Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2001-12-20
2003-10-21
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S501000, C424S422000
Reexamination Certificate
active
06635283
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates generally to biodegradable particles of low density and large size for drug delivery to the pulmonary system.
Biodegradable particles have been developed for the controlled-release and delivery of protein and peptide drugs. Langer, R.,
Science,
249: 1527-1533 (1990). Examples include the use of biodegradable particles for gene therapy (Mulligan, R. C.
Science,
260: 926-932 (1993)) and for ‘single-shot’ immunization by vaccine delivery (Eldridge et al.,
Mol. Immunol.,
28: 287-294 (1991)).
Aerosols for the delivery of therapeutic agents to the respiratory tract have been developed. Adjei, A. and Garren,
J. Pharm. Res.
7, 565-569 (1990); and Zanen, P. and Lamm, J.-W. J.
Int. J. Pharm.
114, 111-115 (1995). The respiratory tract encompasses the upper airways, including the oropharynx and larynx, followed by the lower airways, which include the trachea followed by bifurcations into the bronchi and bronchioli. The upper and lower airways are called the conducting airways. The terminal bronchioli then divide into respiratory bronchioli which then lead to the ultimate respiratory zone, the alveoli, or deep lung. Gonda, I. “Aerosols for delivery of therapeutic and diagnostic agents to the respiratory tract,” in
Critical Reviews in Therapeutic Drug Carrier Systems
6:273-313, 1990. The deep lung, or alveoli, are the primary target of inhaled therapeutic aerosols for systemic drug delivery.
Inhaled aerosols have been used for the treatment of local lung disorders including asthma and cystic fibrosis (Anderson et al.,
Am. Rev. Respir. Dis.,
140: 1317-1324 (1989)) and have potential for the systemic delivery of peptides and proteins as well (Patton and Platz,
Advanced Drug Delivery Reviews,
8:179-196 (1992)). However, pulmonary drug delivery strategies present many difficulties for the delivery of macromolecules; these include protein denaturation during aerosolization, excessive loss of inhaled drug in the oropharyngeal cavity (often exceeding 80%), poor control over the site of deposition, irreproducibility of therapeutic results owing to variations in breathing patterns, the often too-rapid absorption of drug potentially resulting in local toxic effects, and phagocytosis by lung macrophages.
Considerable attention has been devoted to the design of therapeutic aerosol inhalers to improve the efficiency of inhalation therapies. Timsina et. al.,
Int. J. Pharm.
101, 1-13 (1995); and Tansey, I. P.,
Spray Technol. Market
4, 26-29 (1994). Attention has also been given to the design of dry powder aerosol surface texture, regarding particularly the need to avoid particle aggregation, a phenomenon which considerably diminishes the efficiency of inhalation therapies owing to particle aggregation. French, D. L., Edwards, D. A. and Niven, R. W.,
J. Aerosol Sci.
27, 769-783 (1996). Attention has not been given to the possibility of using large particle size (>5 &mgr;m) as a means to improve aerosolization efficiency, despite the fact that intraparticle adhesion diminishes with increasing particle size. French, D. L., Edwards, D. A. and Niven, R. W.
J. Aerosol Sci.
27, 769-783 (1996). This is because particles of standard mass density (mass density near 1 g/cm
3
) and mean diameters >5 &mgr;m are known to deposit excessively in the upper airways or the inhaler device. Heyder, J. et al,
J. Aerosol Sci.,
17:811-825 (1986). For this reason, dry powder aerosols for inhalation therapy are generally produced with mean diameters primarily in the range of <5 &mgr;m. Ganderton, D.,
J. Biopharmaceutical Sciences
3:101-105 (1992); and Gonda, I. “Physico-Chemical Principles in Aerosol Delivery,” in Topics in Pharmaceutical Sciences 1991, Crommelin, D. J. and K. K. Midha, Eds., Medpharm Scientific Publishers, Stuttgart, pp. 95-115, 1992. Large “carrier” particles (containing no drug) have been co-delivered with therapeutic aerosols to aid in achieving efficient aerosolization among other possible benefits. French, D. L., Edwards, D. A. and Niven, R. W.
