Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/007—Pulmonary tract; Aromatherapy
  • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
  • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/19—Cytokines; Lymphokines; Interferons
  • A61K38/21—Interferons [IFN]
  • A61K38/212—IFN-alpha
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

Definitions

• the present invention relates to stable, aqueous solution formulations of alpha-type interferon for aerosolization and pulmonary delivery thereof.
• U.S. Patent 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. Patent 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.
• HSA human serum albumin
• 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.
• 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.
• proper formulations, if any, for a therapeutic dose to be systemically delivered via the lungs are not known.
• 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-l,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.
• 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-l,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 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 per cent.
• 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 has a fine particle fraction of over 50%, preferably about 90 to 100 per cent; and delivering the aqueous droplets to the patient's respiratory tract.
• the alpha interferon is alpha-2b interferon.
• Fig. 1 shows the pharmacokinetic concentrations over time of various alpha interferon formulations administered to patients according to the present invention, in comparison with formulations which were subcutaneously injected.
• Fig. 2 shows mean concentrations of 2,5 AS over time as patient responses to various alpha interferon formulations administered to patients according to the present invention, in comparison with formulations which were subcutaneously injected.
• Fig. 3 is a flow chart describing a study which was conducted to investigate whether or not Polysorbate 20 at varying levels in the formulation can protect the present formulations from forces inherent in the extrusion and aerosolization process.
• Figs. 1 shows the pharmacokinetic concentrations over time of various alpha interferon formulations administered to patients according to the present invention, in comparison with formulations which were subcutaneously injected.
• Fig. 3 is a flow chart describing a study which was conducted to investigate whether or not Polysorbate 20 at varying levels in the formulation can protect the present formulations from forces inherent in the extrusion and aerosolization process.
• FIG. 4A and 4B show SE-HPLC results of the effects of extrusion and aerosolization on formulations according to the present invention.
• Fig. 5 shows an exemplary device for carrying out aerosolization methods according to the present invention.
• Fig. 6 shows an example of a hand-held AERx System which may be used for carrying out aerosolization methods according to the present invention. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
• a stabilizer includes a plurality of such stabilizers and reference to “the nozzle” includes reference to one or more nozzles and equivalents thereof known to those skilled in the art, and so forth.
• Alpha-interferon refers to the class of nonglycosylated cytokine proteins of approximately 19.5 kDa having antiviral, immunomodulating, and antiproliferative actions. These can be derived naturally or synthesized by conventional or recombinant DNA technology.
• Recombinant Human Interferon Alpha-2b refers to Human Interferon Alpha-2b that is produced according to the information coded by the alpha-2 sub-species of interferon alpha gene incorporated into the transformed E coli host cell by recombinant DNA technology.
• the lowercase “b” refers to an arginine residue in the twenty-third position of the protein sequence.
• “Aerodynamic diameter” is the diameter of a particle with unit density that settles at the same velocity as the particle in question under the influence of gravity.
• “Aerosol” means a suspension of particles in a gaseous medium, e.g., air.
• aqueous aerosol is an aerosol formed from an aqueous solution (i.e., a solution containing water as a solvent).
• aqueous aerosol is an aerosol formed from an aqueous solution (i.e., a solution containing water as a solvent).
• Chemical stability refers to the stability of the drug compound itself. To be chemically stable, the chemical structure remains constant and doesn't degrade.
• Physical stability refers to the drug staying in solution, as a clear solution. To be physically stable, the drug cannot denature and come out of solution, i.e., the solution stays clear.
• “Functional stability” refers to the stability of the formulation when used in an aerosolization device. To have functional stability, good aerosol performance must be achieved consistently. The aerosol generated has the same attributes, e.g., consistent viable fraction throughout.
• Emitted dose or "ED” is the amount of aerosolized particles of the active ingredient (e.g., recombinant human interferon alpha-2b) that is emitted from a drug delivery device.
• “Mean emitted dose” is an arithmetic average of the emitted doses released over a repetition of a plurality of deliveries under the same conditions.
• "Fine particle fraction” or “FPF” is the fraction of particles in an emitted dose that are of a size capable of reaching the deep lung or alveolar membranes.
• fine particle fraction is calculated herein as that fraction of the particles which are less than or equal to about 3.5 microns as measured by a Cascade Impactor, light scattering methods, phase Doppler particle sizing or other applicable methods.
• FPD fluoride-dielectric
• FPD ED x FPF
• MMAD mass median aerodynamic diameter
• Particle size distribution is a description of the way the mass of the aerosol is distributed across the range of aerosol particle sizes.
• Dosage form or “DF” is a container closure system that is used to hold a dose (or partial dose) of a formulation prior to aerosolizing it.
• PK Pharmacopeia to determine the quantity of microorganisms present per mL of the formulation.
