Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Reexamination Certificate
2002-05-31
2004-12-14
Page, Thurman K. (Department: 1616)
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
C424S043000, C424S085700, C424S085400
Reexamination Certificate
active
06830744
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to stable, aqueous solution formulations of alpha-type interferon for aerosolization and pulmonary delivery thereof.
BACKGROUND OF THE INVENTION
Although recombinant human alpha-type interferon has been available in isolated form for some time, it is currently produced in formulations specifically designed to be administered by injection, e.g., by subcutaneous or intravenous injection. An important perceived advantage of administration by injection is that the dose and activity of the protein can be carefully controlled. For example, the protein can be prepared in stable aqueous form, stored over extended periods without loss of activity or change in its state of aggregation, then administered in a precisely known volume.
U.S. Pat. No. 4,496,537 to Kwan discloses biologically stable alpha interferon aqueous solution formulations containing alpha interferon, human serum albumin and alanine or glycine, water, and a buffer system to maintain the pH at 6.5-8.0. The human serum albumin acts as a stabilizer for alpha interferon and prevents losses of alpha interferon from solution by coating and/or adsorption of the alpha interferon onto the stainless steel and glass surfaces of compounding vessels, process equipment and storage containers. Solution formulations containing alpha interferon and human serum albumin have maintained the chemical and biological stability of the alpha interferon when such solutions have been stored at 2-8° C. for extended periods, i.e., more than 2 years.
U.S. Pat. No. 5,766,582 to Yuen et al. describes a stable aqueous solution of alpha-type interferon that is formulated for subcutaneous injection. U.S. Pat. No. 5,766,582 notes that the worldwide AIDS epidemic has resulted in health registration agencies requiring manufacturers to place warnings on products, such as alpha interferon, which contain products derived from human blood such as HSA (human serum albumin). For this reason, the patent noted the need to reformulate alpha-interferon solution products to obtain a solution formulation free of human blood-derived products such as HSA while maintaining high chemical, high physical stability and high biological activity for alpha interferon in the aqueous solution formulations for extended storage periods.
Subsequent to the filing for U.S. Pat. No. 5,766,582, increased concerns over the spread of spongiform encephalitis have arisen. Because of this, it is now important to formulate compositions containing alpha interferon so as to be free not only of products derived from human blood, but to be free of products derived from animal (such as bovine, for example) origin as well.
Further, there is a need for improved formulations and delivery mechanisms for the delivery of alpha interferon which are more patient friendly and apt to increase patient compliance. Typically, patients show varying degrees of avoidance patterns when it comes to the need to recurrently inject themselves (or have someone else inject them) to administer a drug subcutaneously. This tends to be a factor in non-compliance, with patients often missing some of their scheduled injections which may be forgotten largely due to subconscious avoidance.
By contrast, administering alpha-interferon via an aerosol to the deep lung by inhalation, requires aerosolizing the protein from a concentrated solution of alpha-interferon, which presents several challenges and which the above-noted solutions are not formulated for. In particular, it has not been known heretofore whether and how alpha-interferon could be aerosolized without loss of activity and/or protein aggregation, particularly where the aerosol is formed under shear conditions necessary to produce a desired aerosol-particle size range. Additionally, it has not been known whether or to what degree the protein would pass through the alveolar membranes for systemic delivery. Nor has it been known whether or how alpha-interferon could be formulated at concentrations so that its activity and molecular-size characteristics are maintained over an extended storage condition, yet still allow the desired protein properties and particle-size distribution profile in an aerosol. Nor has it been known the proper formulations, if any, for a therapeutic dose to be systemically delivered via the lungs.
SUMMARY OF THE INVENTION
The present invention provides concentrated stable, aqueous formulations of alpha interferon for aerosol delivery, which are free of human blood-derived products and animal blood-derived products, and which may be efficiently delivered to the lungs of a patient for systemic absorption. The formulations may include about 0.5 to about 12.0 mg alpha interferon per mL of the formulation; a buffer system capable of maintaining the pH of the formulation within the range of about 7.0 to 8.0; a stabilizer; and water.
The preferred alpha interferon is alpha-2b interferon, although the present invention is not limited to use of alpha-2b interferon as other interferons or combinations of one or more other alpha interferons with or without alpha-2b interferon may be employed.
A preferred stabilizer is a poly(oxy-1,2-ethanediyl) derivative, more preferably Polyoxyyethlene 20 sorbitan monolaurate or sorbitan, monododecanoate, also called Polysorbate 20 or Tween 20, most preferably high purity Polysorbate 20 or Tween 20 derived from non-animal sources with low peroxide and low carbonyl content.
The buffer system is preferably Na2HPO4.7H2O and NaH2PO4.2H2O.
One preferred formulation includes about 5.0 to about 6.0 mg alpha-2b interferon per mL of the formulation, about 5.5 to about 6.0 mg Na2HPO4.7H2O per mL[l] of the formulation; about 0.45 to about 0.60 mg NaH2PO4.2H2O per ml of the formulation; about 1.00 to about 2.00 mg Polysorbate 20 per mL of the formulation; and water for injection as the solvent; wherein the amounts of Na2HPO4.7H2O and NaH2PO4.2H2O are adjusted to bring the pH of the formulation to about 7.4 to 7.6.
Further provided is an article of manufacture comprising at least one sterilized component; and a stable, aqueous formulation of alpha interferon for aerosol delivery. The formulation is free of human blood-derived products and animal blood-derived products, and includes about 0.5 to about 12.0 mg alpha interferon per mL of the formulation; a buffer system capable of maintaining the pH of the formulation within the range of about 7.0 to 8.0; a poly(oxy-1,2-ethanediyl) derivative; and water.
The sterilized component(s) of the article of manufacture may include a single dose container which is adapted to be sealed aseptically after receiving the sterile filtered formulation.
A method of providing alpha interferon in a form and concentration able to be systemically delivered to a patient via the lungs is provided, wherein the method includes the steps of: providing an aqueous alpha interferon solution having a known, selected alpha interferon biological activity, and containing a buffering system and a stabilizing agent; packaging a unit dose into the container-closure system and aerosolizing the solution with a device to form an aerosol of aqueous droplets, wherein the aerosol has a fine particle fraction of greater than 50%, preferably about 90 to 100 percent.
The fine particle fraction comprises particles having a mass median aerodynamic diameter of less than about 6.5 microns, preferably less than about 5 microns, more preferably less than about 3.5 microns.
A method to administer alpha interferon to the deep lung of a patient in a form and concentration able to be systemically absorbed and provide a therapeutic dose is provided to include the steps of: providing an aqueous alpha interferon solution being free of human blood-derived products and animal blood-derived products and comprising about 0.5 to about 12.0 mg alpha interferon per ml; a buffer system capable of maintaining the pH of the solution within the range of about 7.0 to 8.0; a sorbitan, monododecanoate; and water; aerosolizing the solution to form an aerosol of aqueous droplets, wherein the aerosol h
Balwani Gul
Boyd Brooks
Whatley John
Aradigm Corporation
Bozicevic Karl
Bozicevic, Field & Francis
Haghighatian Mina
Page Thurman K.
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