles

Motahare salarvanda, Zeinab Aref Darabi, Vahid Ramezani

Abstract

Introduction: The aim of this study was to improve the dissolution profile of risperidone and increase the compliance of psychotic patients through the design of an oral disintegration tablet­ (ODT) of microparticles containing nanoparticles.

Methods and Results: In order to prepare nanoparticles, the effect of six surfactants on the size and stability of nanoparticles was evaluated. The nanoaggregate fabricated via the spray freeze drying ­(SFD) process using mannitol, lactose and maltodextrin as a matrix agent. Nine formulations were prepared and evaluated on the particle size, dissolution rate , and other physicochemical properties.Finally, the formulations of ODT were designed and evaluated.

The results show that using of cremophore EL and hydroxypropyl methyl cellulose E15 with the synergic effect can develop the risperidone nanosuspension with nano range particle size (~188 nm). Also, it is showed that fabrication of risperidone microparticles containig nanoparticles enhanced the drug dissolution up to 2 min for lactose-based microparticles (as a superior formulation) that is very faster time than coarse risperidone powder with dissolution time of 60 min. the formulations of ODT containing 10% Sodium Starch Glycolate and 88% Microcrystalline Cellulose as Super disintegrants were selected with a disintegration time of fewer than 30 seconds and dissolution time of 10 min in superior formulation.

Conclusions: It is indicated that the simultaneous use of non-ionic surfactants can prepare risperidone nanoparticles by creating a steric barrier around the drug particles. In addition, the dissolution rate of risperidone has increased significantly due to the small particle size of nanoparticles according to Noyes-Whitney equation. The use of sugars maintains the size of the nanoparticles and prevents the formation of irreversible coalescence of nanoparticles. Thus, this investigation shows that the preparation of microparticles containing nanoparticles using SFD is an easy and usable method for improving the dissolution profile of many low solubility drugs.

Keywords

nanoparticles, dissolution, risperidone, oral disintegration tab

Post-Processing Techniques for the Improvement of Liposome Stability

Post-Processing Techniques for the Improvement of Liposome Stability

Ji Young Yu, Piyanan Chuesiang, Gye Hwa Shin, Hyun Jin Park

Abstract

Liposomes have been utilized as a drug delivery system to increase the bioavailability of drugs and to control the rate of drug release at the target site of action. However, the occurrence of self-aggregation, coalescence, flocculation and the precipitation of aqueous liposomes during formulation or storage can cause degradation of the vesicle structure, leading to the decomposition of liposomes. To increase the stability of liposomes, post-processing techniques have been applied as an additional process to liposomes after formulation to remove water and generate dry liposome particles with a higher stability and greater accessibility for drug administration in comparison with aqueous liposomes. This review covers the effect of these techniques including freeze drying, spray drying and spray freeze drying on the stability, physicochemical properties and drug encapsulation efficiency of dry liposomes. The parameters affecting the properties of liposomes during the drying process are also highlighted in this review. In addition, the impact of using a protective agent to overcome such limitations of each process is thoroughly discussed through various studies.

Keywords

post-processing techniques; liposome stability; freeze drying; spray drying; spray freeze drying

Influence of the PuO2 content on the sintering behaviour of UO2-PuO2 freeze-granulated powders under reducing conditions

Influence of the PuO2 content on the sintering behaviour of UO2-PuO2 freeze-granulated powders under reducing conditions

Julie Simeon, Florent Lebreton, Laure Ramond, Nicolas Clavier, Guillaume Bernard-Granger

Abstract

The sintering behaviour of freeze-granulated UO2-PuO2 powders containing 33 and 15 mol% Pu/(U + Pu) was investigated under reducing conditions up to 1700 °C. For both compositions, the “grain size versus relative density” trajectory was constructed. All the experimental points form a single trajectory meaning that a relative density/grain size pair obtained after sintering seems independent of the thermal path (heating rate, soak time, soak temperature) and of the Pu content. Exploiting the “grain size versus relative density trajectory” enabled also to propose that densification was controlled by grain boundary diffusion and grain growth by the grain boundaries whatever the Pu content. An activation energy around 510 kJ/mol was obtained for densification, which was close to the value reported for the grain boundary diffusion of plutonium cations in U1-xPuxO2 polycrystals. Whatever the Pu/(U + Pu) content, the sintered microstructure of 98 % dense samples possesses a homogeneous distribution of plutonium and uranium cations.

