Patent Grant
7367335
The present invention relates to methods and devices for delivering therapeutic agents to a patient's lungs.
A particulate therapeutic agent may be carried by a carrier gas to a patient's lungs to treat the patient. For example, the carrier gas may be oxygen, and the therapeutic agent may be a liquid particulate or solid particulate. Such a mixture may be an aerosol. Such a mixture may be formed by nebulizing a liquid into the carrier gas. This method of administration may be advantageous when the therapeutic agent targets a specific site of action that is readily accessed by inspiration, or when pulmonary uptake of a therapeutic agent from the systemic circulation is suboptimal, or when systemic blood levels of a therapeutic agent are to be minimized. Examples of therapeutic agents that may be administered in this manner include bronchodilators, steroids, antibiotics, mucolytics, DNA lytic enzymes and genetic vectors for the treatment of lung disease. For example, antifungal and antiviral agents have been administered as aerosols. Further, chemotherapeutic agents for pulmonary malignancy and a host of pulmonary therapies having potential systemic toxicity or undesirable systemic side effects have been nebulized. Additional therapies may include surfactant administration, perfluorocarbon delivery and liposomal drug administration.
The respiratory cycle of a human being is comprised of inspiration and expiration. Inspiration accounts for roughly ¼ of the respiratory cycle and expiration accounts for roughly ¾ of the respiratory cycle. If a therapeutic agent is continuously moved past a patient's mouth, roughly ¾ of the therapeutic agent may not be inspired, and therefore may be wasted. Furthermore, the therapeutic agent that is inspired may be only partially taken up by the lung. For certain therapeutic agents, such as surfactant, more than 90% of inspired therapeutic agent may be subsequently expired (rather than retained in the lung) and thus lost in the expired air. This effect may be greatest when the therapeutic mixture has particulates that are especially small, as may be the case when the therapeutic agent has low surface tension (like surfactant and perfluorocarbon) or is a high density liquid (like perfluorocarbons).
One solution to these inefficiencies of dosing is to rebreathe expired gas, thus renewing the opportunity to take up the therapeutic agent rather than lose it to the environment after expiration. If a “single puff” of the therapeutic agent could be repeatedly rebreathed, ultimate uptake could approach 100%. The same would be true for a “puff” followed by prolonged breath-holding. Repeated rebreathing of the same “puff”, or prolonged breath holding may give rise to hypoxia, hypercarbia, discomfort, or may prolong the time required to deliver a requisite dose of the therapeutic agent. Further, a high level of patient cooperation may be required. These problems complicate, if not prevent, use of these approaches to administer a therapeutic agent.
One solution to these problems involves intermittent dosing, in which the therapeutic agent is provided only during inspiration. This solution offers a significant gain in efficiency over continuous dosing, but is still limited in its usefulness by loss of unabsorbed therapeutic agent to the environment during expiration. This solution may be combined with breath-holding to further reduce expiratory losses, but the breath-holding approach may limit the rate of administration of the therapeutic agent and may require a high level of patient cooperation.
A particulate therapeutic agent delivery device according to the invention may include a respiratory-gas channel, a particulate-therapeutic-agent channel in pneumatic communication with the respiratory-gas channel, a scrubber housing in pneumatic communication with the respiratory-gas channel, and a scrubber material situated within the housing. The scrubber material may be used to remove CO2 from gas expired by a patient. Gas that has been acted on by the scrubber material may be provided to the patient, so that the therapeutic agent is returned to the patient.
In a method according to the invention, a particulate therapeutic agent is provided to the respiratory system of a patient. A carbon dioxide scrubber may be provided in pneumatic communication with the respiratory system, and expired gas from the respiratory system may be provided to the scrubber. The expired gas may be passed through the scrubber to provide treated gas, which may be provided to the respiratory system. By such a method, particulate therapeutic agent which was present in the expired gas may be rebreathed by the patient.
For a fuller understanding of the nature and objects of the invention, reference should be made to the following detailed description taken in conjunction with the accompanying drawings, in which:
The delivery device 10 may have a particulate-therapeutic-agent channel 19 in pneumatic communication with the respiratory-gas channel 13. An aerosol generator 28 may be provided in pneumatic communication with the particulate-therapeutic-agent channel 19. The aerosol generator 28 may be a nebulizer, for example, a jet nebulizer or an ultrasonic nebulizer. The respiratory-gas channel 13 may include a mixing chamber 29, which may provide a location for the therapeutic agent to disperse and mix with respiratory gas.
