Inhaleable spray dried 4-helix bundle protein powders having minimized aggregation

Abstract

The present invention provides highly dispersible spray-dried powder compositions, and in particular, inhaleable dry powder compositions for aerosolized delivery to the lungs. The powders of the invention are produced by spray drying a 4 α-helix bundle protein under conditions which both (i) protect the protein from aggregation and (ii) provide particles suitable for inhalation (i.e., demonstrating superior aerosol performance).

Description

[0001] This application claims the benefit of priority of the following U.S. provisional patent applications: Patent Application Ser. No. 60 / 223, 144, filed Aug. 7, 2000; Patent Application Ser. No. 60 / 228,634, filed Aug. 29, 2000; and Patent Application Ser. No. 60 / 240,478 filed Oct. 13, 2000, the contents of which are incorporated herein by reference in their entirety.FIELD OF THE INVENTION [0002] The present invention is directed to highly dispersible spray-dried powder compositions, and in particular, to inhaleable dry powder compositions for aerosolized delivery to the lungs. The powders of the invention are produced by spray drying a 4 (α-helix bundle protein under conditions which both (i) protect the protein from aggregation and (ii) provide particles ideally suited for inhalation (i.e., demonstrating superior aerosol performance). BACKGROUND OF THE INVENTION [0003] Traditionally, inhalation therapy has played a relatively minor role in the administration of biotherapeutics ...

AI Technical Summary

Benefits of technology

[0011] The present invention is based upon the discovery of unique conditions for spray drying 4-α helix bundle proteins to provide respirable protein powder formulations, and in particular, 4 α-helix bundle protein powder formulations that are (i) resistant to protein aggregation during spray drying and upon storage, (ii) highly dispersible, and (iii) in a size range suitable for inhalation. The stabilizing conditions or excipients employed are effective to mask the protein from the extreme conditions of spray drying, such that process parameters which would otherwise (i.e., in the absence of such stabilizing conditions) lead to a large degree of protein aggregation are suitable, and often optimal, for forming particles (i) containing less than 10% total protein aggregates, and more preferably less than 7% total aggregates, and even more preferably less than 5% total aggregates, and (ii) having an emitted dose of at least about 65%, and more preferably of at least about 70%. The spray dried particles of the invention are sized appropriately for inhalation therapy, i.e., having an MMAD less than 10 microns, preferably less than 5 microns, more preferably less than 3.5 microns, and most preferably less than 3 microns.

[0020] In yet another embodiment of the invention, the 4 α-helical bundle protein is spray dried under optimized spray drying conditions such that the presence of additional stabilizers is not required. Surprisingly, the neat spray drying methodology is effective to produce spray dried particles containing minimal amounts (i.e., less than 10%) of protein aggregates (soluble and insoluble aggregates), excellent dispersibilities (greater than 65%, and preferably 70% emitted dose), and small aerodynamic particle sizes (MMADs less than about 4 microns).

Problems solved by technology

Injection is still the customary route of delivery of biotherapeutics (e.g., peptides, proteins and nucleic acids), and due to the many drawbacks associated with injection (e.g., inconvenience, discomfort, patient aversion to needle-based delivery methods), alternative administration routes are needed.

However, despite such results, the role of inhalation therapy in the health care field has not grown as expected over recent years, in part due to a set of problems unique to the development of inhaleable drug formulations.

In particular, dry powder formulations for pulmonary delivery, while offering unique advantages over cumbersome liquid dosage forms and propellant-driven formulations, can be prone to aggregation and low flowability phenomena which considerably diminish the efficiency of dry powder-based inhalation therapies.

While spray-drying has been long employed in the food and pharmaceutical industries to prepare dry powders, its application to therapeutic proteins has been rather limited because of the concern that certain proteins may be thermally degraded during the spray drying process.

Thus, due to their instability, spray-drying and formulating this class of proteins for inhalation presents a unique set of challenges.

Several aspects of the spray-drying process can contribute to protein unfolding for this class of proteins, such as shear stress, high temperatures, exposure of a protein in a droplet to the liquid air interface (surface effects), liquid-wall interactions, and the like, and can result in the formation of dried particles which contain a high degree of protein in aggregated form that are in a size range unsuitable (or at least non-optimal) for inhalation.

Of the 4-α-helix bundle proteins, growth hormone is particularly unstable, and many approaches have been employed to date to arrive at stable therapeutic formulations.

More importantly, aggregate formation in human growth hormone is detrimental, since is can lead to reduced bioactivity and increased immunogenicity (Becker, et al., Biotech. Appl. Biochem., 9:478-487 (1987), Leppert, P., Moore, W. V., J. Clin. Endocrinol., 51: 691-697 (1980)).

Thus, protein denaturation, the formation of aggregates, and production of powders having poor flow properties and low dispersibilities continue to plague development efforts to prepare aerosolizable 4-helix bundle protein powders for inhalation therapy.

Moreover, many of the approaches utilized to date are undesirable or unsuited for powder formulations for inhalation therapies, such as the use of surfactants, which are thought to interfere with the lung pathology and are epithelial irritants, or increasing the protein solids concentration of pre-spray dried solutions, which can result in particles that are too big for efficient delivery to the deep lung.