Delivery of Biotherapeutics by Inhalation Aerosol

Niven, Ralph W.

doi:10.1615/critrevtherdrugcarriersyst.v12.i2-3.20

Cited by 134 publications

(74 citation statements)

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“…In principle, inhalation delivery of proteins offers an attractive, noninvasive alternative to injections and other modes of administration; lungs have a large surface area, are quite tolerant of foreign substances, are much more permeable than gastrointestinal and nasal mucosa or skin, and contain protease inhibitors preventing proteolytic breakdown (6)(7)(8). Consequently, much recent activity has focused on the pulmonary delivery of protein therapeutics (7)(8)(9), culminating in a clinical application, local delivery of Genentech's recombinant human DNase (Pulmozyme) for the treatment of cystic fibrosis (10).…”

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confidence: 99%

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Inhalation delivery of proteins from ethanol suspensions

Choi

Murthy

Edwards

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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To circumvent inherent problems associated with pulmonary administration of aqueous-solution and dry-powder protein drugs, inhalation delivery of proteins from their suspensions in absolute ethanol was explored both in vitro and in vivo. Protein suspensions in ethanol of up to 9% (wt͞vol) were readily aerosolized with a commercial compressor nebulizer. Experiments with enzymic proteins revealed that nebulization caused no detectable loss of catalytic activity; furthermore, enzyme suspensions in anhydrous ethanol retained their full catalytic activity for at least 3 weeks at room temperature. With the use of Zn 2؉ -insulin, conditions were elaborated that produced submicron protein particles in ethanol suspensions. The latter (insulin͞EtOH) afforded respirable-size aerosol particles after nebulization. A 40-min exposure of laboratory rats to 10 mg͞ml insulin͞EtOH aerosols resulted in a 2-fold drop in the blood glucose level and a marked rise in the serum insulin level. The bioavailability based on estimated deposited lung dose of insulin delivered by inhalation of ethanol suspension aerosols was 33% (relative to an equivalent s.c. injection), i.e., comparable to those observed in rats after inhalation administration of dry powder and aqueous solutions of insulin. Inhalation of ethanol in a relevant amount͞time frame resulted in no detectable acute toxic effects on rat lungs or airways, as reflected by the absence of statistically significant inflammatory or allergic responses, damage to the alveolar͞capillary barrier, and lysed and͞or damaged cells.

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mentioning

confidence: 99%

“…Consequently, much recent activity has focused on the pulmonary delivery of protein therapeutics (7)(8)(9), culminating in a clinical application, local delivery of Genentech's recombinant human DNase (Pulmozyme) for the treatment of cystic fibrosis (10).…”

mentioning

confidence: 99%

Inhalation delivery of proteins from ethanol suspensions

Choi

Murthy

Edwards

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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“…Dry powders are of particular interest for the inhalation of proteins. Classic nebulisation methods such as jet nebulisation and ultrasonic nebulisation can lead to protein degradation (29). A dry powder formulation offers a means of improving protein drug stability during aerosolisation by using a dry powder inhaler device that would not subject the protein formulation to the stresses commonly associated with nebulisation.…”

Section: Introductionmentioning

confidence: 99%

A Dry Powder Formulation of Liposome-Encapsulated Recombinant Secretory Leukocyte Protease Inhibitor (rSLPI) for Inhalation: Preparation and Characterisation

2010

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Abstract. Inhaled recombinant secretory leukocyte protease inhibitor (rSLPI) has shown potential for the treatment of inflammatory lung conditions. Rapid inactivation of rSLPI by cathepsin L (Cat L) and rapid clearance from the lungs has limited clinical efficacy to date. Previous studies by us have shown that encapsulation of rSLPI within1,2-dioleoyl-sn-glycero-3-[phospho-L-serine]/cholesterol (DOPS/Chol) liposomes protects rSLPI against Cat L inactivation in vitro. Liquid DOPS-rSLPI preparations were found to be unstable upon long-term storage and nebulisation. The aim of this study was therefore to develop a method of manufacture for preparing DOPS-rSLPI liposomes as a dry powder for inhalation. DOPSrSLPI dry powders were lyophilised and subsequently micronised with a novel micronisation aid. The effects of formulation and processing on rSLPI stability, activity, and uniformity of content within the powders were characterised. Using D-mannitol as the micronisation aid, dry powder particles in the inhalable size range (<5 μm) were prepared. By optimising process parameters, up to 54% of rSLPI was recovered after micronisation, of which there was no significant loss in anti-neutrophil elastase activity and no detectable evidence of protein degradation. Aerosolisation was achieved using a dry powder inhaler, and mass median aerodynamic diameter (MMAD) was evaluated after collection in a cascade impactor. Aerosolisation of the DOPS-rSLPI dry powder yielded 38% emitted dose, with 2.44 μm MMAD. When challenged with Cat L post-aerosolisation, DOPS-rSLPI dry powder was significantly better at retaining a protective function against Cat L-induced rSLPI inactivation compared to the aqueous DOPS-rSLPI liposome dispersion and was also more stable under storage.

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“…4 This route of administration offers several advantages over the conventional gastrointestinal pathway, including large surface area, extensive vasculature, easily permeable membrane, and low intracellular and extracellular enzymatic activity. [5][6][7][8] Recent clinical and preclinical reports reveal that delivery of peptide drugs such as leuprolide acetate and insulin is feasible through the pulmonary route. [9][10][11][12] However, the bioavailability of the drugs having relatively high molecular weight is still poor through the pulmonary route compared with the parenteral route.…”

Section: Introductionmentioning

confidence: 99%