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1.
Mol Pharm ; 16(10): 4165-4180, 2019 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-31448924

RESUMO

Pulmonary delivery of biopharmaceuticals may enable targeted local therapeutic effect and noninvasive systemic administration. Dry powder inhaler (DPI) delivery is an established patient-friendly approach for delivering large molecules to the lungs; however, the complexities of balancing protein stability with aerosol performance require that the design space of biopharmaceutical DPI formulations is rigorously explored. Utilizing four rationally selected formulations obtained using identical atomization conditions, an extensive study of the effect of the particle formation process (spray drying or spray freeze-drying) on powder properties, aerosol performance, and protein stability was performed. Multiple linear regression analysis was used to understand the relationship between powder properties, device dispersion mechanism, and aerosol performance. Spray drying and spray freeze-drying, despite the same spraying conditions, produced powders with vastly different physical characteristics, though similar aerosol performance. The resulting regression model points to the significance of particle size, density, and surface properties on the resulting aerosol performance, with these factors weighing differently according to the device dispersion mechanism utilized (shear-based or impaction-based). The physical properties of the produced spray dried and spray freeze-dried powders have differing implications for long-term stability, which will be explored extensively in a future study.


Assuntos
Composição de Medicamentos , Inaladores de Pó Seco , Liofilização/métodos , Muramidase/metabolismo , Nanopartículas/química , Pós/química , Administração por Inalação , Aerossóis , Dessecação , Humanos , Manitol/química , Muramidase/química , Estabilidade Proteica , Sacarose/química
2.
Int J Pharm ; 549(1-2): 58-66, 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30053488

RESUMO

The number of biologics in the therapeutic development pipeline is increasing including those delivered though inhalation (Morales, 2017; Fathe, 2016). Biologics comprise a broad variety of complex macromolecules with unique physicochemical characteristics. These distinctive characteristics control their pharmacological mechanisms of action, stability, and ultimately affect their processing, formulation, and delivery requirements. This review systematically covers crucial aspects of biologic powders formulations and dry powder inhalers which need to be taken into consideration to establish the drug loading and the payload to be delivered to reach the desired clinical dose.


Assuntos
Produtos Biológicos/administração & dosagem , Química Farmacêutica/métodos , Sistemas de Liberação de Medicamentos , Administração por Inalação , Animais , Produtos Biológicos/farmacologia , Relação Dose-Resposta a Droga , Inaladores de Pó Seco , Humanos
3.
AAPS PharmSciTech ; 19(7): 2755-2766, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29488193

RESUMO

With the growing interest in developing biologics for pulmonary delivery, systematic fast screening methods are needed for rapid development of formulations. Due to the labile nature of macromolecules, the development of stable, biologically active formulations with desired aerosol performance imposes several challenges both from a formulation and processing perspective. In this study, spray-freeze-drying was used to develop respirable protein powders. In order to systematically map the selected design space, lysozyme aqueous pre-formulations were prepared based on a constrained mixture design of experiment. The physicochemical properties of the resulting powders were characterized and the effects of formulation factors on aerosol performance and protein stability were systematically screened using a logic flow chart. Our results elucidated several relevant formulation attributes (density, total solid content, protein:sugars ratio) required to achieve a stable lysozyme powder with desirable characteristics for pulmonary delivery. A similar logical fast screening strategy could be used to delineate the appropriate design space for different types of proteins and guide the development of powders with pre-determined aerodynamic properties.


Assuntos
Composição de Medicamentos/métodos , Excipientes/química , Muramidase/química , Administração por Inalação , Aerossóis , Anti-Infecciosos , Estabilidade de Medicamentos , Inaladores de Pó Seco , Liofilização/métodos , Tamanho da Partícula , Pós
4.
J Phys Chem B ; 117(45): 14029-38, 2013 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-24171386

RESUMO

Monoclonal antibodies (mAbs) contain hinge-like regions that enable structural flexibility of globular domains that have a direct effect on biological function. A subclass of mAbs, IgG2, have several interchain disulfide bonds in the hinge region that could potentially limit structural flexibility of the globular domains and affect the overall configuration space available to the mAb. We have characterized human IgG2 mAb in solution via small-angle neutron scattering (SANS) and interpreted the scattering data using atomistic models. Molecular Monte Carlo combined with molecular dynamics simulations of a model mAb indicate that a wide range of structural configurations are plausible, spanning radius of gyration values from ∼39 to ∼55 Å. Structural ensembles and representative single structure solutions were derived by comparison of theoretical SANS profiles of mAb models to experimental SANS data. Additionally, molecular mechanical and solvation free-energy calculations were carried out on the ensemble of best-fitting mAb structures. The results of this study indicate that low-resolution techniques like small-angle scattering combined with atomistic molecular simulations with free-energy analysis may be helpful to determine the types of intramolecular interactions that influence function and could lead to deleterious changes to mAb structure. This methodology will be useful to analyze small-angle scattering data of many macromolecular systems.


Assuntos
Anticorpos Monoclonais/química , Difração de Nêutrons , Espalhamento a Baixo Ângulo , Anticorpos Monoclonais/metabolismo , Humanos , Imunoglobulina G/química , Imunoglobulina G/metabolismo , Simulação de Dinâmica Molecular , Método de Monte Carlo , Estreptavidina/imunologia , Termodinâmica
5.
J Pharm Sci ; 98(9): 3108-16, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19025898

RESUMO

With increasing protein concentrations, therapeutic protein formulations are increasingly demonstrating significant deviations from ideal dilute solution behavior due to protein-protein interactions. These interactions lead to unique biophysical challenges in the administration of biopharmaceuticals including high apparent viscosity and viscoelasticity as well as challenges in maintaining the physical stability of proteins in solution. Here, we describe a straightforward analytical method to calculate the complex modulus and viscosity of high concentration protein solutions from measurements made using quartz crystal microbalance with dissipation monitoring (QCM-D). Further, this methodology was used to investigate the dependence of the storage and loss moduli (G' and G'', respectively) of a humanized monoclonal antibody solution on solution pH. Unlike recent reports, the effect of protein deposition onto the surface of the quartz sensor crystal was measured and explicitly accounted for during analysis when determining the solution's complex modulus. It was found that the ratio G''/G' was significantly greater than unity for all solutions investigated, but demonstrated a distinct maximum at pH 5.5 indicating that the solution exhibited the greatest liquid-like behavior at this pH. In addition, measurements were made at higher frequencies, which were found to be more sensitive to the changes in pH than those made at lower frequencies. It was also found that the viscoelastic ratio was relatively insensitive to the frequency of measurement at lower pH, but showed greater dependence on frequency as pH increased. The characterization of the rheological properties of high concentration antibody solutions provides insight into protein-protein interactions, and the methodology presented here demonstrates a straightforward way to determine the viscoelastic properties using ultrasonic rheology without the drawbacks of numerical fitting.


Assuntos
Anticorpos Monoclonais/análise , Técnicas de Química Analítica/métodos , Imunoglobulina G/análise , Quartzo , Elasticidade , Humanos , Estabilidade Proteica , Viscosidade
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