A scrubber housing 22 may be in pneumatic communication with the respiratory-gas channel 13. The scrubber housing 22 may include an electrically conductive material so that an electric charge does not develop, and thereby cause therapeutic agent to collect on the scrubber housing 22. The scrubber housing 22 may have an expired-gas orifice 25, which may be used for receiving expired gas from the respiratory-gas-channel 13. A scrubber material 26 may be disposed within the scrubber housing 22. A portion of the scrubber material 26 is illustrated in
A ventilator 85 may be provided in pneumatic communication with the respiratory gas channel 13. Herein, references to “ventilator” are intended to include devices that provide a force intended to move respiratory gas into a patient via the respiratory gas channel 13. This definition is intended to include devices commonly referred to as a “respirator,” as well as devices commonly referred to as a “ventilator.” A portion of the ventilator 85, such as a flexible diaphragm or accordion sleeve, may be moved so as to force therapeutic agent in the respiratory-gas channel 13 into the respiratory system.
The ventilator 85 may be in pneumatic communication with an expiratory reservoir 52. The expiratory reservoir 52 may serve to provide an area where gas having therapeutic agent may be stored for future inspiration by the patient.
The embodiment of
An expiration check valve 82 may be provided in the circle circuit 88. The expiration check valve 82 may be oriented to open during expiration and close during inspiration. The expiration check valve 82 may be positioned and oriented so as to prevent incompletely scrubbed gas from re-entering the respiratory-gas channel, which might otherwise occur during inspiration, to encourage particulate therapeutic agent in the respiratory-gas channel 13 to flow generally toward the patient end 16 during inspiration, encourage treated gas to flow generally away from the expired-gas orifice 25, prevent expired gas from bypassing the scrubber housing 22 during expiration, or any combination of these.
In a method according to the invention, a particulate therapeutic agent may be delivered.
The method may provide a bias flow of elevated oxygen fraction to prevent hypoxia, while maintaining a low rate of bias flow in order to minimize expiratory waste. At a bias (fresh gas) flow of 10% of the normal minute ventilation, it is believed that only about 6% of expiratory flow escapes a circle circuit according to the invention; the remainder is rebreathed. If the particulate therapeutic agent is added during expiration, it is believed that most of the therapeutic agent administered during expiration is inspired during a subsequent breath, thereby eliminating waste of therapeutic agent during the expiration phase. Hypoxia and hypercarbia are averted. No special breathing maneuvers are required, and the patient remains comfortable.
In a method according to the invention, rebreathing therapeutic agent is used to increase the concentration of the therapeutic agent that is delivered to a patient during inspiration, thereby augmenting both delivery and uptake of the therapeutic agent. This should be contrasted with prior art methods in which rebreathing is used merely to conserve volatile agents and gases during anesthesia. In prior art anesthetic applications, the circle circuit anesthetic concentration is regulated to achieve an alveolar gas concentration desired for anesthesia. In such an anesthetic application, lowering the bias flow reduces the quantity of anesthetic agent required for anesthesia, and is not used to raise the concentration of therapeutic agent in order to enhance uptake by the lungs.
The invention should substantially increase the opportunity for pulmonary absorption of a given amount of therapeutic agent, unless the scrubber or rebreathing circuit removes a large amount of therapeutic agent. To assess the extent to which a rebreathing circuit might remove a therapeutic agent administered as a fine particulate aerosol, we measured the rate of loss of cigarette smoke, which is a fine particulate aerosol, from a soda lime circle circuit. We found that only 11% to 13% of particulate smoke was consumed by the circuit in 3 seconds, the approximate duration of one respiratory cycle. Since the rate of removal of a fine particulate aerosol by the rebreather circuit appears to be low, substantial efficiency should be gained by rebreathing particulate therapeutic agents through a carbon dioxide scrubber. In addition, we have found that by administering smoke into a rebreathing circuit, the concentration of smoke in the air delivered to a model lung was increased seven fold.
A method according to the invention may require little or no patient cooperation. In theory, a method according to the invention may be more efficient than prior art methods of delivering therapeutic agents, and therefore may be more cost effective. Further, a method according to the invention may be used during prolonged dosing of both spontaneously breathing patients and mechanically ventilated patients.
Non-rebreathing aerosol administration is safe for the patient breathing room air. However, the rebreathing method described in this application might not be used safely without an elevated fraction of inspired oxygen. Therefore, the method may be limited to patients having access to oxygen or to oxygen enriched gas mixtures.
Although the present invention has been described with respect to one or more particular embodiments, it will be understood that other embodiments of the present invention may be made without departing from the spirit and scope of the present invention. Hence, the present invention is deemed limited only by the appended claims and the reasonable interpretation thereof.
This application claims the benefit of priority to U.S. provisional patent application Ser. No. 60/392,314, filed on Jun. 28, 2002.
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| Number | Date | Country | |
|---|---|---|---|
| 20040003808 A1 | Jan 2004 | US |
| Number | Date | Country | |
|---|---|---|---|
| 60392314 | Jun 2002 | US |
