Particulate drug-containing products and method of manufacture

Details Particulate drug-containing products and method of manufacture Particulate drug-containing products and method of manufacture

2000-12-18

2003-12-30

Spear, James M. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

C424S499000, C424S043000, C424S045000, C424S400000, C514S002600, C514S003100

Reexamination Certificate

active

06669960

ABSTRACT:

FIELD OF THE INVENTION
The invention involves particulate products including an active drug useful for pulmonary delivery applications, manufacture of particles of the product using compressed anti-solvent precipitation, and inhalers actuatable to aerosolize the product and produce aerosols including the active drug. In one aspect, the particles are multi-component particles including the active drug and a biocompatible polymer useful for sustained release applications.
BACKGROUND OF THE INVENTION
Recently, there has been significant interest in pulmonary delivery of a variety of drugs to subjects via inhalation of aerosolized drug powders.
One important consideration for pulmonary delivery is that small particles in a narrow range of aerodynamic diameters of from about 1 micron to about 5 microns appear to be most effective for deposition in the lungs in a manner to contribute to drug delivery. Larger particles tend to become lodged in the throat during inhalation and smaller particles tend to be exhaled without depositing in the lungs. Because it is difficult to manufacture powder batches restricted to the desired particle size, significant losses of drugs are often experienced during administration to a subject, due to the presence of large quantities of excessively large and/or excessively small particles. Another important consideration is that handling the drug micro-powders during dose measurement and packaging is difficult, because of the small size and often cohesive nature of the particles. Significant quantities of powder can be lost during these handling operations. Significant powder losses can also occur during aerosolization of the powder to produce an aerosol for inhalation by a subject. For example, a dry powder inhaler is typically used to aerosolize a dry powder for inhalation. Significant powder losses in a dry powder inhaler can be caused by poor dispersability of the powder due to interparticulate cohesive forces and by particles coating interior surfaces of the inhaler. The cumulative losses can be large due to combined losses from powder handling, aerosolization and less than optimum particle size and size distribution characteristics. Moreover, if the powder has poor dispersability characteristics, then the aerosol may include a significant quantity of large aggregates that are too large for effective deposition in the lungs. The result is that often only a small percentage of a batch of powder originally manufactured for pulmonary delivery is ultimately delivered to the lungs of a subject. Some of these losses can be reduced through careful design of handling operations and careful design of inhalers to promote satisfactory aerosolization. Losses could further be reduced, however, through manufacture of powders having improved particle size and size distribution characteristics, improved flowability for ease of handling and/or improved dispersability for ease of aerosolization.
One drug that has received considerable attention for pulmonary delivery is insulin. Techniques that have been proposed for preparing insulin powders for pulmonary delivery include spray drying, solvent extraction and jet milling of lyophilized insulin. One problem with spray drying, however, is that the insulin is subjected to high temperatures, which can significantly degrade the insulin and may impair its activity. With solvent extraction techniques, there are often significant problems associated with contamination of powders by residual solvents and surfactants used during the manufacturing operation. The presence of these residual contaminants is undesirable. Jet milling can damage the biological activity of the insulin. Also, the characteristics of powders produced by spray drying, solvent extraction and jet milling could be improved to reduce losses during powder handling and aerosolization and to improve delivery of the aerosolized powder to a subject's lungs.
Another method that has been proposed for manufacturing insulin powders is to precipitate insulin from solution by contacting the solution with an anti-solvent fluid under supercritical conditions. Some references discussing supercritical anti-solvent precipitation of insulin include: Yeo, Sang-Do, et al., “Formation of Microparticulate Protein Powders Using a Supercritical Fluid Antisolvent,” Biotechnology and Bioengineering, Vol. 41, pp. 341-346 (1993); Yeo, Sang-Do, et al., “Secondary Structure Characterization of Microparticulate Insulin Powders,” J. Pharmaceutical Sciences, Vol. 83, No. 12, pp. 1651-1656 (1994); Winters, Michael A., et al., “Precipitation of Proteins in Supercritical Carbon Dioxide,” J. Pharmaceutical Sciences, Vol. 85, No. 6, pp. 586-594 (1996); Winters, Michael A., et al., “Long-Term and High-Temperature Storage of Supercritically-Processed Microparticulate Protein Powders,” Pharmaceutical Research, Vol. 14, No. 10, pp. 1370-1378 (1997); and European Patent No. 0 542 314.
The supercritical anti-solvent precipitation technique has the advantages of producing insulin powders with very little, if any, residual solvent contamination without subjecting the insulin to a high temperature. The noted references, however, are primarily focused on supercritical anti-solvent precipitation of insulin powders for use in applications other than pulmonary delivery, such as subcutaneous applications, and do not discuss processing techniques specifically designed to produce powders with characteristics that are advantageous for pulmonary delivery applications.
Furthermore, the same problems that exist for the manufacture of insulin powder for pulmonary delivery applications also apply to a wide range of other drugs.
Also, for a powder to be practically useful for pulmonary delivery applications, it is important that the powder be aerosolizable in an efficient manner, without excessive loss of material. This has been a significant problem in providing products for many pulmonary delivery applications. Additionally, the problem with powder aerosolization is often compounded because a given powder may work well with one inhaler design and not with another, and it is important to find a good match between characteristics of the powder and the inhaler.
There is a significant need for improved techniques to prepare insulin and other drug-containing powders for pulmonary delivery applications and for powder/inhaler combinations that efficiently aerosolize powders for pulmonary deliver.
SUMMARY OF THE INVENTION
With the present invention, it has been found that drug-containing powders often having improved characteristics for pulmonary delivery applications are manufacturable by compressed anti-solvent precipitation when the drug is processed in a feed solution including the drug in a cosolvent system including two or more mutually soluble organic solvents. Surprisingly, it has further been found that the powders so manufactured can be efficiently aerosolized in a variety of inhalers, with a particularly preferred inhaler involving fluidization of the powder in a chamber under certain conditions that effectively disaggregate large particle units manufacturable by the present invention. It has further been surprisingly found that the aerosolizability of powders of the present invention can be modified through modification of the geometry of the precipitation chamber used during the compressed anti-solvent manufacture. In particular, powders having tap densities in a desirable range of from about 0.1 to about 0.5 g/cm
3
can be prepared using a shorter precipitation chamber, while using a longer chamber tends to promote lower tap density powders. The higher tap density powders are particularly preferred for use with certain dry powder inhalers.
In one aspect the present invention provides a method of making drug-containing powders in which a feed solution including the drug in such a cosolvent system is contacted with a compressed anti-solvent fluid, typically compressed carbon dioxide in a near critical or supercritical state, to precipitate drug-containing particles that are then separated from the anti-solve

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