J. Aerosol Sci.
27, 769-783 (1996).
Local and systemic inhalation therapies can often benefit from a relatively slow controlled release of the therapeutic agent. Gonda, I., “Physico-chemical principles in aerosol delivery,” in:
Topics in Pharmaceutical Sciences
1991, D. J. A. Crommelin and K. K. Midha, Eds., Stuttgart: Medpharm. Scientific Publishers, pp. 95-117, (1992). Slow release from a therapeutic aerosol can prolong the residence of an administered drug in the airways or acini, and diminish the rate of drug appearance in the bloodstream. Also, patient compliance is increased by reducing the frequency of dosing. Langer, R.,
Science,
249:1527-1533 (1990); and Gonda, I. “Aerosols for delivery of therapeutic and diagnostic agents to the respiratory tract,” in
Critical Reviews in Therapeutic Drug Carrier Systems
6:273-313, (1990).
The human lungs can remove or rapidly degrade hydrolytically cleavable deposited aerosols over periods ranging from minutes to hours. In the upper airways, ciliated epithelia contribute to the “mucociliary escalator” by which particles are swept from the airways toward the mouth. Pavia, D. “Lung Mucociliary Clearance,” in
Aerosols and the Lung: Clinical and Experimental Aspects
, Clarke, S. W. and Pavia, D., Eds., Butterworths, London, 1984. Anderson et al.,
Am. Rev. Respir. Dis.,
140: 1317-1324 (1989). In the deep lungs, alveolar macrophages are capable of phagocytosing particles soon after their deposition. Warheit, M. B. and Hartsky, M. A.,
Microscopy Res. Tech.
26:412-422 (1993); Brain, J. D., “Physiology and Pathophysiology of Pulmonary Macrophages,” in
The Reticuloendothelial System
, S. M. Reichard and J. Filkins, Eds., Plenum, N.Y., pp. 315-327, 1985; Dorries, A. M. and Valberg, P. A.,
Am. Rev. Resp. Disease
146, 831-837 (1991); and Gehr, P. et al.
Microscopy Res. and Tech.,
26, 423-436 (1993). As the diameter of particles exceeds 3 &mgr;m, there is increasingly less phagocytosis by macrophages. Kawaguchi, H. et al.,
Biomaterials
7:61‥66 (1986); Krenis, L. J. and Strauss, B.,
Proc. Soc. Exp. Med.,
107:748-750 (1961); and Rudt, S. and Muller, R. H., J.
Contr. Rel.,
22: 263-272 (1992). However, increasing the particle size also minimizes the probability of particles (possessing standard mass density) entering the airways and acini due to excessive deposition in the oropharyngeal or nasal regions. Heyder, J. et al.,
J. Aerosol Sci.,
17: 811-825 (1986). An effective dry-powder inhalation therapy for both short and long term release of therapeutics, either for local or systemic delivery, requires a powder that displays minimum aggregation, as well as a means of avoiding or suspending the lung's natural clearance mechanisms until drugs have been effectively delivered.
There is a need for improved inhaled aerosols for pulmonary delivery of therapeutic agents. There is a need for the development of drug carriers which are capable of delivering the drug in an effective amount into the airways or the alveolar zone of the lung. There further is a need for the development of drug carriers for use as inhaled aerosols which are biodegradable and are capable of controlled release of drug within the airways or in the alveolar zone of the lung.
It is therefore an object of the present invention to provide improved carriers for the pulmonary delivery of therapeutic agents. It is a further object of the invention to provide inhaled aerosols which are effective carriers for delivery of therapeutic agents to the deep lung. It is another object of the invention to provide carriers for pulmonary delivery which avoid phagocytosis in the deep lung. It is a further object of the invention to provide carriers for pulmonary drug delivery which are capable of biodegrading and releasing the drug at a controlled rate.
SUMMARY OF THE INVENTION
Improved aerodynamically light particles for drug delivery to the pulmonary system, and methods for their synthesis and administration are provided. In a preferred embodiment, the particles are
Ben-Jebria Abdellaziz
Caponetti Giovanni
Edwards David A.
Hanes Justin
Hrkach Jeffrey S.
Howard S.
Page Thurman K.
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