Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1999-04-27
2001-09-04
Dudash, Diana (Department: 1619)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S489000, C424S045000, C424S046000, C514S002600, C514S012200, C514S013800
Reexamination Certificate
active
06284282
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to spray freeze drying of proteins for pharmaceutical administration.
BACKGROUND OF THE INVENTION
Inhalation therapy involves the administration of a drug in an aerosol from to the respiratory tract. Aerosol delivery is based on the concept that delivery to the deep lung regions (alveoli), which account of 95% of lung epithelia, can significantly enhance the transport of the protein through the epithelial membrane if the molecule is bioavailable.
Two general types of aerosols are employed: liquid particles and solid particles. The liquid aerosols are generated by nebulizing solutions of the drug. Solid particles are either in the form of a powder suspended in a propellant which is administered from a metered dose inhaler or simply as a powder that is administered from a dry powder inhaler. In the case of polypeptide drugs, solid particle aerosols are typically made by lyophilizing (also known as freeze-drying) the drug from solution and then milling or grinding the lyophilized drug to the desired particle size distribution for pulmonary administration.
Recently, the possibility of using spray-drying to formulate aerosol powders of therapeutic proteins has been discussed. Spray drying is a dehydration process that utilizes heat from a hot gas stream (usually air) to evaporate dispersed droplets created by atomization of a continuous liquid feed. Using these methods, products can be dried within a few seconds into fine particles, and this general process has been used for decades to prepare dry pigments and dairy powders. As applied to specific therapeutic proteins, however, thermal denaturation and structural alterations are a concern. This is generally attributed to the loss of hydration water molecules required to form hydrogen bonds to stabilizes the secondary structure; generally spray-drying is done with excipients such as carbohydrates that can act as water-replacing agents.
There are several reports of spray drying therapeutic proteins for pulmonary delivery. Maa et al. report on the use of polysorbate-20 surfactant to form stable, rhGH formulations.
J. Pharm. Sci
. 87(2):152 (1998). See also Mumenthaler et al.,
Pharm. Res
. 11(1):12 (1994); Chan et al.,
Pharm. Res
. 14(2):431 (1997), and WO 97/41833, which discusses the spray-drying of biological macromolecules.
In addition, Gombotz et al. discuss a system for spraying polymers dissolved in solvents into freezing liquids and then extracting the solvents, to form hardened microspheres. The polymers also can contain active agents such as proteins, peptides, nucleic acids, etc., to form microspheres suitable for controlled release of the active agents. See U.S. Pat. No. 5,019,400 and WO 90/13285. Also, there are reports of forming particulate proteins using spraying into super critical fluids; see Yeo et al.,
Biotechnology and Bioengineering
41:341 (1993) and Winters et al.,
J. Pharm. Sci
. 85(6):586 (1996).
Considerable attention has been given to the design of therapeutic aerosol inhalers to improve the efficiencies of inhalation therapies. This includes exploration of the aerosol's surface texture, in an attempt to avoid particle aggregation, a phenomenon that considerably diminishes the efficacy of inhalation therapies. However, there has been little focus on the possibility of using large particle sizes (greater than 5 &mgr;m), despite the fact that intra particle adhesion diminishes with increasing particle size. This is so because particles of greater than 5 &mgr;m are known to deposit excessively in the upper airways to the exclusion of the alveolar regions of the deep lung.
Thus, dry powder aerosols for inhalation therapies are produced with mean diameters of less than 5 &mgr;m. There has been work done using polyester graft copolymers that are have mean diameters from 5 to 30 &mgr;m but are aerodynamically light; see WO 97/44013.
Accordingly, there is a need to provide improved compositions for the aerosol delivery of therapeutic proteins in a form that shows high dispersibility and good respirability properties.
SUMMARY OF THE INVENTION
In accordance with the objects outlined above, the present invention provides spray freeze dried dry powder therapeutic protein compositions for pulmonary administration comprising particles of a protein of an average size 6-8 &mgr;m. The compositions may be substantially free of an excipient.
In an additional aspect, the present invention provides methods of preparing a dry powder composition comprising spray freeze-drying an aqueous mixture of a protein under conditions to provide a respirable dry powder. Preferably, the method comprises atomizing a liquid formulation comprising a therapeutic protein into a cold fluid to prepare frozen droplets. The water is removed from the droplets to form powder particles and the particles are recovered. The method may additionally comprise an annealing step, wherein the temperature of the frozen droplets is raised prior to the removal of the water.
In a further aspect, the invention provides methods for aerosolizing a spray freeze dried dry powder therapeutic protein composition comprising dispersing an amount of the dry powder in a gas stream to form an aerosol. The aerosol may be captured in a chamber suitable for subsequent inhalation by a patient.
In an additional aspect, the invention provides methods of administering a therapeutically effective dose of a therapeutic protein to a patient comprising administering to the alveolar regions of the lungs of the patient a spray freeze dried therapeutic protein dry powder composition.
In an additional aspect, the invention provides methods of treating a disorder associated with the therapeutic protein comprising administering to the alveolar regions of the lungs of a patient a dry powder composition of the invention.
In a further aspect, the invention provides unit dosage receptacles and dry powder inhalers comprising a therapeutically effective amount of the dry powder compositions of the invention.
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Edwards et al. Science. 1997;276:1868-1871.*
Arakawa and Timasheff, “Preferential interactions of proteins with solvent components in aqueous amino acid solutions”Archives of Biochemistry&Biophysics224(1):169-177 (Jul. 1, 1983).
Arakawa and Timasheff, “Stabilization of protein structure by sugars”Biochemistry21(25):6536-6544 (Dec. 7, 1982).
Broadhead et al., “The effect of process and formulation variables on the properties of spray-dried &bgr;-galactosidase”Journal of Pharmacy&Pharmacology46(6):458-467 (Jun. 1994).
Carpenter et al., “Modes of Stabilization of a Protein by Organic Solutes during Desiccation”Cryobiology25:459-470 (1988).
Carpenter et al., “Separation of freezing- and drying-induced denaturation of lyophilized proteins using stress-specific stabilization. I. Enzyme activity and calorimetric studies”Archives of Biochemistry&Biophysics303(2):456-464 (Jun. 1993).
Carpenter et al., “The Mechanism of Cryoprotection of Proteins by Solutes”Cryobiology25:244-255 (1988).
Chan et al., “Spray dried powders and powder blends of recombinant human deoxyribonuclease (rhDNase) for aerosol delivery”Pharmaceutical Research14(4):431
Maa Yuh-Fun
Nguyen Phuong-Anh
Dudash Diana
Genentech Inc.
Sharareh Shahnam
Svoboda Craig G.
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