Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
  • A61K51/1206—Administration of radioactive gases, aerosols or breath tests
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/08—Detecting, measuring or recording devices for evaluating the respiratory organs
  • A61B5/0813—Measurement of pulmonary parameters by tracers, e.g. radioactive tracers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B6/00—Apparatus for radiation diagnosis, e.g. combined with radiation therapy equipment
  • A61B6/42—Apparatus for radiation diagnosis, e.g. combined with radiation therapy equipment with arrangements for detecting radiation specially adapted for radiation diagnosis
  • A61B6/4208—Apparatus for radiation diagnosis, e.g. combined with radiation therapy equipment with arrangements for detecting radiation specially adapted for radiation diagnosis characterised by using a particular type of detector
  • A61B6/4258—Apparatus for radiation diagnosis, e.g. combined with radiation therapy equipment with arrangements for detecting radiation specially adapted for radiation diagnosis characterised by using a particular type of detector for detecting non x-ray radiation, e.g. gamma radiation
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2123/00—Preparations for testing in vivo

Definitions

• This invention relates generally to the field of nuclear medicine. More specifically, the invention relates to methodology which uses a radioactive formulation in diagnosing the patient such as to determine the existence of lung and circulatory system abnormalities, including pulmonary embolisms.
• Nuclear imaging involves introducing radioactive material into a patient, and, more specifically, into a particular tissue or tissues of that patient. After the radioactive material has been introduced, an image can be created based on the radioactive quanta emitted by the material when those particle strike a recording media, ⁇ e.g., an electronic sensory array) which is sensitive to the radioactive emissions. Images recorded electronically can be displayed on a monitor and/or transferred to film and printed for a permanent record. The process can provide life saving information. For example, tens of thousands of individuals in the United States die each year from pulmonary embolisms (PE) .
• PE pulmonary embolisms
• Detecting and diagnosing pulmonary embolisms is particularly difficult in that it often presents nonspecific clinical manifestations caused by the migration of blood clots in the deep veins of the legs (DVP) proceeding through the central venous system and into the pulmonary circulation via the right side of the heart .
• DVP deep veins of the legs
• a clot within the pulmonary circulation results in inadequate gas exchange between the blood and the lungs, which, if sufficiently massive, can be fatal.
• a caretaker may carry out pulmonary arterial angiography. This invasive procedure involves introducing a radiopaque dye into the pulmonary artery via percutaneous placement of a catheter into the right ventricle and through the pulmonic valve.
• Radiographs taken subsequent to the injection of dye through the catheter can be used to visualize perfusion defects associated with a pulmonary embolism.
• Nuclear imaging methodology allows a ventilation-perfusion scan to be used as a screen diagnostic procedure for early evaluation of patients suspected of having a pulmonary embolism.
• Ventilation/perfusion scintigraphy is carried out by producing two separate images and comparing the images.
• a ventilation scan or V-scan
• V-scan is carried out first in order to maximize the quality of the study.
• a radioactive gas or aerosol After inhalation an image can be created of the ventilated areas of the lung where the radioactive material has been deposited using a gamma camera.
• the radioactive material In order for the V-scan image to be useful, the radioactive material must penetrate deep into the lungs and deposit on all ventilated areas of the lungs.
• the tests results will be compromised.
• the compromise is created when an incomplete V-scan image is used as the base for showing the outline of the lung, which outline is compared with the Q-scan in order to determine if all areas of the lung are being supplied with blood.
• the second image necessary in order to carry out ventilation-perfusion centograph is the perfusion scan or Q-scan.
• the goal of the Q-scan is to produce an image of the pulmonary arterial circulation. This image will allow for a direct comparison with the V-scan, which will in turn allow for the detection of mismatches between the V-scan and Q-scan. Mismatches of particular types are indicative of the presence of a pulmonary embolism.
• a radioactive material such 99n Tc macroaggregated albumin (MAA) can be injected into the peripheral venous circulation After injection an image is created using a gamma camera, which includes an electronic sensor array capable of detecting the radioactive particles emitted.
• MAA 99n Tc macroaggregated albumin
• Ventilation images which are created using a radioactive gas are generally preferred in terms of the results obtained.
• radioactive gas is expensive, difficult to handle and use, has a short half life and is often unavailable.
• a radioactive aerosol is more desirable in terms of its convenience of use, lower expense, and greater availability
• the quality of the images obtained are generally not as good as that obtained using radioactive gas
• the present invention endeavors to provide high quality images m a convenient, inexpensive, readily available manner.
• a method of diagnosing a patient comprises creating an aerosolized dose of a formulation containing tagged material such as a radioactive material by moving the formulation through a porous membrane.
• the aerosol created is inhaled into the peripneral areas of the lungs of a patient and allowed to migrate from lung tissue into the circulatory system of the patient.
• a measurement is made of tne amount of radioactive material and the measured amount is compared with a standard.
• the amount measured is a predetermined amount or more below a standard the likelihood of pulmonary embolism can be deduced in that radioactive aerosol delivered to the lung has not been brought into the circulatory system because at least some portion of the lung which is ventilated is not being perfused due to an embolism. More specifically, the tagged or radioactive material has been delivered to ventilated areas of the lung which areas are being perfused due to an embolism. Thus the tagged material remains in the lungs and can not be moved into the circulatory system and detected there.
• a second formulation of radioactive material is aerosolized (preferably by moving it through a porous membrane) and inhaled into the lung.
• the second formulation is designed for being deposited in the lung and not to quickly migrate into the circulatory system.
• the radioactive material is deposited on lung tissue the patient is brought into contact with a medium which is sensitive to radiation emitted by the radioactive material.
• the exposed medium is processed to create an image of all areas of the lung which are being ventilated. When all areas are ventilated such provides a further indication of pulmonary embolism when the initial readings of radioactive material in the circulatory system were substantially decreased.
• the detection of decreased radioactivity in the circulatory system is caused when radioactive material is delivered to, for example, fully ventilated lungs which are not fully profused thereby providing no means for the radioactive material deposited on the lung to reach the circulatory system.
• the degree to which areas of the lung are not ventilated can be related to the amount of decrease of the radioactive material in the circulatory system in order to discount the likelihood of a pulmonary embolism. Patients who have a pulmonary embolism are substantially more likely to have a recurrence of pulmonary embolism as compared with the likelihood of an embolism occurring m an individual who has not had a prior embolism.
• the present invention is particularly valuable in rediagnosing a pulmonary embolism in a patient with a prior pulmonary embolism which patient had been subjected to a measurement (to provide a standard for comparison) via the present invention at the time of the prior pulmonary embolism. More specifically, the process is carried out by instructing the patient to inhale a formulation of aerosolized radioactive material. The inhaled material is allowed to migrate into the circulatory system After a given period of time (e.g., five minutes) a measurement is made of the amount of radioactive material in the patient's circulatory system.
• a given period of time e.g., five minutes
• the same procedure is followed and the earlier measurement compared with the current measurement in order to determine if a further pulmonary embolism nas occurred. Further, repeated measurements can be made on the same patient over a period of hours, days or weeks m order to determine if treatment is effective in dissolving any clot and reestablishing circulation.
• An important object of the invention is to provide a method of diagnosing pulmonary embolisms by delivering a material tagged with a detectable label such as a radioactive material to a patient by aerosol, measuring the amount of material m a patient's circulatory system- after a given point of time r>y detecting the tag and comparing that measurement to a standard m order to deduce the likelmood of embolism based on the degree cf difference between tne measured amount m the standard
• Another object of the invention is to provide a method of diagnosing a patient by forcing a radiolabled formulation through a nozzle which creates particles having a diameter in the range of 1 to 10 microns, creating an image of the particles deposited on the lungs (ventilation image) and comparing the ventilation image with a perfusion image taken after injecting a radiolabled formulation into the pulmonary arterial circulation.