• PD Pharmacodynamics
• Merobe free refers to the formulation being rendered free from microorganisms by aseptically passing it through a sterilized microbial retentive filter membrane.
• Subcutaneous injection is an invasive method of drug delivery in which the drug is injected by a needle beneath the skin. Intramuscular injection or intravenous injection, for example, are other invasive methods of drug delivery utilizing a syringe and a needle for injection.
• System efficiency is defined as the portion of the drug in the container-closure system that reaches the systemic circulation.
• Bioavailability refers to the portion of the emitted or delivered or inhaled dose from the container-closure system that reaches the systemic circulation.
• "High purity” or “specially purified” are descriptors used herein in reference to stabilizers which are chemically pure, i.e., have a peroxide concentration less than or equal to about 0.5 micro moles per gram and a carbonyl concentration less than or equal to about
• a stable, aqueous formulation of alpha interferon was developed according to the present invention as required for successful systemic delivery of alpha interferon via the deep lung tissues (i.e., alveolar membranes).
• the formulation needed to be capable of being manufactured and stored in sterile, sealed dosage forms, and exhibit chemical and physical stability over a period of at least six months and preferably 2 years or more at temperatures of about 2 to 5 °C.
• the formulation also had to be capable of withstanding the stresses of aerosolization during the delivery of the drug.
• a stabilizing agent is included in the solution to help maintain the alpha interferon in solution.
• the stabilizing agent includes apoly(oxy-l,2-ethanediyl) derivative, such as Polysorbate 20 or Polysorbate 80, more preferably Polysorbate 20 that is low in peroxide and low in its carbonyl content, e.g., high purity Polysorbate 20, available from Sigma Aldrich.
• the stabilizing agent is preferably present in an amount of about 0.5 to about 2.00 mg per mL of solution.
• Ethylene diamine terra acetic acid is preferably not used as a stabilizing agent as it has been shown in some studies to cause bronchospasms and was therefor considered to be unsuitable to the present formulations as presenting too high a risk factor for aerosol delivery of the formulations to the lung.
• a buffering system is added to the solution to adjust it to a pH of about 7.0 to 8.0, more preferably within the range of about 7.4 to 7.6.
• a preferable buffering system includes about 5.5 to about 6.0 mg Na2HPO4.7H2O per ml of solution and about 0.45 to about 0.60 mg NaH2PO4.2H2O per mL of solution
• the solvent is water which is preferably microbe free, free of particulate matter, and free of chemical contaminants, preferably water for injection.
• Therapeutic proteins must be formulated so that they are able to withstand a variety of conditions in the course of manufacture, shipping, storage and use. Screening studies were conducted to see whether or not increasing stabilizer levels could potentially improve the stability of aqueous solutions containing alpha interferon during long-term storage in various container-closure systems. The screening studies included subjecting bulk formulations to mechanical shear, thermal cycling, and aerosolization, such as via the AERx® pulmonary delivery system available from Aradigm Corporation, Hayward, California.
• the solutions should contain at least about 0.5 mg Polysorbate 20, preferably about 1.0 to about 2.0 mg Polysorbate 20 per ml of solution for protection during thawing and processing (e.g., filtration, filling dosage forms, freeze/thaw cycling, short term storage at around 2°to 8°C, preferably about 5°C).
• Tween 20R by Sigma Aldrich
• a specially purified, non-animal, low peroxide, low carbonyl surfactant is the preferred stabilizer.
• the bulk formulations containing stabilizer are preferably kept frozen at about -70 °C, and are thawed at about 2 to 8°C, preferably about 5 °C, for at least 12 hours.
• Solutions having other stabilizers were tested including solutions with 0.5 mg/mL Polysorbate 20; solutions with 130mM sodium chloride and EDTA; solutions with 0.1 mg/mL Polysorbate 20; and solutions with 0.1 mg/mL Polysorbate 20 and 130 mM sodium chloride.
• an alpha interferon solution formulated as above can be aerosolized under conditions that produce particles in a selected size range of less than about 5 microns, more preferably less than about 3.5 microns, with little or no loss in biological activity of the alpha interferon and little or no change in the chemical activity of the alpha interferon.
• the aerosol may be produced by any of a number of devices designed to produce particles in the stated ranges from liquid formulations preferably by forcing the formulation, through pores in a membrane wherein the liquid is driven by hydrostatic pressure, preheating the air into which the aerosol is generated, and subsequently delivering the aerosol to a patient.
• many other methods of aerosol generation can be used, or where various other drivers such as piezoelectric oscillators, jet nebulization, ultrasonic nebulization, spinning top aerosolization, magneto- hydrodynarnic (electrospray) aerosolization, or ultrasonic vibration of a porous membrane are employed to generate the aerosol. Examples of applicable aerosolization devices are described in U.S.
