Drug – bio-affecting and body treating compositions – Lymphokine – Interferon
Reexamination Certificate
1997-07-14
2001-05-15
Guzo, David (Department: 1636)
Drug, bio-affecting and body treating compositions
Lymphokine
Interferon
C530S351000, C514S002600
Reexamination Certificate
active
06231851
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to methods and compositions for the dry powder formulation of cytokines, especially interferons. More particularly, the present invention relates to the spray drying of interferons (IFNs) to produce dry powder formulations of high potency.
2. Description of the Background Art
Interferons are cytokines useful in the treatment of a variety of human diseases ranging from cancer to immune system enhancement. Interferons are commonly formulated as isotonic aqueous solutions for parenteral administration. Recently, clinicians have sought alternative routes of administration for interferons more suitable to long term use by patients. Particularly, aerosol formulations of interferons have been produced for pulmonary delivery as described in WO 91/16038. The formulation is dispersed by volatilization of a liquid propellent. The patent teaches adding a surfactant or the like to improve the dispersibility of a human interferon from a freon delivery system.
Methods and compositions for the preparation of solid polypeptide microparticles as a pharmaceutical aerosol formulation are disclosed in WO 91/16038 wherein IFN-beta was prepared in dry powder form by lyophilizing an aqueous solution of IFN and jet milling following lyophilization. The purification of proteins of molecular weight in excess of 12,000, including human IFN is disclosed in U.S. Pat. No.: 4,503,035. Low pH pharmaceutical compositions of recombinant IFN-beta are disclosed in WO 89/05158.
Because interferons are fairly expensive compounds, it is highly desirable to have formulations of high potency with improved flow characteristics that can be used with high efficiency in dry powder inhalers to produce reproducible doses for pulmonary delivery.
An object of the present invention is to provide an interferon-containing composition suitable for long-term pulmonary administration to a patient in need thereof. Another object of this invention is to provide an interferon-containing powdered composition that is administered by inhalation in a manner that is free of a liquid propellant such as a “FREON” or carbon dioxide.
Another object of this invention is to provide an interferon-containing powdered composition that can be easily manufactured by a method that maintains a high percentage of interferon activity.
Still another object of this invention is to provide an interferon-containing composition that exhibits a high level of stability of the interferon over time.
Other objects may be apparent to one of ordinary skill upon reviewing the following specification and claims.
SUMMARY OF THE INVENTION
One aspect of this invention is an interferon-based dry powder composition for pulmonary delivery, said composition comprising a therapeutically effective amount of interferon in combination with a pharmaceutically acceptable carrier.
Another aspect of this invention is a unit dosage form for pulmonary delivery of interferon, which dosage form comprises a unit receptacle containing the interferon-based dry powder composition of this invention.
A third aspect of this invention is a method of treating a disease state responsive to treatment by interferon, which method comprises administering a physiologically effective amount of the interferon-based dry powder composition to the pulmonary region of the lung of a subject in need thereof.
Still another aspect of this invention is a method for aerosolizing the interferon-based dry powder composition that comprises dispersing an amount of the dry powder composition in a gas stream to form an aerosol and capturing the aerosol in a chamber having a mouthpiece for subsequent inhalation by a patient.
Still another aspect of this invention is a method for preparing the interferon-based dry powder composition that comprises spray-drying an aqueous mixture of the interferon and the carrier under conditions to provide a respirable dry powder.
DESCRIPTION OF SPECIFIC EMBODIMENTS
The present invention is based at least in part on the higher potency and improved flow characteristics of interferon-based dry powder compositions produced by spray drying according to the present invention. Higher potency means that the resulting interferon-based composition has a higher percentage of physiologically active interferon than compositions prepared by other methods. The compositions of the invention are readily aerosolized and rapidly absorbed through the lungs of a host when delivered by a dry powder inhaler.
DEFINITIONS
In interpreting the claims to the various aspects of this invention, there are several important definitions that should be considered.
The term “interferon” is meant to include the family of naturally-occurring or recombinantly prepared small proteins and glycoproteins (sometimes referred to as cytokines) with molecular weights between approximately 15,000 and 27,000 daltons and having interferon-like activity. Generally, such activity is exerted by binding to specific membrane receptors on a cell surface. Once bound, interferons initiate a complex series of intracellular events that vary among the various interferons. Interferons are useful in the treatment of a variety of human conditions varying from cancer to immune system suppression. Naturally occurring interferons are produced and secreted by cells in response to viral infections and to synthetic and biological inducers. Some interferons are modified versions of the naturally occurring material and are prepared using recombinant DNA technology. Interferon is sometimes abbreviated as “IFN” and shall be so abbreviated in this application. Examples of interferons include, e.g. IFN-alpha-2A recombinant (“ROFERON®” A-Roche Laboratories), IFN-alpha-2B recombinant (“INTRON®” A-Shering), IFN-alpha-N3 human leukocyte derived (“ALFERON®” N-Purdue Frederick), IFN-gamma-1B (“ACTIMMUNE®”-Genentech), IFN-beta recombinant (“BETASERON®”-Chiron, Berlex), IFN-beta naturally occurring (“FERON®”-Toray, Japan), and the like. U.S. Pat. No. 4,503,035 issued Mar. 5, 1985 to Pestka and Rubinstein gives examples of human leukocyte IFNs. For purposes of this invention IFN-beta is preferred, particularly naturally occurring IFN-beta.
The term “powder” means a composition that consists of finely dispersed solid particles that are free flowing and capable of being readily dispersed in an inhalation device and subsequently inhaled by a subject so that the particles reach the lungs to permit penetration into the alveoli. Thus, the powder is said to be “respirable.” Preferably the average particle size is less than about 10 microns (&mgr;m) in diameter with a relatively uniform spheroidal shape distribution. More preferably the diameter is less than about 7.5 &mgr;m and most preferably less than about 5.0 &mgr;m. Usually the particle size distribution is between about 0.1 &mgr;m and about 5 &mgr;m in diameter, particularly about 2 &mgr;m to about 5 &mgr;m.
The term “dry” means that the composition has a moisture content such that the particles are readily dispersable in an inhalation device to form an aerosol. This moisture content is generally below about 10% by weight (% w) water, usually below about 5% w and preferably less than about 3% w.
The term “therapeutically effective amount” is the amount present in the composition that is needed to provide the desired level of interferon in the subject to be treated to give the anticipated physiological response. This amount is determined for each interferon on a case-by-case basis. Guidelines are given hereafter.
The term “physiologically effective amount” is that amount delivered to a subject to give the desired palliative or curative effect. This amount is specific for each interferon and its ultimate approved dosage level. Guidelines are given hereafter.
The term “pharmaceutically acceptable” carrier means that the carrier can be taken into the lungs with no significant adverse toxicological effects on the lungs.
COMPOSITIONS OF THE INVENTION
One aspect of this invention is an interferon-based dry powder composition for pulm
Foster Linda C.
Kimura Shigenobu
Platz Robert M.
Satoh Yu-ichiro
Cagan Felissa H.
Evans Susan T.
Guzo David
Hurst Stephen L.
Inhale Therapeutic Systems
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