Formulation Development and In Vivo Evaluation of a New Dry Powder Formulation of Albuterol Sulphate in Beagle Dogs

Kuehl, Philip J.; Barrett, Edward G.; McDonald, Jacob D.; Rudolph, Karin; Vodak, David T.; Dobry, Dan E.; K, Lyon, David

doi:10.1007/s11095-010-0084-z

Cited by 19 publications

(7 citation statements)

References 22 publications

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“…Development of inhaled formulations to deliver large, delicate molecules such as mAbs has proven challenging, but success has been achieved using spray drying to generate respirable powders of small molecules for drug delivery to the deep lung [8,[16][17][18][19][20]. In spray drying, the API and excipients are co-dissolved in a solvent.…”

Section: Introductionmentioning

confidence: 99%

Local Treatment of Non-small Cell Lung Cancer with a Spray-Dried Bevacizumab Formulation

et al. 2021

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Local delivery of biotherapeutics to the lung holds great promise for treatment of lung diseases, but development of physically stable, biologically active dry powder formulations of large molecules for inhalation has remained a challenge. Here, spray drying was used to manufacture a dry powder pulmonary formulation of bevacizumab, a monoclonal antibody approved to treat non-small cell lung cancer (NSCLC) by intravenous infusion. By reformulating bevacizumab for local delivery, reduced side effects, lower doses, and improved patient compliance are possible. The formulation had aerosol properties suitable for delivery to the deep lung, as well as good physical stability at ambient temperature for at least 6 months. Bevacizumab’s anti-VEGF bioactivity was not impacted by the manufacturing process. The formulation was efficacious in an in vivo rat model for NSCLC at a 10-fold decrease in dose relative to the intravenous control.

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Section: Introductionmentioning

confidence: 99%

Local Treatment of Non-small Cell Lung Cancer with a Spray-Dried Bevacizumab Formulation

et al. 2021

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“…), intubated with a cuffed endotracheal tube and mechanically ventilated on room air at a tidal volume of 10 ml/kg and 15 breaths/min. A dosimetry system similar to that previously described for use in dogs (Kuehl et al, 2010) was used to deliver inhaled TRE and the LNP formulations (squalane, DOPC, cholesterol-PEG2000) of C12TR, C14TR, and C16TR. The compounds were nebulized with an Aeroneb Laboratory nebulizer (Aerogen) and delivered directly into a 500-ml expansion chamber on the inspiratory limb of the ventilator.…”

Section: Methodsmentioning

confidence: 99%

Preclinical Pharmacology and Pharmacokinetics of Inhaled Hexadecyl-Treprostinil (C16TR), a Pulmonary Vasodilator Prodrug

Corboz

Malinin

et al. 2017

J Pharmacol Exp Ther

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This article describes the preclinical pharmacology and pharmacokinetics (PK) of hexadecyl-treprostinil (C16TR), a prodrug of treprostinil (TRE), formulated in a lipid nanoparticle (LNP) for inhalation as a pulmonary vasodilator. C16TR showed no activity (>10 M) in receptor binding and enzyme inhibition assays, including binding to prostaglandin E receptor 2, prostaglandin D receptor 1, prostaglandin I receptor, and prostaglandin E receptor 4; TRE potently bound to each of these prostanoid receptors. C16TR had no effect (up to 200 nM) on platelet aggregation induced by ADP in rat blood. In hypoxia-challenged rats, inhaled C16TR-LNP produced dose-dependent (0.06-6 g/kg), sustained pulmonary vasodilation over 3 hours; inhaled TRE (6g/kg) was active at earlier times but lost its effect by 3 hours. Single- and multiple-dose PK studies of inhaled C16TR-LNP in rats showed proportionate dose-dependent increases in TRE and area under the curve (AUC) for both plasma and lung; similar results were observed for dog plasma levels in single-dose PK studies. In both species, inhaled C16TR-LNP yielded prolonged plasma TRE levels and a lower plasma TRE compared with inhaled TRE. Inhaled C16TR-LNP was well tolerated in rats and dogs; TRE-related side effects included cough, respiratory tract irritation, and emesis and were seen only after high inhaled doses of C16TR-LNP in dogs. In guinea pigs, inhaled TRE (30 g/ml) consistently produced cough, but C16TR-LNP (30g/ml) elicited no effect. These results demonstrate that C16TR-LNP provides long-acting pulmonary vasodilation, is well tolerated in animal studies, and may necessitate less frequent dosing than inhaled TRE with possibly fewer side effects.

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“…Dextrans have a high glass transition temperature (Tg), and good water solubility allowing formulation of a number of dry powders formulations for inhalation delivery (10). Inhalation performance has been shown to be comparable to several standards of care in a pulmonary preclinical setting (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Biologic Comparison of Inhaled Insulin Formulations: ExuberaTM and Novel Spray-Dried Engineered Particles of Dextran-10

Kuehl

Cherrington

Dobry³

et al. 2014

AAPS PharmSciTech

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Inhaled peptides and proteins have promise for respiratory and systemic disease treatment. Engineered spray-dried powder formulations have been shown to stabilize peptides and proteins and optimize aerosol properties for pulmonary delivery. The current study was undertaken to investigate the in vitro and in vivo inhalation performance of a model spray-dried powder of insulin and dextran 10 in comparison to Exubera™. Dextrans are a class of glucans that are generally recognized as safe with optimum glass transition temperatures well suited for spray drying. A 70% insulin particle loading was prepared by formulating with 30% (w/v) dextran 10. Physical characterization revealed a "raisin like" particle. Both formulations were generated to produce a similar bimodal particle size distribution of less than 3.5 μm MMAD. Four female Beagle dogs were exposed to each powder in a crossover design. Similar presented and inhaled doses were achieved with each powder. Euglycemia was achieved in each dog prior and subsequent to dosing and blood samples were drawn out to 245 min post-exposure. Pharmacokinetic analyses of post-dose insulin levels were similar for both powders. Respective dextran 10-insulin and Exubera exposures were similar producing near identical area under the curve (AUC), 7,728 ± 1,516 and 6,237 ± 2,621; concentration maximums (C max), 126 and 121 (μU/mL), and concentration-time maximums, 20 and 14 min, respectively. These results suggest that dextran-10 and other dextrans may provide a novel path for formulating peptides and proteins for pulmonary delivery.

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Formulation Development and In Vivo Evaluation of a New Dry Powder Formulation of Albuterol Sulphate in Beagle Dogs

Abstract: Results indicate that dextran 10 has promise as a novel excipient for dry powder inhalation drug delivery, in a preclinical setting, over a wide range of drug loadings.

Cited by 19 publications

References 22 publications

Local Treatment of Non-small Cell Lung Cancer with a Spray-Dried Bevacizumab Formulation

Local Treatment of Non-small Cell Lung Cancer with a Spray-Dried Bevacizumab Formulation

Preclinical Pharmacology and Pharmacokinetics of Inhaled Hexadecyl-Treprostinil (C16TR), a Pulmonary Vasodilator Prodrug

Biologic Comparison of Inhaled Insulin Formulations: ExuberaTM and Novel Spray-Dried Engineered Particles of Dextran-10

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