• a feature of the invention is that the tagged formulation such as a radiolabled formulation may be aerosolized directly from its container which is coated with a material such as lead to prevent or hinder the flow of radiation.
• An advantage of the invention is that it exposes the patient and the caregiver to smaller amounts of radiation as compared to current methods.
• Another advantage is that improved efficiency of delivery makes it possible to deliver 10 to 50 MBq of radioactive material (preferably 15 to 25 MBq and most preferably 20 MBq) to the lungs of a patient while using one or two small containers of radioactive material sealed with a radiation seal.
• An object of the invention is to provide a container which holds radioactive formulation (e.g., radioactive DTPA) to be aerosolized, which container comprises a porous membrane which protrudes outward m a stationary state or on the application of force forming a convex surface when radioactive formulation is forced against and through the membrane.
• radioactive formulation e.g., radioactive DTPA
• Another object is to provide such a container with radioactive shielding such as a lead coating and/or lead pacKage surrounding wherein "lead” includes polymeric material impregnated with lead and alloys and materials generally used to provide radioactive shielding
• Another object is to provide a method for creating radioaerosols which comprises drawing air over a surface of a porous membrane in a channel and forcing radioactive formulation against the membrane so as to protrude the membrane through a flow boundary layer into faster moving air of the channel.
• Another object of the invention is to provide a delivery device which creates aerosolized particles of a formulation comprised of radiolabelled compound in a carrier and adds energy to the particles in an amount sufficient to evaporate carrier and reduce total particle size .
• Another object is to provide a radioactive formulation delivery device which includes a desiccator for drying air in a manner so as to remove water vapor and thereby provide consistent particle sizes even when the surrounding humidity varies.
• Another object is to provide a method of radioactive particle delivery which heats the airflow into which an aerosol is released with the heating being varied based on ambient temperature and humidity thereby providing a radioaerosol of consistent particle size to a patient .
• radioactive material can be dispersed or dissolved in a liquid carrier such as water and dispersed to a patient as dry or substantially dry particles.
• the package includes lead shielding.
• the porous membrane has a convex surface or becomes convex because it is flexible and will protrude outward upon the application of force.
• radioactive formulation can be safely and conveniently handled.
• aerosolized radioactive formulation is fully and evenly dispersed in the lung providing a gas-like distribution pattern.
• Another advantage of the invention is that particles do not readily agglomerate because they are released from a convex porous membrane protruding into faster moving air drawn through a channel by a patient.
• Another advantage of the invention is that particle size can be adjusted by adjusting the amount of energy added and thus the amount of evaporation obtained.
• Another advantage is that the size of the particles delivered will be independent of the surrounding humidity.
• Figure 1 is a cross-sectional view of a container of the invention
• Figure 2 is a cross-sectional view of a preferred embodiment of a container of the invention
• Figure 3 is a cross-sectional view of the container of Figure 2 in use in a channel of a radioactive formulation delivery device;
• Figure 4 is a plan view of a radioactive formulation delivery device of the invention.
• Figure 5 is a graph plotting the density of water vapor in air versus temperature
• Figure 6 is a graph plotting the density of ethanol vapor in air versus temperature
• Figure 7 is a perspective view of a lead shield packet of the invention which holds a container of the invention
• Figure 8 is a perspective view of the package of the invention.
• radioactive material shall mean any radioactive compound or substance labelled as a radioactive compound which can be administered to the lungs of a human patient with an acceptable degree of safety, and that when deposited m the lung will emit sufficient radiation such that an image can be created showing the presence of the material m the lung
• a preferred radioactive material is 99m Tc-labelled diethylene triamme pentaacetic acid (DTPA) Otner material can be labelled with 99m Tc such as carbon particles and then placed in a liquid carrier, e.g., water, ethanol, or a mixture thereof.
• DTPA diethylene triamme pentaacetic acid
• tagged material any material which is itself or attached to a tag or label which is detectable by any means.
• labelled material includes radioactive materials
• tags and labels can also be in the form of dyes including fluorescent dyes or any compound which can be formulated and administered to the lungs of a human patient witn an acceptable degree of safety, and when deposited in the lung will migrate into the circulatory system of a numan patient and be detectable withm the circulatory system quantitatively.
• the term "radioactive aerosol” is intended to encompass aerosolized radioactive materials, which materials are generally in the form of a small particles having a size and a range of 0.5 to 10 microns, more preferably 1.0 to 3.0 microns.
• an aerosol may contain some gas (e.g., due to evaporation) , the term is not intended to encompass a pure gas, i.e., the form of a radioactive material wherein all of the particles are molecular in size.
• perfusion image and/or "Q-scan” means an image created on a recording medium of any sort which image is the result of exposure to radioactive particles emitted from the pulmonary arterial circulation after injection of radioactive particles into the circulation.
• the term “ventilation image” and “V-scan” means an image created on any medium as a result of radiation striking any recording medium wherein the radiation is emitted from radioactive particles inhaled into the lungs of a patient.
• velocity of particles shall mean the average speed of particles of radioactive formulation moving from a release point such as a porous membrane or a valve to a patient's mouth.
• bulk flow rate shall mean the average velocity at which air moves through a channel considering that the flow rate is at a maximum in the center of the channel and at a minimum at the inner surface of the channel.
• flow boundary layer shall mean a set of points defining a layer above the inner surface of a channel through which air flows wherein the air flow rate below the boundary layer is substantially below the bulk flow rate, e.g., 50% or less than the bulk flow rate.
• a delivery event shall be interpreted to mean the administration of a radioactive aerosol to a patient by the mtrapulmonary route of administration which event involves the release of radioactive aerosolized particles into the inspiratory flow path of a patient
• a delivery event may include the release of radioactive formulation contained withm one or more containers.
• a delivery event is not interrupted by a monitoring event which would indicate, if followed by further radioactive formulation delivery, the beginning of a new delivery event.
• a dosing event will involve the delivery of a sufficient amount of radioactive material to the lung of a patient such that, when in the lung, the material releases enough radioactivity so as to create an image
• carrier shall mean a liquid, flowable, pharmaceutically acceptable excipient material in which a radioactive material is suspended in or dissolved m.
• Useful carriers do not adversely interact with the radioactive material and have properties which allow for the formation of aerosolized particles preferably particles having a diameter in the range of 0.5 to 12.0 microns when a formulation comprising the carrier is forced through pores having a diameter of 0.25 to 6.0 microns
• Preferred carriers include water, ethanol and mixtures thereof .
• Other carriers can be used provided that they can be formulated to create a suitable aerosol and do not adversely effect the radioactive material or human lung tissue.
• measuring describes an event whereby either tne inspiratory flow rate or inspiratory volume of the patient is measured m order to determine an optimal point in the inspiratory cycle at wmch to release aerosolized radioactive formulation
• An actual measurement of both rate and volume may be made or the rate can be directly measured and the volume calculate ⁇ based on the measured rate
• It is also preferable to continue measuring inspiratory flow during and after any delivery of radioactive material and to record inspiratory flow rate and volume before, during and after the release of radioactive aerosol Such reading makes it possible to determine if radioactive material was properly delivered to the patient.
