Surgery – Respiratory method or device
Reexamination Certificate
1997-02-03
2001-05-08
Weiss, John G. (Department: 3741)
Surgery
Respiratory method or device
C128S898000
Reexamination Certificate
active
06227195
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to methods and materials useful for delivering functional biologic materials into the pulmonary airways and other body cavities of a subject. The materials to be delivered are prepared having certain characteristics which ensure their delivery and availability without untoward consequences both to the materials or to the subject.
BACKGROUND OF THE INVENTION
It is generally difficult to achieve localization of aerosols in particular sites in the respiratory tract by conventional inhalation via the mouth. [Gonda,
Pharmaceutical Inhalation Aerosol Technology
(Ed. A. J. Hickey), Marcel Dekker, Inc., N.Y., pp. 61-82 (1992)]. Others have employed microspray equipment inserted into airways in animal studies and reported achieving good localization of the delivered dose. [Ferron et al.,
J. Aerosol Sci.
22, S867-S870 (1991); Kreyling et al.,
J. Aerosol Sci.
24, S451-S452 (1993); Hoover et al.,
J. Aerosol Med.
6, 67-72 (1993)]. In order to atomize the liquid they employed compressed air. Although no adverse reactions to the treatment were reported in their experimental animals, application to humans runs the risk of rapid gas expansion inside the airways, a result prudently to be avoided.
Previously, larger volumes of bulk liquid were administered by dripping the material into the airways through a conventional washing pipe that is inserted into the channel of a bronchoscope. However, this method may result in bulk fluid motion into the distal airways and alveoli that would be important to prevent in order to avoid adverse reactions such as inflammation, or infection in the case of gene transfer therapy using viral vectors.
Accordingly, it was an object of the present invention to deliver functional biologic materials in the form of liquid via a bronchoscope in order to achieve well defined localization of such biologic materials in human airways, where they would be expected to be readily available locally with minimal overspill into the alveoli.
SUMMARY OF THE INVENTION
The present invention is directed to a method of delivering functional biologic materials into the lung air passageways of an individual. The salient feature is the delivery of such materials in such manner so as to assure their being deposited via a liquid carrier in the conducting air passageways of the individual. Thus, by the present method the biologic materials, indeed the liquid carrying them, are prevented from reaching the distal airways and alveoli. Thus, the present method ensures the delivery of the therapeutics to a localized region of the lung where they are made available for therapeutic, diagnostic or imaging effect. Yet, because the materials do not reach the distal airways, adverse affects such as inflammation or infection are avoided.
Thus, the present invention is directed to such a method which comprises introducing the biologic materials within a solution or suspension carrier into the airways of an individual in the form of discrete droplets. The droplets have a diameter of greater than about 20 microns and less than about 500 microns, most preferably upwards of about 180 microns. The solution or suspension is delivered at a velocity which is greater than the natural air velocity in the airway during the spontaneous breathing of the individual being treated.
The present invention is directed to a method of delivering functional biologic materials into the pulmonary airways comprising introducing said materials within a solution of suspension into the airways in the form of discrete droplets having a diameter greater than about 20 microns and less than about 500 microns, and at a velocity greater than the natural air velocity in the airway during spontaneous breathing.
The biologic materials comprise classes of compounds that have a known therapeutic effect or diagnostic or imaging function. These compounds may thus be selected from diagnostic agents, imaging agents, growth factors, cytokines, cytostatic and cytotoxic drugs and other anti-cancer agents, anti-inflammatory compounds, antivirals, antibiotics, immunosuppressants and immunostimulators, anesthetics, mucolytic and virolytic compounds, that could be presented as solutions, suspensions or in carriers such as microparticles or nanoparticles. In a preferred embodiment herein, viral vectors harboring genetically engineered gene inserts are introduced via solutions or suspensions. In this manner the gene insert can be absorbed by the individual into the lung cells thus providing a means of gene therapy. However, it will be understood that the present invention is directed to most any biologic material that is available for its known effect.
The delivery of the solution or suspension is in the form of discrete droplets and delivery devices are chosen such that such droplets are formed as such. In the preferred embodiment of the present invention, a conventional washing pipe that has a nozzle at its distal end is used. The nozzle must be shaped in such a manner so as to form the discrete droplets for delivery. The washing pipe is inserted into a bronchoscope that allows a visual control of the location of the delivery in the regions of the lung accessible by the bronchoscope. The relatively large size of the droplets, again ranging from about 20 microns to about 500 microns is considered the reasonable range that assure proper delivery in accordance with the present invention. Again, preferred ranges are just above and below the median of about 180 microns.
The second requirement in accordance with the present invention is that the droplets be delivered at a velocity that exceeds the normal velocity of air during the natural breathing process. In this manner, the droplets are able to resist expulsion until they reach the area of localization. The velocity must not be so rapid as to cause delivery of the droplets into the distal airways and alveoli. Thus, a preferred velocity range would be from about 0.2 m/sec. to about 100 m/sec, and most preferably from about 1 m/sec. to about 50 m/sec. Again, a nozzle and air pressure system is chosen and adjusted so as to meet these dual requirements of discrete droplet formation and velocity during administration.
Although focus has been on upper lung application, it will be understood that the present invention is applicable to the delivery of such biologic materials into other body cavities as well. Such cavities would be expected to be gas filled or temporarily emptied of liquid or solid contents. As examples are the bladder, rectum and empty arteries, using catheters adapted to deliver solutions or suspensions of the appropriate biologic material as a coarse spray for localized delivery and availability.
A typical carrier or vehicle is exemplified by sterile water and glycerol. Reference is suggested to Remington's Pharmaceutical Sciences, 16th Edition (1980 as well as later additions), Physician's Desk Reference published by Medical Economics Data Production Co., Montvale, N.J. and other standard compendia on drug formulation. Generally, the volume of the solution/suspension delivered would range from about 10 to about 2000 &mgr;L.
In a model system in accord with the present invention, large droplet spray (with a droplet size of about 180 microns (&mgr;m), has been produced by rapid expulsion of a viral vector formulation through a nozzle located at the end of a washing pipe that is inserted into the channel of a bronchoscope. Accurate and reproducible dosing of small volumes approximating 40 to 150 microliters was achieved while preserving the integrity of the viral vector for ultimate delivery. The nature of the spray is chosen such that the exposure of the sites distal to the application is substantially minimized. Studies using cascade impaction, human lung casts and rabbits indicate that the method applied to human subjects can be expected to yield deposition of the gene transfer therapy predominantly at the site immediately downstream from the position of the nozzle in the airway. In this work a conve
Flehr Hohbach Test Albritton & Herbert LLP
Genentech Inc.
Weiss John G.
Weiss, Jr. Joseph F.
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