• the AERx® pulmonary delivery system available from Aradigm Corporation, Hayward, California is used for aerosol generation according to the present invention.
• the size of the nozzle holes is in the range of 0.25-6 micrometers or preferably 0.4-3 micro meters, more preferably 0.5-1.5 micrometers.
• the amount of liquid aerosolized, per inhalation is in the range of 10-100 microliters, preferably 25-50 microliters, more preferably 35-45 microliters.
• Fig. 5 shows an exemplary device for carrying out the aerosolization methods according to the present invention and is described in detail in U.S. Patent No. 6,131,570.
• the device 40 is loaded with a disposable package 14.
• a patient inhales air from the mouthpiece 18 through the opening 25 in the cylinder 12.
• the air drawn in through the opening 25 (and optionally the desiccator 24) flows through the flow path 11 of the channel 12.
• the disposable package 14 is comprised of a plurality of disposable containers (or "blister packs") 15.
• Each container 15 includes a drug formulation 16 (i.e., an alpha interferon formulation according to the present invention) and is covered by a nozzle array or porous membrane 17.
• the heating element 2 (which is optional for methods according to the present invention) is located in the flow path 11.
• the heating element 2 is preferably positioned such that all or only a portion of the air flowing through the path 11 will pass by the heating element 2, e.g., flow vent flaps can direct any desired portion of air past the heating element 2.
• the device 40 may include a mouth piece 18 at the end of the flow path 11.
• the patient inhales from the mouth piece 18 which causes an inspiratory flow to be measured by flow sensor 19 within the flow path which path may be, and preferably is, in a non-linear flow-pressure relationship.
• This inspiratory flow causes an air flow transducer 20 to generate a signal.
• This signal is conveyed to a microprocessor 4 which is able to convert the signal from the transducer 20 in the inspiratory flow path 11 to a flow rate in liters per minute.
• the microprocessor 4 can further integrate this continuous air flow rate signal into a representation of cumulative inspiratory volume.
• the microprocessor 4 When the device is turned on by the user, the microprocessor 4 will send a signal to send power from the power source 1 (which is preferably a small battery) to the air temperature controller 2 and will continue to preheat the temperature controller 2 until it reaches a predetermined temperature.
• the preheat temperature can be preprogrammed based on such information as the particle size generated, the particle size desired, the formulation concentration, and other parameters.
• the microprocessor 4 may also adjust the preheat temperature to optimize each delivery based on the ambient conditions, using information from the optional hygrometer/temperature sensor 7.
• the microprocessor 4 also sends a signal to an actuator 22 which causes the mechanical means (e.g., the piston 23 to force drug from a container 15 of the package 14 into the inspiratory flow path 11 of the device 40 where the aerosol is formed and entrained into the inhalation air and delivered into the patient's lungs.
• the mechanical means e.g., the piston 23 to force drug from a container 15 of the package 14 into the inspiratory flow path 11 of the device 40 where the aerosol is formed and entrained into the inhalation air and delivered into the patient's lungs.
• the formulations according to the present invention include water as the carrier, it may also be desirable to include a desiccator 24 within the flow path 11.
• the desiccator 24 is preferably located at the initial opening 25 but may be located elsewhere in the flow path 11 prior to a point in the flow path when the formulation is fired into the flow path in the form of aerosol particles.
• water vapor within the air is removed in part or completely. Therefore, only dried air is drawn into the remainder of a flow path. Since the air is completely dried, water carrier within the aerosol particles will more readily evaporate. This decreases the energy needs with respect to the temperature controller 2.
• the actuator 22 may be any type of device such as a solenoid, which then moves the mechanical release member 21 so that the piston 23 is released.
• the piston 23 is forced upward by a spring or other biasing means 28.
• the biasing means may be held within a grip 29 which can be easily held by the user. Where the microprocessor 4 sends the signal through the line 30 to the actuator 22 the spring is released and a container 15 is crushed and the formulation 16 inside the container is released through the membrane 17.
• the container 15 When the container 15 is present in the drug release position below the piston 23 the container 15 may have vibrating devices 31 and 32 positioned on either side or a single device surrounding the container 15. The vibrating device(s) may be actuated by the microprocessor 4 sending a signal through the connection 23. Empty containers 15 are shown to the left of the drug actuation point. Preferably, a new container and new porous membrane are used for each drug release. By using a new porous membrane each time clogging of the porous membranes is avoided. Further, possible contamination of the formulation 16 present in the container 15 is avoided. [67] Those skilled in the art will recognize that a variety of different components could be used in place of some of the components shown within Fig. 5.
• components such as the humidity sensor 7 and temperature sensor 8 could be eliminated without substantial impairment of operability by simply adjusting the amount of energy supplied to the heating element 2 so as to compensate for any humidity or temperature which might be encounter by the user. However, such would acquire the use of unnecessary amounts of power in some situations.