• the term "monitoring” event shall mean measuring lung functions such as inspiratory flow rate, and/or inspiratory volume so that a patient's lung function as defined herein, can be evaluated before and/or after delivery of radioactive material, thereby making it possible to evaluate any effect delivery might have ana advise tne caregiver as to tne patient's lung function
• the term "inspiratory flow rate” shall mean a value of air flow calculated based on the speed of the air passing a given point m a measuring device. Measurements are preferably carried out at atmospheric pressure ⁇ 5% and a temperature n the range of about 10°C to 40°C.
• inspiratory flow profile shall be interpreted to mean data calculated m one or more events measuring inspiratory flow and cumulative volume, whicr profile can be used to determine a point within a patient's inspiratory cycle which is optimal for the release of radioactive formulation to be delivered to a patient
• An optimal point within the inspiratory cycle for the release cf radioactive formulation is base ⁇ , m part, on a point within the inspiratory cycle likely to result in the maximum delivery of radioactive formulation and based, in part, on a point in the cycle most likely to result in the delivery of an even gas-like distribution of radioactive particles.
• Obtaining uniform gas-like distribution is the primary criterion and maximizing the amount delivered is an important but secondary criterion.
• a large number of different release points might be selected and provide for even distribution provided the selected point results in even distribution.
• the point is selected within given parameters.
• formulation and “liquid formulation” and the like are used interchangeably herein to describe any radioactive material with a pharmaceutically acceptable carrier in flowable liquid form having properties such that it can be aerosolized to particles having a diameter of 0.5 to 12.0 microns, preferably 1-3 microns.
• Such formulations are preferably solutions, e.g. aqueous solutions, ethanolic solutions, aqueous/ethanolic solutions, saline solutions and colloidal suspensions.
• lung function and "pulmonary function” are used interchangeably and shall be interpreted to mean physically measurable operations of a lung including but not limited to (1) inspiratory and (2) expiratory flow rates as well as (3) lung volume.
• Methods of quantitatively determining pulmonary function are used to measure lung function. Quantitative determination of pulmonary function is important because lung disease is typically associated with deteriorating pulmonary function. Methods of measuring pulmonary function most commonly employed in clinical practice involve timed measurement of inspiratory and expiratory maneuvers to Hopkinsforduus , , O 97/27804
• forced vital capacity measures the total volume in liters exhaled by a patient forcefully from a deep initial inspiration This parameter, when evaluated in conjunction with the forced expired volume in one second (FEV , allows bronchoconstriction to be quantitatively evaluated.
• FVC forced vital capacity
• a problem with forced vital capacity determination is that the forced vital capacity maneuver (i.e forced exhalation from maximum inspiration to maximum expiration) is largely technique dependent In other words, a given patient may produce different FVC values during a sequence of consecutive FVC maneuvers.
• the FEF 25-75 or forced expiratory flow determined over the mid-portion of a forced exhalation maneuver tends to be less technique dependent than the FVC Similarly, the FEV_ tends to be less technique dependent than FVC
• the flow m liters per minute measured over differing portions of the expiratory cycle can be useful in determining the status of a patient's pulmonary function.
• the peak expiratory flow taken as the highest air flow rate in liters per minute during a forced maximal exhalation, is well correlated with overall pulmonary function m a patient with asthma and other respiratory diseases
• the present invention carries out delivery of radioactive material in a delivery event and monitoring lung function in a monitoring event. A series of such events may be carried out and repeated over time to deliver the desired amount of radioactive material.
• Each of the parameters discussed aoove is measured during quantitative A patient's individual performance can be compared against his personal oest data, individual indices can Joe compared w th eacn other for an individual patient (e.c FEV divi ⁇ ed by FVC, producing a dimensionless index useful in assessing the severity of acute asthma symptoms) , or each of these indices can be compared against an expected value.
• Expected values for indices derived from quantitative spirometry are calculated as a function of the patient's sex, height, weight and age. For instance, standards exist for the calculation of expected indices and these are frequently reported along with the actual parameters derived for an individual patient during a monitoring event such as a quantitative spirometry test.
• substantially dry shall mean that particles of radioactive formulation include an amount of carrier (e.g. water or ethanol) which is equal to (in weight) or less than the amount of radioactive material in the particle.
• carrier e.g. water or ethanol
• the FEV. when taken as a ratio of FVC (i.e. FEV. divided by FVC) , is markedly reduced in patients with acute asthma.
• FEV. divided by FVC the presence of acute bronchoconstrictive disease tends to decrease the peak expiratory flow measured over a typical forced exhalation.
• the a respiratory disease may block the ventilation of a section of the lung and thereby prevent radioactive material from depositing in that area of the lung. In most situations the same area of the lung would receive blood. Accordingly, a comparison of a ventilation image with a perfusion image would indicate to the caregiver that the patient did not have a pulmonary embolism, but rather a blockage and/or restriction of air flow problem.
• anerosolized particles and "aerosolized particles of formulation” shall mean particles of formulation comprised of radioactive material and/or radiolabled material and carrier which are formed upon forcing a radioactive formulation through a nozzle which nozzle is preferably in the form of a flexible porous membrane.
• the particles have a size which is sufficiently small such that when the particles are formed they remain suspended in the air for a sufficient amount of time such that the patient can inhale the particles into the patient's lungs.
• the particles have a size in the range of 0.5 micron to about 12 microns (more preferably 1 to 3 microns) having been created by being forced through the pores of a flexible porous membrane which pores have a diameter in the range of about 0.25 micron to about 6.0 microns (preferably 0.5 to 1.5 microns) -- the pores being present on the membrane in an amount of about ten to 10,000 pores over an area in size of from about 1 sq. millimeter to about 1 sq. centimeter.
• Preferred membranes have more than IC pores and preferably more than 100 pores over 1 sq. cm. or less.
• Devices, packaging and methodology for creating aerosols are provided which allow for efficient and repeatable delivery of tagged materials and in particular radioaerosols to the lungs of a patient.
• Devices may be plug-in units or hand-held, self-contained units which are automatically actuated at the same release point in a patient's inspiratory flow cycle.
• the release point is automatically determined either mechanically or, more preferably calculated by a microprocessor which receives data from a sensor making it possible to determine inspiratory flow rate and inspiratory volume.
• the device is loaded with a single container or a cassette comprised of an outer housing which holds a package of individual collapsible containers of a tagged formulation which is preferably radioactive formulation such as 99m Tc-labelled diethylene-triamine pentaacetic acid (DTPA) .
• DTPA diethylene-triamine pentaacetic acid
• Actuation of the device forces the radioactive formulation through a porous membrane of the container which membrane has pores (preferably more than 10) having a diameter in the range of about 0.25 to 6 . 0 microns.
• the container includes radioactive shielding in the form of a lead coating and/or a lead surrounding packet.
• the porous membrane is positioned in alignment with a surface of a channel through which a patient inhales air.
• the flow profile of air moving through the channel is such that the flow at the surface of the channel is less than the flow rate at the center of the channel.
• the membrane is designed so that it protruded outward at all times or made flexible so that when radioactive formulation is forced against and through the membrane the flexible membrane protrudes outward beyond the flow boundary layer of the channel into faster moving air. Because the membrane protrudes into the faster moving air of the channel the particles of aerosol formed are less likely to collide allowing for the formation of a fine aerosol mist with uniform particle size.
• the present invention does not require making and comparing two different types of images Specifically, the invention does not require the use of conventional methodology whereby the radioactive material is deposited in the lung an image is recorded (ventilation image) .
• a tagged material such as a radioactive formulation is delivered to the lungs of a patient and sufficient time is allowed to pass whereby the tagged material can diffuse into the circulatory system of the patient.
• a sample is then taken from the patient's circulatory system and compared with a known standard If formulation is well distributed in the patient's lungs it will show up in the circulatory system m a known amount. If the amount detected in the circulatory system is low then it is likely the patient has a pulmonary embolism which is blocking circulation to an area of the lung.
