Surgery – Respiratory method or device – Means for mixing treating agent with respiratory gas
Reexamination Certificate
2000-05-30
2003-08-19
Lo, Weilun (Department: 3761)
Surgery
Respiratory method or device
Means for mixing treating agent with respiratory gas
C128S203120, C128S203180, C128S203210, C128S205210, C128S203230
Reexamination Certificate
active
06606992
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates generally to the field of drug delivery, and in particular to the delivery of pharmaceutical formulations to the lungs. More specifically, the invention relates to the aerosolization of pharmaceutical formulations using energy created by patient inhalation.
Effective drug delivery to a patient is a critical aspect of any successful drug therapy, and a variety of drug delivery techniques have been proposed. For example, one convenient method is the oral delivery of pills, capsules, elixirs and the like. However, oral delivery can in some cases be undesirable in that many drugs are degraded in the digestive tract before they can be absorbed. Another technique is subcutaneous injection. One disadvantage to this approach is low patient acceptance. Other alternative routes of administration that have been proposed include transdermal, intranasal, intrarectal, intravaginal and pulmonary delivery.
Of particular interest to the invention are pulmonary delivery techniques which rely on the inhalation of a pharmaceutical formulation by the patient so that the active drug within the dispersion can reach the distal (alveolar) regions of the lung. A variety of aerosolization systems have been proposed to disperse pharmaceutical formulations. For example, U.S. Pat. Nos. 5,785,049 and 5,740,794, the disclosures of which are herein incorporated by reference, describe exemplary powder dispersion devices which utilize a compressed gas to aerosolize a powder. Other types of aerosolization systems include MDI's (which typically have a drug that is stored in a propellant), nebulizers (which aerosolize liquids using compressed gas, usually air), and the like.
Another technique which is of interest to the invention is the use of inspired gases to disperse the pharmaceutical formulation. In this way, the patient is able to provide the energy needed to aerosolize the formulation by the patient's own inhalation. This insures that aerosol generation and inhalation are properly synchronized. Utilization of the patient's inspired gases can be challenging in several respects. For example, for some pharmaceutical formulations, such as insulin, it may be desirable to limit the inhalation flow rate within certain limits. For example, PCT/US99/04654, filed Mar. 11, 1999, provides for the pulmonary delivery of insulin at rates less than 17 liters per minute. As another example, copending U.S. patent application Ser. No. 09/414,384 describes pulmonary delivery techniques where a high flow resistance is provided for an initial period followed by a period of lower flow resistance. The complete disclosures of all the above references are herein incorporated by reference.
Another challenge in utilizing the patient's inspired gases is that the inspiration flow rate can drastically vary between individuals. For instance, as shown in
FIG. 1
, a random sample of 17 individuals which were measured twice a week for four weeks produced flow rates ranging from about 5 liters per minute to about 35 liters per minute. Such variability may affect the ability of the formulation to be dispersed within a gas stream, the ability to deagglomerate a powdered formulation, and/or the ability of the aerosolized formulation to adequately reach the deep lung.
Hence, this invention is related to techniques for regulating the flow of inspired gases that may be utilized when dispersing a pharmaceutical formulation. In one aspect, the invention is related to techniques to enhance the ability of a formulation to be dispersed within a gas stream produced by patient inhalation, to enhance the ability to deagglomerate a powdered formulation, and to enhance the ability of the aerosolized formulation to adequately reach the deep lung.
SUMMARY OF THE INVENTION
The invention provides exemplary systems and methods to provide breath actuated, flow regulated aerosol delivery of pharmaceuticals. In one aspect, the invention utilizes the flow of respiratory gases produced by a patient to aerosolize a pharmaceutical formulation. In another particular aspect of the invention, the invention is able to extract a powdered pharmaceutical formulation from a receptacle, deagglomerate the formulation and deliver the formulation to the lungs using a wide range of patient inhalation flow rates. According to another aspect of the invention, devices and methods are provided which provide efficient delivery of a pharmaceutical aerosol to the deep lung.
According to the invention, the flow of respiratory gases may initially be prevented from flowing to the lungs until a predetermined vacuum is produced by the user, at which point the flow of respiratory gases is abruptly initiated. In one particular embodiment, the abrupt initiation of respiratory gas flow is utilized to aerosolize a pharmaceutical formulation. According to this embodiment, respiratory gases are initially prevented from flowing to the lungs when attempting to inhale through an open mouthpiece at one end of the device. The respiratory gases are then abruptly permitted to flow to the lungs after a predetermined vacuum is produced by the user. The flow of respiratory gases is utilized to extract a pharmaceutical formulation from a receptacle and to place the pharmaceutical formulation within the flow of respiratory gases to form an aerosol.
By initially preventing respiratory gases from flowing to the lungs when attempting to inhale, the devices and methods of the present invention provide a way to ensure that the resulting gas stream has sufficient energy to extract the pharmaceutical formulation from the receptacle. In one aspect, the flow of respiratory gases may initially be prevented from flowing to the lungs by placing a valve within an airway leading to the lungs and opening the valve to permit the flow of respiratory gases. According to the invention, the valve is opened when a threshold actuating vacuum caused by the attempted inhalation is exceeded. In this way, when the valve is opened, the resulting gas stream has sufficient energy to extract and aerosolize the pharmaceutical formulation.
In another embodiment, the invention provides an aerosolization device that comprises a housing defining an airway, and a coupling mechanism to couple a receptacle containing a pharmaceutical formulation to the airway. The device further includes a valve to prevent respiratory gases from flowing through the airway until a threshold actuating vacuum is exceeded. At such a time, the valve opens to permit respiratory gases to flow through the airway and to extract the pharmaceutical formulation from the receptacle to form an aerosol.
A variety of threshold valves may be employed to prevent gases from flowing through the airway as will be discussed in detail below. For example, the valve may comprise an occlusion member having an opening, and a pull through member that is pulled through the opening when the threshold actuating vacuum is produced. As one specific example, the occlusion member may comprise an elastically compliant membrane, and the pull through member may comprise a ball that is pulled through the membrane when the threshold vacuum has been achieved. In another aspect, the threshold actuating vacuum of the valve is in the range from about 20 cm H
2
O to about 60 cm H
2
O. In one particular aspect, the valve is configured to be disposed within the receptacle. In this way, the valve may conveniently be manufactured along with the receptacle.
According to another aspect, the invention provides devices and methods for regulating the flow of respiratory gases to provide consistent airflow, independent of the breathing rate of the user. In another aspect, the system includes a regulation system to regulate the flow of respiratory gases through the airway after the valve has been opened. The combination of flow regulation with the threshold valve according to the present invention results in devices and methods for aerosol delivery that are effective in delivering the aerosolized formulation to the deep lung.
In still another aspect,
Alston, Jr. William W.
Bakshi Aneesh
Clark Andrew
Nason Kevin S.
Paboojian Steve
Cagan Felissa H.
Erezo Darwin
Lo Weilun
Nektar Therapeutics
Tucker Guy V.
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