Keywords

Sintering, Ceramics, Oxides, Microstructure, MOX

Mixed bacteriophage ms2-l2 vlps elicit long-lasting protective antibodies against hpv pseudovirus 51

Mixed bacteriophage ms2-l2 vlps elicit long-lasting protective antibodies against hpv pseudovirus 51

Abstract

Three prophylactic vaccines are approved to protect against HPV infections. These vaccines are highly immunogenic. The most recent HPV vaccine, Gardasil-9, protects against HPV types associated with ~90% of cervical cancer (worldwide). Thus, ~10% of HPV-associated cancers are not protected by Gardasil-9. Although this is not a large percentage overall, the HPV types associated with 10% of cervical cancer not protected by the current vaccine are significantly important, especially in HIV/AIDS patients who are infected with multiple HPV types. To broaden the spectrum of protection against HPV infections, we developed mixed MS2-L2 VLPs (MS2-31L2/16L2 VLPs and MS2-consL2 (69-86) VLPs) in a previous study. Immunization with the VLPs neutralized/protected mice against infection with eleven high-risk HPV types associated with ~95% of cervical cancer and against one low-risk HPV type associated with ~36% of genital warts & up to 32% of recurrent respiratory papillomatosis. Here, we report that the mixed MS2-L2 VLPs can protect mice from three additional HPV types: HPV51, which is associated with ~0.8% of cervical cancer; HPV6, which is associated with up to 60% of genital warts; HPV5, which is associated with skin cancers in patients with epidermodysplasia verruciformis (EV). Overall, mixed MS2-L2 VLPs can protect against twelve HPV types associated with ~95.8% of cervical cancers and against two HPV types associated with ~90% of genital warts and >90% recurrent respiratory papillomatosis. Additionally, the VLPs protect against one of two HPV types associated with ~90% of HPV-associated skin cancers in patients with EV. More importantly, we observed that mixed MS2-L2 VLPs elicit protective antibodies that last over 9 months. Furthermore, a spray-freeze-dried formulation of the VLPs is stable, immunogenic, and protective at room temperature and 37 °C.

Keywords

human papillomaviruses; thermostable vaccines; protection; MS2 bacteriophage; virus-like particles; spray-freeze-drying; longevity

Spray freeze dried lyospheres® for nasal administration of insulin

Spray freeze dried lyospheres® for nasal administration of insulin

Tuğrul Mert Serim, Jan Kožák, Annika Rautenberg, Ayşe Nurten Özdemir, Yann Pellequer, Alf Lamprecht

Abstract

Pharmacologically active macromolecules, such as peptides, are still a major challenge in terms of designing a delivery system for their transport across absorption barriers and at the same time provide sufficiently high long-term stability. Spray freeze dried (SFD) lyospheres® are proposed here as an alternative for the preparation of fast dissolving porous particles for nasal administration of insulin. Insulin solutions containing mannitol and polyvinylpyrrolidone complemented with permeation enhancing excipients (sodium taurocholate or cyclodextrins) were sprayed into a cooled spray tower, followed by vacuum freeze drying. Final porous particles were highly spherical and mean diameters ranged from 190 to 250 µm, depending on the excipient composition. Based on the low density, lyospheres resulted in a nasal deposition rates of 90% or higher. When tested in vivo for their glycemic potential in rats, an insulin-taurocholate combination revealed a nasal bioavailability of insulin of 7.0 ± 2.8%. A complementary study with fluorescently labeled-dextrans of various molecular weights confirmed these observations, leading to nasal absorption ranging from 0.7 ± 0.3% (70 kDa) to 10.0 ± 3.1% (4 kDa). The low density facilitated nasal administration in general, while the high porosity ensured immediate dissolution of the particles. Additionally, due to their stability, lyospheres provide an extremely promising platform for nasal peptide delivery.

Keywords

spray freeze drying, lyophilization, nasal drug delivery, peptide formulations, porous particles, pharmacokinetic