• the aerosolized mist is released into the channel energy is actively added to the particles in an amount sufficient to evaporate carrier and thereby reduce particle size .
• the air drawn into the device is actively heated (to a temperature of from about 25°C to about 50°C) by moving the air through a heating material which material is pre-heated prior to the beginning of a patient's inhalation.
• the amount of energy added can be adjusted depending on factors such as the desired particle size, the amount of the carrier to be evaporated, the water vapor content of the surrounding air and the composition of the carrier.
• the porous membrane is vibrated a frequency m the range of 575 to 17,000 kilohertz to aid in particle formation.
• Particle diameter size is generally about twice the diameter of the pore from which the particle is extruded. In that it is technically difficult to make pores of 2.0 microns or less in diameter the use of evaporation can reduce particle size to 3.0 microns or less even with pore sizes well above 1.5 microns.
• Energy may be added in an amount sufficient to evaporate all or substantially all carrier and thereby provide particles of dry powdered radiolabled material or highly concentrated radiolabled material to a patient which particles are uniform size regardless of the surrounding humidity and smaller due to the evaporation of the carrier.
• Air drawn into the device by the patient may be drawn through a desiccator containing a desiccant which removes moisture from the air thereby improving evaporation efficiency when the carrier is water.
• the invention includes several aspects, its ultimate purpose is to provide information on which to diagnose a patient such as by placing a detectable label in the circulatory system or by providing clear readable images of the lung, which can be used m various types of diagnostic methodology More specifically, the various devices, packaging, and methodology disclosed is directed towards delivering a uniform dispersion of aerosolized tagged particles to the airways of the lung, which particles are deposited uniformly throughout the lung. The particles delivered to the lung can then be detected withm the patient's circulatory system and compared with a standard in order to make a diagnosis. Alternatively, tne formulation delivered to the lung generates radioactivity which creates an image on an image recording device. That image is referred to as a ventilation image or V-scan in certain circumstance, and can be used to compare with a perfusion image, or
• tne diagnostic metnodology of the present invention can include the creation of a perfusion image
• the essence of the invention relates to the particular manner in whicn tne ventilation image is created.
• Ventilation images can be created by using a radioactive gas or radioactive aerosol.
• a gas is preferred.
• images created using an aerosol are more desirable in terms of reduced expenses, convenience, and general availability of material.
• the present invention endeavors to create a gas-like even distribution of particles while providing for the convenience, reduced expense, and availability of aerosol delivery of radioactive particles. We have found that there are a number of factors which are involved in creating an even gas-like distribution of radioactive particles in the lungs.
• a perfusion image is created by injecting radioactive materials into the circulatory system. More particularly, perfusion scintigraphy of the lung is accomplished by microembolization of radionucleotide- labelled particles in the pulmonary arterial circulation. Particulate material embolization causes a minor obstruction to pulmonary arterial blood flow. However, this affect is minor and almost never of physiological significance. The number of particles which impact a particular volume of the lung is proportional to the pulmonary arterial blood flow to that region. Perfusion scintigraphy thus provides a visual presentation of the relative distribution of pulmonary blood flow at the time of the injection of the radioactive material.
• images are obtained in eight views of the thorax, which images include: anterior, posterior, right/left posterior, and anterior oblique, right and left lateral.
• V-scans Ventilation images
• Q perfusion images
• V/Q mismatch comparison can be made using both types of images.
• Abnormalities in the perfusion scan that are mismatched by zones of abnormal ventilation are less likely to represent a pulmonary embolism.
• mismatched abnormalities reduced perfusion with normal ventilation
• have a high correspondence with pulmonary embolisms particularly in situations where the patient shows a normal radiograph.
• the present invention is largely directed towards components and methodology involved in delivering an aerosol of tagged formulation to the lungs for detection in circulator systems or obtaining a ventilation image, and is specifically involved in obtaining an even gas-like distribution of aerosolized tagged particles (e.g. , radioactive particles) in the lungs of the patient. If even, gas-like distribution of aerosolized particles can be obtained, the resulting ventilation image or tagged material detected in and measured in the circulation will provide more reliable information to the caregiver who is carrying out the diagnostic analysis.
• the following section provides further details regarding factors affecting delivery.
• particle size in a range of about 0.5 to 6 microns and more preferably 1.0 to about 3 microns
• the concentration of the radioactive material in the carrier so as to obtain a desired amount of radiation e.g., 1,500 MBq to 2,500 MBq/ml ;
• the amount of heat added to the air about 20 Joules to about 100 Joules and preferably 20 Joules to about 50 Joules per 10 ⁇ l of formulation; (6) the relative volume of air added by patient inhalation per lO ⁇ l of radioactive formulation at about 100 ml to 2 1 and preferably about 200 ml to 1 liter for evaporation and without evaporation 50-750 ml preferably 200-400 ml;
• pore size to a range of about 0.25 to about 6.0 microns in diameter preferably 0.5 to 3 microns and more preferably 1-2 microns;
• the desiccator to maximize removal of water vapor from air;
• the shape of the pore opening to be circular in diameter and a conical in cross-section with the ratio of the diameter of the small to large end of the cone being about l A to l/ic, and the shape of the porous membrane to an elongated oval;
• the thickness of the membrane to 5 to 200 microns; preferably 10 - 50 microns;
• the membrane to have a convex shape or to be flexible so that it protrudes outward in a convex shape beyond the flow boundary layer when formulation is forced through it; and (18) the firing point to be at substantially the same point at each release for the parameters (1-17) , i.e., each release of radioactive formulation is at substantially the same point so as to obtain repeatability of dosing.
• Containers of the mvention are considered disposable in that they are preferably brought into an aerosol release position with a device, subjected to pressure in order to discharge the contents through the porous membrane and then moved out of the aerosol release position after a single use and discarded Reusing the containers is undesirable in that the porous memr>rane includes tiny pores which can be easily clogged which would interfere with repeatability dosing. Further, reusing a container after the opened pores had been exposed to the atmosphere could cause contamination of the contents of the container.
• radioactive formulation In the description put forth below the contents of the container is referred to as a radioactive formulation This is done because a radioactive formulation is preferred and in one embodiment of the invention must be used However, n other embodiments of the invention it is possible to use a formulation which is tagged or labelled with some detectable label which can be delivered to the lungs, brought into the circulatory system and detected quantitatively withm the circulatory system
• one aspect of tne invention includes disposable containers which are filled with a tagged or labelled formulation which formulation is not radioactive formulation and wherein the container does not include radioactive shielding
• radioactive shielding is referred to as is the radioactive formulation.
• Figure 1 is a cross-sectional view of a container 1 of the invention which is shaped by a collapsible wall 2.
• the container 1 has an opening covered by a flexible porous membrane 3 which is covered by a removable layer 4.
• the membrane 3 may be rigid and protrude upward in a convex configuration away from the radioactive formulation 5.
• the layer 4 is removed the wall 2 can be collapsed thereby forcing the formulation 5 against the flexible porous membrane 3 which will then protrude outward a convex shape
• the layer 4 and surrounding sublayer 84 are optionally present However, due to the radioactive properties of the formulation 5 it is desirable that they are present and are the form of a material such as lead, lead alloy, polymer impregnated with lead which provides shielding from nuclear radiation.
• Figure 2 is a cross-sectional view of a more preferred embodiment of a container 1 of the invention.
• the container 1 as shown in Figures 1 and 2 can pe designed without the use of the shielding layer 84
• the packet 85 is comprised of any material known to provide shielding from radiation such as lead material which is sealed around the entire edge 86.