• the preferred dosage forms 15 are of a "blister pack" type design 15 which have a volume of about 50 microliters.
• the packs or containers 15 are filled with about 45 ⁇ 2.5 microliters of alpha interferon formulation. They are not completely filled to provide a space between the formulation and the lid of the pack 15 as it is heat sealed to enclose the package. The space prevents denaturation of the proteins in the formulation which might otherwise occur if in contact with the lid or top of the package as it is heated during heat sealing.
• Formulations were developed for a dose escalation study to compare the safety, pharmacokinetics and pharmacodynamics of the systemic performance of alpha-interferon delivered through the lungs with that of subcutaneously injected Intron® A (Schering Corporation, Kenilworth, New Jersey).
• a therapeutic dose of Intron® A is about 3 million units of the interferon given three times a week for the treatment of Hepatitis C. Based on this value, a formulation for aerosol delivery was back calculated.
• the aerosolization of the formula was optimized to maximize the amount of fine particle fraction (less than 5 microns, more preferably less than about 3.5 microns) to ensure delivery to the deep lungs in an efficient manner.
• the Intron® A formulations that were used in the comparison were prepared from lyophilized product in vials. Each vial contained 5 MIU of Interferon alfa-2b to be reconstituted with 1 mL of the diluent. After reconstitution with the diluent, each mL of the formula contained 0.019 mg or 5 MIU of interferon alfa-2b, 20 mg of glycine, 2.3 mg sodium phosphate dibasic, 0.55 mg of sodium phosphate monobasic, and 1 mg of human albumin. Two vials were used in the clinic to deliver the 10 MIU dose subcutaneously.
• a partial dose (only a portion of one container) a full dose and a double dose of the formulation according to the present invention were administered, as well a subcutaneous dose of Intron® A equivalent to 10 million units of alpha-2b interferon. The 10 million unit dose was necessary to obtain measurable PK parameters for comparison purposes.
• Table 2 shows the contents, emitted doses and lung doses of the partial, single and double extrusions of formulations which were aerosolized.
• 65 MIU/DF is based on specific activity of 2.6 x 108 IU/mg
• Fig. 1 shows the pharmacokinetic results of the various treatments wherein systemic drug concentrations were determined by serum analysis. Concentrations of interferon (IU/mL) are graphed over time (Hrs) for a period of 72 hours. As was expected, the concentration of alpha-interferon delivered by subcutaneous injection 40 gave the highest spike at about 6 hours, with the double dosage form delivery 30, single dosage form 20 and partial dosage form 10 registering peaks only slightly later and in proportionate concentrations. The concentration for each type of administration tapered off substantially by about 24 hours.
• the aerodynamic administration of the double dosage form 30 gives a greater 2-5 AS profile than even the subcutaneous injection 40. Even a partial dose 10 elicits a 2-5 AS response level greater than that of the subcutaneous injection 40 at a period of about 48 hours after administration.
• the current therapy is to subcutaneously inject about 3 million units of alpha interferon, three times a week.
• This routine can be met by aerosol delivery of 1 blister dosage form , three times a week, to give a therapeutic dose that is non- invasive.
• a lower dose may be given.
• it may be of value to maintain a sustained level by daily dosage (people don't want to inject daily, but inhalation daily may be easier to maintain compliance).
• the formulation had to also be made to be physically, chemically and functionally stable, as well as microbe free with endotoxin levels less than threshold level established as safe, i.e., less than 500 IU/mL
• the processed bulk solutions (both pre and post filtered) were assessed for any chemical or physical instability by the following methods: visual inspection with a fiber light, light scatter at 450 nm, RP-HPLC, and reduced and non-reduced SDS-PAGE. Based on the findings of these studies a method for freezing the bulk solution and selection of an appropriate formulation matrix that provided maximum solution stability for alpha-2b interferon was recommended.
• Table 4 lists the results for pre and post filtered bulk solutions.
• the pooled aerosolized samples (-40 ⁇ g/mL after dilution) were concentrated ⁇ 8 fold by ultrafiltration (used Millipore Centricon YM-3) to a target concentration of ⁇ 300 ⁇ g/mL.
• both reference and degraded solutions were spiked (-200 ⁇ g/mL) onto the CI plates and allowed to dry. The dried protein was recovered using diluent. The controls were concentrated via ultrafiltration to a target concentration of - 300 ⁇ g/mL.
• a control to the ultrafiltration process entailed diluting both active and degraded solutions from -200 ⁇ g/mL to -40 ⁇ g/mL with diluent and then concentrating to a target protein content of - 300 ⁇ g/mL.
• HPLC HPLC, non-reduced and reduced SDS-PAGE, and IEF.

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• 2002
  • 2002-05-31 US US10/159,083 patent/US6830744B2/en not_active Expired - Fee Related
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