Investigations into the Formulation of Metered Dose Inhalers of Salmeterol Xinafoate and Fluticasone Propionate Microcrystals

Murnane, Darragh; Martin, Gary P.; Marriott, Christopher

doi:10.1007/s11095-008-9622-3

Cited by 10 publications

(14 citation statements)

References 28 publications

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“…Typically, prior to formulating a drug, the size of the crystalline material needs to be reduced to obtain suspension MDI formulations with particles of a suitable size for inhalation. This can be achieved by milling, spray drying, or using supercritical fluids (88,89). Ball mills and fluid-energy mills (such as jet mills) are the primary modes of milling powders to achieve particles with diameters of 1 to 5 μm (90).…”

Section: Particle Preparation For MDI Formulationsmentioning

confidence: 99%

Advances in Metered Dose Inhaler Technology: Formulation Development

2014

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Pressurized metered dose inhalers (MDIs) are a long-standing method to treat diseases of the lung, such as asthma and chronic obstructive pulmonary disease. MDIs rely on the driving force of the propellant, which comprises the bulk of the MDI formulation, to atomize droplets containing drug and excipients, which ideally should deposit in the lungs. During the phase out of chlorofluorocarbon propellants and the introduction of more environmentally friendly hydrofluoroalkane propellants, many improvements were made to the methods of formulating for MDI drug delivery along with a greater understanding of formulation variables on product performance. This review presents a survey of challenges associated with formulating MDIs as solution or suspension products with one or more drugs, while considering the physicochemical properties of various excipients and how the addition of these excipients may impact overall product performance of the MDI. Propellants, volatile and nonvolatile cosolvents, surfactants, polymers, suspension stabilizers, and bulking agents are among the variety of excipients discussed in this review article. Furthermore, other formulation approaches, such as engineered excipient and drug-excipient particles, to deliver multiple drugs from a single MDI are also evaluated.

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Section: Particle Preparation For MDI Formulationsmentioning

confidence: 99%

Advances in Metered Dose Inhaler Technology: Formulation Development

2014

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“…Laser diffraction studies provide a method to measure the agglomeration state of particles in formulations and have been used to investigate the aerosolization potential of suspended APIs as well as dry powder inhalation systems. Rapid screening tests have been proposed to characterize the de-agglomeration (in terms of the cohesive forces) , of particles from the critical pressure that is required to disperse particles of certain size through laser diffraction techniques.…”

Section: Introductionmentioning

confidence: 99%

Formulation Pre-screening of Inhalation Powders Using Computational Atom–Atom Systematic Search Method

et al. 2014

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The synthonic modeling approach provides a molecule-centered understanding of the surface properties of crystals. It has been applied extensively to understand crystallization processes. This study aimed to investigate the functional relevance of synthonic modeling to the formulation of inhalation powders by assessing cohesivity of three active pharmaceutical ingredients (APIs, fluticasone propionate (FP), budesonide (Bud), and salbutamol base (SB)) and the commonly used excipient, α-lactose monohydrate (LMH). It is found that FP (-11.5 kcal/mol) has a higher cohesive strength than Bud (-9.9 kcal/mol) or SB (-7.8 kcal/mol). The prediction correlated directly to cohesive strength measurements using laser diffraction, where the airflow pressure required for complete dispersion (CPP) was 3.5, 2.0, and 1.0 bar for FP, Bud, and SB, respectively. The highest cohesive strength was predicted for LMH (-15.9 kcal/mol), which did not correlate with the CPP value of 2.0 bar (i.e., ranking lower than FP). High FP-LMH adhesive forces (-11.7 kcal/mol) were predicted. However, aerosolization studies revealed that the FP-LMH blends consisted of agglomerated FP particles with a large median diameter (∼4-5 μm) that were not disrupted by LMH. Modeling of the crystal and surface chemistry of LMH identified high electrostatic and H-bond components of its cohesive energy due to the presence of water and hydroxyl groups in lactose, unlike the APIs. A direct comparison of the predicted and measured cohesive balance of LMH with APIs will require a more in-depth understanding of highly hydrogen-bonded systems with respect to the synthonic engineering modeling tool, as well as the influence of agglomerate structure on surface-surface contact geometry. Overall, this research has demonstrated the possible application and relevance of synthonic engineering tools for rapid pre-screening in drug formulation and design.

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“…Asthma and chronic obstructive pulmonary disease (COPD) are currently treated using either nebulizers, pressurized metered dose inhalers or dry powder inhalers (Dalby and Suman, 2003; Murnane et al, 2008b; Yang et al, 2008a). A major determinant of aerosol deposition in the respiratory tract is the aerodynamic size of particles and the polydispersity (Louey et al, 2004; Pilcer and Amighi, 2010; Pritchard, 2001).…”

Section: Introductionmentioning

confidence: 99%

Nanoparticle agglomerates of fluticasone propionate in combination with albuterol sulfate as dry powder aerosols

El-Gendy

Pornputtapitak

Berkland

2011

European Journal of Pharmaceutical Sciences

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Particle engineering strategies remain at the forefront of aerosol research for localized treatment of lung diseases and represent an alternative for systemic drug therapy. With the hastily growing popularity and complexity of inhalation therapy, there is a rising demand for tailor-made inhalable drug particles capable of affording the most proficient delivery to the lungs and the most advantageous therapeutic outcomes. To address this formulation demand, nanoparticle agglomeration was used to develop aerosols of the asthma therapeutics, fluticasone or albuterol. In addition, a combination aerosol was formed by drying agglomerates of fluticasone nanoparticles in the presence of albuterol in solution. Powders of the single drug nanoparticle agglomerates or of the combined therapeutics possessed desirable aerodynamic properties for inhalation. Powders were efficiently aerosolized (~75% deposition determined by cascade impaction) with high fine particle fraction and rapid dissolution. Nanoparticle agglomeration offers a unique approach to obtain high performance aerosols from combinations of asthma therapeutics.

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Investigations into the Formulation of Metered Dose Inhalers of Salmeterol Xinafoate and Fluticasone Propionate Microcrystals

Abstract: The size of the aggregates in the HFA suspensions was found to correlate directly with the FPFs determined by impaction.

Cited by 10 publications

References 28 publications

Advances in Metered Dose Inhaler Technology: Formulation Development

Advances in Metered Dose Inhaler Technology: Formulation Development

Formulation Pre-screening of Inhalation Powders Using Computational Atom–Atom Systematic Search Method

Nanoparticle agglomerates of fluticasone propionate in combination with albuterol sulfate as dry powder aerosols

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