• a packet such as the lead packet layer 85 shown in Figure 7 could also be used to encompass an entire package as shown within Figure 8.
• Figure 3 is a cross-sectional view of the container 1 of Figure 2 in use without a layer 84.
• the wall 2 is being crushed by a mechanical component such as the piston 9 shown in Figure 3.
• the piston may be driven by a spring, compressed gas, or a motor connected to gears which translate the electric motor's circle motion to linear motion.
• the radioactive formulation 5 is forced into the open channel 6 (breaking the abutment 7 shown in Figure 2) and against and through the membrane 3 causing the membrane 3 to protrude outward into a convex configuration as shown in Figure 3.
• the piston 9 has been forced against the container wall 2 after a patient 10 begins inhalation in the direction of the arrow "I".
• the patient 10 inhales through the mouth from a tubular channel 11.
• the velocity of the air moving through the flow path 29 of the channel 11 can be measured across the diameter of the channel to determine a flow profile 12, i.e., the air flowing through the channel 11 has a higher velocity further away from the inner surface of the channel .
• the air velocity right next to the inner surface of the channel ll i.e., infinitely close to the surface
• a flow boundary layer 13 defines a set of points below which (in a direction from the channel center toward the inner surface of the channel) the flow of air is substantially below the bulk flow rate i.e., 50% or less than the bulk flow rate.
• the upper surface of the flexible porous membrane 3 is substantially flush with (i.e., in substantially the same plane as) the inner surface of the channel 11.
• the membrane 3 protrudes outward through the boundary layer 13 into the faster moving air. This is desirable in that it aids in avoiding the agglomulation of particles. More specifically, when formulation exits the pores the formulation naturally forms spherical particles. Those particles slow down due to the frictional resistance created by the air through which the particles must travel. The particles existing behind them can face reduced air friction because the preceding particle have moved the air aside.
• FIG. 4 A plan view of a simple embodiment of a radioactive material delivery device 40 of the present invention is shown within Figure 4.
• the device 40 is loaded and operates with a strip of containers as shown in Figure 4 or with a single disposable container shown in Figures 3 and 7.
• FIG. 4 A plan view of a simple embodiment of a radioactive material delivery device 40 of the present invention is shown within Figure 4.
• the device 40 is loaded and operates with a strip of containers as shown in Figure 4 or with a single disposable container shown in Figures 3 and 7.
• Some methods involve inhaling a radioactive gas, and others involve inhaling an aerosol created with a nebulizer.
• Conventional nebulizers suffer from a number of disadvantages. These disadvantages result in the inability to use these devices to provide a gas-like distribution of radioactive material to a patient.
• the disadvantages are due, in part, to the inability to (1) control particle size, (2) shield the patient and caregiver from radiation, (3) obtain release of aerosol in discrete dose at the desired point in the patient's respiratory cycle and efficiently deliver aerosolized material from discrete, radiation sealed containers.
• the present invention controls particle size by using a porous membrane with pores of a desired size, and by adding sufficient energy to the particles to evaporate carrier. This reduces particle size to a uniform minimum and reduces particle variability due to humidity variations.
• the dispensing device of the present invention preferably includes nuclear radiation shielding and electronic and/or mechanical components which eliminate direct user actuation releasing discrete pre- easured doses of radiation.
• the device preferably includes a means for measuring inspiratory flow rate and inspiratory volume and sending an electrical signal as a result of the simultaneous measurement of both (so that radioactive aerosol can be released at a desired point each time) and also preferably includes a microprocessor which is programmed to receive, process, analyze and store the electrical signal of the means for measuring flow and upon receipt of signal values within appropriate limits sending an actuation signal to the mechanical means which causes radioactive aerosol to be extruded from the pores of the porous membrane.
• a microprocessor which is programmed to receive, process, analyze and store the electrical signal of the means for measuring flow and upon receipt of signal values within appropriate limits sending an actuation signal to the mechanical means which causes radioactive aerosol to be extruded from the pores of the porous membrane.
• the device 40 shown in Figure 4 is loaded with a disposable package 46.
• a patient see Figure 3 inhales air from the mouthpiece 30.
• the air drawn in through the opening 38 (and optionally the desiccator 41) flows through the flow path 29 of the channel 11.
• the disposable package 46 is comprised of a plurality of disposable containers 1.
• Each container 1 includes a formulation 5 of radioactive material and is covered by the porous membrane 3.
• An air-heating mechanism 14 located in the flow path 29.
• the air heating mechanism 14 is preferably positioned such that all or only a portion of the air flowing through the path 29 will pass by the heater, e.g., flow vent flaps can direct any desired portion of air through the heater 14.
• the heat is preferably turned on for 30 sec or less prior to inhalation and turned off after delivery to conserve power when the device is a hand-held battery powered device. This is not necessary for a plug-m type device.
• the device 40 may be for stationary line powered use or be a hand-held, portable device which is comprised of (a) a device for holding a disposable package with at least one or a number of radioactive material containers, and (b) a mechanical mechanism for forcing the contents of a container (on the package) through a porous membrane.
• the device preferably further includes (c) a heating mechanism for adding energy to the air flow into which particles are released, (d) a monitor for analyzing the inspiratory flow of a patient, (e) a switch for automatically releasing or firing the mechanical means after the inspiratory flow rate and/or volume reaches a predetermined point (f) a means for measuring ambient temperature and humidity and (g) a source of power e.g., conventional batteries or plug-in to standard wall current .
• the device for holding the disposable package may be nothing more than a narrow opening created between two outwardly extending bars 42 and 82 or may include additional components such as one or more wheels, sprockets or rollers notably mounted on the end(s) of such bars.
• the rollers may be spring mounted so as to provide constant pressure against the surface (s) of the package.
• the device may also include a transport mechanism which may include providing drive power to the roller (s) so that when they are rotated, they move the package from one container to the next .
• the power source 43 driving the roller(s) is programmed via the microprocessor 26 to rotate the rollers only enough to move the package 39 from one container 1 to the next.
• the device 40 In order to use the device 40, the device 40 must be "loaded,” i.e. connected to a package 39 which includes dosage units of radioactive material having liquid, flowable formulations of radioactive material therein.
• the entire device 40 may be self-contained, light weight (less than 1 kg preferably less than 0.5 kg loaded) and portable.
• the power source 43 is preferably in the form of standard alkaline batteries. Two 9 volt batteries could supply the heat required to heat the air which contacts the particles by about 20°C for about 100 doses (see Figures 5 and 6 re energy required) . Larger line powered units are also contemplated. Because of the radioactivity, smaller portable devices may be used for a single delivery event and then discarded, e.g. , be produced as disposable units.
• the radioactive formulation is preferably heated after the formulation has been forced through the pores of the membrane 3 and aerosolized i.e., energy is preferably added by heating the surrounding air by means of the air-heating mechanism 14 positioned anywhere within the flow path 29.
• the amount of energy added by the formulation heating mechanism (not shown and for non ⁇ portable embodiment) or air-heating mechanism 14 is controlled by the microprocessor 26 based on the amount of radioactive formulation in the container 1 and other factors such as the concentration of the radioactive material in the formulation and surrounding humidity.
• a hygrometer 50 and thermometer 51 are electrically connected to the microprocessor 26 allowing the amount of heat to be added to be adjusted based on ambient humidity and temperature.
• 99m Tc can be used to "label" many substances ranging from simple ions (e.g., pyrophosphate) to complex molecules such as proteins
• binding requires the presence of donor atoms arranged to form a chelating function.
