Surgery – Diagnostic testing – Detecting nuclear – electromagnetic – or ultrasonic radiation
Reexamination Certificate
2001-04-03
2003-05-20
Yuen, Henry C. (Department: 3747)
Surgery
Diagnostic testing
Detecting nuclear, electromagnetic, or ultrasonic radiation
C128S922000
Reexamination Certificate
active
06567686
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a method of monitoring the role of upper oropharyngeal and laryngeal geometry for the retention and elimination of respiratory drugs when administered by oral inhalation. The method is based primarily upon acquiring real-time MRI images of human subjects while using aerosol inhalation devices. From these image sets and the data accumulated, one may determine design criteria of the delivery device to optimize the delivery of pharmaceutical aerosol to targeted pulmonary sites. Condition variables include particle size, device attributes such as mouthpiece shape and resistance to flow, aerosol exit velocity, and inhalation flow rate.
DESCRIPTION OF THE PRIOR ART
Magnetic resonance imaging techniques have become widely accepted in medical practice as a means of investigating structural and anatomical differences in body tissues and organs: Justin P. Smith, “Magnetic Resonance Imaging Using Pattern Recognition” U.S. Pat. No. 5,311,131; Hiftje, et al. “Method And Device For Spectral Reconstruction” U.S. Pat. No. 4,642,778; and Shendy et al. “Method For Obtaining T1-Weighted and T2-Weighted MNR Images For A Plurality Of Selected Planes In The Course Of A Single Scan” U.S. Pat. No. 4,734,646. In a typical medical application, a patient is placed within the bore of a large, circular magnet. The magnet creates a static magnetic field that extends along the long (head-to-toe) axis of the patient's body. An antenna (e.g., a coil of wire) is also positioned within the bore of the large magnet, and is used to create an oscillating radio frequency field that selectively excites hydrogen atoms (protons) in the patient's body into oscillation. The oscillating field is then turned off, and the antenna is used as a receiving element, to detect the proton oscillations as a function of position within the body. Typically, the intensity of the oscillations is measured throughout a two-dimensional plane. When the intensities are displayed as a function of position in this plane, the result is an image that often bears a striking resemblance to the actual anatomic features in that plane. The intensity of proton oscillations detected at a given point in the patient's body is proportional to the proton density at that point. Because different types of tissues have different proton densities, different tissue types usually have different image intensities, and therefore appear as distinct structures in the MR image. However, the signal intensity also depends on physical and chemical properties of the tissues being imaged. In a simplified model of MRI, the detected signal intensity, as a function of position coordinates x and y in the plane being imaged, is proportional to
(1
−e
−TR
/T
1
)
e
−TE
/T
2
The parameters TR (recovery time) and TE (echo delay time) are under the control of the operator of the MR imaging system, and are constants for any given image. However, T
1
and T
2
are functions of the tissue under examination, and therefore vary with position in the x-y plane. By suitable selection of parameters TR and TE, either the T
1
or the T
2
term in the above equation can be made to dominate, thereby producing so-called “T
1
-weighted” and “T
2
-weighted” images, respectively. Other imaging methods, although very effective, have lower resolution and are not nearly as effective in presenting real time data compared to MRI. For example, gamma cameras performing Single Photon Emission Computed Tomography (SPECT) have been utilized in nuclear medicine for some time, but with introduction of high speed digital computer systems for image acquisition as well as image reproduction, images could be acquired and analyzed almost instantaneously. However, SPECT camera systems utilize a collimator that is installed in front of the scintillation crystal within a scintillation detector. The collimator is used to collimate the incoming gamma rays so only those rays of a certain angle of incidence actually penetrate the crystal. Although SPECT imaging is extensively used in nuclear medicine and provides beneficial image quality, the collimator introduces a source of image degradation in nuclear medicine images and tends to somewhat reduce the resolution and quality of images acquired by SPECT systems. For these reasons, the MRI was chosen to follow organic and geometric changes in the airways during aerosol administration.
The respiratory system principally supplies oxygen to the body and removes carbon dioxide from venous blood. It also removes atmospheric contaminants and particulate matter in inspired air entering the large, conducting airways of the respiratory tract. This becomes especially problematic for drugs that are administered by be inhalation to the lung to treat local as well as systemic diseases. Drugs and a variety of insoluble particles that deposit in the conducting zones of the airways may clear out largely by mucocilliary clearance and the cough reflex mechanism, or by endocytosis [Oberdoster G. Lung clearance of inhaled insoluble and soluble particles. J. Aerosol Med. 1988; 1: 289-330]. Therefore, inhaled particles, i.e., cellular debris, degraded myelinate surfactant materials, micro-organisms, and fine particulate drug matter most often are unable to enter the lower and peripheral airways of the lung. If these particles successfully escape the filtration mechanisms of the lung, they could enter the alveoli and acini depending on their size and deposition characteristics.
The lung contains three basic components, namely air, blood and tissue. The architectural arrangement of these three basic components provides optimal conditions for gas exchange and efficient resistance to the movement of air and blood. But a principle function of the lung is to provide for efficient removal of particulate matter in inspired air by a highly specialized transport mechanism referred to as mucocilliary clearance. This is a homeostatic process that can have significant impact on lung drug delivery. Furthermore, the effect of transient changes in airway geometry during the inspiratory maneuver could have considerable impact on drug deposition as well as transport of aerosolized particles from the conducting airways to the respiratory, peripheral lung. To the degree that this is possible, pharmacological actions of inhaled drugs could be significantly altered at their sites of action in the lung or systemically elsewhere in the body. Implications of upper airway anatomy and physiology on morphology of lung drug delivery may be found elsewhere Kilburn K. H., “Functional Morphology of The Distal Lung”, Int. Rev. Cytol. 37 (1974) 153-270. But it is noteworthy that after the oropharynx, the lung splits off dichotomously through 23 generations or branches beginning with the trachea, each subsequent pair of branches having a smaller diameter than that of the parent. A widely used model for describing these geometric and morphologic changes may be obtained from Weibel and others [Weibel, E. R., “Morphometry of the Human Lung”, Springer-Verlag, Berlin, (1963) pp. 1-151; Bouhuys A., “The Physiology of Breathing”, Grune & Stratton, 1977, New York, pp. 60-79; 173-232]. Thus, after escaping interception and impaction on the tongue, palate, and larynx, the inhaled particle must travel through a series of tubes with increasing resistance and decreasing diameter. The geometric configuration of the tongue base, and the upfront narrowing of the air gap between the posterior pharyngeal wall and the posterior surface of the tongue base become the first line of defense for the body. Accordingly, the probability with which the inhaled particle is removed from the inspired air before it even has the chance to enter the trachea is greatest in the oropharynx. Thus, it is a significant problem for inhaled drugs to escape filtration mechanisms of the oropharynx during aerosol administration as a normal, homeostatic reflex mechanism triggers interception of solid particles by action of the tongue and palate.
In addition to part
Adjei Akwete L.
Genova Perry Arthur
Mancuso Anthony A.
Melker Richard Joel
Schmalfuss Ilona Maria
Frommer & Lawrence & Haug LLP
Gimie Mahmoud
IEP Pharmaceutical Devices Inc.
Santucci Ronald R.
Yuen Henry C.
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