• complex formation usually nullifies the biological properties of the ligand because the positively charged metal ion will have a perturbing effect on the electron cloud of the ligand and higher order complexes (2:1 or 3:1 ligand-metal ratio) are likely to be formed. These factors will be pronounced in small complexes but may not affect the properties of larger peptides or proteins to such a marked extent unless the metal ion occupies active sites or a high metal-protein ratio is used.
• any radioactive material can be used provided the radioactive material can be put into a formulation which formulation can provide aerosolized particles which car- be inhaled by a patient and after inhalation will emit sufficient radiation that a readable image can be obtained.
• the radioactive material can be suspended in the formulation it is desirable to include soluble radioactive materials within a carrier and particularly desirable to include water soluble radioactive materials.
• a radioactive material is contained on a support surface and is eluted off of the surface using a saline solution. More specifically, an anionic component of the radioactive material is eluted off of the surface when replaced with anions of a salt solution.
• molybdenum is on a solid surface and the molybdenum will naturally decay to technetium (Tc) .
• Tc technetium
• a normal saline solution is poured over the surface of the material an anion of TcO "4 is eluted off the surface and into solution.
• the elution is only possible the presence of anions such as chloride ions in the solution.
• the concentration of the anion in the solution should be kept as low as possible while still maintaining the necessary rate of elution of the radioactive material off of the solid support.
• the solution poured over the solid support may have a salt concentration which is less than that of normal saline solution.
• TcO "4 anion is eluted into the aqueous saline solution the solution is generally treated further in order to slow its absorption into the body and eliminate a directed absorption towards particular cells. More specifically, TcO -4 by itself can be absorbed so quickly that the desired image cannot be obtained.
• TcO "4 tends to concentrate in certain cells such as those of the thyroid. To eliminate these problems the anion TcO "4 is combined with diethylene triam e pentaacetic acid (DTPA) to form 99m Tc-labelled diethylene triamine pentaacetic acid.
• DTPA diethylene triam e pentaacetic acid
• the concentration of the radioactive material with the carrier will vary depending upon the radioactive material and carrier i.e., the solubility of the material m the carrier
• the object in formulating is not to obtain a particular concentration based on amount of radioactive material per unit of carrier but rather to obtain a formulation which contains a particular amount of radiation per unit volume of formulation.
• the radioactive material is added to the formulation so as to obtain a formulation which has from about 1,500 MBq to about 2,500 MBq per milliliter of formulation.
• the formulation will include radiation in the amount of 2,000 MBq per milliliter of formulation ⁇ 20% MBq.
• a particularly preferred formulation of the present invention does not include small amounts of extraneous material such as surfactants, and/or antibacterial agents.
• the isotope 99m Tc has a half life of only about six hours.
• the solution containing the radioactive material can be treated in such a manner so as to eliminate the need for other components. By minimizing or not including additional components it is possible to use the solution to create particles which have a particular small size which is desirable in terms of obtaining a "gas-like" distribution of the particles in the l ng.
• a particularly preferred formulation of the invention consists only of 99m Tc-labelled diethylene triamine pentaacetic acid in a saline solution. More specifically the saline solution will have a concentration of that of normal saline or less provided the concentration is sufficiently high to elute the TcO "4 off of the substrate material.
• Figure 5 is a graph which can be used in calculating the amount of energy needed to control the size of delivered droplets by controlling the amount of evaporation of carrier from the aerosolized droplets.
• the graph of Figure 5 contains two types of information, the density of evaporated water vs. temperature and relative humidity, and the cooling of the air as the water evaporates.
• the four lines that show a rapid increase with temperature portray the density of water vapor in air, at 25, 50, 75, and 100% relative humidity.
• the 100% relative humidity curve represents the maximum number of milligrams of water that can be evaporated per liter of air.
• the diagonal lines show the temperature change of the air as the water droplets evaporate (hereafter called the air mass trajectory curves) .
• Figure 6 includes similar information with respect to ethanol which can be used n a similar manner.
• Figure 5 shows the density of water vapor in air at 25, 50 and 75°C and 100% saturation with the air mass trajectory during evaporation also shown. The same is shown in Figure 6 for the density of ethanol m air.
• the evaporation and growth rates of aqueous droplets is a function of their initial diameter, the amount of radioactive material dissolved therein (concentration) and the ambient relative humidity.
• the determining factor is whether the water vapor concentration at the surface of the droplet is higher or lower than that of the surrounding air. Because the relative humidity at the surface of a particle (i.e. droplet of aerosolized formulation) is close to 100% for all the high concentration formulations, a five micron droplet will evaporate to a 1 micron dry particle in 0% humidity in less than 20 ms . However, if a particle of radioactive material 1 micron diameter is inhaled into the lungs (99.5% humidity) it will grow to about 3 microns in diameter in approximately one second by accumulating water from the humid lung environment.
• the opening 38 may have a desiccator 41 positioned therein which desiccator includes a material which removes water vapor from air being drawn into the flow path 29.
• desiccator 41 includes a material which removes water vapor from air being drawn into the flow path 29.
• This signal is conveyed to a microprocessor which is able to convert, continuously, the signal from the transducer 37 m the inspiratory flow path 29 to a flow rate m liters per minute
• the microprocessor 26 can further integrate this continuous air flow rate signal into a representation of cumulative inspiratory volume
• the microprocessor can send a signal to send power from the power source 43 to the air-heat g mechanism 14 which uses information from the hygrometer 50, thermometer 51 and particle size and amount of formulation.
• pores of the membrane 3 are positioned beyond the boundary layer into the faster moving air of the channel advantages are obtained.
• the (1) formulation exiting the pores is moved to an air stream where it can be readily carried to the patient and (2) the particles formed do not exit into slow moving or "dead” air and thus do not rapidly decelerate to a degree such that particles behind them catch up with, collide into and merge with the particle.
• Particle collisions are not desirable because they (a) result in particles which are too large and cannot be efficiently inhaled into the lung; and (b) result in an aerosol with diverse and unpredictable particle sizes. Either or both (a) and (b) can result in erratic dosing.
• the air-heating mechanism 14 heats the surrounding air within the flow path 2S. This causes carrier in the formulation to be evaporated more readily. If sufficient heat is added the only material reaching the patient is the substantially dry powder radioactive material with a particle size of 1 to 3 microns.
• the methodology of the present invention could be carried out with a device that obtains power from a line powered source.
• the device is preferably a self-contained, hand-held device which is battery powered.
• Heating mechanisms of various types can be used. For example, see the heating mechanism in the self-contained, portable sealer for plastic colostomy bags in French patent 2,673,142 which is incorporated herein by reference.
• a portable heater is also taught in European patent applications 0,430,566 A2 for a "Flavor delivering article” and 0,358,002 for "Smoking articles utilizing electric energy, " both of which are incorporated herein by reference to disclose and describe heating components powered by batteries.
• the formulation 5 includes water as all or part of the carrier it is also desirable to include a desiccator 41 within the flow path 29.
• the desiccator 41 is preferably located at the initial opening 38 but maybe located elsewhere in the flow path 29 prior to a point in the flow path when the formulation is fired into the flow path in the form of aerosolized 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 aerosolized particles will more readily evaporate. This decreases the energy needs with respect to the heating devices 14.
• the desiccator material can be any compound which absorbs water vapor from air.
• the firing thresnold of the device is preferably not based on a single criterion such as the rate of air flow through tne device or a specific time after the patient begins inhalation.
• the firing threshold is based on an analysis of the patient's inspiratory flow profile.
• Figure 4 shows a cross-sectional plan view of a hand held, self-contained, portable, breath-actuated inhaler device 40 of the present invention.
• the device 40 is shown with a holder 20 having cylindrical side walls and a hand grip 21.
• the holder 20 is "loaded” in that it includes a container 1.
• a plurality of containers 1 (2 or more) are preferably linked together to form a package 4c
• Any of the components of tne container or the device 40 may be coated with a material which provides a radiation snield, e.g , a lead coating
• the embodiment shown in Figure 4 is a simple version of the invention.
• the device 40 may be manually actuated and loaded. More specifically, the spring 22 may be compressed by the user until it is forced down below the actuation mechanism 23.
• the device must be capable of aerosolizing radioactive formulation in a container and preferably does such forcing formulation through a porous membrane with the release point based on pre ⁇ programmed criteria which may be mechanically set or electronically set via criteria readable by the microprocessor 26.
• the details of the microprocessor 26 and the details of drug delivery devices which include a microprocessor and pressure transducer of the type used in connection with the present invention are described and disclosed within U.S. Patent 5,404,871, issued April 11, 1995, entitled “Delivery of Aerosol Medications for Inspiration" which patent is incorporated in its entirety herein by reference, and it is specifically incorporated in order to describe and disclose the microprocessor and program technology used therewith.
• Microprocessor 26 sends signals via electrical connection 27 to electrical actuation device 28 which actuates the means 23 which fires the mechanical plate 24 forcing radioactive formulation in a container 1 to be aerosolized so that an amount of aerosolized radioactive material is delivered into the inspiratory flow path 29 when the flexible membrane 3 protrudes outward through the flow boundary layer.
• a signal is also sent to the heater 14 to add heat energy to the air in the flow path 29.
• the device 28 can be a solenoid, motor, or any device for converting electrical to mechanical energy.
• microprocessor 26 keeps a record of all dosing times and amounts using a read/write non-volatile memory which is in turn readable by an external device. Alternatively, the device records the information onto an electronic or magnetic strip on the package 1. The recorded information can be read later by the care-giver to determine the effectiveness of the delivery of radioactive material. In order to allow for ease of use, it is possible to surround the inspiratory flow path 29 with a mouth piece 30.
• the flow sensor 31 is in connection with the electrical actuation means 28 (via the connector 39 to the processor 26) , and when a threshold value of air flov; is reached (as determined by the processor 26) , the electrical actuation means 28 fires the release of a mechanical means 23 releasing the plate 24 which forces the release of formulation from a container 1 so that a controlled amount of radioactive formulation is delivered to the patient.
• the microprocessor 26 is optionally connected to an optionally present vibrating device 45 which may be activated.
• a high frequency signal generator drives the piezoelectric crystal. This generator is capable of producing a signal having a frequency of from about 800 kilohertz (Khz) to about 4,000 kilohertz .
• the power output required depends upon the amount of liquid being nebulized per unit of time and the area and porosity of the membrane (generally comprised of a thin sheet of flexible polymeric plastic-like material) .
• Vibration is applied while the radioactive formulation 5 is being forced from the pores of the polycarbonate membrane 3.
• the formulation can be aerosolized with only vibration i.e., without applying pressure.
• the pressure required for forcing the liquid out can be varied depending on the liquid, the size of the pores and the shape of the pores but is generally in the range of about 50 to 600 psi, preferably 100 to 500 psi and may be achieved by using a piston, roller, bellows, a blast of forced compressed gas, or other suitable device.
• the vibration frequency used and the pressure applied can be varied depending on the viscosity of the liquid being forced out and the diameter and length of the openings or pores .
• the thinner membranes make it easier to make small holes in that the holes or pores of the membrane are created using a focussed LASER. It is possible to reduce the pressure further by making the holes conical in cross-section.
• a LASER with a conical focus is used to burn holes through the membrane. The larger diameter of the conical shape is positioned next to the formulation and the smaller diameter opening is the opening through which the formulation ultimately flows.
• the particles When small aerosolized particles are forced into the air, the particles encounter substantial frictional resistance. This may cause particles to slow down more quickly than desired and may result in particles colliding into each other and combining, which is undesirable with respect to maintaining the preferred particle size distribution within the aerosol and ultimately obtaining a gas-like delivery of the radioactive material.
• a means by which air flow and the flexible membrane 3 prevent collisions Specifically, the patient inhales thereby creating an air flow toward the patient over the protruding membrane 3. The air flow carries the formed particles along and aids in preventing their collision with each other.
• the shape of the container opening, the shape of the membrane covering that opening, as well as the positioning and angling of the flow of air through the channel 11 relative to the direction of formulation exiting the pores of the membrane 3 can be designed to aid in preventing particle collision. It is desirable to shape the container opening and matching membrane (i.e., the configuration of the pores on the membrane) so as to minimize the distance between any edge of the opening and the center of the opening. Accordingly, it is not desirable to form a circular opening (i.e., a circular configuration of pores) which would maximize the distance between the outer edges of the circle and the center of the circle, whereas it is desirable to form an elongated narrow rectangular opening (i.e., a configuration of pores) covered by a rigid membrane 80 as shown in Figure 8.
• the microprocessor 26 sends a signal to an actuator release electrical mechanism 28 which actuates the mechanical means 23, thereby releasing a spring 22 and plate 24 or equivalent thereof, forcing aerosolized formulation into the channel 11, and out of the membrane 3 into the flow path 29 where the air surrounding the particles is optionally heated by the air heater 14.
• an actuator release electrical mechanism 28 which actuates the mechanical means 23, thereby releasing a spring 22 and plate 24 or equivalent thereof, forcing aerosolized formulation into the channel 11, and out of the membrane 3 into the flow path 29 where the air surrounding the particles is optionally heated by the air heater 14.
• Microprocessor 26 of Figure 4 includes an external non-volatile read/write memory subsystem, peripheral devices to support this memory system, reset circuit, a clock oscillator, a data acquisition subsystem and a visual annunciator subsystem.
• the discrete components are conventional parts which have input and output pins configured in a conventional manner with the connections being made in accordance with instructions provided by the device manufacturers.
• the microprocessor used in connection with the device of the invention is designed and programmed specifically so as to provide (in a gas-like manner) controlled and repeatable amounts of respiratory radioactive material to a patient upon actuation.
• the microprocessor must have sufficient capacity to make calculations in real time. Adjustments can be made in the program so that when the patient's inspiratory flow profile is changed such is taken into consideration.
• the present invention will result in a gas-like distribution of particles due to a number of features.
• the membrane is permanently convex or is flexible and protrudes into fast moving air aiding the elimination of particle collisions.
• the invention makes it possible to eliminate any carrier from the aerosolized particles and provide dry radioactive material particles to a patient which particles can be manufactured to have a uniform size. By delivering particles of uniform size repeatability of dosing is enhanced regardless of the surrounding environment, e.g. different humidity conditions.
• the device makes it possible to administer radioactive material at the same point with respect to inspiratory flow rate and inspiratory volume at each delivery point thereby providing gas-like delivery.
• the method preferably uses a delivery device which is not directly actuated by the patient or caregiver in the sense that no button is pushed nor valve released by the patient or caregiver.
• the device of the mvention provides that the actuation mechanism which causes radioactive formulation to be forced from a container which is fired automatically upon receipt of a signal from a microprocessor programmed to send a signal based upon data received from a monitoring device such as an airflow rate monitoring device.
• a monitoring device such as an airflow rate monitoring device.
• a patient using the device withdraws air from a mouthpiece and the inspiratory rate, and calculated inspiratory volume of the patient is measured simultaneously one or more times in a monitoring event which determines an optimal point in an inhalation cycle for the release of a dose of radioactive formulation.
• Inspiratory flow is preferably measured and recorded in one or more monitoring events for a given patient in order to develop an inspiratory flow profile for the patient .
• Recorded information is preferably analyzed by the microprocessor in order to deduce a preferred point within the patient's inspiratory cycle for the release of radioactive formulation with the preferred point being calculated based on the most likely point to result in a gas-like delivery of radioactive material in the lungs .
• a flow rate monitoring device continually sends information to the microprocessor, and when the microprocessor determines that the optimal point in the respiratory cycle is reached, the microprocessor actuates a component which fires a mechanical means (and activates the vibration device) which causes radioactive formulation to be forced out of the container and aerosolized. Accordingly, radioactive material is repeatedly delivered at a pre-programmed place in the inspiratory flow profile of the particular patient which is selected specifically to maximize a gas-like delivery profile. It is pointed out that the device of the present invention can be used to, and actually does, improve the efficiency of delivery of radioactive formulation. However, this is not the most important feature.
• a more important feature is the release of a tightly controlled amount of radioactive formulation (with a narrow range of particle size) repeatedly at the same particular point in the respiratory cycle so as to assure the delivery of a controlled and repeatable amount of radioactive material to the lungs of each individual patient with a gas-like delivery profile with tightly controlled dosing.
• the point in the inspiratory cycle of the release can be readjusted based on the particular condition of the patient. For example, patients suffering from asthma have a certain degree of pulmonary insufficiency which may change quickly and which must be considered. Changes in lung function will be taken into account in the monitoring event by the microprocessor which will readjust the point of release of the radioactive formulation a manner calculated to provide for the administration of an amount of radioactive material to the patient presently needed by the patient to produce enough radiation to allow for making a clear readable image.
• the entire dosing event can involve the administration of anywhere from 5 to 200 ⁇ l of 99m Tc-DTPA, but more preferably involves the administration of approximately 50 to 100 ⁇ l of 99m Tc-DTPA or another water soluble radioactive material which results in a deposit of an equivalent amount of radiation generating material in the lung.
• the container will include the formulation having radioactive formulation therein in an amount sufficient to deliver to the lung about 2 to about 200 MBq of radiation, preferably about 35 to 65 MBq and most preferably about 50 MBq.
• Other radioactive isotopes which can be used to create radioactive material for use with the present invention include 111 In l 113m In, and 67 Ga.
• a piston connected to a spring can be withdrawn so that when it is released it will force air through the air dispersion vents.
• Automatic cocking of forced storing systems for both the radioactive formulation and the air flow may be separate or in one unit. Further, one may be manual whereas the other may be done automatically.
• the device is cocked manually but fired automatically and electronically based on monitoring the patients inspiratory flow.
• the formulation may be physically moved through the porous membrane in a variety of different ways. Formulation may be forced through the membrane by a piston or, without applying force to the formulation, the membrane being vibrated at frequencies sufficient to create an aerosol.
• the device 40 schematically shown within Figure 4 can be specifically operated as follows.
• a container 1 is loaded into the device 6.
• the device is then armed meaning that the piston such as the spring-loaded piston 24 is cocked.
• a container 1 of the package is moved into position and any cover such as the cover 4 of Figure 1 is stripped off of the porous membrane 3.
• the patient withdraws air from the mouthpiece 30 and the patient's inhalation profile is developed using the microprocessor 26.
• the microprocessor calculates a point within the inhalation profile at which radioactive formulation should be released in order to maximize re p eatability of the dosing, e.g.
• the device can be set so that the dose will be repeatedly released at approximately the same point with respect to inspiratory flow rate and inspiratory volume. If the device repeatedly fires at the same inspiratory flow rate and inspiratory volume each time the patient will receive substantially the same dose. Both criteria must be measured and used for firing to obtain repeatability.
• the microprocessor of the present invention can be programmed to release radioactive formulation based on all or any of the following parameters.
• Delivery should be at an inspiratory flow rate inside a range of about 0.10 to about 2.0 liters per second (efficiency can be obtained by delivering at a flow rate in a range of 0.2 to about 1.8 liters per second and more preferably 0.15 to 1.7 liters per second) .
• Repeatability of the delivery is obtained by releasing at substantially the same inspiratory flow rate at each release.
• Delivery should be at a point within a patient's inspiratory volume of about 0.15 to about 2.0 liters (further efficiency of delivery can be obtained by delivering within a range of 0.15 to 0.8 liters and more preferably 0.15 to about 0.4 liters) . Repeatability of delivery is obtained by delivering at the same inspiratory volume at each release.
• Delivery is improved by providing a system which creates particles for delivery wherein the particles are in the range of about 0.5 to about 12.0 microns, preferably 0.5 to 6 microns and more preferably 0.5 to about 3 microns.
• Air drawn into the flow path of the aerosolized particles is heated by adding energy to each 10 ⁇ l of formulation in an amount of about 20 Joules to 100 Joules, more preferably 20 Joules to 50 Joules.
• the heated air aids in reducing the effect of humidity and evaporates carrier away from the particles thereby providing smaller particles for inhalation.
• Vibration may be created on the porous membrane in an amount 575 to 32,000, preferably 1,000 to 17,000 and more preferably 2,000 to 4,000 kilohertz.
• the pore size of the membrane is regulated within a range of 0.25 to about 6.0 microns, preferably 0.5 to 3 microns and more preferably 1 to 2 microns . This size refers to the diameter of the pore through which the formulation exits the membrane. The diameter of the opening into which the formulation flows may be 2 to 10 times that size in diameter thereby providing a conical configuration.
• the viscosity of the formulation affects the amount of pressure which needs to be applied to force the formulation through the pores and should be within the range of 25% to 1,000% the viscosity of water.
• the extrusion pressure is regulated within a range of 50 to 600 psi more preferably 100 to 500 psi. Lower pressures may be obtained by using the conical configuration for the pore size.
• the microprocessor should also be provided information regarding the ambient temperature and atmospheric pressure.
• the temperature is preferably close to room temperature i.e., within a range of 15°C to 30°C.
• An atmospheric pressure is generally 1 atmosphere or slightly lower at higher altitudes, e.g., about 75% of 1 atmosphere.
• a desiccator is preferably used to remove water vapor from air drawn into the flow path by the patient .
• the thickness of the membrane is preferably regulated in the range of 5 to 200 microns or more preferably 10 to 50 microns. Thinner membranes are useful in that less pressure is required to force formulation through the membrane.
• the membrane has a tensile strength of 5,000 to 20,000, preferably 8,000 to 16,000 and more preferably 14,000 to 16,000 psi.
• the membrane is configured so as to have a convex configuration which protrudes into faster moving air created by the patient's inhalation or is designed to be flexible so that it will assume a convex configuration when formulation is forced through the membrane .
• radioactive material After radioactive material has been delivered it is possible to discontinue any readings with respect to flow and/or volume. However, it is preferable to continue readings with respect to both criteria after radioactive material has been released. By continuing the readings the adequacy of each patient's particular delivery maneuver can be determined. All of the events are recorded by the microprocessor. The recorded information can be provided to the caregiver for analysis. For example, the caregiver can determine if the patient correctly carried out the inhalation maneuver in order to correctly delivery radioactive material and can determine if the image created is effected by the manner of delivery. If necessary, various adjustments can be made, such as in the release point, to obtain a particular desired result.

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• 1997
  • 1997-02-04 WO PCT/US1997/001888 patent/WO1997027804A1/en not_active Application Discontinuation
  • 1997-02-04 EP EP97906502A patent/EP0955885A1/de not_active Withdrawn
  • 1997-02-04 CA CA 2245079 patent/CA2245079A1/en not_active Abandoned

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